An Active Surveillance to Monitor the Real World Safety in Indian Patients Prescribed Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim

ABCD
TITLE PAGE
Active Surveillance Protocol
1.
TITLE PAGE
Document Number:
c13288600-04
BI Study Number:
1199.280
BI Investigational
Product(s):
Nintedanib
Title:
An active surveillance to monitor the real world safety in Indian 
patients prescribed Nintedanib for the treatment of Idiopathic 
Pulmonary Fibrosis.
Protocol version 
identifier:
5.0
Date of last version of 
protocol:
13 June 2018
PASS:
Yes
EU PAS register 
number:
EUPAS17055
Active substance:
Nintedanib
Medicinal product:
Nintedanib Capsules 150mg
Nintedanib Capsules 100mg
Product reference:
Not applicable
Procedure number:
Not applicable
Marketing authorisation 
holder(s):
Boehringer Ingelheim India Pvt. Ltd.
Joint PASS:
No
Research question and 
objectives:
To evaluate real-world safety of Nintedanib in Indian patients 
with IPF
Country(-ies) of study:
India
Author:
Marketing authorisation 
holder(s):
Boehringer Ingelheim India Pvt. Ltd.
1102, 11th Floor, Hallmark Business Plaza
Gurunanak Hospital Road
Bandra East, Mumbai-400051
MAH contact person:

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EU-QPPV:
Signature of EU-QPPV:
(The signature of the EU-QPPV is provided electronically)
Date:
01 Aug 2018
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© 2018 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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2.
TABLE OF CONTENTS
1.
TITLE PAGE......................................................................................................... 1
2.
TABLE OF CONTENTS....................................................................................... 3
4.
RESPONSIBLE PARTIES.................................................................................... 6
6.
AMENDMENTS AND UPDATES..................................................................... 16
7.
MILESTONES..................................................................................................... 42
8.
RATIONALE AND BACKGROUND................................................................ 43
9.
RESEARCH QUESTION AND OBJECTIVES ................................................. 44
10.
RESEARCH METHODS .................................................................................... 45
10.1
STUDY DESIGN............................................................................................ 45
10.2
SETTING........................................................................................................ 46
10.2.1
Site selection ........................................................................................... 46
10.2.2
Selection of population............................................................................ 46
10.2.2.1
Inclusion / exclusion criteria........................................................... 46
10.2.2.2
Registration period.......................................................................... 47
10.2.2.3
Patient registration method ............................................................. 47
10.2.3
Discontinuation of the study by the sponsor ........................................... 48
10.3
VARIABLES .................................................................................................. 49
10.3.1
Exposures ................................................................................................ 49
10.3.2
Outcomes................................................................................................. 49
10.3.3
Other........................................................................................................ 49
10.4
DATA SOURCES........................................................................................... 52
10.5
SAMPLE SIZE ............................................................................................... 53
10.6
DATA MANAGEMENT................................................................................ 53
10.7
DATA ANALYSIS......................................................................................... 53
10.7.1
Analyses of outcome events.................................................................... 53
10.7.2
Interim analyses....................................................................................... 54
10.8
QUALITY CONTROL................................................................................... 54
10.9
LIMITATIONS OF THE RESEARCH METHODS...................................... 54

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10.10 OTHER ASPECTS ......................................................................................... 54
10.10.1
Informed consent, data protection, study records ................................... 54
10.10.1.1
Study approval, patient information, and informed consent........... 55
10.10.1.2
Data quality assurance .................................................................... 55
10.10.1.3
Records ........................................................................................... 55
10.10.1.4
Statement of confidentiality............................................................ 56
11.
PROTECTION OF HUMAN SUBJECTS .......................................................... 57
12.
MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS....................................................................................................... 58
12.1
DEFINITIONS OF ADVERSE EVENTS...................................................... 58
12.2
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION AND 
REPORTING .................................................................................................. 58
12.3
REPORTING TO HEALTH AUTHORITIES................................................ 61
13.
PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
............................................................................................................................. 62
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.............................................. 64
ANNEX 2. ENCEPP CHECKLIST FOR STUDY PROTOCOLS .............................. 65
ANNEX 3 . THE CLASSIFICATION OF MODIFIED MRC DYSPNEA SCALE.... 72
ANNEX 4. CHILD PUGH CLASSIFICATION OF HEPATIC IMPAIRMENT........ 73

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4.
RESPONSIBLE PARTIES
Contact details and the list of all investigators will be kept in a stand-alone document.

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6.
AMENDMENTS AND UPDATES
Number
Date
Section of 
study protocol
Amendment or update
Reason
1
6 Sep 
2016
Section 2
Change in page numbers 
Boehringer Ingelheim contact 
details.
Incorporation of 
additional text
Section 3
DCGI included in the list of 
abbreviations
It was inadvertently 
missed in previous 
version
Section 4
Boehringer Ingelheim contact 
details
Address for 
regulatory 
communication
Section 5, 8, 
10.1, 10.2.1, 
10.2.2.2, 10.4, 
10.5                   
Number of centres changed from 
30 to “approximately 30”. 
Statement that the number of 
centres may increase depending on 
the enrolment of new centres added
As advised by SEC
Section 5, 10.1
Amend from:
“Patients who will be prescribed 
Nintedanib will have follow up 
visits”
Amend to:
“Patients who will be prescribed 
Nintedanib are suggested to have 
further visits”
For more clarity
Section 5
Amend from
Patients with further follow-up  
possible with participating 
physician during the planned 
period of active surveillance
Amend to:
Patients in whom further 
visit/contact is possible during the 
planned period of active 
surveillance
For more clarity
Section 5, 10.1, 
Flowchart, 
10.2.2.1, 
10.2.2.3, 10.3.3, 
10.4, 10.7, 
10.7.1, 12.2
“Baseline visit” changed to “visit 
1” 
“follow-up visits” changed to 
“further visits”
For more clarity

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Section 5, 
10.2.2.1
“Patients who are being treated 
with Pirfenidone” added in the 
exclusion criteria
As advised by SEC
Section 5
Protocol amendment date added. 
Change in timelines
Timelines changed 
according to the 
anticipated date of 
availability of 
commercial stocks
Flowchart
Date of start administration 
changed to “Drug administration”. 
Foot note # added and asterix *
added to vital signs and physical 
examination 
For more clarity
Flowchart 
Amended from:
In case a patient discontinues 
Nintedanib before 52 weeks, the 
follow up visit will be after 4 
weeks of the date of 
discontinuation
Amended to: 
Patients are suggested to have a 
‘Follow up visit’ at 4 weeks from 
the last dose of Nintedanib whether 
they have completed 52 weeks or 
are prematurely withdrawing from 
the study. 
For more clarity 
Section 10.1
Collection of safety information 
telephonically for patients who are 
lost to follow up.
In order to minimise 
missed data
Section 10.3.2
Secondary outcome changed to 
“percentage of patients requiring 
dose reductions and 
discontinuations due to adverse 
events”
To collect additional 
safety information
Section 10.3.3
In the section on thrombotic risk –
“start date, stop date/ongoing, 
please specify” added
For more clarity
Section 10.7.2
Details of interim analysis added.
For the purpose of 
submitting the 
safety data to DCGI 
at the end of 1 year 
as advised by SEC
Section 
10.10.1.1
Amend from:
The review by Drug controller 
general of India (DCGI), the 
To comply with the 
institutional 
procedures 

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approval of Institutional Review 
Board (IRB) or Ethics Committee 
will be sought before the start of 
this active surveillance.  
Amend to:
In addition to review and approval 
by Drug controller general of India 
(DCGI), the approval of 
Institutional Review Board (IRB) 
or Ethics Committee will be sought 
as per the institutional procedures 
before the start of this active 
surveillance.  

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Section 
10.10.1.1
Amended from:
The Investigator must sign (or 
place a seal on) and date the 
informed consent form.
Amended to:
The Investigator must sign and date 
the informed consent form.
Investigator sign is 
required on ICF
Section 
10.10.1.4
Amend from:
Data generated as a result of this 
active surveillance need to be 
available for inspection on request 
by the participating physicians, the 
sponsor’s representatives, by the 
IRB / IEC and the regulatory 
authorities.
Amend to:
Data generated as a result of this 
active surveillance need to be 
available for inspection on request 
by the sponsor’s representatives, by 
the IRB / IEC and the regulatory 
authorities.
The data will be 
available for 
inspection by the
sponsor’s 
representatives, by 
the IRB / IEC and 
the regulatory 
authorities.
Section 12.2
Amend from:
The following must be collected by 
the investigator in the CRF from 
first 
intake 
of 
Nintedanib
at 
scheduled visits and within 28 days 
(inclusive) after last intake in 
patients exposed to Nintedanib (= 
end of study)
Amend to:
The following must be collected by 
the investigator in the CRF from 
signing 
the 
informed 
consent 
onwards at scheduled visits and up 
to 4 weeks after last intake in 
patients exposed to Nintedanib (= 
follow up visit)
For more clarity
2
17 Jan 
2018
Section 2
Change in page numbers 
Section 9.9 changed to Limitations 
of research method
Incorporation of 
additional text.
Inadvertently 
additional text got 
added
Section 3
SEC included in list of 

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abbreviations
Section 5,8,  
10.1, 10.2.2.2, 
10.2.2.3, 10.5
Amend from:
all IPF patients
Amend to:
at least 200 consecutive IPF 
patients
Number of patients in Pirfenidone
arm changed to 200.
Number of centres (approximately 
30) removed
Timelines of completing the study 
in first two years removed
Addition of following text:
Once a patient is enrolled into the 
Nintedanib group at any given site 
then the next eligible patient 
initiating Pirfenidone at the 
corresponding site should be 
enrolled in the Pirfenidone group.
As advised by SEC
For ensuring clarity 
in patient enrolment
Section 5, 
10.3.2, 10.4, 
10.7.1, 12.1, 
12.2,  Flow 
chart –
Nintedanib
Amend from
Aes (serious and fatal)
Amend to
Serious adverse events (SAEs)
Serious adverse 
events include fatal 
Aes also.
Section 5, 
10.2.2.1
Exclusion criteria of Nintedanib 
Amend from:
Patients who are being treated with 
Pirfenidone.
Amend to:
Patients who are planned to be 
concomitantly treated with 
Pirfenidone.
Number of patients in Pirfenidone 
arm changed to 200.
Inclusion criteria of Pirfenidone, 
following text added:
Patients in whom further 
visit/contact is possible during the 
planned period of active 
surveillance.
Exclusion criteria of Pirfenidone, 
following text added:
Patients who are planned to be 
As advised by SEC
As advised by SEC
To keep the 
inclusion and 
exclusion criteria of 
Nintedanib and 
Pirfenidone arm 
uniform. This will 
avoid selection bias

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concomitantly treated with 
Nintedanib.
Section 5, 
10.2.2.3,10.3.3, 
Flow chart –
Nintedanib, 
Flow chart –
Pirfenidone 
VC – removed
Amend from:
Comorbidities at visit 1 and further 
visits (yes/no/unknown, if yes 
specify)
Amend to:
Comorbidities at visit 1
Amend from:
Laboratory tests at visit 1and 
further visits
Amend to:
Laboratory tests at visit 1
Was added  
inadvertently
Comorbidities in 
further visits will be 
captured as Aes
Section 5, 
10.2.1
Amend from:
This active surveillance is based on 
the newly collected data at 
approximately 30 selected centres 
from all over India where IPF 
patients are regularly treated. The 
number of centres may increase 
depending on the enrolment of new 
centres in this active surveillance.
Amend to:
This active surveillance is based on 
the newly collected data at selected 
centres sites where IPF patients are 
regularly treated.
As advised by SEC
Section 5,7
Date of second amendment 
incorporated.
End of data collection
Amend from:
October 2018
Amend to:
Until the last patient completes the 
follow up period
Final report:
Amend from:
April 2019
Amend to:
6 months after the last patient out
As advised by SEC
Flow chart –
Nintedanib
Foot note 4 of  flow chart for 
patients prescribed Nintedanib:
Abnormal lab values 
at further visits will 

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Amend from:
Performed/not 
performed/unknown/performed but 
missing value and value (units), 
date
Amend to:
Laboratory test results are collected 
in Visit 1 only. For other visits, 
only clinically significant abnormal 
results are collected as Adverse 
Event if they are ADRs and/or 
SAEs.
be captured as Aes.
Section 10.3.3
Previous history of acute 
exacerbation (Yes/No/Unknown) 
added
Co-medications for IPF defined as 
at visit 1 and further visits – units 
added
Got inadvertently 
missed
Section 10.3.3 
and foot note # 
4
Following clarification was added:
After visit 1, abnormal lab values 
that are clinically significant and 
related to Nintedanib will be 
collected as Adverse Event in 
eCRF and will be reported on NIS 
AE form. 
[After visit 1, lab results will be 
collected in eCRF in following 
manner:

Laboratory tests – done/not 
done/unknown

If done – within normal 
range/unknown/out of range

If out of range – clinically 
significant/clinically 
not 
significant 

If clinically significant –
related to the Nintedanib/not 
related to Nintedanib 

If related to the Nintedanib –
it will be reported on the AE 
page (In addition to the AE 
term, actual lab values that 
are 
abnormal, 
clinically 
significant & related to 
Nintedanib will also be 
reported in the CRF)]
In addition to this, any abnormal 
For more clarity

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lab value, which is clinically 
significant and qualifies as SAE, 
will be reported in the eCRF and 
NIS AE form whether or not it is 
related to the Nintedanib. 
Section 10.7
Amend from:
Any patient who meets at least one 
of the following criteria is treated 
as ineligible for all analyses: 

No further visit data are 
available

No required registration
procedure is followed

No valid site contract is 
available
Amend to: 
Any patient who meets at least one 
of the following criteria is treated 
as ineligible for all analyses: 

No further visit data are 
available

No required registration
procedure is followed
To rectify the error 
inadvertently made 
in the previous 
version 
Section 10.7.1
Prior Pirfenidone treatment (add 
on) removed.
Amend from:
Other prior IPF treatment (switch 
and add on)
Amend to:
Other prior treatment used for the 
management of IPF (switch and 
add on)
Concomitant 
treatment with 
Pirfenidone is an 
exclusion criteria        
For ensuring more 
clarity
Section 10.7.2, 
12.3
Interim analysis details 
Amend from:
10 months from the date of active 
surveillance 
Amend to:
No formal interim analysis required
Addition of following text:
Starting from the date of second 
amendment, a status report of the 
active surveillance will be 
submitted to DCGI annually.
As advised by SEC

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Section 10.8
Added
It is the responsibility of the 
investigator to ensure that recorded 
data is as accurate and complete as 
possible. Investigator and site staff 
will be trained on this. Data will be 
entered directly in to e-CRF by the 
site staff; and data quality will be 
ensured by having the process of 
validation and edit checks in-built 
in the system. 
It was inadvertently 
missed in previous 
version 
Section 12.1
Any suspected transmission via a 
medicinal product of an infectious 
agent is also considered a serious 
adverse reaction – Removed
Protocol template 
doesn’t contain this 
information 
anymore.
Section 12.2
<select: studied medical product or 
BI drug taken for the disease in 
scope of the study> - Removed
Inadvertently 
additional text got 
added in the 
previous version
Annex 2
ENCePP Checklist for Study 
Protocols – Page numbers changed
Incorporation of 
additional text.

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Amendm
ent no.
Date
Section no.
Amendment or update
Reason
3
13 June
2018
Section 3
Abbreviation MAH added
Administrati
ve update
3
13 June 
2018
Section 5: 
Rationale 
and 
Background
The proposed active surveillance aims to 
collect real world safety data on at least of
200 patients who will be prescribed 
Nintedanib in treated with nintedanib per  
approved label at selected centres after
the real world from the date of commercial 
availability of the drug in India (23rd
January 2017).
Administrati
ve update 
for better 
clarity.
3
13 June 
2018
Section 5: 
Research 
question and 
objectives
The safety of Nintedanib has been assessed 
in clinical trials. Since only 20 patients 
from India were enrolled in the INPULSIS 
trials, the safety data on Indian patients is 
limited. In this This active surveillance 
aims to collect the safety data of 
Nintedanib in 200 IPF patients will be 
examined in Indian treated with 
nintedanib in approved indication after 
the commercial availability of the drug 
in India (23rd January 2017). The 
objective is to look at safety of 
nintedanib in the real world setting.
Administrati
ve update 
for better 
clarity.
3
13 June 
2018
Section 5: 
Study design
Section 10.1
An active surveillance based on newly 
collected data.
This active surveillance will include at least
200 consecutive IPF patients who have 
been 
newly 
prescribed 
Nintedanib 
according to treated with nintedanib per
the approved Indian label from the date of 
commercial availability of the drug will be 
enrolled in this active surveillance. They 
are classified into following groups.
Group A.
Patients 
who 
started 
treatment with nintedanib after 23rd
January, 2017 and have permanently 
discontinued the drug (as decided by 
the investigator) at the time of 
participation in the active surveillance. 
Group B.
Patients 
who 
started 
treatment with nintedanib after 23rd
January, 2017 and are continuing the 
drug at the time of participation in the 
active surveillance.
Group C.
Patients who have been 
To 
include 
the 
retrospectiv
e 
patient 
data

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newly prescribed nintedanib at the 
time of participation in the active 
surveillance.
The medical records at the selected sites 
will be screened to 26nrol Group A and B 
patients in a retrospective manner. Group 
C patients will be enrolled prospectively. 
The first patient enrolled at a given site 
should be in the nintedanib group.
Once a patient is enrolled into the nintedanib 
group at any given the site then team is 
suggested to enrol the next eligible patient, 
who has initiated or will be, initiating 
pirfenidone at the corresponding same site 
should be enrolled in the pirfenidone group.
The safety data for nintedanib treated 
patients will be collected for at least 52 
weeks or till the discontinuation of the 
drug, whichever is earlier. Patients 
treated with pirfenidone will not be 
followed.
At visit 1, the baseline characteristics (e.g. 
demographics, pulmonary function tests, 
HRCT evaluation etc., see section on 
“Variables” section 10.3.3) will be recorded 
for all patients (either treated with 
nintedanib or pirfenidone).
Patients who The medical records of 
patients belonging to Group A and B will 
be prescribed Nintedanib are suggested to
evaluated to see if any ADRs and SAEs
have further occurred in the nintedanib 
treated arm during the duration of the 
treatment. Group B and Group C 
patients  will be followed up according to 
clinical practice for at least 52 weeks 
from the start of the treatment at regular 
intervals (i.e. approximately every 4 
weekly for the first 3 visits at and 
approximately 
every 
12 
weekly 
thereafter up to week 4, 8, 12, 24, 36 and
52 and an additional follow up visit at 4 
weeks after the last dose of Nintedanib. At 
each visit, all ADRs (serious and non-
serious) associated with nintedanib and 

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SAEs (serious adverse events) will be 
recorded and reported. The reporting and 
recording of ADRs and SAEs have been
as described in section 12.2. In case a 
patient discontinues nintedanib before 52 
weeks due to any reason, the all ADRs and 
SAEs will be collected on the day of 
discontinuation of Nintedanib and up to 4 
weeks of till the date of discontinuation. 
Patients who are prescribed Pirfenidone 
will not be followed of nintedanib. There 
may be unscheduled visits between the 
scheduled visits. All ADRs and SAEs will 
also be collected at these unscheduled 
visits and entered into the eCRF. For 
nintedanib 
treated 
patients, 
certain 
information (e.g. co-medications, see 
flowchart) will also be collected at 
further 
and 
unscheduled 
visits 
(if 
available), as the status may change over 
time.
In case the patient is lost to follow up 
(patients not contactable for further 
vsits), the site should attempt to contact 
the 
patient 
or 
patient’s 
relative 
telephonically to gather the information 
on the vital status and record it in the 
eCRF. 
Additionally, 
whenever 
the 
investigator becomes aware of SAEs 
and/or ADRs occurring in an enrolled 
patient before individual patient’s end of 
study, it needs to be reported as per 
section 12.2. Patients who have taken at 
least one dose of nintedanib will be 
included in the safety analysis.

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2018
Section 5: 
Population
Section 
10.2.2.1
Inclusion criteria for nintedanib treated 
patients:
Patients with documented diagnosis of IPF 
based upon ATS/ERS/JRS/ALAT 2011 
guidelines, and who comply with inclusion 
and exclusion criteria may qualify to be 
included in this active surveillance. The 
diagnosis 
of 
IPF 
as 
per 
ATS/ERS/JRS/ALAT 
2011 
guidelines 
requires the following:

Exclusion of other known causes of 
ILD (e.g., domestic and occupational 
environmental exposures, connective 
tissue disease, and drug toxicity).

The presence of a UIP pattern on 
HRCT in patients not subjected to 
surgical lung biopsy.

Specific combinations of HRCT and 
surgical lung biopsy pattern in patients 
subjected to surgical lung biopsy.
-Inclusion criteria 
1.
Patients 
with 
documented 
diagnosis of
IPF based upon 
ATS/ERS/JRS/ALAT 
2011 
guidelines 
 
(IPF-treatment
nintedanib naïve or pirfenidone
pre-treated) 
who 
are 
newly 
prescribed 
Nintedanib
have 
initiated or will initiate nintedanib
according to the package insert after
the commercial availability of 
drug in India (23rd January 2017).
2.
Patients in whom it is possible to 
obtain voluntary informed consent 
either 
from 
the 
patient 
or 
patient’s legally 28 nrol 28 ized
representative 
(applicable 
for 
Group B and C patients, see 
section 10.1 for details).
3.
Patients in whom data collection is 
possible from the medical records 
(applicable for Group A and B 
patients, see section 10.1
for 
details).  
4.
Patients in whom information on 
baseline characteristics mentioned 
in the section 10.3.3 is available.

Willing 
to 
provide 
the 
informed 
To include 
the 
retrospectiv
e patient 
data

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consent.

Patients in whom further visit/contact is 
possible during the planned period of 
active surveillance.
-Exclusion criteria 
2.
Patients who have taken Nintedanib 
before participation in this active 
surveillance. 
Patients 
who 
are 
planned to be initiated or will 
initiate nintedanib concomitantly 
treated with pirfenidone.
3.
Patients who are participating in a 
clinical trial or other IPF registries.
In addition 200 IPF Inclusion criteria for
patients treated with perfenidone
with documented diagnosis of IPF based 
upon ATS/ERS/JRS/ALAT 2011 guidelines 
who will be newly prescribed Pirfenidone at 
the same sites during the same time period 
will be enrolled.
-Inclusion criteria for patients prescribed 
Pirfenidone

Patients 
with 
IPF 
(IPF-treatment
antifibrotic naïve or pre-treated) who 
are newly prescribed Pirfenidone.

Willingness 
to 
provide 
informed 
consent 
to 
collect 
the 
baseline 
characteristics

Patients in whom further visit/contact is 
possible during the planned period of 
active surveillance.
-Exclusion criteria

Patients who have taken Pirfenidone 
before participation in this active 
surveillance
1.
Patients
with 
documented 
diagnosis of IPF based upon 
ATS/ERS/JRS/ALAT 
2011 
guidelines who (antifibrotic naïve) 
who have initiated or will initiate  
pirfenidone according to the 
package 
insert 
after 
the 
commercial 
availability 
of 
nintedanib (23rd January 2017)
will
be 
newly 
prescribed 

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pirfenidone at the same sites during 
the same time period will be 
enrolled.
2.
Patients in whom it is possible to 
obtain voluntary informed 
consent either from the patient or 
patient’s legally 30nrol30ized
representative (applicable for 
Group II and III patients, see 
section 10.1 for details).
3.
Patients who are planned to be in 
whom data collection is possible 
from 
the 
medical 
records 
(applicable for Group A and B 
patients, see section 10.1
for 
details.
4.
Patients in whom information on 
baseline 
characteristics 
mentioned in the section 10.3.3. is 
available.
Concomitantly 
treated 
with 
Nintedanib. 
Exclusion criteria
1.
Patients who were previously 
treated 
with 
nintedanib 
or 
pirfenidone.
2.
Patients who have or will initiate 
pirfenidone concomitantly treated
with nintedanib.
Patients who are participating in a clinical 
trial. Or other IPF registries

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Section 5: 
Variables
For the Nintedanib cohort treated patients, 
certain information will also be collected at 
further visits, as the status may change over 
time
To include 
the 
retrospectiv
e patient 
data
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2018
Section 5: 
Data sources
Section 10.4 
Data Sources
This active surveillance is based on the
existing and
newly collected data at 
selected sites where IPF patients are 
regularly treated.
In case ADRs (serious or non-serious) 
associated with Nintedanib and/or SAEs 
occur in patients exposed to Nintedanib, the 
data should be immediately entered into 
EDC and reported on the NIS AE form as 
described in the The medical records of 
Group A and B patients will be used to 
collect the data of all ADRs and SAEs 
occurring during the duration of the 
treatment. This data will be entered into 
eCRF. Group B and C patients will be 
followed up according to clinical practice 
for at least 52 weeks from the start of the 
treatment at regular intervals (i.e.
approximately every 4 weeks for the first 
3 visits and approximately every 12 
weeks thereafter up to week 52)). After 
completing the medical examination and 
observation at the suggested time points, 
investigator needs to enter data of the 
registered patients (all ADRs and SAEs 
as described in section 12.2) in the EDC 
system. Additionally information on 
certain covariates will be collected at 
subsequent visits as described in the 
section 10.3.3. For patients being treated 
with 
pirfenidone, 
only 
baseline 
characteristics will be recorded in the 
EDC. These patients will not be followed.
To include 
the 
retrospectiv
e patient 
data
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2018
Section 5: 
Sample size
Section 10.5 
Sample Size
The active surveillance will be conducted 
till at least 200 consecutive IPF patients 
treated with nintedanib from the date of 
commercial availability of the product in 
India 
are 
included. 
The 
inclusion
according to the approved Indian label 
(classified as Group A, B and C, see 
section 10.1) will be enrolled in this 
active surveillance program. The sample 
Administrati
ve change 
for better 
clarity and 
enrolment of 
retrospectiv
e patient 
data.

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size of 200 Nintedanib treated patients is 
per a the request from the regulatory 
requirement agency.
In addition 200 IPF patients who have been 
newly prescribed Pirfenidone will also be 
enrolled from the same study sites treated 
with pirfenidone (classified as Group I, 
II and III, see section 10.1) at the same 
centres and during the same time period. 
Once a patient is enrolled into the 
Nintedanib group at any given site then the 
next eligible patient initiating Pirfenidone 
at the corresponding site should be enrolled 
in the Pirfenidone group. Frame will be 
included. The baseline characteristic of 
these patients will be recorded at visit 1
and they will not be followed.

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Section 5: 
Data 
analysis
Section 10.7: 
Data 
Analysis
The patients, who have taken at least one 
dose of nintedanib and have at least one 
further visit, will be included in the safety 
analysis.
The baseline characteristics of at least 200 
IPF pirfenidone treated patients who have 
been newly prescribed Pirfenidone will be 
used to compare with the patient profiles of 
the nintedanib users. Whenever patient 
profiles differ between those treated with 
Nintedanib 
and 
Pirfenidone, 
cautious 
interpretation is required when comparing 
with Nintedanib treated populations from 
other trials / registries.
Any patient who meets following criteria is 
treated 
as 
ineligible 
for 
all
safety
analysisanalyses: 
No further visit data are available
No Required registration procedure is
was not followed
No valid site contract is available
Administrati
ve update 
for better 
clarity.
3
13 June 
2018
Flow chart 
for patients 
prescribed 
nintedanib: 
Time
Week 4, 8, 12 or at discontinuation
Week 24, 36 and 52 or at discontinuation
Approximately every 4 weekly during first 3 
visits and approximately every 12 weekly 
therafter till week 52; or at discontinuation 
(EOT)
Follow up visit6
Administrati
ve update 
for better 
clarity.
3
13 June 
2018
Flowchart 
footnotes
Evaluation time points/visit schedules are 
approximate. Collected data should be 
reported as those to the closest available 
visit
##: Evaluation time points/visit schedules
are approximate and are same for all 
types of patients (i.e. Group A, B and C 
patients mentioned under section 10.1). 
For Group A patients, data will be 
collected 
retrospectively 
from 
their 
medical records. For Group B patients, 
data will be collected retrospectively 
from their medical records till the date 
For 
inclusion of 
retrospectiv
e patient 
data

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of the start of their participation in this 
active 
surveillance 
program 
and 
prospectively thereafter. For Group C 
patients, 
data 
will 
be 
collected 
prospectively.
There 
may 
be 
unscheduled 
visits 
between 
the 
scheduled visits. All ADRs and SAEs 
will 
also 
be 
collected 
at 
these 
unscheduled visits and entered into the 
eCRF and reported via NIS AE form as 
per section 12.2. In case the patient is 
lost to follow up (patient not contactable 
for further visits), the site should 
attempt 
to 
contact 
the 
patient 
telephonically to gather the information 
on the vital status and record it in the 
eCRF.

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Section 6: 
Flow chart 
for patients 
prescribed
treated with
pirfenidone: 
Footnotes
# For Group I and II patients mentioned 
under section 10.1, baseline data will be 
collected 
retrospectively 
from 
their 
medical records at visit 1.
For 
inclusion of 
retrospectiv
e patient 
data
3
13 June 
2018
Section 
10.2.2.2: 
Registration 
period
This active surveillance will include at 
least 200 consecutive IPF patients treated 
with 
Nintedanib 
per 
the 
inclusion/exclusion criteria at selected sites 
from the date of commercial availability of 
the drug. Patients who have taken at least 
one dose of Nintedanib and have minimum 
of one further visit will be included in the 
safety analysis. In addition, baseline 
characteristics of 200 patients who will be 
newly prescribed Pirfenidone from the 
same study sites during the same time 
period will be collected. Once a patient is 
enrolled into the Nintedanib group at any 
given site, then next the next eligible 
patient 
initiating 
Pirfenidone 
at 
the 
corresponding site should be enrolled in 
the Pirfenidone group. These patients will 
not be followed. There is no specific time 
frame for the enrolment period. It will 
end as soon as 200 patients are enrolled.
To avoid 
repetition.
3
13 June 
2018
10.2.2.3
Patient 
registration 
method
In accordance with the in-inclusion &
exclusion criteria, at least 200 consecutive
IPF patients (at the participating sites) who 
have initiated or will initiate treatment 
with 
Nintedanib 
from 
the 
date 
of 
commercial 
availability 
of 
the 
drug
nintedanib (classified as Group A, B and 
C, see section 10.1) will be registered. In 
addition, 200 IPF patients prescribed 
Pirfenidone from who have initiated or 
will initiate pirfednidone (classified as 
Group I, II and II, see section 10.1) at the 
same sites centers and during the same 
time frame period will also be registered. 
The medical records at the slected sites 
will be screened to 35nrol Group A and 
B patients in a retrospective manner. 
Group C patients will be enrolled 
prospectively. The first patient enrolled 
To include 
retrospectiv
e patient 
data

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at a given site should be in the 
nintedanib group.
Once a patient is 
enrolled into the nintedanib group at any 
given the site, then next team is suggested 
to enrol the next eligible patient, who had 
initiated/will be initiating pirfenidone at 
the corresponding same site should be 
enrolled in the pirfenidone group.

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End 
of 
registration
The patient registration at the selected 
centers will continue till at least 200 IPF 
patients treated with Nintedanib from the 
date 
of 
commercial 
availability 
of 
Nintedanib drug in India (23rd January 
2017) are included; and their safety data 
are collected for at least 52 weeks or till 
the 
discontinuation 
of 
the 
drug, 
whichever 
is 
earlier.
Baseline 
characteristics of 200 IPF patients treated 
with Pirfenidone from at the same sites 
during the same period will also be 
collected.
Administrati
ve change 
for better 
clarity
3
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2018
10.2.3
Discontinuat
ion of the 
study by the 
sponsor
Boehringer 
Ingelheim 
India 
Pvt 
Ltd
reserves the right to discontinue the study 
overall or at a particular study site at any 
point in time for the following reasons
Administrati
ve change 
for better 
clarity
3
13 June 
2018
10.3.1. 
Exposures
Exposure to Nintedanib will be estimated 
as time from the day Nintedanib is initiated 
until 
28 
days 
after
52 
weeks/ 
discontinuation of
the drug is last 
administrated to the patient (or the final 
contact with the patient for the last regular 
observation/end of the study).
Modified to 
match the 
real world 
setting.
3
13 June 
2018
10.3.2
Outcomes
The primary outcome

Occurrence
Incidence of all
ADRs 
(serious and non-serious) in nintedanib 
treated patients

Occurrence
Incidence
of all
SAEs 
(serious adverse events) in nintedanib 
treated patients
Secondary outcome
Percentage of patients who require dose 
reductions, 
interruptions
and 
discontinuation due to adverse events.
Administrati
ve change 
for better 
clarity
3
13 June 
2018
10.3.3 Other
Baseline characteristics
The baseline characteristics will be recorded 
for all patients either prescribed nintedanib 
and pirfenidone from the same centre during 
the same time period. For the nintedanib 
treated patients cohort certain information 
(e.g. co-medications) will also be collected 
at further visits, as the status may change 
over the time (see flow chart in the 
beginning of the protocol).
Administrati
ve change 
for better 
clarity

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10.7.1
Analyses of 
outcome 
events
Safety:
In 
general, 
safety 
analyses 
will 
be 
descriptive in nature, and will be based on 
BI standards, and will focus on any 
suspected
all
ADRs (serious and non-
serious), SAEs (serious adverse events).
To this end, all Aes occurring between first 
intake of Nintedanib prescribed at visit 1
and up to 28 days after the last intake 52 
weeks/discontinuation will be considered 
‘treatment emergent’.
The frequency and incidence of Aes/SAEs 
and ADRs and SAEs will be tabulated by 
system organ class and preferred term.
Modified to 
match the 
real world 
setting.
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2018
10.7.2
Interim 
analyses
Starting from the date of second this
amendment, a status report of the active 
surveillance will be submitted to DCGI 
annually
Administrati
ve change 
for better 
clarity
3
13 June 
2018
10.9
Limitations 
of the 
research 
methods
The scientific objective of this active 
surveillance is to obtain an estimate of the 
occurrence of all ADRs and SAEs in IPF 
patients prescribed Nintedanib per the 
approved label in the real world setting.
For retrospective data, there may be a 
possibility of missed information on 
adverse events. For patients followed 
prospectively, lost to follow up, loss of 
information and recall bias could impose 
limitations.
The possible selection bias will be 
minimised
by 
including 
consecutive
enrolling all patients who have initiated 
or will initiate nintedanib (Group A, B 
and C) from the date of commercial 
availability of drug (23rd January 2017) 
at 
selected 
centres
and 
potential 
channelling bias
will be assessed by 
recording the baseline characteristics of a 
comparator group of equal number of 
patients who have been newly prescribed 
Pirfenidone. However other factors may 
impose limitations such as loss to follow 
up and information and recall bias treated 
with pirfenidone.
To include 
retrospectiv
e patient 
data.

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10.10.1.1
Study 
approval, 
patient 
information, 
and 
informed 
consent
The review by Drug controller general of 
India (DCGI) Institutional Review Board 
(IRB) or Ethics Committee will be sought as 
per the institutional procedures before the 
start of this active surveillance program.
Prior to patient’s participation in this active 
surveillance 
study
program, 
written 
informed consent must be obtained from 
each patient (or the patient’s legally accepted 
representative) according to the regulatory 
and legal requirements of India (applicable 
for Group B and C patients).
Each signature must be personally dated by
each signatory and the informed consent 
and any additional patient-information 
form must be retained by the Investigator 
as part of the study records.
The 
Investigator 
must 
give 
a 
full 
explanation to the participants of this 
active surveillance program, regarding the 
collection of the safety data at specific time 
points to these participants.
Administrati
ve change 
for better 
clarity
3
13 June 
2018
10.10.1.3.2
Direct 
access to 
source data 
and 
documents
The 
Investigator/institution 
will 
permit 
active surveillance study related monitoring, 
audits, IRB/IEC review and regulatory 
inspection, providing direct access to all 
related source data/documents related to 
this active surveillance program.
Administrati
ve change 
for better 
clarity
3
13 June 
2018
10.10.1.4
Statement of 
confidentialit
y
Individual patient’s
medical information 
obtained 
as 
a 
result 
of 
this 
active 
surveillance 
program
is 
considered 
confidential and disclosure to third parties is 
prohibited with the exceptions noted below.
Data generated as a result of this active 
surveillance program needs to be available 
for inspection on request by, the Sponsor’s 
representatives, by the IRB/IEC and the 
regulatory authorities.
Administrati
ve change 
for better 
clarity
3
13 June 
2018
11.
Protection of 
human
subjects
There is no need for a clinical trial type
insurance of to ensure well-being and rights 
of participants because since this is an active 
surveillance 
program
of 
the 
patients 
prescribed nintedanib per the approved label 
in the real world setting; and there is no risk 
of an experimental treatment. There is no 
regulation or requirement for ensuring the 
Administrati
ve change 
for better 
clarity

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well-being and rights of participants.
3
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2018
12.2
Adverse 
event and 
serious 
adverse 
event 
collection
and 
reporting
Collection and Reporting of Aes
The following information
must be 
collected by the investigator in the CRF for 
Group A,B and C patients from signing 
the informed consent onwards the date of 
initiation of nintedanib  until individual 
patient’s end of study (completion of 
follow up visit):
-
All ADRs (serious and non-serious)
associated with nintedanib 
-
All SAEs (Serious Adverse Events) in 
patients exposed to nintedanib
Expedited Reporting of Aes
and Drug 
Exposure During Pregnancy:
The following must be reported by the 
investigator for Group A, B and C patients  
on the NIS AE form from signing the 
informed consent onwards until the date of 
administration 
of 
nintedanib 
until 
individual patient’s end of study (completion 
of follow up visit):
All SADRs associated with Nintedanib: 
immediately within 24 hours
To include 
retrospectiv
e patient 
data.
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2018
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. Starting from the 
date of second this amendment, a status 
report of the active surveillance program
will be submitted to DCGI annually.
Administrati
ve change 
for better 
clarity
3
13 June 
2018
13.
Plans 
for 
disseminatin
g and 
communicati
ng study 
results
The progress reports and final report will 
be submitted in Indian Periodic Safety 
Update Reports (PSUR). And also the final 
report will be submitted in re-examination 
documents.
A final report summarizing the results of 
the study and the analysis will be 
submitted to the Indian regulatory agency 
at the end of the active surveillance 
program.
Administrati
ve change 
for better 
clarity

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Amendm
ent no.
Date
Section no.
Amendment or update
Reason
4
01 Aug
2018
10.2.2.1
Inclusion / 
exclusion 
criteria
Exclusion criteria:
Patients who have initiated or will 
initiate nintedanib concomitantly 
with pirfenidone.
Typographical error 
correction. This was 
already mentioned in 
the abstract of the 
Protocol.
4
01 Aug
2018
10.2.2.3
Patient 
Registration 
method
In addition, 200 IPF patients who 
have initiated or will initiate 
pirfednidone (classified as Group 
I, II and III, see section 10.1) at 
the same centers and during the 
same time frame will also be 
registered.
Typographical error 
correction.
4
01 Aug
2018
10.4
Data Sources
This data will be entered into 
eCRF and reported via NIS AE 
form as per section 12.2. Group B 
and C patients will be followed-
up according to clinical practice 
for at least 52 
weeks/discontinuation (whichever 
is earlier) from the start of the 
treatment, at regular intervals (i.e. 
approximately every 4 weeks for 
the first 3 visits and every 12 
weeks thereafter till week 52)
Typographical error 
correction. This was 
already mentioned in 
the abstract of the 
Protocol.

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7.
MILESTONES
Milestone
Planned Date
Final protocol
26 April, 2016
First Protocol amendment
6 September 2016
Start of data collection
6 April 2017
Second Protocol amendment
17 January 2018
Third Protocol amendment
13 June 2018
Fourth protocol amendment
01 Aug 2018
End of data collection
Until the last patient completes the follow up period
Registration in the EU PASS 
register
EUPAS17055
Final report of study results
6 months after the last patient out

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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. 
Nintedanib 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 signalling cascade. 
Pharmaceutical treatments indicated for IPF are limited. Various pharmacologic options like 
corticosteroids, azathioprine, cyclophosphamide, and N-acetylcysteine are currently being used for the 
management of IPF, albeit none of these has been proven efficacious in clinical trials compared with 
placebo [P11-07084]. The only drug that has been registered in India for the treatment of IPF is 
Pirfenidone. The recommended dose of Pirfenidone is 1800-2400mg. Data suggests that lot of Indian 
patients do not tolerate Pirfenidone at the recommended doses [P16-04690]. Thus, despite the 
availability of Pirfenidone, the 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 
Nintedanib 150 mg b.i.d. for 52 weeks significantly reduced the annual decline in FVC compared to 
placebo. The tolerability and safety of Nintedanib was comparable to placebo with a slightly higher 
incidence of AEs in the Nintedanib group compared to the placebo group. There was no difference in 
the proportion of patients experiencing serious adverse events between the treatment groups. 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 Nintedanib 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 [P14-07514].
A total of 20 Indian patients in both trials (1199.32 and 1199.34) were administered Nintedanib 150 
mg b.i.d. The safety and efficacy of Nintedanib in this small number of patients was in line with the 
global data [c03113022-01]. Indian regulatory authority (Drug Controller General of India) 
recommended the approval of Nintedanib for IPF patients with a waiver for a local clinical trial and a 
requirement for an active surveillance of all IPF patients prescribed with the drug to generate 
additional safety data. The proposed active surveillance aims to collect real world safety data of 200 
patients treated with nintedanib per the approved label at selected centres after the commercial 
availability of the drug in India (23rd January 2017).

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9.
RESEARCH QUESTION AND OBJECTIVES
This active surveillance aims to collect the safety data of 200 IPF patients treated with nintedanib in 
approved indication after the commercial availability of the drug in India (23rd January 2017). The 
objective is to look at safety of nintedanib in the real world setting.

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10.
RESEARCH METHODS
10.1
STUDY DESIGN
200 IPF patients treated with nintedanib per the Indian label will be enrolled in this active surveillance 
program. They are classified into following groups:
Group A.
Patients who started treatment with nintedanib after 23rd January, 2017 and have 
permanently discontinued the drug (as decided by the investigator) at the time of 
participation in the active surveillance. Data for these patients will be collected in 
anonymized manner after getting approval from the Ethics Committees for data 
collection and sharing.
Group B.
Patients who started treatment with nintedanib after 23rd January, 2017 and are 
continuing the drug at the time of participation in the active surveillance.
Group C.
Patients who have been newly prescribed nintedanib at the time of participation in the 
active survellinace. 
In addition 200 IPF patients treated with pirfenidone will also be enrolled. They are classified into 
following groups:
Group I.
Patients who started treatment with pirfenidone after the 23rd January, 2017 and have 
permanently discontinued the drug (as decided by the investigator) at the time of 
participation in the active surveillance. Data for these patients will be collected in 
anonymized manner after getting approval from the Ethics Committees for data 
collection and sharing.  
Group II.
Patients who started treatment with pirfenidone after the 23rd January, 2017 and are 
continuing the drug at the time of participation in the active surveillance.
Group III.
Patients who have been newly prescribed pirfenidone at the time of participation in 
the active surveillance.
The medical records at the slected sites will be screened to enroll Group A and B patients in a 
retrospective manner. Group C patients will be enrolled prospectively. The first patient enrolled at a 
given site should be in the nintedanib group. Once a patient is enrolled into the nintedanib group, the
site team is suggested to enrol the next eligible patient, who has initiated or will be initiating 
pirfenidone at the same site in the pirfenidone group. 
The safety data for nintedanib treated patients will be collected for at least 52 weeks or till the 
discontinuation of the drug, whichever is earlier. Patients treated with pirfenidone will not be 
followed.
At visit 1, the baseline characteristics (e.g. demographics, pulmonary function tests, HRCT evaluation 
etc., see section 10.3.3) will be recorded for all patients (either treated with nintedanib or pirfenidone).
The medical records of patients belonging to Group A and B will be evaluated to see if any ADRs and  
SAEs have occurred in the nintedanib treated arm during the duration of the treatment/ 52 weeks, 
whichever is earlier. Group B and Group C patients will be followed up according to clinical practice 

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for at least 52 weeks /discontinuation (whichever is earlier) from the start of the treatment at regular 
intervals (i.e. approximately every 4 weeks for the first 3 visits and approximately every 12 weeks 
thereafter till week 52). At each visit, all ADRs  associated with nintedanib and SAEs  will be 
recorded and reported per section 12.2. In case a patient discontinues nintedanib before 52 weeks, all 
ADRs and SAEs will be collected till the date of discontinuation of nintedanib. There may be 
unscheduled visits between the scheduled visits. All ADRs and SAEs will also be collected at these 
unscheduled visits and entered into the eCRF. For nintedanib treated patients, certain information (e.g. 
co-medications, see flowchart) will also be collected at further and unscheduled visits (if available), as 
the status may change over time.
In case the patient is lost to follow up (patients not contactable for further visits), the site should
attempt to contact the patient or patient’s relative telephonically to gather the information on the vital 
status and record it in the eCRF.
Additionally, whenever the investigator becomes aware of SAEs and/or ADRs occurring in an 
enrolled patient before individual patient’s end of study and it needs to be reported as per section 12.2.
Patients who have taken at least one dose of nintedanib will be included in the safety analysis.
As this is an active surveillance of patients treated with nintedanib in the real world setting, no 
specific treatment is mandated or withheld from the patients. The choice of maintenance treatment for 
IPF must be according to the regular medical practice and at the discretion of the physician. The 
assignment of the patient to nintedanib or any other treatment falls within current practice and prior to 
the decision to talk to the patient about the study, so that the decision to prescribe nintedanib is clearly 
separated from the decision to include the patient in this active surveillance program. The decision of 
treatment, including the intended duration of treatment, is at the discretion of the physician providing 
care for the patient.
10.2
SETTING
10.2.1
Site selection
This active surveillance will be done at selected sites where IPF patients are regularly treated.
10.2.2
Selection of population
10.2.2.1
Inclusion / exclusion criteria
Inclusion criteria for nintedanib treated patients: 
Inclusion criteria:
1.
Patients with documented diagnosis of IPF based upon ATS/ERS/JRS/ALAT 2011 guidelines 
(nintedanib naïve or pirfenidone pre-treated) who have initiated or will initiate nintedanib
according to the package insert after the commercial availability of drug in India (23rd January 
2017).
2.
Patients in whom it is possible to obtain voluntary informed consent either from the patient or 
patient’s legally authorised representative (applicable for Group B and C patients, see section 10.1
for details).

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3.
Patients in whom data collection is possible from the medical records (applicable for Group A and 
B patients, see section 10.1 for details).  
4.
Patients in whom information on baseline characteristics mentioned in the section 10.3.3 is 
available.
-Exclusion criteria:
1.
Patients who were previously treated with nintedanib.
2.
Patients who have initiated or will initiate nintedanib concomitantly with pirfenidone.
3.
Patients who are participating in a clinical trial.
Inclusion criteria for pirfenidone treated patients: 
Inclusion criteria:
1.
Patients with documented diagnosis of IPF based upon ATS/ERS/JRS/ALAT 2011 guidelines 
(antifibrotic naïve) who have initiated or will initiate pirfenidone according to the package insert 
after the commercial availability of nintedanib in India (23rd January 2017) 
2.
Patients in whom it is possible to obtain voluntary informed consent either from the patient or 
patient’s legally authorised representative (applicable for Group II and III patients, see section 
10.1 for details).
3.
Patients in whom data collection is possible from the medical records (applicable for Group I
and II patients, see section 10.1 for details). 
4.
Patients in whom information on baseline characteristics mentioned in the section 10.3.3. is 
available.
Exclusion criteria:
1.
Patients who were previously treated with nintedanib or pirfenidone.
2.
Patients who have initiated or will initiate pirfenidone concomitantly with nintedanib. 
3.
Patients who are participating in a clinical trial.
10.2.2.2
Registration period
There is no specific time frame for the enrolment period. It will end as soon as 200 patients are 
enrolled.
10.2.2.3
Patient registration method
In accordance with the inclusion & exclusion criteria, 200 IPF patients who have initiated or will 
initiate nintedanib (classified as Group A, B and C, see section 10.1) will be registered. In addition,
200 IPF patients who have initiated or will initiate pirfednidone (classified as Group I, II and III, see 
section 10.1) at the same centers and during the same time frame will also be registered. 
The medical records at the slected sites will be screened to enroll Group A and B patients in a 
retrospective manner. Group C patients will be enrolled prospectively. The first patient enrolled at a 
given site should be in the nintedanib group. Once a patient is enrolled into the nintedanib group, the 

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site team is suggested to enrol the next eligible patient, who has initiated/will be initiating pirfenidone
at the same site in the pirfenidone group. 
Patients will be registered by entering following necessary information in the electronic data capture 
(EDC) system. This information will be mandatory for registration:

Demographics

Pulmonary function tests at visit 1 and further visits [FVC, FVC % predicted, FEV1 (mL), 
FEV1 % predicted, DLCO] – Yes/No/Unknown. If yes specify the values with the dates.

Family history

Time since IPF diagnosis (date)

Chest HRCT evaluation (UIP pattern, Possible UIP pattern, Inconsistent UIP pattern, emphysema)

Surgical lung biopsy (yes/no/unknown) (UIP pattern, probable UIP pattern, possible UIP pattern, 
inconsistent with UIP or non-classifiable, not available) 

Previous history of acute exacerbation (Yes/ No/unknown)

Vital signs and physical examination [Heart rate (beats per minute), blood pressure (systolic blood 
pressure, diastolic blood pressure) weight and height] - available/not available/unknown, value, 
date. 

Symptoms

Known hepatic/renal impairment (yes/no/unknown)

Comorbidities at visit 1 (yes/no/unknown, if yes specify)

Bleeding and thrombotic risk (yes/no/unknown)

Previous medications for IPF (yes/no/unknown, if yes specify)

Co-medications [at visit 1 and further visits (whether used or not, unknown, start and stop date 
and dose)]

Laboratory tests at visit 1 e.g. LFT (performed/not performed/unknown/performed but missing 
value and value, date)]
End of registration:
The patient registration at the selected centers will continue till 200 IPF patients treated with 
Nintedanib from the date of commercial availability of drug in India (23rd January 2017) are included;
and their safety data are collected for at least 52 weeks or till the discontinuation of the drug, 
whichever is earlier. Baseline characteristics of 200 IPF patients treated with Pirfenidone at the same 
sites during the same period will also be collected. 
10.2.3
Discontinuation of the study by the sponsor
A log of all patients included into the active surveillance study will be maintained at participating 
sites.

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Boehringer Ingelheim India Pvt Ltd reserves the right to discontinue the study overall or at a 
particular study site at any point in time for the following reasons:

Emergence of any new information on the safety of Nintedanib which mandates the 
discontinuation of the study 

Violation of the protocol, or the contract by a study site or investigator, disturbing the appropriate 
conduct of the study
The site will be reimbursed for reasonable expenses incurred in case of study termination (except in 
case of the second reason).
10.3
VARIABLES
10.3.1
Exposures
Exposure to Nintedanib will be estimated as time from the day Nintedanib is initiated until 52 weeks/ 
discontinuation of the drug (or the final contact with the patient for the last regular observation/end of 
the study).
Dosage and administration: Usually initial dose in adult patients is Nintedanib 150 mg twice daily; 
oral administration with food in morning and evening.
According to the Indian label the dosage should be reduced to Nintedanib 100 mg twice daily
according to the patient’s symptoms or in case of adverse events.
10.3.2
Outcomes
Safety
The primary outcome

Incidence of all ADRs in nintedanib treated patients

Incidence of all SAEs in nintedanib treated patients
Secondary outcome

Percentage of patients who require dose reductions, interruptions and discontinuation due to 
adverse events.
How to assess and report AEs (including its definitions) are described in section 12.
10.3.3
Other
Baseline characteristics
The following variables based on physician’s report will be considered as the minimum baseline 
characteristics and potential confounders for the events of interest. The baseline characteristics will be 
recorded for all patients either prescribed nintedanib and pirfenidone from the same centre during the 
same time period. For the nintedanib treated patients certain information (e.g. co-medications) will 
also be collected at further visits, as the status may change over the time (see flow chart in the 
beginning of the protocol).

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Demographics:

Age

Gender

Weight

Height

Pregnancy status

Smoking status
o
Never / Past / Current / Unknown
o
For the Past/Current, specify packs/year and for Past (number of years smoking one pack 
per day equivalent)

Drugs of abuse
o
Alcohol (Drinker/ex-drinker/non-drinker/unknown)
o
Cocaine (Never/past/current /unknown)
o
Other (please specify)
Baseline characteristics of disease (date of assessment):

Pulmonary function test  (FVC, FVC % predicted, FEV1 [mL], FEV1 % predicted, DLCO) –
Yes/No/Unknown, values and date

Family history

Time since IPF diagnosis (date)

Chest HRCT evaluation (UIP pattern, Possible UIP pattern, Inconsistent UIP pattern, 
emphysema)

Surgical lung biopsy (yes/no/unknown) (UIP pattern, Probable UIP pattern, Possible UIP pattern, 
Inconsistent with UIP, Not available )

Previous history of acute exacerbation (Yes/No/Unknown)

Vital signs and physical examination at visit 1 and further visits [yes/no/unknown, value, date, 
heart rate (beats per minute), blood pressure (systolic blood pressure, diastolic blood pressure; 
mmHg)].

Symptoms (Dyspnoea on exertion (If yes, classify by modified MRC dyspnea scale (The 
classification are described in ANNEX 3), cough, clubbing, bibasilar crackles, weight loss, 
fatigue, dizziness, chest pain; whether or not)

Known Renal impairment (yes/no/unknown)
Mild (Cr Clearance – 50-80 ml/min), moderate (Cr Cl – 30-49 ml/min) and severe (Cr Cl - <30 
ml/min)

Known Hepatic impairment (yes/no/unknown) by Child Pugh Score (ANNEX 4)
Comorbidities: (yes/no/unknown, start/stop dates/ongoing)

History of surgery within four weeks before administration

Cardio and cerebrovascular comorbidities:
Arterial hypertension, coronary artery disease, myocardial infarction, congestive heart failure, 
ischaemic stroke, haemorrhagic central nervous system, transient ischaemic attack, peripheral 
artery disease, AF, other thromboembolic events (e.g. acute limb ischaemia, acute mesenteric 
ischaemia, renal infarction etc.), deep venous thrombosis, pulmonary embolism, pulmonary 
hypertension, Anemia, hemorrhage , Haemoptysis, haematuria

Respiratory comorbidities:
Chronic obstructive pulmonary disease (COPD), emphysema (radiologic), asthma, pneumonia, 
obstructive sleep apnea, Respiratory failure, Renal comorbidities: chronic renal failure 

Hepatic comorbidities: cirrhosis, chronic hepatic failure

Gastrointestinal comorbidities:

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Gastroesophageal reflux disease (GERD), gastric ulcer, appendicitis, abdominal surgery, 
inflammatory bowel disease (e.g. Crohn’s disease, ulcerative colitis), GI cancer, diverticulitis, 
superior mesenteric artery syndrome

Metabolic comorbidities: Diabetes mellitus T1/T2, hyperlipidaemia, hypothyroidism

Depressive disorder, anxiety disorder

Neoplasms: Lung, liver, stomach, colorectal, breast and oesophageal, prostate and cervix cancer

Others, please specify
Bleeding risk (unknown, no, yes – start date, stop date/ongoing, please specify)

Genetic predisposition

History of bleeding

Gastrointestinal ulcers,

Major injury or surgery

Use of anticoagulants

Others
Thrombotic risk (yes/no/unknown – start date, stop date/ongoing, please specify)
If yes:

History of thrombosis

Genetic predisposition (please specify)

Trauma

Immobilization due to injury or after surgery
Previous drug for IPF defined as usage before visit 1 assessment [whether used or not, unknown, 
start/stop dates, dosage, reason of discontinuation (side effects, physician’s recommendation for 
alternative treatment)]:

Pirfenidone 

N-acetylcysteine

Corticosteroids

Immunosuppressant (Azathioprine, Cyclophosphamide, cyclosporine A, others please specify)

Others
Co-medications for IPF defined as at visit 1 and further visits (whether used or not, unknown start and 
stop date and dose, units):

Pirfenidone 

N-acetylcysteine

Corticosteroids

Immunosuppressant (Azathioprine, Cyclophosphamide, cyclosporine A, others please specify)

Others

Co-medications:
o
Anticoagulant
o
Vit-K antagonist
o
Heparin
o
NOAC
o
Antiplatelet therapy (if yes high-dose antiplatelet therapy)
o
Aspirin (if yes please specify, if used as antiplatelet)
o
GERD medication
o
PDE-5 inhibitor
o
Endothelin receptor antagonist
o
Long-term Oxygen therapy

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o
Listed for lung transplantation
o
NSAIDs
o
Hormonal contraceptives
o
Hormone replacement therapy
o
Anti-VEGF drugs
o
Chemotherapy
o
Other, please specify
Laboratory tests at visit 1 (performed/not performed/unknown/performed but missing value and value 
(units), date):

Liver function test (ALT, AST, GGT, ALP, Total Bilirubin)

Other biochemical test (Cr, CK, BNP, CRP, LDH)

Coagulation test (PT-INR, APTT)

Immunological test (ANA, RF at visit 1 only)

Urinalysis (Occult blood in urine by dipstick)

Arterial blood gas (PaO2, PaCOs)
After visit 1, abnormal lab values that are clinically significant and related to Nintedanib will be 
collected as Adverse Event in eCRF and will be reported on NIS AE form. 
[After visit 1, lab results will be collected in eCRF in following manner:

Laboratory tests – done/not done/unknown

If done – within normal range/unknown/out of range

If out of range - clinically significant/clinically not significant 

If clinically significant – related to the Nintedanib/not related to Nintedanib 

If related to the Nintedanib – it will be reported on the AE page (In addition to the AE term, 
actual lab values that are abnormal, clinically significant & related to Nintedanib will also be 
reported in the CRF)]
In addition to this, any abnormal lab value, which is clinically significant and qualifies as SAE, will 
be reported in the eCRF and NIS AE form whether or not it is related to the Nintedanib.
10.4
DATA SOURCES
This active surveillance is based on existing and newly collected data at selected centers where IPF 
patients are regularly treated.
Data of the individual patients will be gathered using electronic data capture (EDC) system. The 
medical records of Group A and B patients will be used to collect the data of covariates as described 
in section 10.3.3 and all ADRs and SAEs occurring during the duration of the treatment/ 52 weeks, 
whichever is earlier. This data will be entered into eCRF and reported via NIS AE form as per section 
12.2. Group B and C patients will be followed-up according to clinical practice for at least 52 
weeks/discontinuation (whichever is earlier) from the start of the treatment, at regular intervals (i.e. 
approximately every 4 weeks for the first 3 visits and every 12 weeks thereafter till week 52). After 
the completion of medical examination and observation at the suggested time points, investigator 
needs to enter data of the registered patients (all ADRs and SAEs) in the EDC system and report via 
NIS AE form as per section 12.2. Additionally information on certain covariates will be collected at 
subsequent visits as described in the section 10.3.3. For patients treated with Pirfenidone, only 
baseline characteristics will be recorded in EDC and these patients will not be followed.

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10.5
SAMPLE SIZE
200 IPF patients treated with nintedanib according to approved Indian label (classified as Group A, B 
and C, see section 10.1) will be enrolled in this active surveillance program. The sample size of 200 is 
as per the request from the regulatory agency.
In addition 200 IPF patients who were treated with pirfenidone (classified as Group I, II and III, see 
section 10.1) at the same centres and during the same time frame will also be included. The baseline 
characteristic of these patients will be recorded at visit 1 and they will not be followed. 
10.6
DATA MANAGEMENT
Patients’ data will be gathered in the EDC system and outsourced to a CRO.
10.7
DATA ANALYSIS
Analyses will be descriptive in nature including means, medians, standard deviation and interquartile 
range for continuous variables, and frequencies and percentages for binary and categorical variables
with the corresponding 95% confidence intervals. For safety outcomes, incidence rates with 
corresponding 95% confidence intervals will be calculated. The baseline characteristics of 200 
pirfenidone treated patients will be used to compare with the patients profile of the Nintedanib users. 
Whenever patient profiles differ between those treated with nintedanib and pirfenidone, cautious 
interpretation is required.
Subgroup analysis will be performed according to prior treatment (see section 10.7.1).
Any patient who meets the following criteria is treated as ineligible for safety analysis: 
Required registration procedure was not followed
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 for all analysis will be stratified by (i) no prior IPF 
treatment (ii) prior Pirfenidone treatment (switch) (iii) other prior treatment used for the management 
of IPF (switch) (iv) other prior treatment used for the management of IPF (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.
Safety:
In general, safety analyses will be descriptive in nature, and will be based on BI standards, and will 
focus on all ADRs and SAEs. 
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 Nintedanib prescribed at visit 1 and up to 52 weeks/discontinuation 
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’.

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The frequency and incidence of ADRs and SAEs will be tabulated by system organ class and 
preferred term. 
No imputation is planned for missing AE data except for missing onset dates which will be handled 
according to BI standard.
Descriptive statistics will be calculated for laboratory tests, vital signs and physical examination.
10.7.2
Interim analyses
Starting from the date of this amendment, a status report of the active surveillance will be submitted 
to DCGI annually. No formal interim analysis is required. 
10.8
QUALITY CONTROL
It is the responsibility of the investigator to ensure that recorded data is as accurate and 
complete as possible. Investigator and site staff will be trained on this. Data will be entered 
directly in to e-CRF by the site staff; and data quality will be ensured by having the process 
of validation and edit checks in-built in the system. 
10.9
LIMITATIONS OF THE RESEARCH METHODS
The scientific objective of this active surveillance is to obtain an estimate of the occurrence of all 
ADRs and SAEs in IPF patients prescribed Nintedanib per the approved label in the real world
setting. For retrospective data, there may be a possibility of missed information on adverse events. For 
patients followed prospectively, lost to follow up, loss of information and recall bias could impose 
limitations. Since only the cohort treated with Nintedanib will be followed up, it is impossible to 
assess the safety of Nintedanib compared to other drugs. The possible selection bias will be 
minimised by enrolling all patients who have initiated or will initiate nintedanib (Group A, B and C) 
from the date of commercial availability of drug (23rd January 2017) at selected centres and potential 
channelling bias will be assessed by recording the baseline characteristics of a comparator group of
equal number of patients who have been treated with pirfenidone.
10.10
OTHER ASPECTS
10.10.1
Informed consent, data protection, study records
The active surveillance will be carried out in compliance with the protocol, and the latest revision of 
the Declaration of Helsinki, as well as the Guidelines for Good Pharmacoepidemiological Practice 
(GPP) 
from 
Epidemiological 
Society 
for 
Pharmacoepidemiology 
(ICPE), 
 
guideline, Guideline on good pharmacovigilance practice, 
relevant BI SOPs and relevant local regulations.
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 this active 
surveillance will be described in the contract. As a general rule, no results should be published prior to 
finalization of the Study Report.

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10.10.1.1
Study approval, patient information, and informed consent
The review by Drug controller general of India (DCGI), Institutional Review Board (IRB) or Ethics 
Committee will be sought as per the institutional procedures before the start of this active surveillance
program.
Prior to patient’s participation in this active surveillance program, written informed consent must be 
obtained from each patient (or the patient’s legally accepted representative) according to the 
regulatory and legal requirements of India (applicable for Group B/C and II/III patients). Each 
signature must be personally dated by each signatory and the informed consent and any additional 
patient-information form must be retained by the Investigator as part of the study records. A signed 
copy of the informed consent and any additional patient information must be given to each patient or 
the patient’s legally accepted representative.
The Investigator must give a full explanation of this active surveillance program, regarding the 
collection of the safety data at specific time points to these participants. The Investigator obtains 
written consent of the patient’s own free will with the informed consent form after confirming that the 
patient understands the contents. The Investigator must sign and date the informed consent form.
10.10.1.2
Data quality assurance
Automatic checks at data entry will reduce the error while entering data. A quality assurance 
audit/inspection of this active surveillance may be conducted by the sponsor, sponsor’s designees, or 
by IRB/IEC or by regulatory authorities. The quality assurance auditor will have access to all medical 
records, the study related files and correspondence, and the informed consent documentation.
10.10.1.3
Records
Electronic data capture (EDC) system 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. Data reported on the eCRF 
must be consistent with the source data or the discrepancies must be explained. The Investigator may 
need to request previous medical records or transfer records. Current medical records must also be 
available. 
10.10.1.3.2 Direct access to source data and documents
The Investigator/institution will permit monitoring, audits, IRB/IEC review and regulatory inspection, 
providing direct access to all source data/documents related to this active surveillance program.
CRF/eCRF and all source documents, including progress notes and copies of laboratory and medical 
test results must be available at all times for review. 
The Clinical Research Associate (CRA)/on site monitor and auditor may review all CRF/eCRF, and 
written informed consents.

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10.10.1.4
Statement of confidentiality
Individual patient’s medical information obtained as a result of this active surveillance program 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 this active surveillance program needs to be available for inspection on 
request by, the Sponsor’s representatives, by the IRB/IEC and the regulatory authorities.

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11.
PROTECTION OF HUMAN SUBJECTS
There is no need for a clinical trial insurance to ensure well-being and rights of participants since this 
is an active surveillance program of the patients prescribed nintedanib per the approved label in the 
real world setting; and there is no risk of an experimental treatment. 

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12.
MANAGEMENT AND REPORTING OF ADVERSE 
EVENTS/ADVERSE REACTIONS
12.1
DEFINITIONS OF ADVERSE EVENTS
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An adverse event can therefore be any 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 an event in which the patient was at risk of death at the time 
of the event; it does not refer to an event 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 adverse events, 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. 
No adverse events of special interest (AESI) have been defined for this active surveillance.
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

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The design of this active surveillance is of non-interventional nature and will be 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 information must be collected for Group A,B and C patients from the date of initiation 
of nintedanib  until individual patient’s end of study:
-
All ADRs associated with nintedanib
-
All SAEs in patients exposed to nintedanib
All ADRs and SAEs 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. pre-existing or 
concomitant diseases, or co-medications).
•
The event is typically drug-related and infrequent in the general population not exposed to 
drugs (e.g. Stevens-Johnson syndrome).
-
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal 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).

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•
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 CRF.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject prescribed Nintedanib has been 
enrolled into the study, after having taken Nintedanib, 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, otherwise 
the NIS AE form is to be completed and forwarded as well within the respective timelines. 
Expedited Reporting of AEs and Drug Exposure During Pregnancy: 
The following must be reported for Group A, B and C patients  on the NIS AE form from the date of 
administration of nintedanib until individual patient’s end of study:
Type of Report
Timeline
All SAEs in patients exposed to Nintedanib
Immediately within 24 hours
All 
non-serious 
ADRs
associated 
with
Nintedanib
In 7 calendar days
All pregnancy monitoring forms
In 7 calendar days
The same timelines apply if follow-up information becomes available for the respective events. In 
specific occasions the Investigator could inform the Sponsor upfront via telephone. This does not 
replace the requirement to complete and fax the NIS AE form.
Information required
For each reportable adverse event, the investigator should provide the information requested on the 
appropriate (e) CRF pages and the NIS AE form.
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 
Nintedanib according to the local regulatory requirements for spontaneous AE reporting at the 

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investigator’s discretion by using the locally established routes and AE report forms. The term AE 
includes drug exposure during pregnancy, and, regardless of whether an AE occurred or not, any 
abuse, off-label use, misuse, medication error, occupational exposure, lack of effect, and unexpected 
benefit.
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. Starting from the date of this amendment, a status report of the 
active surveillance program will be submitted to DCGI annually.

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13.
PLANS FOR DISSEMINATING AND COMMUNICATING 
STUDY RESULTS
The progress reports and final report will be submitted in Indian Periodic Safety Update Reports
(PSUR). 
A final report summarizing the results of the study and the analysis will be submitted to the Indian 
regulatory agency at the end of the active surveillance program.

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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: 
An active surveillance to monitor the real world safety in Indian patients prescribed Nintedanib for the 
treatment of Idiopathic Pulmonary Fibrosis.     
Study reference number: BI Study Number: 1199.280
European Network of Centres for 
Pharmacoepidemiology and 
Pharmacovigilance

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Section 1: Milestones
Yes
No
N/A
Page 
Number(s)
1.1 Does the protocol specify timelines for 
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.
23
23
40
23
23
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?
25
25
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?
27
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) 
26
3.2 Does the protocol specify the primary and secondary (if 
applicable) endpoint(s) to be investigated?
29

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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)
24
Comments:
     None
Section 4: Source and study populations
Yes
No
N/A
Page 
Number(s)
4.1 Is the source population described?
27
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?
27
27
4.3 Does the protocol define how the study population will be 
sampled from the source population? (e.g. event or 
inclusion/exclusion criteria)  
27
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) 
27
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?

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Comments:
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? 
33
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)
29
7.2 Does the protocol address known effect modifiers? (e.g. 
collection of data on known effect modifiers, anticipated 
direction of effect)
29
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? 
29
29
32
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 
29
29
32

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Section 8: Data sources
Yes
No
N/A
Page 
Number(s)
history, co-morbidity, co-medications, life style, etc.)
8.3 Is a coding system described for:
8.3.1 Diseases? (e.g. International Classification of 
Diseases (ICD)-10)
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)
33
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? 
32
Comments:
None    
Section 10: Analysis plan
Yes
No
N/A
Page 
Number(s)
10.1
Does the plan include measurement of excess risks?
33
10.2
Is the choice of statistical techniques described? 
33
10.3
Are descriptive analyses included?
33
10.4
Are stratified analyses included?
33
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?
33
11.2
Does the protocol provide information on data storage? 
(e.g. software and IT environment, database 
33

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Section 11: Data management and quality control
Yes
No
N/A
Page 
Number(s)
maintenance and anti-fraud protection, archiving)
11.3
Are methods of quality assurance described?
34, 35
11.4 Does the protocol describe possible quality issues 
related to the data source(s)?
35
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)
34
34
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? 
34
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?
34
13.2
Has any outcome of an ethical review procedure been 
addressed?
34
13.3
Have data protection requirements been described?
34
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? 
15
Comments:

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None 
Section 15: Plans for communication of study results
Yes
No
N/A
Page 
Number(s)
15.1
Are plans described for communicating study results 
(e.g. to regulatory authorities)? 
34, 40
15.2
Are plans described for disseminating study results 
externally, including publication?
41
Comments:
     None

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ANNEX 3 . THE CLASSIFICATION OF MODIFIED MRC DYSPNEA 
SCALE
Grade
Questionnaire
0
I only get 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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ANNEX 4. CHILD PUGH CLASSIFICATION OF HEPATIC 
IMPAIRMENT
Assessment 
Degree of abnormality Score
Score
Encephalopathy
None
Moderate
Severe
1
2
3
Ascites
Absent
Slight
Moderate
1
2
3
Bilirubin (mg/dl)
<2
2.1-3
>3
1
2
3
Albumin (g/dl)
>3.5
2.8-3.5
<2.8
1
2
3
Prothrombin Time (seconds > 
control)
0-3.9
4-6
>6
1
2
3
Total Score
Group
Severity
5-6
A
Mild
7-9
B
Moderate
10-15
C
Severe

 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c13288600
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active-surveillance-protocol-amendment-04
An active surveillance to monitor the real world safety in Indian patients prescribed
Nintedanib for the treatment of Idiopathic Pulmonary Fibrosis.
Author-Trial Clinical Monitor
02 Aug 2018 13:28 CEST
Approval-Team Member Medical
Affairs
02 Aug 2018 13:32 CEST
Approval-Team Member Drug
Safety
02 Aug 2018 13:33 CEST
Approval-
 Safety Evaluation
Therapeutic Area
02 Aug 2018 13:48 CEST
Approval-Therapeutic Area 
02 Aug 2018 14:32 CEST
Approval-EU Qualified Person
Pharmacovigilance
02 Aug 2018 17:31 CEST
Approval-Biostatistics
03 Aug 2018 03:57 CEST
Verification-Paper Signature
Completion
04 Aug 2018 09:41 CEST

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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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