Conditions: Idiopathic Pulmonary Fibrosis
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 37
Healthy volunteers: no

Brief summary:
The primary objective of this study is to investigate the effect of steady state pirfenidone on the pharmacokinetics of nintedanib and its metabolites following oral administration of 2403 mg/day pirfenidone and to investigate the effect of steady state nintedanib on the pharmacokinetics of pirfenidone at steady state following oral administration of 150 mg bid nintedanib. There will be two cohorts of patients; the first one will consist of patients not treated with pirfenidone or nintedanib, while the second one will consist of patients on pirfenidone treatment.

Detailed description:

Arms:
arm 1: Treatment naïve to pirfenidone arm 2: Treatment before with pirfenidone

Interventions: intervention 1: nintedanib intervention 2: pirfenidone
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_001.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03463451-08
EudraCT No.:
2015-000732-15
BI Trial No.:
1199.229
BI Investigational 
Product(s):
Nintedanib (Ofev®)
Title:
Investigation of drug-drug interaction between nintedanib and 
pirfenidone in patients with IPF (an open label, multiple-dose,
two group study)
Brief Title:
A study to compare the amount of nintedanib and pirfenidone in 
the blood when nintedanib and pirfenidone are given separately or 
in combination
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone : 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol, based on Global Amendments
1, 2 and 3)
Version and Date:
Version: 4.0
Date: 29 July 2016
Page 1 of 118
Proprietary confidential information.
2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
Ofev®
Name of active ingredient:
Nintedanib
Protocol date:
17 July 2015
Trial number:
1199.229
Revision date:
29 July 2016
Title of trial:
Investigation of drug-drug interaction between nintedanib and 
pirfenidone in patients with IPF (an open label, multiple-dose, two 
group study)
Coordinating
Investigator:
Phone: 
Fax: 
Trial site(s):
Trial conducted in approximately 9 sites in the UK
Clinical phase:
IV
Objective(s):
The primary objective of this study is to investigate the effect of steady 
state pirfenidone on the pharmacokinetics of nintedanib and its 
metabolites following oral administration of 2403 mg/day pirfenidone 
and to investigate the effect of steady state nintedanib on the 
pharmacokinetics of pirfenidone at steady state following oral 
administration of 150 mg bid nintedanib. There will be two cohorts of 
patients; one group will be patients who are currently not treated with 
pirfenidone or nintedanib and one group will be patients treated with 
pirfenidone.


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Name of company:
Boehringer Ingelheim
Name of finished product:
Ofev®
Name of active ingredient:
Nintedanib
Protocol date:
17 July 2015
Trial number:
1199.229
Revision date:
29 July 2016
Methodology:
Open-label, multiple dose, two-group PK trial.
An optional Named Patient Programme of nintedanib will be 
discussed with patients at the end of the trial.  This Named Patient 
Programme will not be part of the study.
No. of patients: 
total entered:
Approximately 34 patients
each treatment:
Group 1: 16 patients 
Group 2: 18 patients
Diagnosis:
Idiopathic Pulmonary Fibrosis (IPF)
Main criteria
for inclusion:
Male or female patients aged ≥ 40 years at visit 1;
IPF diagnosis based on the ATS/ERS/JRS/ALAT 2011 IPF guidelines;
Chest High-Resolution Computed Tomography (HRCT) performed 
within 18 months of visit 1;
FVC ≥ 50% predicted of normal at visit 1.


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Name of company:
Boehringer Ingelheim
Name of finished product:
Ofev®
Name of active ingredient:
Nintedanib
Protocol date:
17 July 2015
Trial number:
1199.229
Revision date:
29 July 2016
PK EVALUATION 
PERIOD GROUP 1:
Trial product 1:
Nintedanib soft gelatin capsule
Dose:
Single dose of 150 mg on Day 1 and 23 only
Mode of administration:
Oral administration with food
Trial product 2:
Pirfenidone hard capsule
Dose:
Titrated up to 2403 mg daily according to the following schedule:

Day 2 to 8: one capsule tid (267 mg tid / 801 mg daily)

Day 9 to 15: two capsules tid (534 mg tid / 1602 mg daily)

Day 16 to 23: three capsules tid (801 mg tid / 2403 mg daily)
Mode of administration:
Oral administration with food
Duration of treatment:
23 days
PK EVALUATION 
PERIOD GROUP 2:
Trial product 1:
Nintedanib soft gelatine capsule
Dose:
Day 9 – Day 15 300 mg daily (150 mg bid) 
Day 16 150 mg morning dose only (this is the last dose in the PK 
period)
Mode of administration:
Oral administration with food
Trial product 2:
Pirfenidone
Dose:
Day1 – Day 15  - three capsules tid (801 mg tid / 2403 mg daily) with 
possibility to reduce to two capsules tid (534 mg tid / 1602 mg daily) 
Day 16 three capsules in the morning only (801 mg; this is the last dose 


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Name of company:
Boehringer Ingelheim
Name of finished product:
Ofev®
Name of active ingredient:
Nintedanib
Protocol date:
17 July 2015
Trial number:
1199.229
Revision date:
29 July 2016
in the PK period)
Mode of administration:
Oral administration with food
Duration of treatment:
16 days
Endpoints
Pharmacokinetic Parameters:
Group 1:
Primary endpoints:  AUC0-tz and Cmax of nintedanib
Secondary endpoints: AUC0-∞of nintedanib
Group 2:
Primary endpoints: AUCτ,ss and Cmax,ss of pirfenidone
Safety criteria:
Incidence and intensity of adverse events, physical examination, vital 
signs, ECG, change from baseline in laboratory parameters
Statistical methods:
Descriptive statistics and analysis of variance (ANOVA) for AUC0-tz, 
Cmax and AUC0-∞of nintedanib with and without the association with 
pirfenidone (group 1) and for AUCτ,ss and Cmax,ss for pirfenidone with 
and without the association with nintedanib (group 2).


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FLOW CHART - GROUP 1
Trial Periods
Screening 
Period1
PK evaluation Period10
PK Follow-up 
Period18
Visit
1
2
Phone 
call6
313
4
Weeks
0
2
311
7
Days 
-28 to -1
1-2
15
23-24
52
Time window for visits
+6 days
+3 days
Informed consent2
X
Demographics
X
Medical history
X
Review of in-/exclusion criteria
X
X
Drug and alcohol testing at site
X
X
Physical examination
X
X
X
X
Vital signs3
X
X
X
X
Laboratory tests
X
X
X
Pregnancy test (urine)9
X
X
X
X
PK sample7
X17
X17
X
X14
X14
X
X14
X14
12 lead-Electrocardiogram (ECG)
X
X
Spirometry12
X
X
X
X
DLCO19
X
(X)19
Register screening / start of treatment
X
X
Dispense trial drugs4
X17
X
Collect trial drug & compliance check
X
Dispense and/or collect & review diary5
X17
X
AEs and Concomitant therapy16
X
X17
X
X17
X
Conclusion of PK evaluation period
X
Conclusion of subject participation
X15


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FOOTNOTES – GROUP 1
1.
The screening period between Visit 1 and 2 should last a maximum of 28 days.  Eligible patients can be started on 
treatment once central lab results have been received and are found to be consistent with eligibility criteria.
2.
At site discretion, informed consent may be obtained on one day and the remainder of the screening procedures can 
follow.
3.
Vital signs to include blood pressure and pulse rate.
4.
Patient will be dispensed three wallets of pirfenidone.  They will use one wallet to uptitrate for 14 days (Day 2 to Day 
15) and then the next wallet for the complete dose of 801 mg tid daily (Day 16 to Day 22).  On Day 23 the patient 
should bring their medication into clinic and will be given the morning and the 14:00 of pirfenidone at the clinic.  They 
will take their evening dose at home and this will be their final dose during the PK period.  The patient will also be 
dispensed a single 150mg dose of nintedanib on Day 1 and Day 23.  (See Section 4.1.4).
5.
Patients will be supplied with a diary and a dosing card and they will be asked to document the number of capsules 
they have taken each day and also to record any adverse events during this period.
6.
At the end of the 14 day uptitration (Day 15) a call will be made to the patient to check whether there have been any 
issues with uptitration and when the patient has reached the full dose (the phone call should be documented in the 
patient notes).  The patient will then continue on full dose (801 mg tid) for 7 consecutive days (Day 16 to Day 22) 
before returning to the clinic for the next PK day (Day 23). The patient would have their final PK sample taken on 
Day 24.
7.
Please see separate PK flowchart Group 1 for details during the PK evaluation period Section 10.2.
8.
 
 
 
9.
Urine dipstick pregnancy tests will be provided by central lab and should be performed in all women of childbearing 
potential.  
10. If a patient withdraws from the PK evaluation period or does not tolerate uptitration then the patient should be 
managed according to Figure 4.1.4:1  
11. The patient will stop all trial medication on Day 23 and have a washout period from study drug until the PK FU visit.
12. Spirometry should be conducted using local standard equipment.
13. The uptitration phase between Visit 2 and Visit 3 can be extended by a maximum of 6 days if the patient needs longer 
to uptitrate or to achieve 7 consecutive stable days at full dose.  
14.
 
15. At Visit 4 (PK FU) the optional nintedanib Named Patient Programme will be discussed with the patient.
16. AEs and concomitant therapy should be checked at regular intervals during the PK days.
17. At Visit 2 Day 2 and Visit 3 Day 24 only these procedures need to be done see Section 6.2.2.
18. The PK Follow Up visit should occur at least 28 days after last drug intake.
19. DLCO testing will be performed once at visit 1 or 2, or during the screening period (visit 1 to visit 2).  The results will 
be corrected for haemoglobin by the site, see section 10.3 for further details.


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FLOW CHART - GROUP 2
Trial Periods
Screening 
Period1
PK evaluation period9
PK Follow-
up Period16
Visit
1
2
3a
3b12
4
Weeks
0
1
2
6
Days 
-28 to -1
1
8
1610
44
Time window for visits
+3 days
+3 days
+3 days
Informed consent 2
X
Demographics
X
Medical history
X
Review of in-/exclusion criteria
X
X
Drug and alcohol testing at site
X
X
Physical examination 
X
X
X
X
X
Vital signs3
X
X
X
X
X
Laboratory tests
X
X
X
X
Pregnancy test (urine)8
X
X
X
X
X
PK sample6
X
X
X
X
X13
X13
X
X
X13
X13
X
X
Spirometry11
X
X
X
X
X
DLCO17
X
(X)17
Register screening / start of treatment
X
X
Dispense trial drugs4
X
X
X
Collect trial drug & compliance check
X
X
Dispense and/or collect & review diary5
X
X
AEs and Concomitant medication15
X
X
X
X
X
Conclusion of PK evaluation period
X
Conclusion of subject participation
X14


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FOOTNOTES – GROUP 2
1.
The screening period between Visit 1 and 2 should last a maximum of 28 days.  Eligible patients can be started on 
treatment once central lab results have been received and are found to be consistent with eligibility criteria.
2.
At site discretion, informed consent may be obtained on one day and the remainder of the screening procedures can 
follow.
3.
Vital signs to include blood pressure, pulse rate and weight.
4.
Patient will be dispensed two wallets of pirfenidone at Visit 2 and take the full dose (801 mg tid) for 7 consecutive 
days (Day 1 to Day 7) and then return to the clinic for Visit 3a (Day 8). At Visit 3a they will be dispensed one wallet of 
pirfenidone and one bottle of nintedanib and be given the remaining wallet of pirfenidone that was dispensed at the 
previous visit.  The will take nintedanib 150mg bid and pirfenidone 801mg  tid (or 534mg tid) from Day 9 to Day 15 
and then come in to the clinic at Day 16 where they will receive only the morning dose of each drug.  (See Section 
4.1.4).
5.
Patients will be supplied with a diary and a dosing card and they will be asked to document the number of capsules 
they have taken each day and also to record any adverse events during this period.
6.
Please see separate PK flowchart Group 2 for details during the PK evaluation period Section 10.2.
7.
 
 
 
8.
Urine dipstick pregnancy tests will be provided by central lab and should be performed in all women of childbearing 
potential.  
9.
If a patient withdraws from the PK evaluation period then the patient should be managed according to Figure 4.1.4:1.  
10. The patient will stop all trial medication on Day 16 (except for the doses given at clinic) and have a washout period 
from study drug until the PK FU visit.  
11. Spirometry should be conducted using local standard equipment.
12. During the PK evaluation period the patient must have seven consecutive days of both nintedanib 150mg bid and 
pirfenidone 801mg  tid (or 534mg tid) before they should have the PK day on Visit 3b.
13.
14. At Visit 4 (PK FU) optional nintedanib Named Patient Programme will be discussed with the patient
15. AEs and concomitant therapy should be checked at regular intervals during the PK days.
16. The PK Follow Up visit should occur at least 28 days after last drug intake.
17. DLCO testing will be performed once at visit 1 or 2, or during the screening period (visit 1 to visit 2).  The results will 
be corrected for haemoglobin by the site, see section 10.3 for further details..


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART - GROUP 1...................................................................................................6
FOOTNOTES – GROUP 1 .....................................................................................................7
FLOW CHART - GROUP 2...................................................................................................8
FOOTNOTES – GROUP 2 .....................................................................................................9
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................16
MEDICAL BACKGROUND.............................................................................16
1.1
DRUG PROFILE................................................................................................17
1.2
1.2.1
Nintedanib............................................................................................................17
1.2.2
Pirfenidone...........................................................................................................19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....21
RATIONALE FOR PERFORMING THE TRIAL.........................................21
2.1
TRIAL OBJECTIVES........................................................................................22
2.2
BENEFIT - RISK ASSESSMENT.....................................................................22
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.1
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.3
CONTROL GROUP(S)......................................................................................26
SELECTION OF TRIAL POPULATION .......................................................26
3.4
MAIN DIAGNOSIS FOR TRIAL ENTRY......................................................27
3.5
INCLUSION CRITERIA...................................................................................27
3.6
EXCLUSION CRITERIA..................................................................................27
3.7
REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENTS........29
3.8
3.8.1
Removal of individual patients ..........................................................................29
3.8.2
Discontinuation of the trial by the sponsor.......................................................31
4.
TREATMENTS...................................................................................................32
TREATMENTS TO BE ADMINISTERED.....................................................32
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........32
4.1.2
Method of assigning patients to treatment groups...........................................33
4.1.3
Selection of doses in the trial..............................................................................33
4.1.4
Drug assignment and administration of doses for each patient......................33
Nintedanib and pirfenidone...................................................................................38
4.1.4.1


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4.1.5
Blinding and procedures for unblinding...........................................................39
Blinding.................................................................................................................39
4.1.5.1
Unblinding and breaking the code ........................................................................39
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................39
4.1.7
Storage conditions...............................................................................................40
4.1.8
Drug accountability.............................................................................................40
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................41
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....41
Recommendations for adverse events considered drug related (exceptions include 
4.2.1.1
diarrhoea and photosensitivity/rash):....................................................................41
Recommendations for managing diarrhoea ..........................................................41
4.2.1.2
Recommendations for managing phototoxicity and/or rash (PK evaluation period 
4.2.1.3
only) ......................................................................................................................41
Management of liver enzyme elevations ..............................................................42
4.2.1.4
4.2.2
Restrictions ..........................................................................................................42
Restrictions regarding concomitant treatment ......................................................42
4.2.2.1
Restrictions on diet and life style..........................................................................44
4.2.2.2
Restrictions regarding women of childbearing potential......................................44
4.2.2.3
TREATMENT COMPLIANCE........................................................................44
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................45
TRIAL ENDPOINTS..........................................................................................45
5.1
5.1.1
Primary Endpoints..............................................................................................45
5.1.2
Secondary Endpoints..........................................................................................45
5.1.3
Further Endpoints...............................................................................................45
ASSESSMENT OF EFFICACY........................................................................46
5.2
ASSESSMENT OF SAFETY.............................................................................46
5.3
5.3.1
Physical examination ..........................................................................................47
5.3.2
Vital Signs............................................................................................................47
5.3.3
Safety laboratory parameters ............................................................................47
5.3.4
Electrocardiogram ..............................................................................................48
5.3.5
Spirometry...........................................................................................................48
5.3.6
Other safety parameters.....................................................................................48
5.3.7
Assessment of adverse events.............................................................................48
Definitions of AEs ................................................................................................48
5.3.7.1
5.3.8
Adverse event collection and reporting.............................................................51
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................53
5.4.1
Assessment of Pharmacokinetics.......................................................................53
5.4.2
Methods of sample collection .............................................................................53
5.4.3
Analytical determinations ..................................................................................53
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................53
5.5
5.5.1
DNA Banking.......................................................................................................54
OTHER ASSESSMENTS...................................................................................55
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................55
5.7


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6.
INVESTIGATIONAL PLAN.............................................................................56
VISIT SCHEDULE.............................................................................................56
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................56
6.2
6.2.1
Screening period..................................................................................................56
6.2.2
Treatment period(s)............................................................................................57
6.2.3
Follow Up Period and Trial Completion...........................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE62
STATISTICAL DESIGN - MODEL.................................................................62
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.2
PLANNED ANALYSES.....................................................................................62
7.3
7.3.1
Primary endpoint analyses.................................................................................63
7.3.2
Secondary endpoint analyses .............................................................................64
7.3.3
Further endpoint analyses..................................................................................64
7.3.4
Safety analyses.....................................................................................................64
7.3.5
Pharmacokinetic analyses ..................................................................................65
7.3.6
Biomarker analyses.............................................................................................65
INTERIM ANALYSES ......................................................................................65
7.4
HANDLING OF MISSING DATA ...................................................................65
7.5
7.5.1
Safety....................................................................................................................65
7.5.2
Plasma concentration - time profiles.................................................................65
7.5.3
Pharmacokinetic parameters.............................................................................66
RANDOMISATION ...........................................................................................66
7.6
DETERMINATION OF SAMPLE SIZE .........................................................66
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........69
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................69
DATA QUALITY ASSURANCE ......................................................................70
8.2
RECORDS...........................................................................................................70
8.3
8.3.1
Source documents ...............................................................................................70
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS.....................70
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS70
8.5
LISTEDNESS......................................................................................................70
8.6
EXPEDITED REPORTING TO HEALTH AUTHORITIES AND IEC / IRB
8.7
...............................................................................................................................71
STATEMENT OF CONFIDENTIALITY........................................................71
8.8
END OF TRIAL..................................................................................................71
8.9
9.
REFERENCES....................................................................................................72
PUBLISHED REFERENCES............................................................................72
9.1
UNPUBLISHED REFERENCES......................................................................75
9.2
10.
APPENDICES.....................................................................................................76
PHARMACOKINETIC ANALYSES...............................................................76
10.1
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD SAMPLING
10.2
...............................................................................................................................78


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LUNG FUNCTION CRITERIA........................................................................80
10.3
CHILD-PUGH CLASSIFICATION (R99-1243) .............................................81
10.4
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................82


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALAT
Latin American Thoracic Association
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANOVA
ANalysis Of VAriance
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
ATS
American Thoracic Society
AUC
Area under the Curve
b.i.d.
Bis in die (twice daily dosing)
BI
Boehringer Ingelheim
CA
Competent Authority
CI
Confidence Interval
CML
Local Clinical Monitor 
CNS
Central Nervous System
CRA
Clinical Research Associate
CRF
CrCl
CTCAE
Case Report Form
Creatinine Clearance
Common Terminology Criteria
for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DDI
Drug-drug interaction
DEDP
Drug exposure during pregnancy
DILI
Drug induced liver injury
DLCO
Diffusing capacity of the Lung for Carbon monoxide
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
EOT
End of Treatment
eCRF
Electronic Case Report Form
EDTA
Ethylenediamine-tetraacetic acid
EMA
European Medicines Agency
ERS
European Respiratory Society
EudraCT
European Clinical Trials Database
FC
Flow Chart
FGFR
Fibroblast growth factor/receptor
FVC
Force Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
Hb
Haemoglobin
HRCT
High-Resolution Computed Tomography
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation


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IEC
Independent Ethics Committee
INR
International normalised radio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
JRS
Japanese Respiratory Society
LC-MS/MS
Liquid chromatography-tandem mass spectrometry
LDH
Lactate dehydrogenase
LTx
Lung Transplant
MedDRA
Medical Dictionary for Drug Regulatory Activities
NAC
NCI
N-acetylcysteine
National Cancer Institute
NGS
Next Generation Sequencing
NICE
National Institute for Health and Care Excellence
nRTKs
Non-receptor tyrosine kinases
PDGFR
Platelet derived growth factor/receptor
PFS
Progression-free survival
P-gp
P-glycoprotein
PKS
PT
PK analysis set
Prothrombin time
PTT
Partial thromboplastin time
RDC
Remote data capture
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
Ribonucleic acid
RTKs
Receptor Tyrosine Kinases
SAE
Serious Adverse Event
s.c.
Subcutaneous
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reactions
t.i.d.
Ter in die (3 times a day)
TMF
Trial Master File
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
VEGFR
Vascular endothelial growth factor receptor


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Idiopathic Pulmonary Fibrosis (IPF) is a rare disease of unknown aetiology that is characterized 
by progressive fibrotic of the interstitium of the lung, resulting in progressive pulmonary 
insufficiency (P11-07084).
The course of the disease in individual patients is variable: some patients progress rapidly; others 
have periods of relative stability punctuated by acute exacerbations and others progress 
relatively slowly. Acute exacerbations of IPF are events of respiratory deterioration of 
unidentified cause that occur in 5–10% of patients annually and are associated with a very poor 
outcome (R12-2786). 
IPF is most prevalent in middle aged and elderly patients, and usually presents between the ages 
of 40 and 70 years. The median life expectancy in IPF patients after diagnosis is 2 to 3 years 
[P11-07084].
The 2011 evidence-based guideline on diagnosis and management of IPF, jointly issued by the 
American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory 
Society (JRS) and Latin American Thoracic Association (ALAT) did not give a positive 
recommendation for any pharmacologic treatment (P11-07084). Conventional IPF treatments 
such as n-acetylcysteine (NAC), corticosteroids, cyclophosphamide, cyclosporine and 
azathioprine are not approved treatments for IPF, and their efficacy is questionable or even 
harmful [P11-07084; P12-06085; P14-07665].  Non-pharmacological therapies such as 
pulmonary rehabilitation and long-term oxygen therapy are recommended for some patients, but 
their efficacy in patients with IPF has not been established. Lung transplant (LTx) has been 
shown to positively impact survival in patients with IPF. Median survival after LTx in IPF 
patients is approximately 4-5 years, and 5-year survival is estimated at 39-50% (R11-5086; R12-
2785). Although the number of patients transplanted due to IPF has increased steadily over the 
last years, the scarce availability of donor organs, as well as the comorbidities and advanced age 
preclude many patients from referral to lung transplant [R12-3676; R12-3474].
These guidelines have been updated, presented during the 2015 International ATS Conference in 
Denver and are expected to be published before mid-2015.  These guidelines will include, for the 
first time in IPF, recommendations favouring pharmacological treatment.  
The PANTHER trial showed that NAC, commonly used off label, offered no significant benefit 
with respect to the preservation of forced vital capacity (FVC) as compared with placebo in 
patients with idiopathic pulmonary fibrosis [P14-07665]. 
Pirfenidone is a compound, which demonstrated anti-fibrotic activity in non-clinical models and
was first licensed in Japan in 2008 based on two local trials which showed a reduced decline of 
vital capacity under treatment with the compound [R06-2070; R10-4316]. In the international 
Phase III CAPACITY program, pirfenidone demonstrated efficacy on the primary FVC lung 
function endpoint in only one of two confirmatory trials [R11-4827]. The confirmatory 


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ASCEND Phase III trial met the primary endpoint of change from baseline FVC % predicted 
[R14-2103]. Pirfenidone has been licensed since February 2011 for the treatment of mild to 
moderate IPF in Europe and since October 2014 for the treatment of IPF in US. It is also 
licensed in several other countries. 
Nintedanib is a small molecule intracellular tyrosine kinase inhibitor which has demonstrated 
anti-fibrotic and anti-inflammatory activity in preclinical models [P08-08684; P14-02860]. The 
two replicate Phase III INPULSIS trials and the Phase II TOMORROW trial consistently 
showed positive results for the efficacy of nintedanib 150 mg twice daily versus placebo in 
patients with IPF. Both INPULSIS trials showed that nintedanib reduced the annual rate of 
decline in FVC (mL/year) by approximately 50%, consistent with slowing disease progression 
[P14-07514; P11-11216]. Based on these three clinical trials, nintedanib was approved for the 
treatment of IPF in US in October 2014 and in the EU in January 2015. It has been submitted for 
marketing authorization in other countries across the world.
With the future introduction of these new drugs in the evidence-based treatment algorithm of 
IPF, there is an additional need to further characterize their profile, including their use in 
potential combination treatment regimens.
DRUG PROFILE
1.2
1.2.1
Nintedanib
Nintedanib is a small molecule that inhibits a distinct spectrum of receptor tyrosine kinases 
(RTKs) and non-receptor tyrosine kinases (nRTKs) at pharmacologically relevant 
concentrations. Among them, FGFR (fibroblast growth factor/receptor), PDGFR (platelet 
derived growth factor/receptor) and VEGFR (vascular endothelial growth factor/receptor) have 
been implicated in IPF pathogenesis. Nintedanib binds competitively to the adenosine 
triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling 
which is crucial for the proliferation, migration, and transformation of fibroblasts representing 
essential mechanisms of the IPF pathology [P08-08684; P14-02860]. 
A soft gelatine capsule formulation of nintedanib is used in humans. Nintedanib is absorbed 
moderately fast, with maximum plasma concentrations occurring between 2 - 4 hours after oral 
administration. Exposure to nintedanib increases in a dose proportional manner. The terminal 
half-life is in the range of 7 to 19 h and steady state is reached at the latest within one week of 
dosing. After food intake, a trend towards an increased systemic exposure (around 15 to 20%) 
and a delayed absorption was observed compared to administration under fasted conditions. 
Nintedanib is recommended to be taken with food. Nintedanib is preferentially distributed in 
plasma, with a blood to plasma ratio of 0.87. The absolute bioavailability of the capsule 
formulation of nintedanib was slightly below 5%. Nintedanib is mainly eliminated via faeces, 
with renal elimination playing a very minor role (0.7% of an orally administered radioactive 
dose).
Co-administration of nintedanib with the P-glycoprotein (P-gp) inhibitor ketoconazole increased 
exposure to nintedanib by 60-70% based on area under the curve (AUC) and by 80% based on a 
maximum measured concentration of the analyte in plasma (Cmax) in a dedicated drug-drug 


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interaction (DDI) study. Patients taking potent P-gp inhibitors (e.g ketoconazole, erythromycin 
or cyclosporine) should be monitored closely for tolerability of nintedanib. 
In a DDI study with the P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% 
based on AUC and to 60.3% based on Cmax upon co-administration with rifampicin compared to 
administration of nintedanib alone. Since potent P-gp inducers may decrease exposure to 
nintedanib, selection of alternate treatment with no or minimal P-gp induction should be 
considered. 
Based on a multiple-dose study in Japanese IPF patients, exposure to nintedanib decreased to 
68.3% based on AUC and to 59.2% based on Cmax upon co-administration with pirfenidone 
compared to administration of nintedanib alone. Further studies are needed to confirm this 
finding [P14-17347].
The clinical efficacy of nintedanib has been studied in over 1400 patients with IPF in one phase 
II dose finding study (TOMORROW) including four different doses of nintedanib, and two 
replicate phase III (INPULSIS 1 and 2) trials. These were randomized, double-blind, placebo-
controlled studies comparing treatment with nintedanib twice daily to placebo for 52 weeks. A 
statistically significant reduction in the annual rate of decline of FVC (in mL) was demonstrated 
in patients receiving nintedanib 150 mg bid compared to patients receiving placebo. The 
treatment effect on FVC was consistent in all 3 studies, i.e. a relative reduction of approximately 
50% between nintedanib and placebo. Furthermore, nintedanib 150 mg bid significantly reduced 
the risk of first acute exacerbation compared with placebo in INPULSIS-2 and in the 
TOMORROW trial, and reduced the risk of adjudicated confirmed/suspected acute 
exacerbations by 68% in a pre-specified sensitivity analysis of pooled data from the INPULSIS 
trials, supporting the effect of nintedanib on slowing disease progression [P14-07514; P11-
11216].
The safety profile of nintedanib has been investigated comprehensively. The proportion of 
patients with serious adverse events was similar in the nintedanib and placebo groups. 
The risks of treatment with nintedanib in adult patients are primarily related to the 
gastrointestinal tract (nausea, vomiting, diarrhoea, abdominal pain) and to increases in liver 
enzymes (aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase 
(ALP), gamma-glutamyl transferase (GGT) and bilirubin. The most frequently reported adverse 
event was diarrhoea, which was mild to moderate in intensity for the vast majority of patients 
and lead to treatment discontinuation in less than five percent of patients treated with nintedanib. 
Weight decrease and decreased appetite have also frequently been reported in studies with 
nintedanib. 
Potential risks of nintedanib treatment also include arterial hypertension, gastrointestinal 
perforations, thromboembolism and bleeding. Patients treated with full-dose anticoagulation or 
at known risk for bleeding were excluded from the INPULSIS trials. This has led to 
recommendations stating that patients at known risk for bleeding should be treated with 
nintedanib only if the anticipated benefit outweighs the potential risk. Although cardiac 
disorders adverse events were balanced between the nintedanib and placebo groups, a higher 
proportion of patients in the nintedanib groups had myocardial infarctions. Conversely, a lower 


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proportion of patients in the nintedanib groups had other ischemic heart disease. The clinical 
significance of this finding is unknown, and further observation is needed.
For patients finalizing the 52-week study treatment in the TOMORROW and INPULSIS trials, 
participation in open label extension trials (1199.35 and 1199.33) was offered. Long term 
treatment in these still ongoing open label extension trials confirm the safety profile observed in 
the phase II and III trials.
Nintedanib has also demonstrated efficacy and tolerable safety in patients with non-small cell 
lung cancer who failed first treatment [P11-00203] as well as in patients with advanced renal cell 
cancer [P13-06268], ovarian cancer [P11-10116] and hepatocellular carcinoma [P13-12693]. 
Furthermore, nintedanib is also being investigated in other oncological indications, such as 
mesothelioma [P14-08020].
For a more detailed description of the drug profile refer to the current Investigator’s Brochure 
(IB) [U07-1248] which is included in the Investigator Site File (ISF).
1.2.2
Pirfenidone
The mechanism of action of pirfenidone in the treatment of IPF has not been established.
After single oral-dose administration of 801 mg pirfenidone, Cmax was achieved between 30 
minutes and 4 hours (median time of 0.5 hours). Food decreased the rate and extent of 
absorption. Median tmax increased from 0.5 hours to 3 hours with food. Maximum plasma 
concentrations and AUC0-inf decreased by approximately 49% and 16% with food, respectively. 
A reduced incidence of adverse reactions was observed in the fed group when compared to the 
fasted group. Pirfenidone was taken with food in controlled studies with IPF patients. The 
absolute bioavailability of pirfenidone has not been determined in humans. The mean terminal 
half-life is approximately 3 hours in healthy subjects and, as such, steady state accumulation is 
expected to be minimal. Pirfenidone is excreted predominantly in the urine (approximately 80% 
of the dose).
Pirfenidone is a substrate of cytochrome P450 1A2. Co-administration with the strong CYP1A2 
inhibitor fluvoxamine increased exposure to pirfenidone by approximately 4-fold in non-
smokers and 7-fold in smokers. Co-administration with ciprofloxacin (moderate inhibitor of 
CYP1A2) increased the exposure to pirfenidone by 81%. Agents or combinations of agents that 
are moderate or strong inhibitors of both CYP1A2 and one or more other CYP iso-enzymes 
involved in the metabolism of pirfenidone (i.e., CYP2C9, 2C19, 2D6, and 2E1) should be 
avoided during treatment with pirfenidone.
The efficacy of pirfenidone 2403 mg/day (3 capsules tid) was evaluated in patients with IPF in 
three phase III, randomized, double-blind, placebo-controlled, multi-centre trials (CAPACITY 
and ASCEND trials). The CAPACITY 2 trial showed a positive result on the primary endpoint 
of change from baseline in FVC % predicted at week 72, as well as on the secondary endpoint of 
progression-free survival (PFS).  In the CAPACITY 1 trial there was no statistically significant 
difference at Week 72 for the primary endpoint. The ASCEND trial reported a positive result on 
the primary endpoint of change from baseline in FVC % predicted at week 52, as well as 
positive results on both key secondary endpoints of PFS and change from baseline in 6-minute 
walk test distance [R11-4827; R14-2103].


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The safety of pirfenidone has been evaluated in more than 1400 subjects with over 170 subjects 
exposed to pirfenidone for more than 5 years in clinical trials. Adverse events included 
gastrointestinal events (nausea, abdominal pain, diarrhoea, dyspepsia, vomiting, anorexia and 
weight decrease) and skin disorders (e.g. rash, photosensitivity) that were generally mild or 
moderate and led to few treatment discontinuations.
For a more detailed description of the drug profile refer to the current local Prescribing
Information or Summary of Product Characteristics, which is included in the Investigator Site 
File (ISF)


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
The prognosis of IPF is devastating, with 50% of patients dying within 3 years of diagnosis. The 
course of the disease ranges from relative stability for several years to rapid deterioration to 
death over months, sometimes punctuated by episodes of rapid decline (acute IPF exacerbations)
[P12-03241]. Until recently, IPF was essentially an untreatable disease. It appears to be 
characterized by abnormalities in multiple pathways involved in the fibrotic process. Clinical 
trials of targeted therapies (e.g. bosentan and etanercept) have shown no benefit, whereas drugs 
that are pleiotropic in their activity, such as nintedanib and pirfenidone, have proven to be 
clinically efficacious by reducing the decline in lung function [P15-01243]. However, the 
disease continues to progress, albeit more slowly, and the scientific community, in search of 
better outcomes, is now looking for new treatment approaches including combination regimens. 
This is in line with several other serious chronic diseases including most solid tumours, infection 
with human immunodeficiency virus and pulmonary arterial hypertension [P14-16496].
Nintedanib is an inhibitor of tyrosine kinases (including the PDGF, VEGF and FGF receptors). 
By inhibiting these receptors, nintedanib regulates cellular proliferation, survival, migration and 
differentiation, processes, which are involved in the profibrotic process [P08-08684; P14-
02860]. Although the mechanism of action of pirfenidone is not fully understood, it also has 
been shown to have anti-fibrotic, anti-inflammatory and antioxidant properties in animal models
[R12-4811]. Pirfenidone has not been shown to inhibit tyrosine kinases similar to nintedanib 
and combining these two drugs with different molecular targets might ultimately provide 
additive efficacy benefits to patients and therefore is an attractive option for treating physicians
[U12-2505-01;  P14-16496].  
Although both drugs do not share similar mechanisms of action and metabolism routes, the side 
effect profile of nintedanib and pirfenidone overlaps (gastrointestinal side effects and liver 
enzyme elevations) and therefore there is also a potential for additive adverse effects when 
combining both treatments. 
To date, there is only limited evidence for combined treatment, from a double-blind, 
randomized, placebo-controlled phase II study in Japanese patients in which nintedanib was 
added to pre-existing treatment with pirfenidone. In this study (1199.31), 13 patients received 
nintedanib 150 mg bid on top of standard doses of pirfenidone used in Japan, and 11 patients 
received 150 mg bid nintedanib alone for maximum treatment duration up to 28 days. In the 150 
mg bid dose group, exposure to nintedanib decreased by 31.7% based on mean AUC and by 
40.8% based on mean Cmax upon co-administration with pirfenidone compared to administration 
of nintedanib alone. Nintedanib had no effect on the PK of pirfenidone. Due to the short duration 
of concomitant exposure and low number of patients, no conclusion on the safety and efficacy of 
the combination can be drawn [P14-17347].  
This study is conducted at the request of the European Medicines Agency (EMA) as a post-
approval commitment and will examine the relative bioavailability for nintedanib and 


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pirfenidone when administered together versus when administered alone.    
TRIAL OBJECTIVES
2.2
The primary objective of this study is to investigate the effect of steady state pirfenidone on the 
pharmacokinetics of nintedanib and its metabolites following oral administration of 2403 
mg/day pirfenidone and to investigate the effect of steady state nintedanib on the 
pharmacokinetics of pirfenidone at steady state following oral administration of 150 mg bid 
nintedanib.  There will be two cohorts of patients; the first one will consist of patients not treated 
with pirfenidone or nintedanib, while the second one will consist of patients on pirfenidone 
treatment.  
BENEFIT - RISK ASSESSMENT
2.3
All patients in this trial will be treated with nintedanib. As described in section 1, patients with 
IPF may benefit from lesser decline in lung function and hence slower disease progression as a 
result of treatment with nintedanib. In addition, nintedanib significantly reduced the risk of first 
acute exacerbation in 2 out of 3 clinical trials [P11-11216, P14-07514].
All patients in this trial will also be treated with pirfenidone for a limited period in addition to 
nintedanib. Pirfenidone has shown a similar effect on slowing the decline of lung function in 2 
out of 3 large phase III clinical trials [R11-4827; R14-2103]. As this period of combination 
treatment during the PK part of the trial is short, there is expected to be no additional benefit to 
the patient.  An optional nintedanib Named Patient Programme to allow patients to continue on 
nintedanib will be discussed at the end of the trial.  Patients participating in this PK trial will 
help to elucidate the pharmacokinetic characteristics of the combination of pirfenidone and 
nintedanib.  The risks of the treatments with nintedanib and pirfenidone are described in section 
1.2. The side effect profile of both drugs partially overlaps, especially in terms of gastrointestinal 
events (diarrhoea, nausea, vomiting, abdominal pain), as well as liver enzyme elevations.
Safety monitoring in this trial will consist of regular visits to the investigational site, blood 
analyses and specific monitoring procedures to follow-up potential hepatic enzyme elevations.
In case of lack of tolerability, symptomatic treatment, dose adjustments and/or interruptions of 
one or both trial drugs (at the discretion of the investigator) will have to be considered to allow 
for resolution of the symptoms (Section 4.2.1).
Potential risks of nintedanib treatment also include arterial hypertension, gastrointestinal 
perforations, thromboembolism and bleeding. Therefore, patients requiring full dose 
concomitant anticoagulation, fibrinolysis or high-dose antiplatelet therapy will be excluded from 
this trial.
The mode of action of nintedanib indicates a high potential for teratogenicity and/or 
embryotoxicity, including fetotoxicity/lethality. In women of childbearing potential receiving 
nintedanib, contraceptive measures must be employed 28 days before treatment initiation, during 
the treatment and for a period of 3 months after last drug intake.


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Overall, the clinical safety profile of both nintedanib and pirfenidone as established during the 
development programs is interpreted as favourable for the intended indication of IPF.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a multi-centre, single country, open-label, multiple-dose, two-group trial to investigate 
the relative bioavailability of nintedanib and pirfenidone when administered alone and after co-
administration in patients with IPF.  The study will be performed in approximately nine centres 
in the United Kingdom.  
Patients with IPF will sign informed consent before or at Visit 1 (screening visit).  After a 
screening visit, if the patient complies with all inclusion and exclusion criteria, they will start 
treatment at Visit 2.  The trial will not be randomised.  Patients who are currently not being 
treated with either nintedanib or pirfenidone will enter Group 1, and patients who are chronic 
pirfenidone users will enter Group 2.  Within each group, a fixed sequence design will be 
followed. At the end of the PK evaluation period there will be a 4-week period where the patient 
will take no study drugs.  After the end of the trial an optional Named Patient Programme of 
nintedanib will be discussed with patients..  See Figure 3.1:1 below, Section 6 and the flowchart 
1 and flowchart 2 for details of each study visit.
Group 1 – 16 patients
Figure 3.1:1
Trial design diagram for each group for PK evaluation period


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Group 2 – 18 patients
Figure 3.1:1
Trial design diagram for each group for PK evaluation period continued
ADMINISTRATIVE STRUCTURE OF THE TRIAL
3.2
The sponsor of this trial is Boehringer Ingelheim (BI).
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, in 
order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
order the materials as needed for the trial, 
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.
A Coordinating Investigator will be nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. Tasks and responsibilities 
will be defined in a contract. Relevant documentation on the participating (Principal) 
Investigators and other important participants, including their curricula vitae, will be filed in ISF.
Sites selected for participation will consist of specialised referral centres experienced in the 
management of IPF.
A central laboratory will perform all protocol specified blood analysis of the trial.


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.3
CONTROL GROUP(S)
For relative bioavailability studies the intra-individual comparison design is viewed favorably
due to its efficiency: since each subject serves as his own control, the comparison between 
treatments is based on a comparison within subjects rather than between subjects. This means 
that the inter-subject variability is removed from the comparison between treatments (cf. R94-
1529). The design is expected to deliver valid results on the PK of a single oral dose of 
nintedanib with and without co-administration of pirfenidone at steady state (Group 1), as well 
as steady state pirfenidone with and without co-administration of nintedanib at steady state 
(Group 2). The current study design for Group 1 allows the perpetrator drug, pirfenidone, to 
reach a stable therapeutic dose, while minimizing the potential impact on nintedanib, the victim 
drug, which has previously shown a decrease in exposure upon co-administration with 
pirfenidone. Furthermore, as it is unknown whether there may be additive AEs when 
administering nintedanib and pirfenidone together, increasing the duration of concomitant 
administration of nintedanib and pirfenidone may elevate the potential for AEs unnecessarily. 
Therefore, the current study design for Group 1 minimizes both the risk of intolerability due to 
increasing AEs, as well as the risk of dropouts due to reduced drug efficacy, during co-
administration of pirfenidone and nintedanib. 
For Group 2, it is expected that there will already be patients stable on pirfenidone, as this drug 
is currently available for IPF in the UK. As such, using a steady state design for both the 
perpetrator (nintedanib) and the victim drug (pirfenidone) allows patients to remain at a stable
therapeutic dose of pirfenidone, while reducing the likelihood of intolerability during an up-
titration phase and, at the same time, reducing the likelihood of patients dropping out.
SELECTION OF TRIAL POPULATION
3.4
A total of approximately 34 patients with an IPF diagnosis will be treated.  Each group will have 
a different number of patients.  Approximately 16 patients who are not currently treated with 
pirfenidone or nintedanib will go into Group 1 and 18 patients who are currently treated with 
pirfenidone will go into Group 2.  
Each group requires at least 12 evaluable patients to complete each arm.  Once 12 evaluable 
patients in a group have completed treatment, recruitment into that group will stop.  The other 
group may continue to recruit until 12 evaluable patients in that group also complete treatment. 
Any patient still in the PK evaluation period when their group closes to recruitment may 
complete the PK evaluation period.
Approximately 9 sites are each expected to include a minimum of 3 patients.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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Patients who have screen failed may be permitted to be re-screened following agreement by the 
Sponsor.  Screening procedures may not need to be repeated if they are within 28 days of visit 2.  
The decision on what screening procedures do not need to be repeated will be made by the 
Sponsor.
MAIN DIAGNOSIS FOR TRIAL ENTRY
3.5
Any patients diagnosed with IPF and who comply with eligibility requirements may qualify for 
participation in the trial.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements pertaining 
to the in- and exclusion criteria.
INCLUSION CRITERIA
3.6
1. Written informed consent consistent with ICH-GCP and local laws, signed prior to any 
study procedures being performed (including any required washout).  
2. Male or female patients aged ≥40 years at visit 1.
3. IPF diagnosis, based upon the ATS/ERS/JRS/ALAT 2011 guideline (P11-07084) and 
chest high-resolution computed tomography (HRCT) scan. 
4. FVC ≥ 50% of predicted normal (refer to Section 10.3) at visit 1. 
5. DLCO (corrected for Hb [visit 1]): 30%-79% predicted of normal (refer to Section 10.3) 
at visit 2 (test can be performed at visits 1 or 2, or during the screening period).
6. Currently treated with pirfenidone at full dose (this is only for patients going into Group 
2). 
EXCLUSION CRITERIA
3.7
1. ALT, AST >1.5 fold upper limit of normal (ULN) at visit 11.
2. Total bilirubin >1.5 fold ULN at visit 11.
3. Underlying chronic liver disease (Child Pugh A, B, or C hepatic impairment1, 6)
4. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7 at visit 1).
5. History of myocardial infarction within 6 months of visit 1 or unstable angina within 1 
month of visit 1.
6. Bleeding Risk:

Known genetic predisposition to bleeding


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
Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. 
vitamin K antagonists, dabigatran, heparin, hirudin, etc.) or high dose antiplatelet 
therapy2.

History of haemorrhagic central nervous system (CNS) event within 12 months 
prior to visit 1.

History of haemoptysis or haematuria, active gastro-intestinal bleeding or ulcers 
and/or major injury or surgery within 3 months prior to visit 1.

International normalised ratio (INR) >2 at visit 1.

Prothrombin time (PT) and partial thromboplastin time (PTT) >150% of 
institutional ULN at visit 1.
7. Planned major3 surgery during the trial participation, including lung transplantation, 
major abdominal or major intestinal surgery. 
8. History of thrombotic event (including stroke and transient ischemic attack) within 12 
months of visit 1.
9. Severe renal impairment (Creatinine clearance <30 mL/min calculated by Cockcroft–
Gault formula at visit 1) or end-stage renal disease requiring dialysis. 
10. Treatment with n-acetylcysteine, prednisone >15 mg daily or >30 mg every 2 days OR 
equivalent dose of other oral corticosteroids or fluvoxamine within 2 weeks of visit 2. 
11. Treatment with azathioprine, cyclophosphamide, cyclosporine as well as any other 
investigational drug within 8 weeks of visit 2. 
12. Previous treatment with pirfenidone in the past three months prior to Visit 2 (Group 1 
only). 
13. Previous treatment with nintedanib in the past 14 days prior to Visit 2.
14. Permanent discontinuation of nintedanib or pirfenidone in the past due to adverse events 
considered drug-related.
15. Known hypersensitivity to nintedanib, pirfenidone or their excipients; or to peanut or 
soya.
16. A disease or condition which in the opinion of the investigator may interfere with testing 
procedures or put the patient at risk when participating in this trial.


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17. Alcohol or drug abuse, which in the opinion of the treating physician would interfere with 
treatment.
18. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
19. Women of childbearing potential4 not using highly effective methods of birth control per 
ICH M3 [R09-1400], note 3, highly effective methods of birth control are defined as 
those, alone or in combination, that result in a low failure rate of less than 1% per year 
when used consistently and correctly5 such as implants, injectables, combined oral 
contraceptives, some intrauterine devices (IUDs), sexual abstinence or vasectomised 
partner.  Barrier contraceptives (e.g. male condom or diaphragm) are acceptable if used 
in combination with spermicides (e.g. foam, gel).  Contraception must be used for 28 
days prior to and 3 months after nintedanib and pirfenidone administration.
20. Patients not able to understand and follow study procedures including completion of 
diaries without help.
21. Current smoker (vaping and e-cigarettes are acceptable)
1Laboratory parameter may be re-tested within the permitted timeframe, if found abnormal at Visit 1 
and thought to be a measurement error or was the result of a temporary and reversible medical 
condition.
2Exceptions: prophylactic low dose heparin or heparin flush as needed for maintenance of an indwelling 
intravenous device (e.g., enoxaparin 4000 IU s.c. per day) and prophylactic use of antiplatelet therapy (e.g., 
acetyl salicylic acid up to 325 mg/d, or clopidogrel at 75 mg/d, or equivalent doses of other antiplatelet 
therapy).
3Definition of major is per investigator judgement.
4Women of childbearing potential are defined as: Any female who has experienced menarche and does not 
meet the criteria for "women not of childbearing potential” defined as: Women who are postmenopausal 
(12 months with no menses without an alternative medical cause) or who are permanently sterilized (e.g., 
tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy). 
5A list of contraception methods meeting these criteria is provided in the patient information.
6Child Pugh classification does not need to be performed at screening.
REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENTS
3.8
3.8.1
Removal of individual patients
An individual patient is to be withdrawn from all trial drugs (nintedanib and pirfenidone) if:

The patient withdraws consent for study treatment or study participation, without the 
need to justify the decision.

The patient needs to take restricted therapy that may interfere with the investigational 
product (section 4.2.2).


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
The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient experiences liver function impairment as follows:

ALT and/or AST ≥5 fold ULN

ALT and/or AST ≥3 fold ULN with signs or symptoms of severe liver damage 
(section 4.2.1.4) (including total bilirubin >2 fold ULN). 
For potential drug induced liver injury (DILI) follow up requirements please see 
section 5.3.7.1. 

In the opinion of the investigator, the patient experiences unacceptable toxicity despite 
dose adjustments and supportive care.

CrCl <30mL/min during the course of the trial.  Study medication should be stopped and 
a repeat test performed as soon as feasible.  If this second measurement confirms a CrCl 
<30mL, the patient should be permanently discontinued.
Treatment with nintedanib must be permanently discontinued in the following situations:

Gastrointestinal perforation

Major surgery including abdominal or intestinal surgery 

Signs or symptoms of acute myocardial ischemia, stroke, deep vein thrombosis and 
pulmonary embolism
In addition, permanent discontinuation of nintedanib should be considered in the following 
situations:

Patients who require full dose therapeutic anticoagulation or high dose antiplatelet 
therapy

Increased risk of bleeding (e.g., gross/ frank haemoptysis or haematuria, active gastro-
intestinal bleeding or ulcers).
In such cases as above, continuation of nintedanib should be discussed with the patient and the 
decision documented in the source data. 
Treatment with pirfenidone must be permanently discontinued in the following situations:

ALT and/or AST ≥ 5 fold ULN

Patient develops signs or symptoms of angioedema
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the FC and section 6.2.3.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the (e)CRF. 
These data will be included in the trial database and reported.


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3.8.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site 
at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the trial.
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1 Nintedanib (investigational drug)
Substance:
Nintedanib
Pharmaceutical formulation:
Soft gelatine capsule
Source:
BI Pharma GmBH & Co. KG
Unit Strength:
150 mg
Posology:
Group 1:  Day 1 and Day 23: one 150 mg capsule in 
the morning
Group 2: Days 9-15: one 150 mg capsule in the 
morning and one in the evening
Day 16: one 150 mg capsule in the morning
Route of administration:
Oral (swallowed) administration with food
Table 4.1.1: 2 Pirfenidone (investigational drug)
Substance:
Pirfenidone
Pharmaceutical formulation:
Capsule
Source:
Roche Registration Limited (previously InterMune 
UK Ltd)
Unit Strength:
267 mg
Posology:
Group 1
Days 2-8: one capsule three times a day
Days 9-15: two capsules three times a day
Days 16-23: three capsules three times a day
Group 2
Days 1-15: three capsules three times a day
Day 16: three capsules in the morning only
Route of administration:
Oral (swallowed) administration with food


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4.1.2
Method of assigning patients to treatment groups
Patients are allocated to either Group 1 or Group 2 based on their current treatment at screening.  
There will be no randomisation required in this trial. Patients who are not being treated for IPF
and fulfil all eligibility criteria will enter Group 1.  Patients who are chronic users of pirfenidone
and fulfil all eligibility criteria will enter Group 2.  
4.1.3
Selection of doses in the trial
Nintedanib:  A dose of 150 mg bid (total daily dose of 300 mg) was selected for this trial, as this 
is the recommended dose based on prescribing information in the participating country. Dose 
adjustments are permitted as described in section 4.2.
Pirfenidone: A dose titrated up to 801 mg tid (total daily dose of 2403 mg) was selected for this 
trial as this is the recommended dose based on prescribing information in the participating 
country.  Dose adjustments permitted as per section 4.2.
4.1.4
Drug assignment and administration of doses for each patient
Drug is dispensed by the investigator, study coordinator or pharmacist, depending on the site 
structure.  If the patient is currently not being treated for IPF at screening and they fulfil the 
inclusion/exclusion criteria, they will be assigned manually by the study site personnel to Group 
1 and if they are a chronic pirfenidone user at screening and they fulfil the inclusion/exclusion 
criteria they will be assigned manually by the site to Group 2.  There will be no IRT used in this 
trial.  Sites will be required to inform the Sponsor of each screening and each start of treatment 
using the form provided in the ISF.  The Sponsor will monitor recruitment to each group and 
inform sites when recruitment is close to complete.
Group 1 
Visit 2 will be over two days.  The patient is not required to stay in the clinic overnight between 
Day 1 and Day 2.  At Visit 2, Day 1, eligible patients will receive one 150 mg nintedanib capsule 
in the clinic in the morning (Table 4.1.4:2 see Flowchart for Group 1 patients and Section 10.2
for timings of dosing and PK samples).  This will be given to the patient by the site staff from a 
nintedanib bottle (this bottle should be kept at clinic and be used for patients who are in Group 1 
for the first and second PK day).  Gloves should be worn by the person giving the capsule to the 
patient and the capsule should be tipped out into a pot where the patient can then pick it up and 
take it.  The patient should swallow nintedanib, unchewed, with food and a glass of water at the 
clinic. 
At Visit 2, Day 2, the patient will return to clinic for their 24 hour PK sample (see Section 10.2) 
and they will be dispensed three wallets of pirfenidone.  The patient will take the first dose at the 
clinic in the morning with food and a glass of water, under supervision and then go home and 
continue dosing at home.  A dosing card will be provided to the patient, which will explain how 
they should uptitrate during the trial.  
The patient will use the first wallet for 14 days titrating according to Table 4.1.4:1.  Once the 
patient has completed the uptitration then they would use the second wallet and take 3 capsules 3 


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times a day for the next 7 days.  Once the patient has had 7 consecutive, stable days on 801 mg 
tid they would then come to the clinic for the next PK day (Visit 3, Day 23; there is a 6 day 
window during the uptitration phase and Visit 3.  This allows for extending the uptitration if 
required and ensuring that there are 7 consecutive, stable days at 801 mg tid before the patient 
returns to clinic for the second PK day Visit 3. The third wallet of pirfenidone can be used if 
required during this period). 
The patient will return to the clinic for Visit 3.  They should not take their medication at home, 
but should bring it to the clinic with them.  At the clinic, they will be given their morning dose of 
801mg pirfenidone and they will also receive one 150 mg capsule of nintedanib at the clinic with 
food and a glass of water. They will also be given their second dose of pirfenidone at the clinic 
at 14:00.  They will take their final dose of pirfenidone at 20:00 in the evening at home once 
they have left the clinic.  They should be advised to take this with food and a glass of water.  The 
following day (Visit 3, Day 24), the patient will return to the clinic for their 24 hour PK sample 
(see Section 10.2).  The patient will then have a washout of 28 days where no study medication 
is taken and then they will return to clinic for the PK Follow-Up visit (see Flowchart).
If the patient does not achieve 7 consecutive, stable days prior to Visit 3 plus the 6 day window
then the patient would stop medication and attend the clinic for Visit 3, but would not have the 
PK samples taken (See Figure 4.1.4:1).  
Table 4.1.4:1
Schedule for the titration phase of pirfenidone (Group 1)
Titration Period 
Administration
Dose
Total daily 
Dose
Day 2 to Day 8 of 
titration
1 capsule tid
267 mg tid
801 mg 
Day 9 to Day 15 of 
titration
2 capsules tid
534 mg tid
1602 mg 
Table 4.1.4:2
Quantity of medication kits dispensed to the patient
Group 1
Visit
Nintedanib 
bottle
Pirfenidone 
wallet
2
0 (1 capsule
given in clinic)
3
3
0 (1 capsule
given in clinic)


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Table 4.1.4:2
Quantity of medication kits dispensed to patient continued
Group 2
Visit
Nintedanib 
bottle
Pirfenidone 
wallet
2
0
2
3a
1
1
3b
0
Group 2
The patient will come to the clinic for Visit 2 (this is not a PK day).  They should take their full 
dose of commercial supply of pirfenidone the previous day and then stop taking their 
commercial supply.  At the clinic, eligible patients will receive two wallets of pirfenidone. The 
patient will take the first dose at the clinic in the morning with food and a glass of water, under 
supervision and then go home and continue dosing at home.  A dosing card will be provided to 
the patient which will explain how they should take their study medication during the trial.  
Once the patient has had 7 consecutive, stable days on 801 mg tid (3 capsules 3 times a day; this 
can be reduced to 534 mg tid) they would then come to the clinic for the next PK visit (Visit 3a, 
Day 8; see flowchart and section 10.2; there is a 3 day window to ensure that the patient has 7 
consecutive days at full dose).
The patient will return to the clinic for Visit 3a.  They should not take their medication at home, 
but should bring it to the clinic with them.  At the clinic, they will be given their morning dose of 
801mg pirfenidone (or 534mg if they have dose reduced) at the clinic with food and a glass of 
water. They will also be given their second dose of pirfenidone at the clinic at 14:00.  They will 
take their final dose of pirfenidone at 20:00 in the evening at home once they have left the clinic.  
They should be advised to take this with food and a glass of water.  Before they leave the clinic 
they will be given another wallet of pirfenidone and a bottle of nintedanib to take home (they 
should also be given the remaining pirfenidone wallet from the previous visit once compliance 
has been assessed).  They will be advised to start the nintedanib with the morning and evening 
doses of pirfenidone.  
For the next 7 days the patient will continue on pirfenidone 801 mg tid (3 capsules 3 times a day; 
or 534 mg tid) and take nintedanib 150 mg twice a day.  Once the patient has had 7 consecutive 
stable days on 801 mg (or 534 mg) pirfenidone tid and nintedanib 150 mg twice a day then they 
would come to the clinic for the next PK day (Visit 3b, Day 16; there is a three day window for 
this visit to allow for 7 consecutive days if required; see Figure 3.1:1).
  
The patient will return to the clinic for Visit 3b.  They should not take their medication at home, 
but should bring it to the clinic with them.  At the clinic, they will be given their morning dose of 
801mg pirfenidone and they will also receive one 150 mg capsule of nintedanib at the clinic with 


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food and a glass of water. The patient will then have a washout of 28 days where no study 
medication is taken and then they will return to clinic for the PK Follow-Up visit (see Flowchart).
If the patient does not achieve 7 consecutive, stable days prior to visit 3b plus the 3 day window 
then the patient would stop medication and attend the clinic for Visit 3b, but would not have the 
PK samples taken (See Figure 4.1.4:1) .  
Group 1 patients
Figure 4.1.4: 1
Guidance for patients who withdraw or do not tolerate uptitration during 
the PK evaluation period


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Group 2 patients Day 1-7
Figure 4.1.4:1  Guidance for patients who withdraw or do not tolerate uptitration during the PK 
evaluation period continued


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Group 2 patients Day 9-15
Figure 4.1.4:1  Guidance for patients who withdraw or do not tolerate uptitration during the PK 
evaluation period continued
Nintedanib and pirfenidone
4.1.4.1
The Investigator should emphasise to the patient the importance of taking all doses of trial 
medication in order to avoid missed doses throughout the PK period.
Group 1

If a dose of pirfenidone is missed, administration should resume at the next scheduled 
time at the recommended dose.  Double doses should not be taken to make up for the 
forgotten capsules.

It is recommended that pirfenidone is administered at the same time in the morning and 
evening with food and a glass of water, with the third pirfenidone dose administered at 
the midpoint with food and a glass of water.


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
If a patient withdraws from the PK period or is unable to tolerate uptitration please refer 
to Figure 4.1.4:1.
Group 2

The patient should swallow nintedanib unchewed with food and a glass of water twice 
daily and should observe a dosing interval of approximately 12 hours.  

If a dose of pirfenidone or nintedanib is missed, administration should resume at the next 
scheduled time at the recommended dose.  Double doses should not be taken to make up 
for forgotten capsules.

It is recommended that nintedanib and pirfenidone are administered together at the same 
time in the morning and evening with food and a glass of water, with the third 
pirfenidone dose administered at the midpoint with food and a glass of water.

If a patient withdraws from the PK period or is unable to tolerate uptitration please refer 
to Figure 4.1.4:1.
Patients experiencing adverse events may require drug interruption or reduction of dose.  For 
additional details refer to section 4.2.1.
2403 mg daily (801 mg tid) pirfenidone may be reduced to 1602 mg daily (534 mg tid) to 
manage adverse events (in Group 2 only).  If dose reduction is required for pirfenidone then the 
patient must have 7 stable days at the reduced dose along with the nintedanib for the second PK 
day.  Further dose reductions for pirfenidone are not permitted within the trial.  If the patient has 
tolerability issues they should contact the Investigator immediately.  
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
In this open-label trial, treatment allocation will not be concealed throughout the trial. The CRF 
will contain information on the group to which a patient has been allocated.
Unblinding and breaking the code
4.1.5.2
Not applicable.  This is an open label trial.
4.1.6
Packaging, labelling, and re-supply
The medication kit for nintedanib is a 75cc PE bottle and contains 30 capsules.  These will be 
provided by BI.  
Medication kits for pirfenidone will comprise of a blister package of 63 capsules in a blister 
package (wallet).  These will be provided by BI.  
For details of packaging and the description of the label, refer to the ISF.
Medication will be provided by the Department of Pharmaceutical Development of Boehringer 
Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.


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No re-supply is planned.
The nintedanib used in the nintedanib Named Patient Programme does not form part of the study 
supplies.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage area 
according to the recommended storage conditions on the medication label. A temperature log 
must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor (as 
provided in the list of contacts) must be contacted immediately.
All unused trial medication must be returned to the sponsor.  Receipt, usage and return must be 
documented on the respective forms.  Account must be given for any discrepancies. 
4.1.8
Drug accountability
The Investigator and/or Pharmacist and/or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head of 
the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol

Availability of the proof of a medical license for the principal Investigator
The Investigator and/or Pharmacist and/or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each patient, 
and the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, and 
the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor< and/or >appointed CRO, the Investigator / Pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.


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CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medications to reverse the action of nintedanib or pirfenidone are not available.
Recommendations for adverse events considered drug related (exceptions include 
4.2.1.1
diarrhoea and photosensitivity/rash):
If a patient experiences adverse events considered drug related, symptomatic treatment should be 
initiated (if appropriate). 

If necessary, dose reduction for pirfenidone to 534 mg tid is allowed in Group 2 only. 
Further dose reduction to 267 mg tid or temporary interruption of pirfenidone should be 
considered (at the discretion of the investigator) to allow for resolution of the symptoms.1

After resolution of AE, re-introduction and re-escalation of pirfenidone should be 
considered on a stepwise approach.1

If symptoms persist, then the patient should stop all trial medication during the PK 
evaluation period and return to clinic for Visit 3 (Group 1) or Visit 3b (Group 2) as per 
Figure 4.1.4:1.
Recommendations for managing diarrhoea
4.2.1.2
Symptomatic treatment should be initiated at first signs or symptoms of diarrhoea (hydration, 
antidiarrhoeal treatment e.g. loperamide).

Interruption of nintedanib should be considered (at the discretion of the investigator; for 
patients in Group 2) to allow for resolution of symptoms.1

If diarrhoea persists: dose reduction or interruption of pirfenidone should be considered 
(at the discretion of the physician) to allow for resolution of symptoms.1
Recommendations for managing phototoxicity and/or rash (PK evaluation period 
4.2.1.3
only)

Symptomatic treatment should be considered at first signs or symptoms of 
phototoxicity/rash

Dose reduction or interruption of pirfenidone should be considered (at the discretion of 
the investigator) to allow for resolution of symptoms.1  

After resolution of phototoxicity/rash, re-introduction and re-escalation of pirfenidone 
should be considered on a stepwise approach.1


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
If phototoxicity/rash persists despite dose adjustment, permanent discontinuation of 
pirfenidone should be considered. 
Footnote:
1
If dose reduction, interruption or re-escalation does not allow for 7 consecutive stable 
days prior to Visit 3 for Group 1 patients or Visit 3a or Visit 3b for Group 2 patients then the 
patient should stop all trial medication during the PK evaluation period and return to clinic for 
Visit 3 (Group 1) or visit 3b (Group 2) as per Figure 4.1.4:1.
Management of liver enzyme elevations
4.2.1.4
Patients who experience:

AST /ALT ≥3 ULN with signs or symptoms of severe liver damage* (including total 
bilirubin >2 fold ULN)
or

ALT and/or AST ≥5 fold ULN
Should interrupt all study drugs and return to clinic for a visit 3 (Group 1) or Visit 3b (Group 2). 
* Signs of severe liver damage are defined as:

ALT/AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN 

ALT/AST ≥ 3 x ULN and unexplained INR > 1,5

ALT/AST ≥ 3 x ULN and unexplained eosinophilia (>5%)

ALT/AST ≥ 3 x ULN and appearance of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever and/or rash
For potential drug induced liver injury (DILI) follow up requirements please see section 5.3.7.1.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Concomitant medications (or therapy) to provide adequate care may be given as assessed by the 
Investigator to be clinically necessary. 
If restricted concomitant therapy is necessary, treatment with study medication should be permanently 
discontinued, see table 4.2.2.1:1 for details of restricted medications. 


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Table 4.2.2.1:1
Permitted and Restricted Concomitant therapy 
Therapy
Prior to Study
Screening 
Period
PK evaluation 
period 
PK Follow-Up 
period)
N-acetylcysteine1 /  Prednisone / 
other oral corticosteroid2
Permitted
Not permitted
(2w prior to 
visit 2)
Not permitted
Not permitted
Azathioprine / 
Cyclophosphamide  /
Cyclosporine
Not permitted
(8w prior to 
visit 2)
Not permitted
Not permitted
Not permitted
Investigational Medication
Not permitted
(8w prior to 
visit 2)
Not permitted
Not permitted
Not permitted
Potent P-gp Inhibitors (e.g. 
ketoconazole, erythromycin) or 
Inducers (e.g. Rifampicin, 
Phenytoin, St. John’s Wort)
Not permitted
(8w prior to 
visit 2)
Not permitted
Not permitted
Not permitted
Potent or moderate CYP1A2 
inhibitors (e.g. Fluvoxamine1, 
enoxacin, ciprofloxacin, 
amiodarone) and inducers (e.g. 
rifampicin, omeprazole).
Permitted
Not permitted
(2w prior to 
visit 2)
Not permitted
Not permitted
Oramorph, dextromethorphan
(Opioids for the treatment of 
diarrhoea e.g. loperamide may
be used as per section 4.2.1.2.  
Other opioids to be discussed 
with Sponsor beforehand).  
Permitted
Permitted
Not Permitted 
on PK days6.
Permitted
Anticoagulation at full dose3 /   
Antiplatelet therapy at high 
dose 4 / Fibrinolysis
Permitted
Not permitted
Not permitted
Not permitted
Pirfenidone
Group 1 not 
permitted 3 
months prior to 
visit 2
Group 2 
permitted
Group 1 not 
permitted
Group 2 
permitted
Trial drug only
Not permitted
Nintedanib
Permitted
Not permitted 
(14 days prior 
to visit 2)
Trial drug only
Not permitted
1.
Washout should not occur until after patient has signed informed consent
2.
Prednisone >15 mg daily or >30 mg every 2 days OR equivalent dose of other oral corticosteroids.  This will 
need to be recorded in the eCRF.
3.
Anticoagulation at full dose (vitamin K antagonists, dabigatran, heparin, hirudin, etc). Exceptions: prophylactic 
low dose heparin or heparin flush as needed for maintenance of an indwelling intravenous device (e.g. 
enoxaparin 4000 I.U s.c per day).  This will need to be recorded in the eCRF.


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4.
Antiplatelet therapy at high dose. Exceptions: prophylactic use of antiplatelet therapy (e.g. acetylsalicylic acid 
up to 325 mg/day or clopidrogrel at 75 mg/day or equivalent doses of other antiplatelet therapy) is allowed.  
This will need to be recorded in the eCRF.
5.
Patients should not receive treatment for IPF during the PK follow-up period unless they have an acute 
worsening of their disease. Should this occur then the investigator may use any standard of care treatment 
available to them.  The treatments to be administered should be done after due consideration of the SPCs for 
nintedanib and pirfenidone.  It is preferable that nintedanib and pirfenidone are not used during the PK follow-
up period so that there is a clear Residual Effect Period.  Investigational Medicinal Products must not be used 
during this period.
6.
There should be at least a 2-4 hour gap between the opioid intake and nintedanib/pirfenidone intake prior to the 
first PK sampling.
Restrictions on diet and life style
4.2.2.2
Patients, when taking pirfenidone, should not smoke and should avoid exposure to direct and 
indirect sunlight, use an effective sunblock (at least SPF 50 against UVA and UVB) and wear 
protective clothing. Grapefruit juice is an inhibitor of CYP1A2 and, thus, consummation should 
be avoided while taking pirfenidone.
Restrictions regarding women of childbearing potential 
4.2.2.3
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity and/or 
embryotoxicity, including fetotoxicity/lethality. In women of childbearing potential receiving 
nintedanib, contraceptive measures must be employed 28 days before treatment initiation, during 
the trial and for a period of 3 months after last drug intake. 
TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package material 
with them when attending visits.  Based on capsule counts, treatment compliance will be 
calculated as the number of capsules taken for each treatment, divided by the number of capsules 
which should have been taken according to the scheduled period, multiplied by 100. A 
compliance worksheet will be provided in the ISF. 
Treatment compliance (%) =
Number of capsules actually taken 100
Number of capsules which should have been taken
If the number of doses taken is not between 80-120% without identified cause like AE or 
consent withdrawal, site staff will explain to the patient the importance of treatment compliance. 
In addition, the compliance calculation should be cross checked with the patient diary and 
discrepancies documented in the eCRF accordingly (Section 5.3.6).
Compliance will be verified by the on-site monitor authorized by the Sponsor.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoints
Primary endpoints are pharmacokinetic endpoints defined as:

Group 1:
o
AUC0-tz area under the concentration-time curve of nintedanib in plasma over 
the time interval from 0 to the last measured time point
o
Cmax maximum measured concentration of nintedanib in plasma after single 
dose administration

Group 2:
o
AUCτ,ss area under the concentration-time curve of pirfenidone in plasma over a 
dosing interval
o
Cmax,ss  maximum measured concentration of pirfenidone in plasma at steady 
state
5.1.2
Secondary Endpoints
Secondary endpoints are pharmacokinetic endpoints defined as:
Group 1:
AUC0-∞area under the concentration-time curve of nintedanib in plasma over the time interval 
from 0 extrapolated to infinity
5.1.3
Further Endpoints


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ASSESSMENT OF EFFICACY
5.2
Not applicable, there are no efficacy endpoints.
ASSESSMENT OF SAFETY
5.3
These assessments are applicable throughout the trial.


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5.3.1
Physical examination
Physical examination includes assessment of heart, lung, abdomen and measurement of weight.  
Height will be measured at Visit 1.  Abnormal finding at the time of screening will be recorded 
as baseline conditions on the appropriate eCRF page.  New abnormal findings or worsening of 
baseline conditions detected at subsequent physical examinations will be recorded as adverse 
events on the appropriate eCRF page.
5.3.2
Vital Signs
Vital signs including measurements of systolic and diastolic blood pressure and pulse rate, will 
be measured with the patient seated after having rested for at least 5 minutes.  
5.3.3
Safety laboratory parameters
The laboratory tests will include:

Haematology: complete blood count, with platelet count, haemoglobin and automated 
differential.

Chemistry: sodium, potassium, creatinine, aspartate aminotransferase (AST), alanine 
transaminase (ALT), gamma-glutamyl transferase (GGT), total protein, alkaline 
phosphatase (ALP), total bilirubin, lactate dehydrogenase (LDH), creatine kinase and 
thyroid stimulating hormone (TSH), serum albumin (if required for liver assessment), 
Creatinine Clearance (according to Cockcroft-Gault formula)

Coagulation: International normalised ratio (INR) and partial thromboplastin time (PTT), 
Prothrombin Time.

Urine: pregnancy testing.
If laboratory values indicate toxicity, adequate and more frequent blood sampling will be 
performed at the discretion of the Investigator.
Laboratory analysis during main visits will be done using central laboratory services.  Venous 
whole blood will be collected in appropriate syringes provided by the sponsor through the 
assigned central laboratory.  Details regarding centrifuge, processing, storage and shipment of 
samples will be determined by the central laboratory in accordance with the sponsor.  The 
Investigators will be informed and instructed by the central laboratory and detailed 
documentation will be included in the ISF.
In case of liver enzyme elevation, close monitoring must be ensured by the Investigator (section 
4.2.1.3).
Renal Function Measurements
CrCl will be calculated using the Cockcroft-Gault formula, as follows:

For creatinine in µMol/L:
(140-age [years]) x weight [kg] x 1.23 (x 0.85 if female)
serum creatinine [µMol/L]


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
For creatinine in mg/dL:
(140-age [years]) x weight [kg] (x 0.85 if female)
72 x serum creatinine [mg/dL]
Please refer to Section 3.8.1 for guidance if a patient has started IMP and their CrCl is 
<30mL/min.
5.3.4
Electrocardiogram
ECGs are to be conducted with site equipment as specified in flowchart 1 and flowchart 2.  
Changes should be examined, compared to previous test, and assessed for clinical relevance.  
Clinically relevant findings at Visit 1 will be recorded as baseline conditions, new abnormal 
findings thereafter will be recorded as adverse events.
5.3.5
Spirometry
Spirometry (FVC measurements) is to be conducted with site equipment as specified in 
flowchart 1 and flowchart 2.  Changes should be examined, compared to previous test, and 
assessed for clinical relevance.  Clinically relevant findings at Visit 1 will be recorded as 
baseline conditions, new abnormal findings thereafter will be recorded as adverse events.
5.3.6
Other safety parameters
A patient diary will be used by all patients in this trial to record symptoms and number of 
capsules taken per day whilst they are taking study treatment.  The diary will be used to prompt 
patient recollection during adverse event and medication compliance discussions at clinic visits.  
A dosing card will also be provided to the patient so they are aware of what dosing they should 
complete each day (one for each group).  A copy of the diary and dosing cards will be provided 
in the ISF.
5.3.7
Assessment of adverse events
Definitions of AEs 
5.3.7.1
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 to 
have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including 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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,


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
requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
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.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be considered 
to be “serious” even though they may not have met the criteria of an SAE as given above.
The latest list of “Always Serious AEs” can be found in the RDC. These events should always 
be reported as SAEs as described in section 5.3.7.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being of 
particular concern for prospective safety monitoring and safety assessment within this trial, e.g. 
the potential for AEs based on knowledge from other compounds in the same class. AESI need 
to be reported to the Sponsor’s Pharmacovigilance Department within the same timeframe that 
applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Adverse events relating to gastrointestinal perforation
and 
Hepatic injury
In this study protocol, signs of hepatic injury are defined as: 

ALT and/or AST ≥ 8 fold ULN

ALT and/or AST ≥ 3 fold ULN and total bilirubin ≥ 2 fold ULN*

ALT and/or AST  ≥ 3 fold ULN and unexplained INR > 1.5*

ALT and/or AST  ≥ 3 fold ULN and unexplained eosinophilia ( > 5%)*

ALT and/or AST  ≥ 3 fold ULN and appearance of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever and/or rash
*in the same blood draw sample.


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These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via the RDC-
system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, unexplained 
coagulopathy, right upper quadrant abdominal pain, etc.) without lab results (ALT, AST, total 
bilirubin) available, the investigator should make sure these parameters are analysed, if 
necessary in an unscheduled blood test. Should the results meet the criteria of hepatic injury 
alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that 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 diarrhoea, nausea and vomiting AEs should be classified and recorded in the 
(e)CRF according to the Common Terminology Criteria for Adverse Events (CTCAE) version 
4.03 (R10-4848):
Table 5.3.7:1 CTCAE Categorization (R10-4848)
CTCAE 
Grade
Diarrhoea
Nausea
Vomiting
1
Increase of <4 stools per day
over baseline; mild increase 
in ostomy output compared 
to baseline
Loss of appetite without 
alteration in eating habits
1-2 episodes (separated 
by 5 minutes) in 24 
hours
2
Increase of 4 - 6 stools per
day over baseline; moderate
increase in ostomy output
compared to baseline
Oral intake decreased 
without significant weight 
loss, dehydration or 
malnutrition
3-5 episodes (separated 
by 5 minutes) in 24 
hours
3
Increase of >=7 stools per 
day over baseline; 
incontinence; hospitalization 
indicated; severe increase in 
ostomy output compared to 
baseline; limiting self care 
ADL
Inadequate oral caloric or 
fluid intake; tube feeding, 
TPN, or hospitalization 
indicated
≥6 episodes (separated 
by 5 minutes) in 24 
hours ; tube feeding, 
TPN or hospitalization 
indicated
4
Life-threatening 
consequences; urgent 
intervention indicated
Not applicable
Life threatening 
consequences; urgent
intervention indicated
5
Death
Not applicable
Death


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Causal relationship of AEs
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.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
5.3.8
Adverse event collection and reporting
AE Collection:
The following must be collected and documented on the appropriate eCRF by the Investigator:
•
From signing the informed consent onwards through the Residual Effect period (REP), 
until the end of the REP (for this trial it will be classed as 28 days after the end of the PK 
evaluation period):
- all AEs (non-serious and serious) and all AESIs.
•
After the individual patient’s end of trial: 
the investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the investigator may become aware of. 
Figure 5.3.8:1 Adverse Event Collection and Reporting 
The REP is defined as 28 days after the last trial medication application (for this trial it will be 
classed as 28 days after the end of the PK evaluation period; this is a general diagram and there 
will be no run-in period in this trial.  Treatment will be classed as the PK evaluation period). All 
AEs which occurred through the treatment phase and throughout the REP will be considered as 


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on treatment please see section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.
AE reporting to sponsor and timelines:
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). The 
same timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial information.
Information required:
For each AE, the Investigator should provide the information requested on the appropriate eCRF 
pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, outcome, 
seriousness, and action taken with the investigational drugs. The Investigator should determine
the causal relationship to the trial medication and any possible interactions between the 
investigational drugs.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed up 
until they have resolved, have been sufficiently characterized, or no further information can be 
obtained.
Pregnancy:
In rare cases, pregnancy might occur in a study. Once a subject has been enrolled into the 
clinical trial after having taken trial medication 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 to the Sponsor’s unique entry 
point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring Form 
for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, only 
the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. If 


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there is an SAE associated with the pregnancy then the SAE has to be reported on the SAE form 
in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Plasma concentration monitoring of pirfenidone, nintedanib, 
 
 will be performed in order to characterize any potential drug-drug interaction 
between pirfenidone and nintedanib (see Section 10.2).
Date and exact time points of plasma sampling and drug intake at the clinical site will be 
documented in the eCRFs by the medical personnel. 
5.4.2
Methods of sample collection
A detailed description of sample collection and handling is provided in the Lab Manual in the 
ISF. For quantification of drug plasma concentrations of pirfenidone, nintedanib (BIBF 1120) 
and its metabolites 
, venous blood will be collected 
using a pre-labeled potassium ethylenediamine-tetraacetic acid (EDTA) containing blood 
drawing tube. The obtained plasma will be transferred into 3 vials (nintedanib, pirfenidone and 
one back-up sample).
5.4.3
Analytical determinations
Nintedanib (in form of its free base BIBF 1120 BS), its metabolites 
 
) plasma 
concentrations will be determined by a validated assay based on liquid chromatography-tandem 
mass spectrometry (LC-MS/MS). Pirfenidone plasma concentrations will be determined by a 
validated HRCT-MS/MS assay.
The procedures and specifications of the analytical method are available at the bioanalytical site 
)
ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5


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OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements conducted in the trial are using standard methods.
The pharmacokinetic parameters and measurements outlined in section 5.4 are generally used as 
measurements to assess drug exposure.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
Informed consent of all study patients will be obtained in compliance with ICH and GCP 
guidelines and the principles stipulated in the Declaration of Helsinki prior to any study related 
procedures, including washout of restricted medications.
The study will consist of three sequential periods; a screening period, a PK evaluation period, 
and the follow-up period.   
Screening will be up to 4 weeks (28 days) in duration.  The PK evaluation period will be 24 days 
in Group 1 and 16 days in Group 2 plus a follow up period of 28 days.  
All patients are to adhere to the visit schedule as outlined in flowchart 1 and flowchart 2.  Some 
flexibility is allowed in scheduling the visits according to the visit time windows specified.  The 
trial medication dispensed allows for these time windows.  All deviations from the planned 
schedule will be documented.  If any visit is to be rescheduled, subsequent visits should follow 
the previous visit date schedule.  No protocol waivers will be given (e.g. sponsor will not grant 
permission to include a known ineligible patient).
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening period
No study related procedures will be performed until the patient has signed informed consent. 
The study will be explained to patients and those who meet entry criteria (Section 3.3) will be 
invited to participate.
Visit 1

Informed consent
After informed consent is obtained, the following procedures will be performed:

Patient demographics

Medical history, including pre-existing conditions

Assessment of inclusion/exclusion criteria 

Drug and alcohol test performed at site

Physical examination including height and weight

Vital signs

Blood sample for laboratory tests (Section 5.3.3)

Urine sample for pregnancy test as required for women of childbearing potential

12 Lead ECG using standard site equipment

Spirometry using standard site equipment

Register screening by emailing the form provided in the ISF to the Sponsor. 

Assess adverse events since informed consent (if obtained on a previous date)


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
Review of concomitant therapy including previous medication taken within the last three 
months.  Dose of all medication to be recorded.

Schedule next visit to occur within 28 days.
6.2.2
Treatment period(s)
Group 1
The PK evaluation period for Group 1 is a minimum of 24 days plus 28 days follow-up and 
begins at Visit 2.
Visit 2 Day 1
The patient should attend the clinic at approximately 07:00 so that the following assessments can 
be started before breakfast is given:

Review concomitant therapy and any adverse events since screening and throughout the 
day at regular intervals.

A drug and alcohol test will be done at the clinic.

Physical examination and vital signs.

Urine pregnancy test for women of childbearing potential.

Spirometry

Reassessment of inclusion/exclusion criteria.

Pre-dose PK samples should be taken according to PK Flowchart (Group 1; this should 
be taken prior to the other blood samples).

 

Registration of treatment start by emailing the form provided in the ISF to the sponsor.

One 150 mg nintedanib capsule should be given to the patient at 08:00 during breakfast 
(See PK Flowchart - Group 1).

PK samples should be taken according to PK Flowchart (Group 1).

The patient should be given lunch at 12:00 and a snack at 16:00.

After the 10-hour PK time point PK collection, the patient can leave the clinic and return 
to the clinic the next day.
Visit 2 Day 2

The patient must return to the clinic the next morning (Visit 2 Day 2) for the 24 hour 
time point at 07:55 (See PK Flowchart – Group 1).

AEs and concomitant medications should also be assessed.

Dispense two wallets of pirfenidone and instruct the patient to begin the uptitration of 
pirfenidone, the first dose should be given at the clinic with a snack.

Provide dosing instructions regarding uptitration to the patient.

Dispense patient diary.

Schedule Visit 3 for Day 23.

Other assessments listed for Visit 2 in the PK Flowchart are conducted at Day 1.


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Phone call Day 15
At the end of the planned uptitration, there will be a phone call made to the patient, the following 
assessments should be covered:

Assessment of adverse events.

Review concomitant therapy including dose.

Remind patient to uptitrate to the full dose of three capsules three times a day from the 
second wallet of pirfenidone.  If the patient is not tolerating the full dose then the patient 
has a six-day time window to reach full dose for 7 consecutive days. If the patient is not 
tolerating the uptitration then refer to Figure 4.1.4:1 for instructions.

Remind patient of Visit 3 scheduled for Day 23.

Remind patient not to take morning dose of study medication on the day of Visit 3 and to 
bring their study medication with them to the clinic and also the diary card.
Visit 3 Day 23
Once the patient has been on stable, full dose pirfenidone for 7 days (a 6 day window is allowed 
to ensure 7 consecutive days) they will return to clinic for the next PK day.
The patient should attend the clinic at approximately 07:00 so that the following assessments can 
be started before breakfast is given:

Physical examination and vital signs.

Urine pregnancy test for women of childbearing potential.

Blood sample for laboratory tests (Section 5.3.3)

Pre-dose PK samples should be taken according to PK Flowchart (Group 1, this should 
be taken prior to the other blood samples).

 

Spirometry.

Review concomitant therapy and any adverse events since previous visit and throughout 
the day at regular intervals.

Patients will return all unused medication.  Medication compliance will be assessed by 
counting returned (unused) capsules.

The patient will return the diary card and this will be reviewed to check that the patient 
has received seven consecutive, stable days of treatment.

One 150mg nintedanib capsule and three 267 mg pirfenidone capsules should be given to 
the patient at should be given to the patient at 08:00 during breakfast (See PK Flowchart
– Group 1).  

PK samples should be taken according to PK Flowchart (Group 1).

The patient should be given lunch at 12:00.

Three 267 mg pirfenidone capsules will be given to the patient at 14:00 along with a 
snack.

A snack will also be given to the patient at 16:00.

After the PK time point at 18:00, the patient can leave the clinic.

The patient should take the final dose of three 267 mg pirfenidone capsules at home at 
approximately 20:00 with food and a glass of water.


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Visit 3 Day 24

The patient must return the next morning (Visit 3 Day 24) for the 24 hour PK time point 
at 07:55 the next day.

AEs and concomitant medications should also be assessed.

Other assessments listed for Visit 3 in the PK Flowchart are conducted at Day 23

No study drugs are given.

Remind patient of PK FU visit scheduled for 28 days after this visit.
PK Follow-up/ End of Trial
The patient should return to the clinic 28 days or more after Visit 3 Day 24 for their PK Follow-
up/ End of Trial Visit as detailed in section 6.2.3.
Group 2
The PK evaluation period for this group is for a minimum of 16 days plus 28 days follow-up and 
begins at Visit 2.
Visit 2 Day 1

Review concomitant therapy and any adverse events since screening.

A drug and alcohol test will be done at the clinic.

Physical examination and vital signs.

Urine pregnancy test for women of childbearing potential.

Spirometry

Reassessment of inclusion/exclusion criteria.

 

Registration of treatment start by emailing the form provided in the ISF to the sponsor.

No PK samples are taken on this day.

Dispense two wallets of pirfenidone and instruct the patient to take 801mg tid, the first 
dose should be given at the clinic with food and a glass of water.

Provide patient with dosing instructions.

Dispense diary.

Remind patient of Visit 3a scheduled for Day 8.
Visit 3a Day 8
Once the patient has been on stable, full dose pirfenidone for 7 days (a 3 day window is allowed 
to ensure 7 consecutive days) they will return to clinic for the first PK day.
The patient should attend the clinic at approximately 07:00 so that the following assessments can 
be started before breakfast is given:

Physical examination and vital signs.

Urine pregnancy test for women of childbearing potential.

Blood sample for laboratory tests (Section 5.3.3)


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
Pre-dose PK samples should be taken according to PK Flowchart (Group 2, this should 
be taken prior to the other blood samples).

 

Spirometry.

Review concomitant therapy and any adverse events since previous visit and throughout 
the day at regular intervals.

Patients will return all unused medication.  Medication compliance will be assessed by 
counting returned (unused) capsules.

The patient will return the diary card and this will be reviewed to check that the patient 
has received seven consecutive, stable days of treatment.

Three 267 mg pirfenidone capsules should be given to the patient at 08:00 during 
breakfast (See PK Flowchart – Group 2).  

PK samples should be taken according to PK Flowchart (Group 2).

The patient should be given lunch at 12:00.

Three 267 mg pirfenidone capsules will be given to the patient at 14:00 with a snack.

After the PK time point at 14:00, the patient can leave the clinic.

The patient should be given the remaining pirfenidone from the previous visit and also 
one new wallet of pirfenidone and one bottle of nintedanib to take home.

The patient should take the final dose of three 267 mg pirfenidone capsules at home at 
approximately 20:00 with food and a glass of water.

The patient should be reminded to take pirfenidone and nintedanib from Day 9 at home 
for seven consecutive days.

Remind patient of Visit 3b scheduled for Day 16.
Once the patient has received nintedanib and pirfenidone for 7 consecutive days, they will return 
to clinic for Visit 3b for the next PK day.  If the patient needs to dose reduce the pirfenidone 
then this is allowed see Section 4.1.4.
Visit 3b Day 16
Once the patient has been on stable, pirfenidone and nintedanib for 7 days (a 3 day window is 
allowed to ensure 7 consecutive days) they will return to clinic for the next PK day.
The patient should attend the clinic at approximately 07:00 so that the following assessments can 
be started before breakfast is given:

Physical examination and vital signs.

Urine pregnancy test for women of childbearing potential.

Blood sample for laboratory tests (Section 5.3.3)

Predose PK samples should be taken according to PK Flowchart (Group 2, this should be 
taken prior to the other blood samples).

 
.

Spirometry.

Review concomitant therapy and any adverse events since previous visit and throughout 
the day at regular intervals.


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
Patients will return all unused medication.  Medication compliance will be assessed by 
counting returned (unused) capsules.

The patient will return the diary card and this will be reviewed to check that the patient 
has received seven consecutive, stable days of treatment.

One 150mg nintedanib capsule and three 267 mg pirfenidone capsules should be given to 
the patient at 08:00 during breakfast (See section 10.2; this will be the last study 
medication that the patient will receive in the PK evaluation period of the trial).

PK samples should be taken according to PK Flowchart (Group 2).

The patient should be given lunch at 12:00.

After the PK time point at 14:00, the patient can leave the clinic.

No study drugs are given.

Remind patient of PK FU visit scheduled for 28 days after this visit.
PK Follow-up/ End of Trial
The patient should return to the clinic 28 days or more after Visit 3b Day 16 for their PK 
Follow-up/ End of Trial Visit as detailed in section 6.2.3.
6.2.3
Follow Up Period and Trial Completion
A minimum of 28 days after the end of treatment all patients who started treatment are asked to 
come for a final follow up visit.
Follow up visit:
Assessments at this visit include:

Physical examination and vital signs.

 

Urine sample for pregnancy test for women of childbearing potential.

ECG. 

Review concomitant therapy and any adverse events.

Spirometry.

At the end of this visit the patient will have concluded their time in the trial.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
The objectives of the current study are to investigate the effect of steady state pirfenidone on the 
pharmacokinetics of nintedanib and its metabolites following oral administration of 2403 
mg/day pirfenidone and to investigate the effect of steady state nintedanib on the 
pharmacokinetics of pirfenidone at steady state following oral administration of 150 mg bid 
nintedanib. 
This open-label, multiple-dose study consists of two groups. In total, 34 patients will participate 
in the trial, 16 patients in group 1 and 18 patients in group 2. Within each group, there will be a 
fixed sequence design: in group 1, a single oral dose of nintedanib of 150mg will be 
administered alone (reference treatment, R1) and in combination with 801mg tid pirfenidone 
(test treatment, T1; cf. Section 3.1) and in group 2, 7 days of 801mg tid pirfenidone will be 
administered alone (reference treatment, R2) and in combination with 7 days 150mg bid of 
nintedanib (test treatment, T2). 
For each comparison between test and reference treatment, the statistical model used will be an 
ANOVA (analysis of variance) model on the logarithmic scale (see Section 7.3.1)
NULL AND ALTERNATIVE HYPOTHESES
7.2
For the comparisons described in Section 7.1, there is no hypothesis to be tested in a 
confirmatory sense. Instead, the ratios of adjusted geometric means (test/reference) for the 
primary PK endpoints and their two-sided 90% confidence intervals (CIs) will be provided. 
PLANNED ANALYSES
7.3
The statistical analysis will be based on the following populations:
Treated Set:
The treated set consists of patients who receive at least one dose of study medication.
PK analysis set:
PK concentrations and parameters of a subject will be included in the analysis if they are not 
flagged for exclusion, e.g. due to PK non-evaluability or a protocol violation relevant to the 
evaluation of PK endpoints, which will be decided no later than in the Report Planning Meeting.


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A PK concentration or parameter will be considered non-evaluable, if for example

the subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment for this treatment period (median tmax is to be determined excluding the 
subjects experiencing emesis),

a pre-dose concentration is > 5% of the Cmax value of that subject.
Relevant protocol violations may be for example

Administered dose (amount of drug) is not in compliance with the protocol, i.e. is too low or 
too high 

Restricted medication use
Criteria for important protocol violations may be updated and more details will be provided in 
the TSAP.
The PK analysis set (PKS) includes all subjects in the treated set who provide at least one 
primary or secondary PK endpoint value not excluded according to the description above. Thus, 
a subject will be included in the PKS, even if he/she contributes only one PK endpoint value for 
one of the two PK days to the statistical assessment. The PKS will be used for the primary and 
secondary endpoint analyses.
7.3.1
Primary endpoint analyses
For each comparison between test and reference treatment, the statistical model used will be an 
ANOVA (analysis of variance) model on the logarithmic scale. Thus, prior to fitting the 
ANOVA model, the PK parameters described in section 5.1.1 will be log transformed (natural 
logarithm). The difference between the expected means for log (T)-log(R) will be estimated by 
the difference in the corresponding Least Squares Means (point estimate).
Furthermore, the two-sided 90% confidence intervals based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to give the point 
estimator (geometric mean) and interval estimates for the ratio between response under test 
treatment and response under reference treatment.
The above mentioned ANOVA model will include effects accounting for the following sources 
of variation:  ‘subject’ and ‘treatment’. The effect ‘subject’ will be considered random, whereas 
the ‘treatment’ effect will be considered fixed. The model is described by the following 
equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response (AUC0-tz / Cmax for group 1 and AUC0-tau / Cmax,ss for group 2) measured on 
subject m receiving treatment k
= the overall mean,
sm = the effect associated with the mth subject 
k = the kth treatment effect, k = 1, 2,
emk = the random error associated with the mth subject who received treatment k.
All patients from the PKS will be included in the analysis of relative bioavailability (see Section 
7.3).  


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As a sensitivity analysis, the model above will be fitted with the “subject” as a fixed effect.
7.3.2
Secondary endpoint analyses
The secondary PK parameters described in Section 5.1.2 will be analysed as described for the 
primary PK endpoints. 
7.3.3
Further endpoint analyses
7.3.4
Safety analyses
All treated patients will be included in the safety analysis.
All adverse events with an onset between start and end of the residual effect period (REP), a 
period of 28 days after the last dose of trial medication will be assigned to the treatment period 
for evaluation and displayed by group (group 1 and group 2). 
AEs recorded prior to intake of trial medication will be assigned to ‘screening’, those between 
first intake until the last intake of trial medication plus 28 days will be assigned to the ‘on-
treatment’ period. Events occurring after the on-treatment period will be summarized as ‘follow-
up’ period and those after the end of trial visit will be assigned to ‘post-study’ period.
Safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned.
Frequency, severity, and causal relationship of adverse events will be tabulated by system organ 
class and preferred term after coding according to the current version of the Medical Dictionary 
for Regulatory Activities (MedDRA).
Laboratory data will be analysed both quantitatively, as well as qualitatively. The latter will be 
done via comparison of laboratory data to their reference ranges. Values outside the reference 
range as well as values defined as clinically relevant will be highlighted in the listings. 
Laboratory data will be described with regard to distribution parameters as well as with regard to 
frequency and percentage of patients with abnormal values or clinically relevant abnormal 
values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, baseline, 
during the course of the trial and at the end-of-trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment.


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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Sections 5.1.1, 5.1.2 and 5.1.3 will be calculated 
according to the relevant BI internal procedures.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
The PKS will be used for the primary and secondary endpoint analyses.
The following descriptive statistics will be calculated for plasma concentrations and PK 
parameters: number (N), arithmetic mean, standard deviation, minimum, median, maximum, 
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. The 
exception to this is
 where only median, minimum and maximum will be calculated. The 
data format for descriptive statistics of concentrations will be identical with the data format of 
the respective concentrations. Thereafter, the individual values, as well as the descriptive 
statistics, will be reported with three significant digits in the clinical trial report. 
For handling of missing data, please refer to Section 7.5. 
Analyses will be carried out using Phoenix® WinNonlin® 6.3 (or later) and/or SAS® software, 
version 9.4 (or later).
7.3.6
Biomarker analyses
INTERIM ANALYSES
7.4
Interim analysis will be performed if required by the regulatory agencies.
HANDLING OF MISSING DATA
7.5
7.5.1
Safety 
For partial or missing AE onset and/or end dates, BI internal rules will be followed for 
imputation (see Reference Document 001-MCG-156_RD01 “Handling of missing and 
incomplete AE dates”).
7.5.2
Plasma concentration - time profiles
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analyzed), and BLQ (below the limit of quantification) will be ignored and not replaced by zero 
at any time point (applies also to the lag phase). Descriptive statistics of concentrations at 
specific time points will be calculated only when at least 2/3 of the individuals have 
concentrations within the validated concentration range. The overall sample size to decide 


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whether the “2/3 rule” is fulfilled will be based on the total number of samples intended to be 
drawn for that time point (i.e. BLQ, NOR, NOS, NOA are included).
7.5.3
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA will 
not be considered. BLQ values in the lag phase will be set to zero. The lag phase is defined as 
the period between time zero and the first time point with a concentration above the 
quantification limit. All other BLQ values of the profile will be ignored. Every effort will be 
made to include all concentration data in an analysis. If not possible, a case-to-case decision is 
required whether the value should only be excluded from half-life estimation or the complete 
analysis. 

If a concentration is only excluded from half-life determination, it will be used for all
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter
determination. However, the excluded concentration itself will be listed in the tables in
section 15 of the clinical trial report associated with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual
parameter estimates of a certain parameter are available. If the actual sampling time is not 
recorded or is missing for a certain time point, the planned time will generally be used for this 
time point instead. Pharmacokinetic parameters which cannot be determined will be identified 
by "not calculated" (NC).
RANDOMISATION
7.6
Not applicable.
DETERMINATION OF SAMPLE SIZE
7.7
The primary endpoints for this study upon which sample size calculations have been based are 
AUC0-tz and Cmax of nintedanib for group 1 and AUCτ,ss and Cmax,ss of pirfenidone for 
group 2.
It is planned to have at least a total of 12 patients with both evaluable PK assessments (see 
Section 7.3) per group in the trial, because this sample size is considered sufficient to achieve the 
aims of this exploratory trial. With this sample size, the following precision in estimating the 
ratio of geometric means (test/reference; T/R) can be expected with 95% probability. Precision is 
defined as the ratio of upper confidence interval limit to the relative BA estimate for both 
groups. Note that the precision is independent of the actual ratio of geometric means.
In the case that less than 12 patients have both PK assessments, the Trial Clinical Monitor 
together with the Trial Pharmacokineticist and the Trial Statistician will decide if and how many 
patients will be additionally included.


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The observed intra-individual geometric coefficient of variation (gCV) for nintedanib in
previous trials in healthy volunteers (U13-1925-01; U13-1478-01) was roughly 30% for Cmax
and 20% for AUC0-tz.
For three assumptions on the intra-individual gCV of nintedanib (taking into account that the 
variability will be higher in patients than in healthy volunteers), Table 7.7: 1 provides an 
overview of the achievable precision for estimating the ratio of geometric means (T/R) for 
nintedanib. For illustrative purposes, the expected 90% confidence intervals with 95% coverage 
probability are displayed for different values of the ratios T/R of geometric means.
Table 7.7:1
Precision and illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R) for different intra-individual gCVs and ratios (T/R) in a fixed design trial 
(N=12)
Intra-individual 
gCV [%]
Ratio1 [%]
Precision 
upper CL/Ratio
90% CI [%]
30
100
1.33
75 – 133
110
1.33
82 – 147
35
100
1.40
72 – 140
110
1.40
79 – 153
40
100
1.42
69 – 146
110
1.42
75 – 161
1) Ratio of the geometric means (test/reference) for a PK endpoint defined by exp(µT)/exp(µR)
The expected 90% confidence interval limits in the table were derived by
CI limitupper,lower = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale.
Accounting for up to 4 dropouts (around 25%), a total of 16 patients (12 + 4) will be entered in 
the trial.
The observed total gCV in a previous parallel group trial in patients (c01787180-03) was 
roughly up to 40% for Cmax,ss and 40% for AUCτ,ss for pirfenidone, whereby the most relevant 
scenarios in this trial yielded total gCVs of up to 31% for both parameters. The corresponding 
intra-individual gCVs can be estimated based on an assumption on the correlation between two 
responses of the same subject.
For three assumptions on the total gCV of pirfenidone, and assuming a ratio T/R of geometric 
means of 100%, Table 7.7: 2 provides an overview of the achievable precision for estimating the 
ratio of geometric means (T/R) for pirfenidone. For illustrative purposes, the expected 90% 
confidence intervals with 95% coverage probability are displayed for different values of the 
correlation between two responses of the same subject.


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Table 7.7:2
Precision and illustrative two-sided 90% confidence intervals around the ratios of 
geometric means (T/R; assumed to be 100%) for different total gCVs and intro-subject 
correlations in a fixed sequence design trial (N=12)
Total gCV 
[%]
Correlation
Intra-individual 
gCV [%]
Precision 
upper CL/Ratio1
90% CI [%]
30
0.5
21
1.23
82 – 123
0.7
16
1.17
85 – 117
35
0.5
24
1.27
79 - 127
0.7
19
1.19
83 – 120
40
0.5
28
1.31
77 – 131
0.7
21
1.21
81 – 123
1) Ratio of the geometric means (test/reference) for a PK endpoint defined by exp(µT)/exp(µR)
Accounting for up to 6 dropouts (around 30%), a total of 18 patients (12 + 6) will be entered in 
the trial.
For these calculations the MOC3 routine from commercial software nQuery Advisor® 7.0 
(Statistical Solutions, Ltd., Cork, Ireland (R15-1331) was used.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) and 
the harmonized standards for Medical Devices (ISO 14155-01 and ISO 14155-02).
The trial will be carried out in compliance with the protocol, the ethical principles laid down in 
the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and relevant 
regulations*.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP*.
The rights of the Investigator and of the Sponsor with regard to publication of the results of this 
trial are described in the Investigator contract. As a rule, no trial results should be published 
prior to finalization of the Clinical Trial Report.
The rights of the investigator / trial site and of the sponsor with regard to publication of the 
results of this trial are described in the investigator contract / trial site’s contract. As a general 
rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be personally 
dated by each signatory and the informed consent and any additional patient-information form 
retained by the Investigator as part of the trial 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.”


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DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial 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 Investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms eCRF for individual patients will be provided by the Sponsor. See Section 
4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
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 CRF 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, 
depending on the trial; current medical records must also be available.
For eCRFs all data must be derived from source documents.
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS
8.4
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review and 
regulatory inspection, providing direct access to all related source data / documents. CRF/eCRF 
and all source documents, including progress notes and copies of laboratory and metical test 
results must be available at all times for review by the Sponsor’s clinical trial monitor, auditor 
and inspection by health authorities (e.g. FDA). The Clinical Research Associate (CRA) / on site 
monitor and auditor may review all CRF / eCRF, and written informed consents. The accuracy 
of the data will be verified by reviewing the documents described in section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.5
LISTEDNESS
8.6
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For nintedanib this is the IB and pirfenidone this is the SmPC. The current versions of these 
reference documents are provided in the ISF. No AEs are classified as listed for trial design, or 
invasive procedures.


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EXPEDITED REPORTING TO HEALTH AUTHORITIES AND IEC / IRB
8.7
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.8
Individual patient medical information obtained as a result of this trial 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.
Treatment data may be given to the patient’s personal physician or to other appropriate medical 
personnel responsible for the patient’s welfare. Data generated as a result of the trial need to be 
available for inspection on request by the participating physicians, the Sponsor’s representatives, 
by the IRB / IEC and the regulatory authorities.
END OF TRIAL
8.9
The end of the trial is defined as last patient out (see section 6.2.3). The IEC / competent 
authority in the participating EU member state will be notified about the end or early termination 
of the trial.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
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Hilberg F, Roth GJ, Krssak M, Kautschitsch S, Sommergruber W, Tontsch-Grunt 
U, Garin-Chesa P, Bader G, Zoephel A, Quant J, Heckel A, Rettig WJ BIBF 1120: triple 
angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy. Cancer Res
68 (12), 4774 - 4782 (2008)
P11-00203
Reck M, Kaiser R, Eschbach C, Stefanic M, Love J, Gatzemeier U, Stopfer P, 
Pawel J von. A phase II double-blind study to investigate efficacy and safety of two doses of the 
triple angiokinase inhibitor BIBF 1120 in patients with relapsed advanced non-small-cell lung 
cancer. Ann Oncol 22 (6), 1374 - 1381(2011)
P11-07084  
Raghu G, et al, ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary 
Fibrosis.  An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-
based guidelines for diagnosis and management. Am J Respir Crit Care Med 183 (6), 788 - 824 
(2011)
P11-10116
Ledermann JA, Hackshaw A, Kaye S, Jayson G, Gabra H, McNeish I, Earl H, 
Perren T, Gore M, Persic M, Adams M, James L, Temple G, Merger M, Rustin G.  Randomized 
phase II placebo-controlled trial of maintenance therapy using the oral triple angiokinase 
inhibitor BIBF 1120 after chemotherapy for relapsed ovarian cancer.  45th Ann Mtg of the 
American Society of Clinical Oncology (ASCO), Orlando, 29 May - 2 Jun 2009 J Clin Oncol 29 
(28), 379838 (2011)
P11-11216
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown
KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Klueglich M, Bois RM du
Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 365 (12), 
1079 - 1087 (2011)
P12-03241 
King TE, Pardo A, Selman M Idiopathic pulmonary fibrosis.Lancet 378 (9807), 
1949 - 1961 (2011)
P12-06085
Idiopathic Pulmonary Fibrosis Clinical Research Network Prednisone, 
azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 366 (21), 1968 - 1977 
(2012)
P13-06268
Eisen T, Shparyk Y, Jones R, MacLeod NJ, Temple G, Finnigan H, Kaiser R, 
Studeny M, Loembe AB, Bondarenko I Phase II efficacy and safety study of nintedanib versus 
sunitinib in previously untreated renal cell carcinoma (RCC) patients. 49th Ann Mtg of the 
American Society of Clinical Oncology.  (ASCO), Chicago, 31 May - 4 Jun 2013 J Clin Oncol 
31 (Suppl), Abstr 4506 (2013)


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Yen CJ, Kim TY, Feng YS, Chao Y, Lin DY, Studeny M, Hocke J, Huang DCL, 
Ryoo BY, Cheng AL Efficacy and safety of nintedanib versus sorafenib in Asian patients with 
advanced hepatocellular carcinoma: a randomised phase II trial. 38th Ann Cong of the European 
Society for Medical Oncology (ESMO), Amsterdam, 27 Sep - 1 Oct 2013 (Poster) 
P14-02860
Wollin L, Maillet I, Quesniaux V, Holweg A, Ryffel B Anti-fibrotic and anti-
inflammatory activity of the tyrosine kinase inhibitor, nintedanib, in experimental models of 
lung fibrosis. J Pharmacol Exp Ther 349, 209 - 220 (2014)
P14-07514 
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of nintedanib 
in idiopathic pulmonary fibrosis. N Engl J Med 370 (22), 2071 - 2082 (2014)
P14-07665 
Idiopathic Pulmonary Fibrosis Clinical Research Network Randomized trial of 
acetylcysteine in idiopathic pulmonary fibrosis.N Engl J Med 370 (22), 2093 - 2101 (2014)
P14-08020 
Scagliotti GV, Leighl NB, Nowak AK, Pavlakis N, Popat S, Sorensen JB, 
Barrueco J, Kaiser R, Loembe AB, Mueller M, Wangenheim U von, Reck M
Nintedanib plus pemetrexed/cisplatin followed by maintenance nintedanib for unresectable 
malignant pleural mesothelioma (MPM): an international, multicenter, randomized, double-
blind, placebo-controlled phase II study.  50th Ann Mtg of the American Society of Clinical 
Oncology (ASCO), Chicago, 30 May - 3 Jun 2014
P14-16496
Wuyts WA, Antoniou KM, Borensztajn K, Costabel U, Cottin V, Crestani B, 
Grutters JC, Maher TM, Poletti V, Richeldi L, Vancheri C, Wells AU Combination therapy: the 
future of management for idiopathic pulmonary fibrosis? Lancet Respir Med 2, 933 - 942 (2014)
P14-17347
Ogura T, Taniguchi H, Azuma A, Inoue Y, Kondoh Y, Hasegawa Y, Bando M, 
Abe S, Mochizuki Y, Chida K, Klueglich M, Fujimoto T, Okazaki K, Tadayasu Y, Sakamoto W, 
Sugiyama Y. Safety and pharmacokinetics of nintedanib and irfenidone in idiopathic pulmonary 
fibrosis. Eur Respir J, (2014)
P15-01243 
Spagnolo P, Wells AU, Collard HR. Pharmacological treatment of idiopathic 
pulmonary fibrosis: an update. Drug Discov Today, (2015)
R06-2002 Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, Brusasco V, et 
al. Standardisation of the single-breath determination of carbon monoxide uptake in the lung. 
Eur Respir J 2005; 26 (4) :720 -735
R06-2070 
Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, Taguchi Y, Nagai S, 
Itoh H, Ohi M, Sato A, Kudoh S, Research Group for Diffuse Lung Diseases in Japan, Raghu G 
Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary 
fibrosis.Am J Respir Crit Care Med 171, 1040 – 1047 (2005)
R09-1400
European Medicines Agency (EMEA)  ICH topic M3 (R2) non-clinical safety 
studies for the conduct of human clinical trials and marketing authorization for pharmaceuticals: 
step 4: note for guidance on non-clinical safety studies for the conduct of human clinical trials 


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and marketing authorization for pharmaceuticals (June 2009, CPMP/ICH/286/95).  
http://www.emea.europa.eu (2009)
R10-4316
Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, Taguchi Y, 
Takahashi H, Nakata K, Sato A, Takeuchi M, Raghu G, Kudoh S, Nukiwa T, Pirfenidone 
Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 35 (4), 
821 - 829 (2010)
R10-4848 
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), revised June 2010, 
reprinted June 2010). http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf
R11-4827 
Noble PW, Albera C, Bradford WZ, Costabel U, Glassberg MK, Kardatzke D, 
King TE, Lancaster L, Sahn SA, Szwarcberg J, Valeyre D, Bois RM du, CAPACITY Study 
Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two 
randomised trials. Lancet 377, 1760 - 1769 (2011)
R11-5086 
Thabut G, Christie JD, Ravaud P, Castier Y, Dauriat G, Jebrak G, Fournier M, 
Leseche G, Porcher R, Mal HSurvival after bilateral versus single-lung transplantation for 
idiopathic pulmonary fibrosis. Ann Intern Med 151 (11), 767 - 774 (2009)
R12-2785
Keating D, Levvey B, Kotsimbos T, Whitford H, Westall G, Williams T, Snell G. 
Lung transplanation in pulmonary fibrosis: challenging early outcomes counterbalanced by 
surprisingly good outcomes beyond 15 years. Transplant Proc 41, 289 - 291 (2009)
R12-2786 
Kim DS, Collard HR, King TE Classification and natural history of the idiopathic 
interstitial pneumonias. Proc Am Thorac Soc 3, 285 - 292 (2006)
R12-3474 
Kotloff RM, Thabut G Lung transplantation. Am J Respir Crit Care Med 184, 159 
- 171 (2011)
R12-3676 
McCurry KR, Shearon TH, Edwards LB, Chan KM, Sweet SC, Valapour M, 
Yusen R, Murray S, Lung transplantation in the United States, 1998 - 2007. Am J Transplant 9, 
942 - 958 (2009)
R12-4811 
Schaefer CJ, Ruhrmund DW, Pan L, Seiwert SD, Kossen K. Antifibrotic activities 
of pirfenidone in animal models. Eur Respir Rev 20 (120), 85 - 97 (2011)
R14-2103 
King TE, Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg 
MK, Gorina E, Hopkins PM, Kardatzke D, Lancaster L, Lederer DJ, Nathan SD, Pereira CA, 
Sahn SA, Sussman R, Swigris JJ, Noble PW, ASCEND Study Group A phase 3 trial of 
pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 370 (22), 2083 - 2092 
(2014)


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R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. 
http://www.statsols.com/wp-content/uploads/2013/10/nQ70_version2_manual.pdf (access date: 
20 March 2015) ; Los Angeles: Statistical Solutions 2007  
R94-1408 
Quanjer PH et al, Lung volumes and forced ventilatory flows.Report Working
Party Standardization of Lung Function Tests, European Community for Steel and Coal.Official 
Statement of the European Respiratory Society, Eur Respir J 1993; 6 (Suppl 16), 5-40
R94-1529
Chow SC, Liu JP, Design and Analysis of Bioavailability and Bioequivalence 
Studies. New York: Marcel Dekker Inc (1992)
R99-1243 
Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R, 
Transsection of the oesophagus for bleeding oesophageal varices. Br J Surg 60 (8), 646 - 649 
(1973)
R99-1244
Trey C, Burns DG, Saunders SJ, Treatment of hepatic coma by exchange blood 
transfusion, Postgraduate Medical Sem, 15 Sep 1965, N Engl J Med 274 (9), 473 - 481 (1966)
UNPUBLISHED REFERENCES
9.2
U07-1248 
 Investigator's brochure: BIBF 1120, Indication:Idiopathic Pulmonary 
Fibrosis. 1199.P3.  
U12-2505-01
, Ph.D. The effect of pirfenidone on selective in vitro tyrosine 
kinase activity assays. 07 December 2011
U13-1478-01
 
 
 
. Relative bioavailability 
of a single oral dose of nintedanib given alone and in combination with multiple oral doses of 
rifampicin in healthy male volunteers (an open-label, two-period, fixed-sequence Phase I trial). 
08-Aug-2013
U13-1925-01
, 
, 
 
: Relative bioavailability of nintedanib
given alone and in combination with ketoconazole at steady state in healthy male volunteers (an 
open-label, randomised, two-way cross-over clinical Phase I study). Study 1199.161. 4 July 
2013
c01787180-03 
 
 
, 
 double-blind, randomised, 
placebo-controlled (within a dose group) study to evaluate safety and pharmacokinetics of 
multiple rising doses of BIBF 1120 at 50 mg b.i.d. (14 days), 100 mg b.i.d. (14 days), and 150 
mg b.i.d. (28 days) po, on top of standard medical care with stratification according to 
pirfenidone use, in Japanese patients with idiopathic pulmonary fibrosis. Study no 1199.31. 
Clinical Report 5 Feb 2015
001-MCG-156_RD01 Handling of missing and incomplete AE dates


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10.
APPENDICES
PHARMACOKINETIC ANALYSES
10.1
For the calculation of pharmacokinetic parameters, only concentrations within the validated 
concentration range will be used. The actual sampling times will be used. For predose samples, 
the actual sampling time will be set to zero.
Noncompartmental pharmacokinetic parameters will be determined using WinNonlin or another 
validated program.
AUCt1-t2: The areas under the curve spanning various time intervals will be calculated using the 
linear up/log down algorithm. If a drug concentration is equal to or higher than the preceding 
concentration, the linear trapezoidal method will be used. If the drug concentration is smaller 
than the preceding concentration, the logarithmic method will be used.
Linear trapezoidal rule (t2 > t1 and C2 ≥C1):
The area of the trapezoid between the two data points (t1, C1) and (t2, C2) will be computed
by:
Logarithmic trapezoid rule (t2 > t1 and C2 < C1):
The area of the trapezoid between the two data points (t1, C1) and (t2, C2) will be computed
by:
Cmax and tmax: Individual Cmax and tmax values will be directly determined from the plasma 
concentration time profiles of each subject. If the same Cmax concentration occurs at different 
time points, tmax is assigned to the first occurrence of Cmax.
Estimation of λz: The apparent terminal rate constant λz will be estimated from a regression of 
ln(C) versus time over the terminal log-linear drug disposition portion of the concentration-time 
profiles. The log-linear profiles, which include the regression line through the terminal points, 
will be checked via visual inspection, and it will be determined whether the regression 
appropriately represents the terminal slope. Only data points that describe the terminal log-linear 
decline will be included in the regression. A minimum of three points will be used in the 
determination of λz. If the last concentration-time point increases, this time point may be 
included if the t1/2 estimate is reasonable. If λz is not determinable then consequently only 
parameters not requiring λz will be reported. In addition, the lower (tλz, start) and upper (tλz, end) 
limit on time for values to be included in the calculation of λz will be listed.


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t1/2: The terminal half-life will be calculated from the terminal rate constant using the
equation:
%AUCtz-∞: The percentage of the AUC0-∞will be obtained by extrapolation according to the 
following equation:
The parameter %AUCtz-∞is used to judge the reliability of the estimate for the parameter AUC0-
∞. 
MRTpo: The mean residence time after extravascular administration (MRTpo) will be calculated 
as follows:





0
0
po
AUC
AUMC
MRT
The area under the first moment curve from time 0 to infinity (AUMC0-) is calculated according 
to:








z
tz
z
z
tz
tz
-
0
-
0
C'
t
C'
AUMC
AUMC
CL/F: The apparent clearance after extravascular administration will be determined according to 
the following equation:



0
AUC
Dose
CL/F
(F = absolute bioavailability factor)
Vz/F: The apparent volume of distribution during the terminal phase after extravascular 
administration (at steady state) will be determined according to the following equation:
z
z
F
CL
F
V


The geometric mean (gMean) and coefficient of variation, gCV (given in %), will be calculated 
by the formulae:

)
ln(x
exp
)
ln(x
exp
gMean
i
n
1
i
i
n
1









1
))
Var(ln(x
exp
100
gCV(%)
i



where


2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x







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TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD SAMPLING
10.2
GROUP 1 – PK time points
Visit
Day
Window
Planned Time
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
PKblood for nintedanib 
PKblood for pirfenidone 
2
1
-1:00
7:00
Predose1
X
X
0:00
8:00
Breakfast2, Drug administration 
nintedanib3
0:30
8:30
X
1:00
9:00
X
2:00
10:00
Glass of water
X
3:00
11:00
X
4:00
12:00
Glass of water, Lunch
X
6:00
14:00
X
8:00
16:00
Snack
X
10:00
18:00
X
2
23:55
7:55
X
24:00
8:00
Snack, Drug administration of 
pirfenidone and begin uptitration6
3
23
+6
527:00
7:00
Predose
X
X
528:00
8:00
Breakfast2, Drug administration 
nintedanib and pirfenidone
528:30
8:30
X
X
529:00
9:00
X
X
530:00
10:00
Glass of water
X
X
531:00
11:00
X
X
532:00
12:00
Glass of water, Lunch
X
X
534:00
14:00
Snack, Drug administration 
pirfenidone4,5
X
X
536:00
16:00
X
X
538:00
18:00
X
X
24
551:55
7:55
X
X
Footnotes Group 1
1.
Predose PK sample can be taken prior to breakfast and administration of trial drugs.
2.
Breakfast should consist of a continental breakfast and drug should be administered with the meal.
3.
Single 150 mg dose of nintedanib given to the patient at the clinic with a glass of water. 
4.
On PK day 23, it is requested that the patient take their midday pirfenidone dose at 2pm so that there will be a 6 hour 
profile.
5.
On Day 23, the evening dose of pirfenidone will be taken at home at approximately 20:00.  This will be the last dose of 
pirfenidone taken.
6.
The midday and evening doses of pirfenidone will be taken at home.


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GROUP 2 – PK time points
Visit
Day
Window
Planned Time
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
PKblood for nintedanib 
PKblood for pirfenidone 
3a
8
+3
-1:00
7:00
Predose1
X
X
0:00
8:00
Breakfast2, Drug administration 
pirfenidone
0:30
8:30
X
1:00
9:00
X
2:00
10:00
Glass of water
X
3:00
11:00
X
4:00
12:00
Glass of water, Lunch
X
5:55
13:55
X
6:00
14:00
Snack, Drug administration 
pirfenidone3 and dispense 
nintedanib5
3b
16
+3
191:00
7:00
X
X
192:00
8:00
Breakfast, Drug administration 
nintedanib and pirfenidone4
192:30
8:30
X
X
193:00
9:00
X
X
194:00
10:00
Glass of water
X
X
195:00
11:00
X
X
196:00
12:00
Glass of water, Lunch
X
X
198:00
14:00
X
X
Footnotes Group 2
1.
Predose PK sample can be taken prior to breakfast and administration of trial drugs.
2.
Breakfast should consist of a continental breakfast and drug should be administered with breakfast.
3.
On PK day 8, it is requested that the patient take their midday dose at 14:00 so that there will be a 6 hour profile. On
PK day 16, this is not applicable, as the last pirfenidone dose is taken in the morning.
4.
The last dose of pirfenidone and nintedanib during the PK evaluation period will be in the morning at 08:00.  
5.
The evening dose of pirfenidone will be taken at home.  Dosing with nintedanib and pirfenidone will start on Day 9.


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LUNG FUNCTION CRITERIA
10.3
At visit 1, FVC must fulfil the following criteria:

50% predicted of normal ≤ FVC of predicted normal
Predicted normal values will be calculated according to ESCS (R94-1408):  

Males: FVC predicted (L) = 5.76 x height (meters)- 0.026 x age (years) -4.34

Females: FVC predicted (L) = 4.43 x height (meters)- 0.026 x age (years) -2.89
At visit 2, DLCO must fulfil the following criteria:

30% predicted of normal ≤ DLCO corrected for Hb < 80% predicted of normal
For predicted normal values, different sites may use different prediction formulas, based on the 
method used to measure DLCO. In any case, the method used must be in compliance with the 
ATS/ERS guideline on DLCO measurements (R06-2002), and the prediction formula
appropriate for that method. Raw data (gas mixture, equation used for prediction of normal,
further adjustments made if so) must be traced.
DLCO corrected for haemoglobin (R06-2002):

Males: DLCO corrected for Hb = DLCO measured x (10.22+Hb) /1.7Hb

Females: DLCO corrected for Hb = DLCO measured x (9.38+Hb)/ 1.7Hb
where Hb is expressed in g·dL-1.
For decision on inclusion/ exclusion, DLCO results taken from the tests at visits 1 or 2, or during 
the screening period (visit 1 to visit 2) will be corrected for haemoglobin by the site.  The 
haemoglobin sample does not need to be taken on the same day that the DLCO is performed.  
The haemoglobin value used can be from the central laboratory results or from a local result,


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CHILD-PUGH CLASSIFICATION (R99-1243)
10.4
Clinical and Biochemical 
Measurements
Points Scored for Increasing Abnormality
1 point
2 points
3 points
Total bilirubin, μmol/l 
(mg/dl)
<34
(<2)
34-50
(2-3)
>50
(>3)
Serum albumin, g/dl
>3.5
2.8-3.5
<2.8
Prothrombin time, prolongation 
(secs)
<4.0
4.0-6.0
> 6.0
Ascites
Absent
Slight
Moderate
Encephalopathy (grade)*
None
1 – 2  
3  –  4
*According to Trey, Burns and Saunders (1966) R99-1244
Total Score:
Child-Pugh A: 5 or 6 points;
Child-Pugh B: 7–9 points;
Child-Pugh C: >9 points


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
29 October 2015
EudraCT number
2015-000732-15
BI Trial number
1199.229
BI Investigational Product(s)
Nintedanib
Title of protocol
Investigation of drug-drug interaction between 
nintedanib and pirfenidone in patients with IPF (an 
open label, multiple-dose, two group study followed by 
nintedanib open label treatment)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authority

To be implemented 
immediately in order to 
eliminate hazard – IRB / IEC / 
Competent Authority to be 
notified of change with request 
for approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Cover Page – BI Investigational Product(s) and Clinical 
Trial Protocol Synopsis – BI Investigational Product(s)
Description of change
Addition of Ofev® to identify the BI Investigational 
Product and finished product
Rationale for change
To ensure full identification of nintedanib (Ofev®)
Section to be changed
Cover Page – Trial Clinical Monitor
Description of change
 
 
Phone : 
  
Fax: 
Has been changed to 
 


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Phone : +
  
Fax: +
Rationale for change
Change in Trial Clinical Monitor
Section to be changed
Cover Page – Coordinating Investigator and Clinical 
Trial Protocol Synopsis – Coordinating Investigator
Description of change
Phone: 
 
Fax: (
Has been changed to 
Phone: 
 
Fax: 
Rationale for change
To provide the correct dialing format 
Section to be changed
3.6 – Inclusion Criteria
Description of change 
5. DLCO (corrected for Hb [visit 1]): 30%-79% 
predicted of normal (refer to Section 10.3) at visit 2
Has been changed to
5. DLCO (corrected for Hb [visit 1]): 30%-79% 
predicted of normal (refer to Section 10.3) at visit 2 
(test can be performed at visits 1 or 2, or during the 
screening period).
Rationale for change
To clarify that the DLCO test can be performed either 


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at visit 1 or visit 2, or at any point during the screening 
period (visit 1 to visit 2), rather than having to be done 
at visit 2. 
This change has been made to allow flexibility to the 
site and to the patient as the test results should be 
available prior to the patient receiving IMP.  This is 
particularly important for the patients in Group 1 who 
are dosed early in the morning.
Section to be changed
3.7 – Exclusion Criteria
Description of change
14. Known hypersensitivity to nintedanib, pirfenidone 
or their excipients.
Has been changed to 
14. Known hypersensitivity to nintedanib, pirfenidone 
or their excipients; or to peanut or soya.
Rationale for change 
To bring the exclusion criteria in line with the SPC for 
nintedanib, which states that nintedanib is 
contraindicated in patients with “Hypersensitivity to 
nintedanib, to peanut or soya, or to any of the 
excipients listed in section 6.1.”
Section to be changed
3.8.1 – Removal of individual patients
Description of change 
For potential drug induced liver injury (DILI) follow 
up requirements please see section 5.3.6.1. 
Has been changed to 
For potential drug induced liver injury (DILI) follow up 
requirements please see section 5.3.7.1
Rationale for change
Typo – incorrect section reference
Section to be changed
5.3.8 – Adverse Event Collection and Reporting
Description of change 
Addition of a title and numbering for Figure 5.3.8:1 
Adverse Event Collection and Reporting 
Rationale for change
The figure did not previously have a number or title for 
the figure
Section to be changed
6.2.1 – Screening period


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Description of change 
Blood sample for laboratory tests (Section 5.1.3)
Has been changed to 
Blood sample for laboratory tests (Section 5.3.3)
Rationale for change
To correct a typographical error with the link
Section to be changed
6.2.2 – Treatment Periods
Description of change 
Group 1
The PK evaluation period for Group 1 is a minimum of 
24 days plus 28 days follow-up and begins at Visit 2.
Visit 2 Day 1
The patient should attend the clinic at approximately 
07:00 so that the following assessments can be started 
before breakfast is given:

Reassessment of inclusion/exclusion criteria.

A drug and alcohol test will be done at the 
clinic.

Physical examination and vital signs.

Urine pregnancy test for women of childbearing 
potential.

Pre-dose PK samples should be taken according 
to PK Flowchart (Group 1; this should be taken 
prior to the other blood samples).

 

Registration of treatment start by emailing the 
form provided in the ISF to the sponsor.

One 150 mg nintedanib capsule should be given 
to the patient at 08:00 during breakfast (See PK 
Flowchart - Group 1).

PK samples should be taken according to PK 
Flowchart (Group 1).

Spirometry.

Review concomitant therapy and any adverse 
events since screening and throughout the day at 
regular intervals.

The patient should be given lunch at 12:00 and a 
snack at 16:00.

After the 10-hour PK time point PK collection, 


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the patient can leave the clinic and return to the 
clinic the next day.
Has been changed to
Group 1
The PK evaluation period for Group 1 is a minimum of 
24 days plus 28 days follow-up and begins at Visit 2.
Visit 2 Day 1
The patient should attend the clinic at approximately 
07:00 so that the following assessments can be started 
before breakfast is given:

Review concomitant therapy and any adverse 
events since screening and throughout the day at 
regular intervals.

A drug and alcohol test will be done at the 
clinic.

Physical examination and vital signs.

Urine pregnancy test for women of childbearing 
potential.

Spirometry

Reassessment of inclusion/exclusion criteria.

Pre-dose PK samples should be taken according 
to PK Flowchart (Group 1; this should be taken 
prior to the other blood samples).

 

Registration of treatment start by emailing the 
form provided in the ISF to the sponsor.

One 150 mg nintedanib capsule should be given 
to the patient at 08:00 during breakfast (See PK 
Flowchart - Group 1).

PK samples should be taken according to PK 
Flowchart (Group 1).

The patient should be given lunch at 12:00 and a 
snack at 16:00.

After the 10-hour PK time point PK collection, 
the patient can leave the clinic and return to the 
clinic the next day.
Rationale for change
The assessments have been re-ordered to ensure that the 
activities that need to be performed to ensure the 
inclusion & exclusion criteria can be assessed are done 
prior to IMP being given. 


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Section to be changed
6.2.2 – Treatment Periods
Description of change 
Group 2
The PK evaluation period for this group is for a 
minimum of 16 days plus 28 days follow-up and begins 
at Visit 2.
Visit 2 Day 1

Reassessment of inclusion/exclusion criteria.

A drug and alcohol test will be done at the 
clinic.

Physical examination and vital signs. 

Urine pregnancy test for women of childbearing 
potential.

 

Registration of treatment start by emailing the 
form provided in the ISF to the sponsor.

No PK samples are taken on this day.

Spirometry.

Review concomitant therapy and any adverse 
events since screening.

Dispense two wallets of pirfenidone and instruct 
the patient to take 801mg tid, the first dose 
should be given at the clinic with food and a 
glass of water.

Provide patient with dosing instructions.

Dispense diary.

Remind patient of Visit 3a scheduled for Day 8.
Has been changed to
Group 2
The PK evaluation period for this group is for a 
minimum of 16 days plus 28 days follow-up and begins 
at Visit 2.
Visit 2 Day 1

Review concomitant therapy and any adverse 
events since screening.

A drug and alcohol test will be done at the 
clinic.

Physical examination and vital signs. 

Urine pregnancy test for women of childbearing 


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potential.

Spirometry

Reassessment of inclusion/exclusion criteria.

 

Registration of treatment start by emailing the 
form provided in the ISF to the sponsor.

No PK samples are taken on this day.

Dispense two wallets of pirfenidone and instruct 
the patient to take 801mg tid, the first dose 
should be given at the clinic with food and a 
glass of water.

Provide patient with dosing instructions.

Dispense diary.

Remind patient of Visit 3a scheduled for Day 8.
Rationale for change
The assessments have been re-ordered to ensure that the 
activities that need to be performed so inclusion & 
exclusion criteria can be assessed are done prior to IMP 
being given. 
Section to be changed
10.3 – Lung Function Criteria
Description of change 
For decision on inclusion/ exclusion, DLCO results 
from visit 2 will be corrected for haemoglobin by the 
site.
Has been changed to
For decision on inclusion/ exclusion, DLCO results 
taken from the tests at visits 1 or 2, or during the 
screening period (visit 1 to visit 2) will be corrected for 
haemoglobin by the site.
Rationale for change
This is to allow the DLCO assessment to be made at 
visits 1 or 2, or during the screening period rather than 
only at visit 2.
This change has been made to allow flexibility to the 
site and to the patient as the test results should be 
available prior to the patient receiving IMP.  This is 
particularly important for the patients in Group 1 who 
are dosed early in the morning.


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Number of global amendment
2
Date of CTP revision
16 February 2016
EudraCT number
2015-000732-15
BI Trial number
1199.229
BI Investigational Product(s)
Nintedanib
Title of protocol
Investigation of drug-drug interaction between 
nintedanib and pirfenidone in patients with IPF (an 
open label, multiple-dose, two group study followed by 
nintedanib open label treatment)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authority

To be implemented 
immediately in order to 
eliminate hazard – IRB / IEC / 
Competent Authority to be 
notified of change with request 
for approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be 
changed
Cover Page and Synopsis – title:
Description of 
change
Investigation of drug-drug interaction between nintedanib and pirfenidone in
patients with IPF (an open label, multiple-dose, two group study followed 
by nintedanib open label treatment)
Has been changed to:
Investigation of drug-drug interaction between nintedanib and pirfenidone in 
patients with IPF (an open label, multiple-dose, two group study)
Rationale for 
change
Removal of the Open-label Period
Section to be 
changed
Cover Page and Synopsis – trial sites:
Description of 
change
Trial conducted in approximately 7 sites in the UK
Has been changed to:
Trial conducted in approximately 9 sites in the UK
Rationale for 
change
Nine sites are already confirmed as participating


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Section to be 
changed
Synopsis - objectives
Description of 
change
The following text has been removed:
The trial will also collect safety information during open label 
administration of nintedanib.
Rationale for 
change
Removal of Open-Label Period
Section to be 
changed
Synopsis – main criteria for inclusion
Description of 
change
IPF diagnosis based on the ATS/ERS/JRS/ALAT 2011 IPF guidelines; 
Chest High-Resolution Computed Tomography (HRCT) performed within 
12 months of visit 1;
Has been changed to: 
IPF diagnosis based on the ATS/ERS/JRS/ALAT 2011 IPF guidelines; 
Chest High-Resolution Computed Tomography (HRCT) performed within 
18 months of visit 1;
Rationale for 
change
To allow scans that have been performed within 18 months prior to visit 1 to 
be used
Section to be 
changed
Synopsis - Methodology
Description of 
change
Open-label, multiple dose, two-group study. This study will have two 
periods; the first will be the PK evaluation period and patients will then 
move on to the open label nintedanib treatment period. 
Has been changed to: 
Open-label, multiple dose, two-group PK study.
An optional Named Patient Programme of nintedanib will be discussed with 
patients at the end of the trial.  This Named Patient Programme will not be 
part of the study.
Rationale for 
change
Removal of the Open-Label Period
Section to be 
changed
Synopsis – open-label treatment
Description 
of change
OPEN LABEL 


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NINTEDANIB 
TREATMENT 
PERIOD:
Trial product 1:
Nintedanib soft gelatine capsule
Dose:
3 0 0 m g d a i l y ( 1 5 0 m g b i d ) with possibility to 
reduce to 200 mg daily (100 mg bid) to manage 
adverse events (AE)
Mode of 
administration:
Oral administration with food
Duration of 
treatment:
6 months
This section of the table has been removed.  
Rationale for 
change
Removal of the Open-Label Period.
Section to be 
changed
Synopsis – safety criteria
Description of 
change
Proportion of patients with at least one adverse event in the open label 
nintedanib treatment period.
Additional further endpoints may be described in the TSAP.
Has been changed to:
Incidence and intensity of adverse events, physical examination, vital signs, 
ECG, change from baseline in laboratory parameters
Rationale for 
change
Removal of the Open-Label Period and to clarify the safety criteria that will 
be reviewed
Section to be 
changed
Flow Chart – Group 1
Description of 
change
Laboratory tests has been added at visit 3
Rationale for 
change
To allow safety lab tests to be collected 
Section to be 
changed
Flow Chart – Group 1
Description of 
change
All of the Open-label treatment Period assessments have been removed.
In addition the PK Follow-up period has been separated from the PK 
Evaluation Period  
Rationale for 
Removal of the Open-Label Period and clarity of the PK follow-up period


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change
Section to be 
changed
Flow Chart – Group 1 – footnote 4
Description of 
change
The following text has been removed:
…… At the PK FU visit they will start the nintedanib for the Open label 
nintedanib treatment period and will be dispensed nintedanib every two 
months for 6 months….
Rationale for 
change
Removal of the Open-Label Period
Section to be 
changed
Flow Chart – Group 1 – footnote 10
Description of 
change
If a patient withdraws from the PK evaluation period or does not tolerate 
uptitration then the patient should be managed according to Figure 4.1.4:1. 
If the patient withdraws during the Open label nintedanib treatment period 
of the trial then the patient should come in for the Open label nintedanib 
treatment period End of treatment visit at the time of withdrawal and then a 
follow-up visit 28 days after this.
has been changed to
If a patient withdraws from the PK evaluation period or does not tolerate 
uptitration then the patient should be managed according to Figure 4.1.4:1
Rationale for 
change
Removal of the Open-Label Period
Section to be 
changed
Flow Chart – Group 1 – footnote 15
Description of 
change
At Visit 4 (PK FU) the decision can be made by the Investigator as to 
whether the patient can start the open label nintedanib treatment period. At 
this visit the patient will be dispensed nintedanib for the open label 
nintedanib treatment period see Table 4.1.4: 2 
has been changed to:
At Visit 4 (PK FU) the optional nintedanib Named Patient Programme will 
be discussed with the patient.
Rationale for 
change
Removal of the Open-Label Period
Section to be 
changed
Flow Chart – Group 1 – Addition of DLCO test and footnote 19
Description of 
change
DLCO Testing has been added to the flow chart along with footnote 19 –
DLCO testing will be performed once at visit 1 or 2, or during the screening 


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period (visit 1 to visit 2).  The results will be corrected for haemoglobin by 
the site, see section 10.3 for further details.
Rationale for 
change
The protocol already states that DLCO testing is to be performed but this 
had not been specified in the Flow Chart
Section to be 
changed
Flow Chart – Group 2
Description of 
change
Laboratory tests has been added at visits 3a and 3b
Rationale for 
change
To allow safety lab tests to be collected 
Section to be 
changed
Flow Chart – Group 2
Description of 
change
All of the Open-label treatment Period assessments have been removed.
In addition the PK Follow-up period has been separated from the PK 
Evaluation Period  
Rationale for 
change
Removal of the Open-Label Period and clarity of the PK follow-up period
Section to be 
changed
Flow Chart – Group 2 – footnote 4
Description of 
change
The following text has been removed:
…… At the PK FU visit they will start the nintedanib for the Open label 
nintedanib treatment period and will be dispensed nintedanib every two 
months for 6 months….
Rationale for 
change
Removal of the Open-Label Period
Section to be 
changed
Flow Chart – Group 2 – footnote 9
Description of 
change
If a patient withdraws from the PK evaluation period then the patient should 
be managed according to Figure 4.1.4:1. If the patient withdraws during the 
Open label nintedanib treatment period of the trial then the patient should 
come in for the Open label nintedanib treatment period End of treatment 
visit at the time of withdrawal and then a follow-up visit 28 days after this.
has been changed to
If a patient withdraws from the PK evaluation period then the patient should 
be managed according to Figure 4.1.4:1. 
Rationale for 
change
Removal of the Open-Label Period


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Section to be 
changed
Flow Chart – Group 2 – footnote 14
Description of 
change
At Visit 4 (PK FU) the decision can be made by the Investigator as to 
whether the patient can start the open label nintedanib treatment period. At 
this visit the patient will be dispensed nintedanib for the open label 
nintedanib treatment period see Table 4.1.4: 2 
has been changed to
At Visit 4 (PK FU) the optional nintedanib Named Patient Programme will 
be discussed with the patient.
Rationale for 
change
Removal of the Open-Label Period
Section to be 
changed
Flow Chart – Group 2 – Addition of DLCO test and footnote 17
Description of 
change
DLCO Testing has been added to the flow chart along with footnote 17 –
DLCO testing will be performed once at visit 1 or 2, or during the screening 
period (visit 1 to visit 2).  The results will be corrected for haemoglobin by 
the site, see section 10.3 for further details
Rationale for 
change
The protocol already states that DLCO testing is to be performed but this 
had not been specified in the Flow Chart
Section to be
changed
Abbreviations
Description of 
change
The following have been added:
CrCl – Creatinine Clearance
CTCAE – Common Terminology for Adverse Events
NCI – National Cancer Institute
PKS – PK analysis set
Rationale for 
change
CrCl has been added to the protocol
CTCAE grading will be performed on AEs of diarrhoea, nausea and 
vomiting (as per NCI)
PKS was missing
Section to be 
changed
Section 2.1, last paragraph
Description of 
change
This study is conducted at the request of the European Medicines Agency 
(EMA) as a post-approval commitment and will examine the relative 
bioavailability for nintedanib and pirfenidone when administered together 
versus when administered alone. There will also be an open label nintedanib 
treatment period to collect additional safety data.
 
 


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.
Has been changed to: 
This study is conducted at the request of the European Medicines Agency 
(EMA) as a post-approval commitment and will examine the relative 
bioavailability for nintedanib and pirfenidone when administered together 
versus when administered alone. 
 
Rationale for 
change
Removal of the open-label period
Section to be 
changed
2.2 Trial Objectives
Description of 
change
The last sentence has been removed : 
This trial will also collect safety information during open label 
administration of nintedanib and throughout the trial.
Rationale for 
change
Removal of the open-label period
Section to be 
changed
2.3 Benefit-risk Assessment
Description of 
change
The second paragraph 
…... The patient will be offered to continue on nintedanib at the end of the 
PK part of the trial and their participation in the PK part will help to 
elucidate the pharmacokinetic characteristics of the combination of 
pirfenidone and nintedanib.….
Has been changed to: 
….. An optional nintedanib Named Patient Programme to allow patients to 
continue on nintedanib will be discussed at the end of the trial.   Patients 
participating in this PK trial will help to elucidate the pharmacokinetic 
characteristics of the combination of pirfenidone and nintedanib.  
Rationale for 
change
To clarify there will be an optional nintedanib Named Patient Programme 
after the PK Period.  This will not be part of the Trial
Section to be 
changed
3.1 Overall trial and design
Description of 
change
The study will be performed in approximately seven centres in the United 
Kingdom.
Has been changed to: 


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The study will be performed in approximately nine centres in the United 
Kingdom.
Rationale for 
change
9 sites are already confirmed as participating
Section to be 
changed
3.1 Overall trial and design - Paragraph 2
Description of 
change
There will then be an open label nintedanib treatment period for 6 months 
after the PK Follow up visit to collect additional safety data. See Figure 
3.1:1 below, Section 6 and the flowchart 1 and flowchart 2 for details of 
each study visit.
Has been changed to: 
After the end of the trial an optional Named Patient Programme of 
nintedanib will be discussed with patients.
Rationale for 
change
Removal of the open-label period
Section to be 
changed
3.3 
Description of 
change
The following text has been removed:
Two different designs are being used, as nintedanib is licensed but not 
currently NICE approved in the UK……
and
…….In the open label nintedanib treatment period patients will receive 
150mg bid nintedanib with the option of dose reduction to 100 mg bid 
and/or dose interruption to manage adverse events. Safety and tolerability 
will be assessed.
Rationale for 
change
NICE guidance has been published
Removal of the open-label period
Section to be 
changed
3.4 Selection of the Trial Population
Description of 
change
Addition of:
Each group requires at least 12 evaluable patients to complete each arm.  
Once 12 evaluable patients in a group have completed treatment, 
recruitment into that group will stop.  The other group may continue to 
recruit until 12 evaluable patients in that group also complete treatment. 
Any patient still in the PK evaluation period when their group closes to 
recruitment may complete the PK evaluation period.


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Rationale for 
change
Clarification of the end of recruitment
Section to be 
changed
3.4 Selection of the Trial Population
Description of 
change
Approximately 7 sites are each expected to include a minimum of 3 patients.
Has been changed to: 
Approximately 9 sites are each expected to include a minimum of 3 patients.
Rationale for 
change
9 sites are already confirmed as participating 
Section to be 
changed
Section 3.6 – Inclusion Criteria
Description of 
change
IPF diagnosis based on the ATS/ERS/JRS/ALAT 2011 IPF guidelines; 
Chest High-Resolution Computed Tomography (HRCT) performed within 
12 months of visit 1;
Has been changed to: 
IPF diagnosis based on the ATS/ERS/JRS/ALAT 2011 IPF guidelines; 
Chest High-Resolution Computed Tomography (HRCT) performed within 
18 months of visit 1;
Rationale for 
change
To allow scans that have been performed within 18 months prior to visit 1 to 
be used
Section to be 
changed
Section 3.7 – Exclusion Criteria
Description of 
change
The criteria have been re-numbered
Rationale for 
change
Two new criteria have been added (see below).  As there are already criteria 
relating to liver function it was appropriate to add the chronic liver disease 
at this point rather than at the end of the list of exclusion criteria 
Section to be 
changed
Section 3.7 – Exclusion Criteria
Description of 
change
8
– History of end-stage renal disease requiring dialysis.
Has been changed to: 
9 – Severe renal impairment (Creatinine clearance <30 mL/min calculated 
by Cockcroft–Gault formula at visit 1) or end-stage renal disease requiring 


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dialysis.
Rationale for 
change
Clarification is added to match the SPC of pirfenidone.
Section to be 
changed
Section 3.7 – Exclusion Criteria
Description of 
change
The following has been added:
3 – Underlying chronic liver disease (Child Pugh A, B, or C hepatic 
impairment)
21 – Current Smoker
Rationale for 
change
Patients with underlying chronic liver disease have also been excluded
Current smokers have been excluded to match the SPC of pirfenidone.  
Patients who smoke could affect the bioavailability of pirfenidone.
Section to be 
changed
3.8.1 Removal of individual patients
Description of 
change
The patient experiences liver function impairment as follows:

ALT and/or AST ≥8 fold ULN

ALT and/or AST ≥3 fold ULN with signs or symptoms of severe 
liver damage (section 4.2.1.3) (including total bilirubin >2 fold 
ULN).
For potential drug induced liver injury (DILI) follow up requirements please 
see section 5.3.7.1.

In the opinion of the investigator, the patient experiences 
unacceptable toxicity despite dose adjustments and supportive care.
Has been changed to:

The patient experiences liver function impairment as follows:

ALT and/or AST ≥5 fold ULN

ALT and/or AST ≥3 fold ULN with signs or symptoms of 
severe liver damage (section 4.2.1.4) (including total 
bilirubin >2 fold ULN). 
For potential drug induced liver injury (DILI) follow up 
requirements please see section 5.3.7.1. 

In the opinion of the investigator, the patient experiences 
unacceptable toxicity despite dose adjustments and supportive care.

CrCl <30mL/min during the course of the trial.  Study medication 
should be stopped and a repeat test performed as soon as feasible.  If 
this second measurement confirms a CrCl <30mL, the patient should 
be permanently discontinued.


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Rationale for 
change
The recommendations for managing liver elevations in section 4.2.1.4 have 
been updated (see below), this text has been updated accordingly.
Severely decreased CrCl can affect PK results.  This is also in-line with the 
pirfenidone SPC
Section to be 
changed
Section 3.8.1 Removal of individual Patients
Description of 
change
Treatment with pirfenidone must be permanently discontinued in the 
following situations:

ALT and/or AST ≥ 5 fold ULN
Has been changed to: 
Treatment with pirfenidone must be permanently discontinued in the 
following situations:

ALT and/or AST ≥ 5 fold ULN

Patient develops signs or symptoms of angioedema
Rationale for 
change
Clarification is added to match the SPC of pirfenidone.  
Section to be 
changed
Table 4.1.1: 1 Nintedanib (investigational drug)
Description of 
change
The following text has been removed:
100mg
and
Open label nintedanib treatment period: one 150 mg capsule in the morning 
and one in the evening (can be reduced to 100 mg to manage adverse 
events)
Rationale for 
change
Removal of the open-label period
Section to be 
changed
Table 4.1.4:2 Quantity of medication kits dispensed to the patient (Group 1 
and Group 2)
Description of 
change
The following text has been removed:
4 (PK FU)
5
5
5
6
5
Rationale for 
change
Removal of the open-label period


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Section to be 
changed
4.1.4 Drug assignment and administration of doses for each patient – last 
paragraph
Description of 
change
The following text has been removed:
Open label nintedanib treatment period 
The patient will have a washout period from the end of the last PK day 
(Visit 3, Day 24 for Group 1 and Visit 3b, Day 16 for Group 2) until the PK 
Follow-Up visit where no study drugs are taken. At the PK Follow-Up visit, 
if assessed by the Investigator medically indicated, the patient will be 
supplied with nintedanib for the open label nintedanib treatment period. 
During this phase the patient will be dosed at 150 mg bid with the 
possibility to reduce to 100 mg bid for management of adverse events.
Rationale for 
change
Removal of the open-label period
Section to be 
changed
Figure 4.1.4:1 (all three flow charts)
Description of 
change
Have been updated to remove the open-label period
Rationale for 
change
Removal of the open-label period
Section to be 
changed
Section 4.1.6 Packaging, labelling, and re-supply
Description of 
change
The following Test has been removed:
There will be one shipment to each site.
Rationale for 
change
To allow for more than one shipment to site if required
Section to be 
changed
Section 4.1.6 Packaging, labelling, and re-supply
Description of 
change
The following text has been added:
The nintedanib to be used in the nintedanib Named Patient Programme does 
not form part of the study supplies
Rationale for 
change
To clarify that the nintedanib in the Named Patient Programme is not part of 
the trial supplies
Section to be 
changed
4.2.1.1 Recommendations for adverse events considered drug related 
(exceptions include diarrhoea and photosensitivity/rash):
Description of 
The following text has been removed:


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change
PK evaluation period
And
Open label nintedanib treatment period

Dose reduction or interruption of nintedanib should be considered 
(at the discretion of the investigator) to allow for resolution of 
symptoms.
Rationale for 
change
Removal of the open-label period
Section to be 
changed
4.2.1.2 Recommendations for managing diarrhoea
Description of 
change
The following text has been removed:
PK evaluation period
And
Open label nintedanib treatment period

Interruption of nintedanib should be considered (at the discretion of 
the investigator) to allow for resolution of symptoms.
Rationale for 
change
Removal of the open-label period
Section to be 
changed
4.2.1.4 Management of liver enzyme elevations
Description of 
change
The following text has been removed, as well as Table 4.2.1.4:
For a detailed description of recommendations for management of liver 
enzyme elevations, please refer to table 4.2.1.4:1……
……NINT: nintedanib
* Laboratory tests include ALT, AST, total bilirubin, eosinophils, INR
This has been replaced with:
Patients who experience:

AST /ALT ≥3 ULN with signs or symptoms of severe liver damage* 
(including total bilirubin >2 fold ULN)
or


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
ALT and/or AST ≥5 fold ULN
Should interrupt all study drugs and return to clinic for a visit 3 (Group 1) or 
Visit 3b (Group 2). 
* Signs of severe liver damage are defined as:

ALT/AST ≥ 3 x ULN and total bilirubin ≥ 2 x ULN 

ALT/AST ≥ 3 x ULN and unexplained INR > 1,5

ALT/AST ≥ 3 x ULN and unexplained eosinophilia (>5%)

ALT/AST ≥ 3 x ULN and appearance of fatigue, nausea, vomiting, 
right upper abdominal quadrant pain or tenderness, fever and/or rash
For potential drug induced liver injury (DILI) follow up requirements please 
see section 5.3.7.1.
Rationale for 
change
The table included recommendations during the open-label period.
Section to be 
changed
Table 4.2.2.1:1 Permitted and Restricted Concomitant therapy
Description of 
change
The columns for the open-label period have been removed.  
In addition the PK evaluation period (incl PK FU period) has been separated 
to PK evaluation Period and PK Follow-Up Period
The PK follow-up period does not permit pirfenidone or nintedanib.
Footnote 5 has also been added:
5.
Patients should not receive treatment for IPF during the PK follow-up 
period unless they have an acute worsening of their disease. Should this 
occur then the investigator may use any standard of care treatment 
available to them.  The treatments to be administered should be done 
after due consideration of the SPCs for nintedanib and pirfenidone.  It is 
preferable that nintedanib and pirfenidone are not used during the PK 
follow-up period so that there is a clear Residual Effect Period.  
Investigational Medicinal Products must not be used during this period.
Rationale for 
change
To remove the open-label period.  To separate the PK Evaluation Period and 
Follow-up Period and clarify the restricted medications in this period.
Section to be 
changed
4.2.2.2   Restrictions on diet and life style
Description of 
change
Patients, when taking pirfenidone should avoid exposure to direct and 
indirect sunlight, use an effective sunblock (at least SPF 50 against UVA 


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and UVB) and wear protective clothing. Grapefruit juice is an inhibitor of 
CYP1A2 and, thus, consummation should be avoided while taking 
pirfenidone.
Has been changed to 
Patients, when taking pirfenidone, should not smoke and should avoid 
exposure to direct and indirect sunlight, use an effective sunblock (at least 
SPF 50 against UVA and UVB) and wear protective clothing. Grapefruit 
juice is an inhibitor of CYP1A2 and, thus, consummation should be avoided 
while taking pirfenidone.
Rationale for 
change
To align with the pirfenidone SPC
Section to be 
changed
5.1.3 Further Endpoints
Description of 
change
The following has been removed:
Safety endpoints
Proportion of patients with at least one adverse event in the open label 
nintedanib treatment period.
Rationale for 
change
This has been removed as it was connected to the open-label period
Section to be 
changed
5.3.3 Safety laboratory parameters
Description of 
change
Creatinine Clearance (according to Cockcroft-Gault formula) has been 
added to chemistry assessments
Prothrombin Time has been added to coagulation assessments
Rationale for 
change
Creatinine Clearance has been added as this now needs to be measured in 
the protocol
Prothrombin time has been added to allow the Child-Pugh Score to be
calculated.
Section to be 
changed
5.3.3 Safety laboratory parameters
Description of 
change
The following test was added:
Renal Function Measurements
CrCl will be calculated using the Cockcroft-Gault formula, as follows:

For creatinine in µMol/L:
(140-age [years]) x weight [kg] x 1.23 (x 0.85 if female)
serum creatinine [µMol/L]


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
For creatinine in mg/dL:
(140-age [years]) x weight [kg] (x 0.85 if female)
72 x serum creatinine [mg/dL]
Please refer to Section 3.8.1 for guidance if a patient has started IMP and 
their CrCl is <30mL/min.
Rationale for 
change
This has been added due to the addition of creatinine clearance testing
Section to be 
changed
5.3.6 Other safety parameters
Description of 
change
A patient diary will be used by all patients in this trial to record symptoms 
and number of capsules taken per day during the PK Period only
Has been changed to
A patient diary will be used by all patients in this trial to record symptoms 
and number of capsules taken per day whilst they are taking study treatment. 
Rationale for 
change
Clarification as to when the diary should be completed.
Section to 
be changed
5.3.7.1 Definitions of AEs
Description 
of change
The following text has been added:
The intensity of diarrhoea, nausea and vomiting AEs should be classified and 
recorded in the (e)CRF according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03 (R10-4848):
Table 5.3.7:1 CTCAE Categorization (R10-4848)
CTCAE 
Grade
Diarrhoea
Nausea
Vomiting
1
Increase of <4 stools 
per day
over baseline; mild 
increase in ostomy 
output compared to 
baseline
Loss of appetite 
without alteration in 
eating habits
1-2 episodes 
(separated by 5 
minutes) in 24 
hours
2
Increase of 4 - 6 stools 
per
day over baseline; 
moderate
increase in ostomy 
output
compared to baseline
Oral intake 
decreased without 
significant weight 
loss, dehydration or 
malnutrition
3-5 episodes 
(separated by 5 
minutes) in 24 
hours


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3
Increase of >=7 stools 
per day over baseline; 
incontinence; 
hospitalization 
indicated; severe 
increase in ostomy 
output compared to 
baseline; limiting self 
care ADL 
Inadequate oral 
caloric or fluid 
intake; tube feeding, 
TPN, or 
hospitalization 
indicated
≥6 episodes 
(separated by 5 
minutes) in 24 
hours ; tube 
feeding, TPN or 
hospitalization 
indicated
4
Life-threatening 
consequences; urgent 
intervention indicated
Not applicable
Life threatening 
consequences; 
urgent
intervention 
indicated
5
Death
Not applicable
Death
Rationale 
for change
CTCAE grading has been added for these AEs as they are AEs of particular 
note 
Section to be 
changed
5.3.8 Adverse event collection and reporting
Description of 
change
From signing the informed consent onwards through the Residual Effect 
period (REP), until the end of the REP (for this trial it will be classed as 28 
days after the end of the open label nintedanib treatment period or 28 days 
after the end of the PK evaluation period) if the patient doesn’t go intot he 
open label nintedanib treatment peiod: 
Has been changed to:
From signing the informed consent onwards through the Residual Effect 
period (REP), until the end of the REP (for this trial it will be classed as 28 
days after the end of the PK evaluation period): 
Rationale for 
change
Removal of the open-label period
Section to be 
changed
5.3.8 Adverse event collection and reporting
Description of 
change
The REP is defined as 28 days after the last trial medication application (for 
this trial it will be classed as 28 days after the end of the open label 
nintedanib treatment period or 28 days after the end of the PK evaluation 
period if the patient doesn’t go into the open label nintedanib treatment 
period; this is a general diagram and there will be no run-in period in this 
trial. Treatment will be classed as the PK evaluation period and the open 
label nintedanib period). 
Has been changed to:


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The REP is defined as 28 days after the last trial medication application (for 
this trial it will be classed as 28 days after the end of the PK evaluation 
period; this is a general diagram and there will be no run-in period in this 
trial.  Treatment will be classed as the PK evaluation period). 
Rationale for 
change
Removal of the open-label period
Section to be 
changed
6.1 Visit Schedule
Description of 
change
The study will consist of four sequential periods; a screening period, a PK 
evaluation period, the open label nintedanib treatment period and the follow-
up period.
Screening will be up to 4 weeks (28 days) in duration. The PK evaluation 
period will be 24 days in Group 1 and 16 days in Group 2 plus a follow up 
period of 28 days. The open label nintedanib treatment period will be for 6 
months and this will be completed with a follow up visit 4 weeks after the 
end of treatment.
Has been changed to:
The study will consist of three sequential periods; a screening period, a PK 
evaluation period, and the follow-up period.   
Screening will be up to 4 weeks (28 days) in duration.  The PK evaluation 
period will be 24 days in Group 1 and 16 days in Group 2 plus a follow up 
period of 28 days.  
Rationale for 
change
To allow safety samples to be collected during the PK period
Section to be 
changed
6.2.2 Treatment period(s) – Group 1 (visit 3 day 23)
Description of 
change
The following text has been added:
Blood sample for laboratory test (section 5.3.3)
Rationale for 
change
To allow safety samples to be collected during the PK period
Section to be 
changed
6.2.2 Treatment period(s) – Group 1 (PK Follow-up)
PK Follow-up
The patient should return to the clinic 28 days or more after Visit 3 Day 24.
Assessments at this visit include:


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
Physical examination and vital signs.

 

Spirometry.

ECG.

Urine pregnancy test for women of childbearing potential.

Dispense nintedanib (if patient will enter into the open label 
nintedanib treatment period).

Review concomitant therapy and any adverse events.

At this point the PK evaluation period is complete.
Has been changed to: 
PK Follow-up/ End of Trial
The patient should return to the clinic 28 days or more after Visit 3 Day 24 
for their PK Follow-Up/ End of Trial Visit as detailed in section 6.2.3.
Rationale for 
change
To combine the PK Follow-up and End of Trial visit
Section to be 
changed
6.2.2 Treatment period(s) – Group 2 (visit 3a day 8)
Description of 
change
The following text has been added:
Blood sample for laboratory test (section 5.3.3)
Rationale for 
change
To allow safety samples to be collected during the PK period
Section to be 
changed
6.2.2 Treatment period(s) – Group 2 (visit 3b day 16)
Description of 
change
The following text has been added:
Blood sample for laboratory test (section 5.3.3)
Rationale for 
change
To allow safety samples to be collected during the PK period
Section to be 
changed
6.2.2 Treatment period(s) – Group 2 (PK Follow-up)
Description of 
change
PK Follow-up
The patient should return to the clinic 28 days or more after Visit 3b Day 24.
Assessments at this visit include:

Physical examination and vital signs.

 


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
Spirometry.

ECG.

Urine pregnancy test for women of childbearing potential.

Dispense nintedanib (if patient will enter into the open label 
nintedanib treatment period).

Review concomitant therapy and any adverse events.

At this point the PK evaluation period is complete.
Has been changed to: 
PK Follow-up/ End of Trial
The patient should return to the clinic 28 days or more after Visit 3 Day 16 
for their PK Follow-Up/ End of Trial Visit as detailed in section 6.2.3.
Rationale for 
change
To combine the PK Follow-up and End of Trial visit
Section to be 
changed
6.2.2 Treatment period(s) – (Open label nintedanib treatment period for 
Group 1 and Group 2)
Description of 
change
The following has been removed:
Open label nintedanib treatment period for Group 1 and Group 2
Visit 4 to Visit 7 (End of treatment)
During this period the patient will receive an additional six months of open 
label nintedanib treatment. Patients will be seen in clinic every two months 
from this point.
Assessments at these visits include:

Physical examination and vital signs.

Urine pregnancy test for women of childbearing potential.

 

Spirometry.

ECG (EOT visit only).

Dispense nintedanib (except at EOT).

Patients will return all unused medication. Medication compliance 
will be assessed by counting returned (unused) capsules.

Review concomitant therapy and any adverse events.

No diary is required during this period.
If the patient requires a dose interruption or dose reduction to manage 
Adverse Events during this period this should be discussed with the 
Investigator. Guidance should be followed in Section 4.
If the patient withdraws during the open label nintedanib period they should 


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come in for Visit 7 (EOT) when they stop the medication and then 28 days 
later they should attend Visit 8 (FU).
Rationale for 
change
Removal of the open-label period
Section to be 
changed
6.2.3 Follow-up Period and Trial Completion
Description of 
change
A minimum of 28 days after the end of treatment in the open label 
nintedanib treatment period, all patients who started treatment are asked to 
come for a final follow up visit.
Follow up visit:

Physical examination and vital signs.

Urine sample for pregnancy test for women of childbearing 
potential.

Review concomitant therapy and any adverse events.

Blood sample for laboratory tests.

Spirometry.

At the end of this visit the patient will have concluded their time in 
the trial.
Has been changed to: 
A minimum of 28 days after the end of treatment all patients who started 
treatment are asked to come for a final follow up visit.
Follow up visit:
Assessments at this visit include:

Physical examination and vital signs.

 

Urine sample for pregnancy test for women of childbearing 
potential.

ECG

Review concomitant therapy and any adverse events.

Spirometry.

At the end of this visit the patient will have concluded their time in 
the trial.
Rationale for 
change
Due to the removal of the open-label period
Section to be 
changed
7.1 STATISTICAL DESIGN – MODEL (paragraph 1)
Description of 
The following text has been removed:


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change
The trial will also collect safety information during open label 
administration of nintedanib and throughout the trial.
Rationale for 
change
Due to the removal of the open-label period
Section to be 
changed
7.3 PLANNED ANALYSES
Description of 
change
The statistical analysis will be based on the following populations:
Treated Set in PK evaluation period:
The treated set in PK evaluation period consists of patients who receive at 
least one dose of study medication in the PK evaluation period.
Treated Set in open label nintedanib treatment period:
The treated set in open label nintedanib treatment period consists of patients 
who receive at least one dose of study medication (nintedanib) in the open 
label nintedanib treatment period.
Has been changed to: 
The statistical analysis will be based on the following populations:
Treated Set:
The treated set consists of patients who receive at least one dose of study 
medication.
Rationale for 
change
Due to the removal of the open-label period
Section to be 
changed
7.3 PLANNED ANALYSES (PK analysis set:)
Description of 
change
The PK analysis set (PKS) includes all subjects in the treated set in PK 
evaluation period who provide at least one primary or secondary PK 
endpoint value not excluded according to the description above.
Has been changed to: 
The PK analysis set (PKS) includes all subjects in the treated set who 
provide at least one primary or secondary PK endpoint value not excluded 
according to the description above.
Rationale for 
change
Due to the removal of the open-label period
Section to be 
changed


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Description of 
change
 
 
 
 
 
 
 
Rationale for 
change
Section to be 
changed
7.3.4 Safety analyses
Description of 
change
PK evaluation period
All treated patients in the PK evaluation period will be included in the safety 
analysis. Adverse events with an onset between start and end of treatment 
plus a period of 28 days after the last dose of trial medication within that 
period will be assigned to the PK evaluation period for evaluation and 
displayed by group (group 1 and group 2).
AEs recorded prior to intake of trial medication will be assigned to 
‘screening’, those between first intake until the last intake of trial 
medication plus 28 days will be assigned to the ‘ontreatment’period. Events 
occurring after the on-treatment period until the first intake of treatment in 
the open label nintedanib treatment period will be assigned to the “PK 
follow-up”period.
Open label nintedanib treatment period
All treated patients in the open label nintedanib treatment period will be 
included in the safety analysis.
Adverse events with an onset between start and end of treatment in the open 
label nintedanib treatment period plus a period of 28 days after the last dose 
of trial medication within that period will be assigned to the open label 
nintedanib treatment period for evaluation and displayed overall (all patients 
treated in the open label nintedanib treatment period).
AEs recorded between first intake until the last intake of open label trial 


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medication plus 28 days will be assigned to the ‘on-treatment’ period. 
Events occurring after the on-treatment period will be summarized as 
‘follow-up’ period and those after the end of trial visit will be assigned to 
‘post-study’ period.
Has been changed to: 
All treated patients will be included in the safety analysis.
All adverse events with an onset between start and end of the residual effect 
period (REP), a period of 28 days after the last dose of trial medication will 
be assigned to the treatment period for evaluation and displayed by group 
(group 1 and group 2). 
AEs recorded prior to intake of trial medication will be assigned to 
‘screening’, those between first intake until the last intake of trial 
medication plus 28 days will be assigned to the ‘on-treatment’ period. 
Events occurring after the on-treatment period will be summarized as 
‘follow-up’ period and those after the end of trial visit will be assigned to 
‘post-study’ period.
Rationale for 
change
Removal of the open-label period
Section to be 
changed
7.4 INTERIM ANALYSES
Description of 
change
An interim analysis will be performed after the last patient reaches the PK 
FU visit. For this purpose an interim database lock will be performed. All 
analyses related to the PK evaluation period including safety evaluation will 
be done except for the
 that will be provide for the final analysis. 
Has been changed to: 
Interim analysis will be performed if required by the regulatory agencies.
Rationale for 
change
Due to the removal of the open-label period there is no longer a need to do 
an interim analysis after the PK period
Section to be 
changed
9.1 Published References
Description of 
change
The following text has been added:
R10-4848 
Common terminology criteria for adverse events (CTCAE): 
version 4.0 (NIH publication no. 09-5410, published: May 28, 2009 (v4.03: 
June 14, 2010), revised June 2010, reprinted June 2010). 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf


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Rationale for 
change
To reference the CTCAE guide
Section to be 
changed
10.3 Lung Function Criteria
Description of 
change
The following text has been added:
The haemoglobin sample does not need to be taken on the same day that the 
DLCO is performed.  The haemoglobin value used can be from the central 
laboratory results or from a local result, 
Rationale for 
change
To allow flexibility in performing the DLCO test as this is not being 
performed as a measure of efficacy.
Section to be 
changed
10.4 Child-Pugh Classification
Description of 
change
The following text has been added:
Clinical and 
Biochemical 
Measurements
Points Scored for Increasing Abnormality
1 point
2 points
3 points
Total bilirubin, μmol/l 
(mg/dl)
<34
(<2)
34-50
(2-3)
>50
(>3)
Serum albumin, g/dl
>3.5
2.8-3.5
<2.8
Prothrombin time, 
prolongation (secs)
<4.0
4.0-6.0
> 6.0
Ascites
Absent
Slight
Moderate
Encephalopathy 
(grade)*
None
1 – 2  
3  –  4
*According to Trey, Burns and Saunders (1966) R99-1244
Total Score:
Child-Pugh A: 5 or 6 points;
Child-Pugh B: 7–9 points;
Child-Pugh C: >9 points
Rationale for 
change
Due to the addition of Child-Pugh Classification within the protocol


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Number of global amendment
3
Date of CTP revision
29 July 2016
EudraCT number
2015-000732-15
BI Trial number
1199.229
BI Investigational Product(s)
Nintedanib
Title of protocol
Investigation of drug-drug interaction between 
nintedanib and pirfenidone in patients with IPF (an 
open label, multiple-dose, two group study followed by 
nintedanib open label treatment)
To be implemented only after 
approval of the IRB / IEC / 
Competent Authority

To be implemented 
immediately in order to 
eliminate hazard – IRB / IEC / 
Competent Authority to be 
notified of change with request 
for approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be 
changed
Cover Page and Header
Description of 
change
Updated from version 3.0 to version 4.0, 27 July 2016
Rationale for 
change
Documentation of new version
Section to be 
changed
3.4 Selection of Trial Population
Description of 
change
The following text was added:
Patients who have screen failed may be permitted to be re-screened 
following agreement by the Sponsor.  Screening procedures may not need to 
be repeated if they are within 28 days of visit 2.  The decision on what 
screening procedures do not need to be repeated will be made by the 
Sponsor.
Rationale for 
change
Re-screening will only be permitted following a discussion between the 
Investigator and Trial Team. 
To avoid additional burden on the patient screening procedures within 28 


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days of visit 2 may not need to be repeated.
Section to be 
changed
3.6 Inclusion Criteria
Description of 
change
3. IPF diagnosis, based upon the ATS/ERS/JRS/ALAT 2011 guideline 
(P11-07084) and chest high-resolution computed tomography (HRCT) 
scan performed within 18 months of visit 1. 
3. IPF diagnosis, based upon the ATS/ERS/JRS/ALAT 2011 guideline 
(P11-07084) and chest high-resolution computed tomography (HRCT) 
scan. 
Rationale for 
change
Patients with IPF may not undergo HRCT assessment regular in routine 
clinical practice.  For the group 2 patients in particular their scans may be 
several years old.  Recruitment into group 2 is therefore proving challenging 
and this change should address this.
In this PK study we only need to be reassured that a patient has IPF to avoid 
them receiving unsuitable treatment with nintedanib/pirfenidone rather than 
needing to have a scan as a measure of efficacy following treatment.
Section to be 
changed
3.7 Exclusion Criteria
Description of 
change
3. Underlying chronic liver disease (Child Pugh A, B, or C hepatic 
impairment1)
Was changed to 
3. Underlying chronic liver disease (Child Pugh A, B, or C hepatic 
impairment1)
Rationale for 
change
To correct a typographical error, the footnote “1” reference should have 
been written in a superscript font in black rather than in a normal sized font 
in red
Section to be 
changed
3.7 Exclusion Criteria
Description of 
change
3. Underlying chronic liver disease (Child Pugh A, B, or C hepatic 
impairment1)
Was changed to 


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3. Underlying chronic liver disease (Child Pugh A, B, or C hepatic 
impairment1, 6)
Later in the same section the following footnote has been added:
6Child Pugh classification does not need to be performed at screening. 
Rationale for 
change
This is to clarify that Child Pugh Classification is a historical measure and 
does not need to be assessed at screening.  Child Pugh Classifications are 
used as a measure of the current status of a patient with liver disease.  If the 
classification is applied to healthy person i.e. without liver disease then 
these people would score A – we do not wish to exclude these people.
Section to be 
changed
3.7 Exclusion Criteria
Description of 
change
21. Current Smoker
Was changed to 
21. Current smoker (vaping and e-cigarettes are acceptable)
Rationale for 
change
Additional clarification
Section to be 
changed
4.2.2.1 Restrictions regarding concomitant treatment
Description of 
change
Concomitant medications (or therapy) to provide adequate care may be 
given as assessed by the Investigator to be clinically necessary. Potent P-gp 
inhibitors (e.g. ketoconazole, erythromycin) or p-gp inducers (e.g.
rifampicin, phenytoin, St. John’s Wort) should not be taken concomitantly 
with nintedanib. Fluvoxamine, as well as other potent or moderate CYP1A2 
inhibitors (e.g. enoxacin) and inducers (e.g. rifampicin), are contraindicated 
when taking pirfenidone. Moderate CYP1A2 inhibitors (e.g. ciprofloxacin, 
amiodarone) should also be avoided during pirfenidone administration. If 
restricted concomitant therapy is necessary, treatment with study medication
should be permanently discontinued
Was Changed to
Concomitant medications (or therapy) to provide adequate care may be 
given as assessed by the Investigator to be clinically necessary.
If restricted concomitant therapy is necessary, treatment with study 
medication should be permanently discontinued, see table 4.2.2.1:1 for 


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details of restricted medications.
Rationale for 
change
The permitted and Restricted Concomitant therapy table (4.2.2.1:1) has been 
updated to include this information so that all restrictions are in one place
Section to be 
changed
Table 4.2.2.1:1 Permitted and Restricted Concomitant therapy
Description 
of change
N-acetylcysteine1 / Fluvoxamine1 / Prednisone / other oral corticosteroid2
Was changed to 
N-acetylcysteine1 / Prednisone / other oral corticosteroid2
The following has been added to the table.
Potent or moderate CYP1A2 
inhibitors (e.g. Fluvoxamine1, 
enoxacin, ciprofloxacin, 
amiodarone) and inducers (e.g. 
rifampicin, omeprazole).
Permitted
Not permitted
(2w prior to 
visit 2)
Not permitted
Not permitted
Oramorph, dextromethorphan
(Opioids for the treatment of 
diarrhoea e.g. loperamide may 
be used as per section 4.2.1.2.  
Other opioids to be discussed 
with Sponsor beforehand).  
Permitted
Permitted
Not 
Permitted on 
PK days6.
Permitted
A new footnote was also added
6.
There should be at least a 2-4 hour gap between the opioid intake and 
nintedanib/pirfenidone intake prior to the first PK sampling.
Rationale 
for change
To move restrictions listed in 4.2.2.1 into the table and to also add additional 
restrictions.
Section to be 
changed
5.3.3 Safety laboratory paramters
Description of 
change
Chemistry: sodium, potassium, creatinine, aspartate aminotransferase 
(AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), 


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total protein, alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH), creatine kinase and thyroid stimulating hormone 
(TSH). Creatinine Clearance (according to Cockcroft-Gault formula)
Was changed to 
Chemistry: sodium, potassium, creatinine, aspartate aminotransferase 
(AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), 
total protein, alkaline phosphatase (ALP), total bilirubin, lactate 
dehydrogenase (LDH), creatine kinase and thyroid stimulating hormone 
(TSH), serum albumin (if required for liver assessment), Creatinine 
Clearance (according to Cockcroft-Gault formula)
Rationale for 
change
Serum albumin may be tested at the discretion of the Investigator if required 
for liver assessment.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03463451
8.0
clinical-trial-protocol-revision
Investigation of drug-drug interaction between nintedanib and pirfenidone in patients
with IPF (an open-label, multiple-dose,  two group study)
Author-Statistician
29 Jul 2016 15:38 CEST
Author-Trial Clinical
Pharmacokineticist
29 Jul 2016 15:39 CEST
Approval-Trial Clinical Monitor
29 Jul 2016 15:39 CEST
Approval-Therapeutic Area 
15 Aug 2016 17:02 CEST
Approval-Team Member Medicine
15 Aug 2016 17:25 CEST
Verification-Paper Signature
Completion
15 Aug 2016 17:28 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03463451
8.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c03766311-01
BI Trial No.:
1199.229
Title:
Investigation of drug-drug interaction between nintedanib and 
pirfenidone in patients with IPF (an open label, multiple-dose, two 
group study)
Including Amendments 1, 2 & 3 [c03463451-08]
Investigational
Product:
Ofev®, nintedanib
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
09 MAR 2017 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINTS....................................................................................9
5.2
SECONDARY ENDPOINTS..............................................................................9
5.2.1
Key secondary endpoints................................................................................9
5.2.2
Secondary endpoints .......................................................................................9
5.3
FURTHER ENDPOINTS....................................................................................9
5.4
OTHER VARIABLES.........................................................................................9
5.4.1
Demographics and other baseline characteristics........................................9
5.4.1.1
Demographic data.......................................................................................10
5.4.1.2
Trial indication ...........................................................................................10
5.4.1.3
Smoking status............................................................................................10
5.4.1.4
Other baseline characteristics .....................................................................10
5.4.2
Treatment exposure ......................................................................................10
5.4.3
Treatment compliance ..................................................................................11
5.4.4
Liver enzyme and bilirubin elevations ........................................................12
6.
GENERAL ANALYSIS DEFINITIONS...........................................13
6.1
TREATMENTS..................................................................................................13
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................13
6.3
PATIENT SETS ANALYSED..........................................................................14
6.4
SUBGROUPS .....................................................................................................15
6.5
POOLING OF CENTRES ................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................16
7.
PLANNED ANALYSIS.......................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........19
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................19
7.2.1
Baseline conditions ........................................................................................19
7.2.2
Concomitant therapies..................................................................................19
7.3
TREATMENT COMPLIANCE .......................................................................20
7.4
PRIMARY ENDPOINTS..................................................................................20
7.5
SECONDARY AND FURTHER ENDPOINTS..............................................21
7.5.1
Key secondary endpoints..............................................................................21
7.5.2
Secondary endpoints .....................................................................................21
7.6
FURTHER ENDPOINTS..................................................................................21
7.7
EXTENT OF EXPOSURE................................................................................22
7.8
SAFETY ANALYSIS.........................................................................................22
7.8.1
Adverse events ...............................................................................................22


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7.8.2
Laboratory data.............................................................................................23
7.8.3
Vital signs.......................................................................................................24
7.8.4
ECG ................................................................................................................24
7.8.5
Others .............................................................................................................24
8.
REFERENCES.....................................................................................25
................................................................26
9.1
STATISTICAL ANALYSES SOFTWARE (SAS) CODE FOR PK 
ANALYSES ........................................................................................................26
...............................................................27
10.
HISTORY TABLE...............................................................................28


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LIST OF TABLES
Table 6.2: 1
Important protocol violations...........................................................................14
Table 6.3: 1
Patient sets analysed.........................................................................................15
Table 6.7: 1
Time windowing rules for physical examination, vital signs - Group 1..........16
Table 6.7: 2
Time windowing rules for physical examination, vital signs - Group 2..........17
Table 6.7: 3
Time windowing rules for laboratory measurements – Group 1 .....................17
Table 6.7: 4
Time windowing rules for laboratory measurements – Group 2 .....................18
Table 7.4: 1: Primary and secondary endpoints for inferential PK analysis .........................20
Table 10: 1
History table .....................................................................................................28


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
ALT
Alanine transaminase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to the last measured time point
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma over a 
dosing interval
BI
Boehringer Ingelheim
bid
Bis in die (twice daily dosing)
RPM
Report planning meeting
BSA
Body surface area
Cmax
Maximum measured concentration of the analyte in plasma
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady 
state
CRF
Case Report Form
CT
Concomitant therapy
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Coefficient of variation
DBL(M)
Data Base Lock (Meeting)
DLCO
Diffusing capacity of the Lung for Carbon monoxide
ECG
Electrocardiogram
EMA
European Medicines Agency
EoT
End-of-Text
FU
Follow-up
gCV
Geometric coefficient of variation
gMean
Geometric mean


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Term
Definition / description
ICH
International Conference on Harmonisation
IPF
Idiopathic Pulmonary Fibrosis
(I)PV
(Important) Protocol violation
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
Min
Minimum
MQRM
Medical Quality Review Meeting
NA
Not applicable
PK
Pharmacokinetics
PKS
Pharmacokinetic analysis set
PN
Preferred Name
PT
Preferred term
qd
Quaque die (everydDay)
RNA
Ribonucleic acid
SAS
Statistical analyses software
SD
Standard deviation
SOC
System organ class
SSC
Special Search Categories
tid
Ter in die (3 times a day)
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size.
SAS® Version 9.4 or later version will be used for all analyses.
Pharmacokinetic (PK) parameters will be calculated using WinNonlinTM software 
(professional Network version 6.3, Pharsight Corporation, Mountain View, CA 94041-1530, 
USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses described in this TSAP are in accordance with the statistical methods described 
in the CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary endpoints will be used as defined in Section 5.1.1 of the CTP as 
pharmacokinetic endpoints:

Group 1
o
AUC0-tz area under the concentration-time curve of nintedanib in plasma over 
the time interval from 0 to the last measured time point (quantifiable 
concentration)
o
Cmax maximum measured concentration of nintedanib in plasma after single 
dose administration

Group 2
o
AUCτ,ss area under the concentration-time curve of pirfenidone in plasma 
over a dosing interval
o
Cmax,ss maximum measured concentration of pirfenidone in plasma at steady
state
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
5.2.2
Secondary endpoints
Secondary endpoints will be used as defined in Section 5.1.2 of the CTP as pharmacokinetic 
endpoints:

Group 1
o
AUC0-∞area under the concentration-time curve of nintedanib in plasma over 
the time interval from 0 extrapolated to infinity
5.3
FURTHER ENDPOINTS
5.4
OTHER VARIABLES
5.4.1
Demographics and other baseline characteristics
Demographics and other baseline characteristics will include the following. Baseline is 
defined in Section 6.7.


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5.4.1.1
Demographic data

Gender

Ethnicity

Race 

Age [years] will be calculated as : integer part of [(date of informed consent - date of 
birth) / 365.25]

Age by category [years] (<65; ≥65-<75; ≥75 and <65; ≥65-<75; ≥75-<85; ≥85)

Weight [kg] as continuous variable and by category (<30; ≥30 - <60; ≥60 - <90; ≥90)

Height [cm]

Body mass index [kg/m2]: Weight[kg] / Height [m]*Height[m], as continuous variable 
and by category (< 18.5; ≥18.5-<25; ≥25-<30, ≥30)

Body surface area [m2] (according to Dubois Formula : BSA = 0.007184 * 
Height[cm]0.725 * Weight[kg]0.425), as continuous variable and by category (<1.73; 
≥1.73)
5.4.1.2
Trial indication

Time elapsed since the first diagnosis of IPF [years] will be calculated as : (date of entry
– date of  first diagnosis)/365.25

Time elapsed since the first diagnosis of IPF coded by category (≤1 year; > 1 year to ≤ 
3 years; > 3 years to ≤ 5 years; > 5 years)
5.4.1.3
Smoking status

Smoking history (never smoked, ex-smoker, currently smokes) 
5.4.1.4
Other baseline characteristics

Diffusing capacity of the Lung for Carbon monoxide (DLCO) [% predicted] corrected 
for haemoglobin by the site
5.4.2
Treatment exposure
Treatment exposure will be calculated separately for nintedanib and for pirfenidone.
Time on drug [days] = date of last administration – date of first administration +1 day 


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Time on actual drug (150 mg bid for nintedanib; 267 or 534 or 801 mg tid for pirfenidone)
[days]: sum of time on-treatment for each dose effectively taken
For group 1, time on drug for pirfenidone whatever the dose is will be displayed.
For group 2, time on drug for nintedanib 150 mg bid will be displayed as well as time on drug 
for pirfenidone whatever the dose is. 
Total dose [mg]: Time on actual drug [days] * actual dose [mg]
For pirfenidone, dose reductions are defined as decreases to either 2*267mg tid or 1*267mg
tid. 
5.4.3
Treatment compliance
Compliance for nintedanib (group 2 only) and compliance for pirfenidone will be calculated 
separately over the study as:
Number of capsules actually taken
over the period
Compliance [%]
=
x 100
Number of capsules which should
have been taken over the period
The number of capsules which should have been taken over the period will be calculated as:
Number of capsules which should have been taken over the period [capsules] = (date of last 
administration – date of first administration + 1) [days] × (number of capsules which should 
be taken per day) [1]
[1] The time of first/ last administration are taken into account, so fewer capsules may be expected to be taken on 
some days.
For nintedanib, the number of capsules which should be taken per day at dose 150 mg qd is 1.
The number of capsules which should be taken per day at dose 150 mg bid is 2.
For pirfenidone, the number of capsules which should be taken per day is 3 at dose 267 mg 
tid, 6 at dose 534 mg tid, and 9 at dose 801 mg tid.
Only treatment interruptions not due to AE will be considered a compliance issue and will be 
taken into account in the calculation (duration of interruptions due to AE will be subtracted 
from the duration of the study period).
Compliance will be categorised as follow: <50%, >=50% to <80%, >=80% to <= 120%, > 
120%.


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5.4.4
Liver enzyme and bilirubin elevations
Liver enzyme and bilirubin elevations will be reported using the two following definitions:

(ALT ≥3xULN and/or AST ≥3xULN) AND bilirubin ≥2xULN (1)

ALT ≥ 5xULN and/or AST ≥5xULN
These elevations are defined within a time window of 30 days i.e. the elevation of bilirubin 
should appear within 30 days of the elevation of AST and/or ALT. Potential Hy's law cases, 
using the definition (1) above, will be presented using graphs.
Depending on the number of patients experiencing liver enzyme elevations, other cut-offs 
may be considered.
Maximum individual elevations based on worst value on treatment will be defined as:

≥3*ULN; ≥5*ULN; ≥8*ULN for AST and ALT

≥1.5*ULN; ≥2*ULN for Bilirubin

≥1.5*ULN; ≥2*ULN for alkaline phosphatase

≥1*ULN; ≥3*ULN for Gamma-Glutamyl-Transferase


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For treatment specifications, see Section 4 of CTP.
The following trial periods will be defined: screening, post-entry, treatment period, off-
treatment, Residual Effect Period, follow-up and post-study as follows:
Note: the last day of each of the following periods is excluded.

Screening: from informed consent to date of entry

Post-entry (if applicable): from entry to first trial drug intake.

Treatment period: from first trial drug intake (or re-start of treatment if interruption) 
to last trial drug intake (or the day before start date of interruption, if interruption)  
plus one day

Off-treatment (if applicable): from start date of interruption to re-start of treatment

Residual Effect Period: from the last trial drug intake plus one day to last trial drug 
intake plus 28 days plus one day.

Follow-up (if applicable): from last trial drug intake plus 29 days up to the beginning 
of post-study period. This period is only created if last trial drug intake took place 
more than 28 days before trial completion (i.e. date of the follow-up visit or date 
where the patient discontinued prematurely the trial).

Post-study: from the latest of last trial drug intake plus 29 days or date of trial 
completion plus 1 day to database lock
For safety analyses, data up to 28 days after last trial drug intake (inclusive) will be 
considered on-treatment.
6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important PVs. The final column 
describes which PVs will be used to exclude patients from the PKS. If the data show other 
important PVs, this table will be supplemented accordingly by the time of the 
MQRM/RPM/DBLM.


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Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria not met
Inclusion criteria 2 to 
6
Automatic IPV
None
A2
Exclusion criteria met
Exclusion criteria 1 
to 21
Automatic IPV and 
Medical review of 
MQRM listings
None
B
Informed consent
B1
Informed consent not given or given too late
Inclusion criteria 1
Automatic IPV
None
B2
Informed consent not given for pharmacogenetics 
samples (unspecified part) but pharmacogenetics test 
done
According to 
pharmacogenetics 
database and CRF
Automatic IPV
None
B3
Informed consent not given for 
 
 but 
 test done
According to 
 
and CRF
Automatic IPV
None
C
Trial medication and randomisation
C1
Incorrect trial medication taken
Manual IPV (see 
monitoring manual)
and Medical review 
of MQRM listings
None
C2
Drug not permanently discontinued despite criteria of 
Section 3.8.1 of CTP met
Medical review of 
MQRM listings
None
D
Concomitant medication
D1
Patient received restricted concomitant therapies 
during treatment phase
Medical review of 
MQRM listings.
PKS
E
Missing data
E4
Certain violations of procedures used to measure 
primary data
Medical review of 
MQRM listings, to be 
decided no later than 
RPM.
PKS
F
Incorrect timing
F5
Certain violations of time schedule used to measure 
primary data1.
Medical review of 
MQRM listings, to be 
decided no later than 
RPM.
PKS
1 Time deviations will only be flagged as important PV, when leading to exclusion of the entire subject from an analysis set
Source: BI reference document "Protocol Violation Handling Definitions" (001-MCS-50-413_RD-01) (1)
6.3
PATIENT SETS ANALYSED

Screened set
This patient set includes all patients having signed informed consent and performed 
visit 1.


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
Treated set (TS)
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment.

Pharmacokinetic analysis set (PKS)
The PKS will be used as defined in section 7.3 of the CTP.
The following table shows which patient set will be used for which study period and which 
class of endpoints.
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
Screened set
TS
PKS
Primary endpoint 
X
Secondary endpoints 
X
Further endpoints 
X
Safety analyses
X
Demographic/baseline characteristics / extent of exposure
X
X
Note that the number of patients with available data for an endpoint may differ. 
6.4
SUBGROUPS
This section is not applicable.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
The endpoints will be used as defined in Section 7.5 of the CTP.
Data of treated subjects who failed to complete all stages of the study (subjects who withdraw 
consent or are removed from the trial) will be reported as far as data are available. It is not 
planned to impute missing values.


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For previous/concomitant therapies, in case of (partially) missing start and end dates of 
concomitant therapies, the dates will be imputed so that the extent of exposure to the 
concomitant therapy is maximal, i.e. the first day (month) of the month (year) for incomplete 
start dates and the last day (month) of the month (year) for incomplete end dates.
Missing or incomplete AE dates will be imputed according to BI standards (see "Handling of 
missing and incomplete AE dates") (3).
Handling of missing PK data will be performed according to the BI standard procedure
"Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies"
(001-MCS-36-472_RD-01) (2).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, last assessment before first trial drug intake (included) will be used as 
baseline. If the baseline value is missing and the screening value is available, then the 
baseline value will be defined as the screening value taken closest to baseline date.
A windowing will be performed as described in Tables 6.7: 1, 6.7: 2, 6.7: 3 and 6.7: 4, in
order to assign data to the relevant study visit based on the actual day of the assessment. Data 
will be analysed using the re-calculated visits in the statistical tables. However, in the listings, 
all visits performed will be displayed (even if outside time-window), along with the re-
calculated visit.
Table 6.7: 1
Time windowing rules for physical examination, vital signs - Group 1
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window
[days]
Visit 
number
Visit name
Planned day 
of the visit
1
1
1
1, or 2[2]
Baseline
1
2
29
28
3
3 weeks
23
30
Last treatment 
intake + 27 [3]
variable
NA
Between 3
weeks - FU
NA
Last 
treatment 
intake + 28
Last treatment 
intake + 31 
4
4
Follow-up
52
[1] First trial drug intake date is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition
[3] This period only exists if last treatment intake occurs after 2 days (later than 28 days before 30 days)


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Table 6.7: 2
Time windowing rules for physical examination, vital signs - Group 2
Time window of actual day [1]
Allocated to
Start day
End day 
(included)
Length of the 
time-window
[days]
Visit 
number
Visit name
Planned day 
of the visit
1
1
1
1, or 2[2]
Baseline
1
2
12
11
3a
1 week
8
13
19
7
3b
2 weeks
16
20
Last treatment 
intake + 27 [3]
variable
NA
Between 2 
weeks - FU
NA
Last 
treatment 
intake + 28
Last treatment 
intake + 31 
4
4
Follow-up
44
[1] First trial drug intake date is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition
[3] This period only exists if last treatment intake occurs after 6 days (later than 28 days before 20 days)
Table 6.7: 3
Time windowing rules for laboratory measurements – Group 1
Time window of actual day [1]
Allocated to
Start
day
End day 
(included)
Length of the 
time-window
[days]
Visit number
Visit name
Planned day of 
the visit
1
1
1
1
Baseline
1
2
38
37
3
3 weeks
23
39
No upper limit
NA
4
Follow-up
52
[1] First trial drug intake date is taken into account as a reference to calculate time windows


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Table 6.7: 4
Time windowing rules for laboratory measurements – Group 2
Time window of actual day [1]
Allocated to
Start
day
End day 
(included)
Length of the 
time-window
[days]
Visit number
Visit name
Planned day of 
the visit
1
1
1
1
Baseline
1
2
12
11
3a
1 week
8
13
30
18
3b
2 weeks
16
31
No upper limit
NA
4
Follow-up
44
[1] First trial drug intake date is taken into account as a reference to calculate time windows
If after windowing of visits at baseline, two values fall within the same baseline interval, then 
the last value will be taken into account. If after windowing of post-baseline visits, two visits 
fall in the same interval, then the measurement closest to the planned visit will be taken into 
account. In case two measurements are equidistant from the planned visit, then the last one 
will be picked. The same rules will be applied for laboratory measurements.
For physical examination and vital signs only, if after windowing of post-baseline visits, two 
values fall within the same interval “Follow-up” then only the first value will be taken into 
account.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective group (unless otherwise specified, all patients in the respective patient set whether 
they have non-missing values or not). Percentages will be rounded to the nearest integer. The 
category missing will be displayed only if there are actually missing values.
For PK analysis, continuous data will be summarised by the following statistics: N/ gMean / 
gCV / Mean / CV / SD / Min / 10th percentile / 25th percentile / Median / 75th percentile / 90th 
percentile / Max.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.2.1
Baseline conditions
A summary of baseline conditions will be provided by group, System Organ Class (SOC) and 
Preferred Term (PT). SOC will be sorted according to the standard sort order specified by 
EMA and PT by descending frequency over both groups. 
7.2.2
Concomitant therapies
Concomitant therapies will be described over several study periods:
Previous therapies will be defined as treatments with an end date before first trial drug intake. 
Baseline therapies will be defined as treatments with a start date before first trial drug intake 
and a stop date after or on the day of the first trial drug intake.
On-treatment concomitant therapies are defined as treatments with a start date after or on the 
day of first trial drug intake and before or on the day of last drug intake.
The following concomitant therapies categories have been created:
-
Previous concomitant therapies
-
Baseline concomitant therapies
-
All on-treatment concomitant therapies (including baseline CTs)


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Summaries of the CT categories will be provided by treatment group, ATC3 codes and 
Preferred Name (PN) (sorted by alphabetical ATC class and decreasing frequency of 
preferred names in group 1 within ATC class).
Relevant groups of therapies have been defined as Special Search Categories (SSC). These 
are listed in Section 9.2.
Summaries of baseline CTs and all on-treatment CTs (including baseline CTs) will also be 
performed by SSC and PN (sorted by alphabetical SSC and decreasing frequency of preferred 
names within SSC).
Finally, a specific table for all on-treatment concomitant therapies (including baseline CTs)
that were restricted during the study will be provided (by PN).
Treatments that were restricted during the treatment period and that will be presented in this 
specific table are described in section 4.2.2.1 of the CTP.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINTS
The analysis will be performed as defined in Section 7.3.1 of the CTP.
Table 7.4: 1: 
Primary and secondary endpoints for inferential PK analysis 
Treatment 
group
Analyte
Parameter
Test 
treatment (T)
Reference
treatment (R)
Group 1
Nintedanib
AUC0-tz, Cmax, 
AUC0-∞
Nintedanib + 
Pirfenidone
Nintedanib
alone
Group 2
Pirfenidone
AUCτ,ss, Cmax,ss
Pirfenidone + 
Nintedanib
Pirfenidone
alone
The inferential statistical analysis of the endpoints above will be performed by use of the 
macro XPKISTAT and the option BWU (Bioavailability/Bioequivalence, within-subject 
design, uncontrolled for time). The SAS code is done in Section 9.1.
Descriptive statistics of plasma concentrations and PK endpoints will be done by the 
department of Translational Medicine and Clin. Pharmacology at BI and will be presented in 
Section 15.6 of the CTR.
The analysis of PK parameters, as well as the tables and graphs for the pharmacokinetic non-
compartmental analyses will follow specific definitions of this TSAP or, otherwise, the BI 
standard procedure "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics" (001-MCS-36-472) (7).


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Exclusion of PK parameters
The analysis data set (ADS) PK6+ contains column variables KPEXC and KPEXCX 
indicating inclusion/exclusion (KPEXC) of a PK parameter and an analysis flag comment 
(KPEXCX). All analyses based on the PKS will include parameters if they are not flagged for 
exclusion, that is KPEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS PK4+ (PK concentrations per time-point) contains column variables PKEXC or 
PKEXCX indicating inclusion/exclusion (PKEXC) of a concentration and an analysis flag 
comment (PKEXCX). Exclusion of a concentration depends on the analysis flag comment 
PKEXCX. For example, if PKEXCX is set to ‘ALL CALC’, the value will be excluded for 
all types of analyses based on concentrations. If PKEXCX is set to ‘DESC STATS’, the value 
will be excluded from descriptive evaluations per planned time point/ time interval. If 
PKEXCX contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’, the value 
can be used for further analyses based on actual times. If PKEXCX is set to ‘HALF LIFE’,
the value will be excluded from half-life calculation only; the value is included for all other 
analyses.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (001-MCS-36-472_RD-01) (2) and "Description of Analytical 
Transfer Files and PK/PD Data Files" (001-MCS-36-472_RD-03) (8).
7.5
SECONDARY AND FURTHER ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The analysis will be performed as defined in Section 7.3.2 of the CTP and as described above 
for primary endpoints.
Descriptive statistics of plasma concentrations and PK endpoints will be done by the
department of Translational Medicine and Clin. Pharmacology at BI and will be presented in 
Section 15.6 of the CTR.
7.6
FURTHER ENDPOINTS


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7.7
EXTENT OF EXPOSURE
A table displaying the disposition of patients and the conclusion of patients’ participation,
and a table displaying the primary reason for non-inclusion/entry will be provided. 
Summary tables showing the duration on treatment, the total dose of nintedanib and 
pirfenidone and the duration on actual treatment dose (see Section 5.4.2) will be performed
for nintedanib and for pirfenidone on the TS.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
For further details on summarization of AE data, please refer to the guidelines "Handling of 
missing and incomplete AE dates" (3) and "Analysis and presentation of adverse event data 
from clinical trials" (4).
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till 28 days 
after last drug intake (inclusive) will be assigned to the treatment. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after last drug intake + 28 days will be assigned to ‘post-treatment’, ‘follow-up’ or 
‘post-study’ (for listings only). Also, all AEs occurring between the start of an interruption 
and the end of interruption will be assigned to ‘off-treatment’ period in the listings. For 
details on the treatment definition, see Section 6.1.
According to ICH E3 (5), AEs classified as ‘other significant’ will include those non-serious 
and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or


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(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Report Planning Meeting. 
An overall summary of adverse events will be presented. 
The frequency of patients with adverse events will be summarised by treatment group, 
primary system organ class and preferred term (mention MedDRA levels to be displayed in 
the tables). Separate tables will be provided for 

patients with serious adverse events

patients with other significant adverse events according to ICH E3 (5) 

patients with investigator defined drug related adverse events

patients with adverse events of special interest

patients with adverse events leading to permanent dose reduction of pirfenidone

patients with adverse events leading to premature discontinuation from nintedanib or 
pirfenidone

for patients with adverse events leading to death
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency in group 2 (within system organ class).
Specific tables will be created in order to describe the adverse events of particular note
diarrhea, nausea and vomiting:
-
Summary of adverse events including number and duration of episodes
-
Summary of adverse events including seriousness, clinical consequences (dose 
reduction, drug discontinuation or drug interruption) , intensity, drug relationship and 
outcome
Specific tables will be created to summarise the diarrhea and bleeding specific items of the
CRF.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6).
Please refer to Section 7.3.4 of the CTP.
Specific tables will be presented to describe liver enzyme elevations as defined in Section 
5.4.4:

Summary table of liver enzyme elevation including number of patients with liver enzyme 
elevation

Summary table of individual maximum liver enzyme and bilirubin elevations


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7.8.3
Vital signs
Only descriptive statistics (by visit and change from baseline) are planned for this section of 
the report.
7.8.4
ECG
Not applicable, relevant ECG findings are recorded as baseline condition or AEs.
7.8.5
Others
Not applicable, relevant physical examinations and spirometry findings are recorded as 
baseline condition or AEs.


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8.
REFERENCES
R08-2251
European Medicines Agency (EMEA). ICH topic E 9: statistical principles
for clinical trials: step 5: note for guidance on statistical principles for
clinical trials (CPMP/ICH/363/96). London: EMEA 1998
1
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", 
current version, IDEA for CON.
2
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version, IDEA for 
CON.
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version, IDEA for CON.
4
001-MCG-156_RD-02: "Analysis and presentation of adverse event data 
from clinical trials", current version, IDEA for CON.
5
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", 
ICH Guideline Topic E3; Note For Guidance on Structure and Content of 
Clinical Study Reports, current version.
6
001-MCG-157: "Display and Analysis of Laboratory Data", current 
version, IDEA for CON.
7
001-MCS-36-472: "Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics", current version, IDEA for 
CON.
8
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and 
PK/PD Data Files", current version, IDEA for CON.


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9.1
STATISTICAL ANALYSES SOFTWARE (SAS) CODE FOR PK 
ANALYSES
Model for inferential analysis on PK endpoints
For the primary and secondary PK endpoints, inferential analyses will use. The XPKISTAT 
macro will be used for the analyses. The following parameters will have to be used:
%xpkistat  (design = bwu,
disptab = #DISP = BAGM,
rage = YES,
dispnum = , 
/* output number or prefix */
runtype = report,
listlog = YES,
smatrix = 'plasma EDTA',
sanalyte = 'BIBF 1120 BS', /*PIRFENIDONE*/
skpnm = 'AUClast'
         /* 'Cmax' 'AUCINF_pred' 'AUC_TAU_ss' or 'Cmax_ss' */
spairtrt = ,
        /* nintedanib + pirfenidone / nintedanib alone =>for group 1
       pirfenidone + nintedanib / pirfenidone alone =>for group 2*/
anaset = 'PKS',
limitp = no
);
The SAS model behind is the following:
PROC MIXED;
CLASS ptno pktrt;
MODEL <PKendpoint> = pktrt / HTYPE=2 SOLUTION;
RANDOM ptno;
RUN;
Where
-
ptno = unique number of the subject
-
pktrt = treatment ie nintedanib alone or nintedanib + pirfenidone for patients in 
group 1 and pirfenidone alone or pirfenidone + nintedanib for patients in group 2
-
<PKendpoint> = AUC0-tz, Cmax and AUC0-∞for group 1 and AUCτ,ss and Cmax,ss for 
group 2
For sensitivity analysis, the SAS model is the following:
PROC MIXED;
CLASS ptno pktrt;
MODEL <PKendpoint> = pktrt ptno / HTYPE=2 SOLUTION;
RUN;


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
09-Mar-17
None
This is the final TSAP without any 
modification