Clinical trial NCT02802345
Conditions: Idiopathic Pulmonary Fibrosis
Sponsor: Boehringer Ingelheim
Start date: 2016-06-30; Completion date: 2018-04-13
Enrollment: 274 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To assess efficacy and safety of concomitant treatment with nintedanib and sildenafil in Idiopathic Pulmonary Fibrosis (IPF) patients with advanced lung function impairment.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Nintedanib intervention 2: Placebo intervention 3: Sildenafil
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03484701-03
EudraCT No.:
2015-002619-14
BI Trial No.:
1199.36
BI Investigational 
Product:
Nintedanib (Ofev®)
Title:
INSTAGETM: A 24-week, double-blind, randomized, parallel-
group study evaluating the efficacy and safety of oral 
nintedanib co-administered with oral sildenafil, compared to 
treatment with nintedanib alone, in patients with idiopathic 
pulmonary fibrosis (IPF) and advanced lung function 
impairment
Brief Title:
Efficacy and safety of nintedanib co-administered with 
sildenafil in IPF patients with advanced lung function 
impairment
Clinical Phase:
III b
Trial Clinical 
Monitor:
Phone :
Fax : 
Coordinating 
Investigator:
Phone
ext 
 (Division),
(Clinic) 
Fax
Status:
Revised Protocol based on Global Amendment 2
Version and Date:
Version:
Date:
3.0
18 AUG 2016
Page 1 of 100
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:
30 Dec 2015
Trial number:
1199.36
Revision date:
18 Aug 2016
Title of trial:
INSTAGETM: A 24-week, double-blind, randomized, parallel-group 
study evaluating the efficacy and safety of oral nintedanib co-
administered with oral sildenafil, compared to treatment with 
nintedanib alone, in patients with idiopathic pulmonary fibrosis (IPF) 
and advanced lung function impairment
Coordinating
Investigator:
Phone
ext 
(Division), 
(Clinic) 
Fax 
Trial sites:
Multi-centre trial
Clinical phase:
III b
Objective(s):
To assess efficacy and safety of concomitant treatment with 
nintedanib and sildenafil in IPF patients with advanced lung 
function impairment. 
Methodology:
Double-blind, randomized, parallel design comparison of 
nintedanib 150 mg bid and sildenafil 20 mg tid to nintedanib 150 
mg bid and placebo matching sildenafil tid over 24 weeks
No. of patients: 
total entered:
250 patients
each treatment:
Randomization 1:1
125 patients assigned to each treatment arm.
Diagnosis :
Idiopathic Pulmonary Fibrosis (IPF)
Main criteria
for inclusion:
Written informed consent;


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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Ofev®
Name of active ingredient:
Nintedanib
Protocol date:
30 Dec 2015
Trial number:
1199.36
Revision date:
18 Aug 2016
Male or female patients aged ≥ 40 years at visit 1;
IPF diagnosis based upon the ATS/ERS/JRS/ALAT 2011 guideline 
for < 6 years; confirmation of diagnosis by investigator based on  
chest HRCT performed within 18 months of visit 1 and surgical 
lung biopsy (if available);
DLCO (corrected for Hb) ≤ 35% predicted of normal at visit 1
Test product(s):
Nintedanib and sildenafil
dose:
Nintedanib: 300 mg daily (150 mg bid) with possibility to reduce 
to 200 mg daily (100 mg bid) to manage adverse events
Sildenafil: 60 mg daily (20 mg tid)
mode of 
administration:
p.o.
Comparator products:
Nintedanib and placebo matching sildenafil
dose:
Nintedanib: 300 mg daily (150 mg bid) with possibility to reduce 
to 200 mg daily (100 mg bid) to manage adverse events
Placebo matching sildenafil: Not applicable
mode of 
administration:
p.o.
Duration of treatment:
24 weeks of randomized treatment
Endpoints
Primary Endpoint: Change from baseline in SGRQ total score at 
week 12
Secondary Endpoints:

Change from baseline in dyspnea using UCSD SOBQ at
week 12;

Change from baseline in SGRQ total score at week 24;

Change from baseline in dyspnea using UCSD SOBQ at
week 24;


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Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Ofev®
Name of active ingredient:
Nintedanib
Protocol date:
30 Dec 2015
Trial number:
1199.36
Revision date:
18 Aug 2016

Percentage of patients with on-treatment SAEs from baseline 
to week 24.
Safety criteria:
Adverse events (especially SAE and other significant AE), physical 
examination including weight, 12 lead electrocardiogram and vital 
signs, laboratory evaluations.
Statistical methods:
Mixed Effects Model for Repeated Measures (MMRM) for 
continuous endpoints and Kaplan-Meier and Cox model for time to 
event endpoints, Cochran-Mantel-Haenszel test for binary endpoints


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FLOW CHART
Trial Periods
Screening 
Period
Randomized Treatment Period
Follow
-up 
period
Visit
11
214
3
4
5
6
715
Dose 
Adjustment 
visit16
Early
EOT17
FUP18
Weeks
0
4
8
12
18
24
+4
Days
-28 to -1
1
29
57
85
127
169
+28
Time window for visits
none
±3
days
±3
days
±3
days
±7
days
±7
days
+7
days
Informed consent2
X
Demographics
X
Medical history
X
SGRQ, UCSD-SOBQ, EQ-
5D3
X
X
X
X
X
Physical examination4
X
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Laboratory tests
X
X
X
X
X
X
X
X
X
 
 
 
 
 
Pregnancy test (urine)7
X
X
X
X
X
X
X
X
X
12 lead-ECG
X
X
X
X
X
Spirometry
X
X
X
X
X
X
X
X
DLCO, VA8
X
X
X
X
Resting SpO2
X
X
X
X
X
Resting PaO2 and PaCO2
9
X
X
X
X
Echocardiogram
X
Review of in-/exclusion 
criteria
X
X
Randomization
X
Access IRT
X
X
X
X
X
X
X
X
Dispense trial drugs
X
X
X
X
X
Collect trial drugs & 
compliance check
X
X
X
X10
X
X
X
Dispense or review patient 
diary11
X
X
X
X
X
X
X
X
Adverse events
X12
X
X
X
X
X
X
X
X
X
Acute exacerbations
X
X
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
Completion of patient 
participation
X
Vital status collection13
X


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1.
The period between visit 1 and 2 should last a maximum of 28 days. Eligible patients can be randomized 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.
SGRQ, UCSD-SOBQ and EQ-5D are to be completed in this order and prior to any other trial related procedures. 
4.
Physical examination to include weight measurement at all visits. At visit 1, height measurement should be included. 
 
 
 
 
 
 
7.
Urine dipstick pregnancy tests will be provided by central lab and should be performed in all women of childbearing 
potential. If urine test is not acceptable to local authorities, a blood test can be done at a local laboratory.
8.
The DLCO/VA assessment should always be performed after the FVC assessment.
9.
Arterialised blood gases (PaO2 and PaCO2) will be measured at selected sites experienced in earlobe blood gas 
sampling.
10. At visit 6 drug supplies should be collected for accountability and compliance check and re-dispensed to the patient.
11. Patient diary will be issued at visit 2 until visit 7. Diary to be reviewed with patient at every visit. Content to be 
discussed as it pertains to AEs, concomitant therapy, medication compliance and drug administration preceding PK
sampling. 
12. Adverse events should only be collected at this visit if occurring after obtaining the informed consent. Medical 
conditions present at time of the informed consent should be recorded in the medical history.
13. Patients who complete an early End of Treatment visit and don’t accept to attend all remaining planned visits will be 
contacted for vital status collection at week 24. This can be done by phone.
14. Visit 2 is defined as baseline assessment if the respective parameter is planned to be collected at that visit. Otherwise, 
visit 1 will serve as baseline assessment.
15. Visit 7 is the End of Treatment (EOT) visit for patients who complete the treatment period as planned.
16. In case of dose change of nintedanib (reduction or re-escalation), dose adjustment visit must be conducted to allow 
dispensing of new medication kit.  
17. Early end of treatment visit to be completed for all patients who withdraw or discontinue all study drugs prematurely.
These patients will be invited to attend all remaining visits as planned until week 24 (Visit 7). The following procedures 
are no longer required in the visits to be conducted after the early EOT visit: laboratory tests, biomarker sampling, 
pharmacokinetic sampling and ECG.
18. A follow up visit needs to be completed 28 days (+7 days) after the last drug administration for all patients. Patients 
who prematurely discontinue all study drugs but accept to conduct all remaining study visits as planned and the 
remaining duration in the trial is longer than 28 days after the last drug administration are exempted from this visit.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................13
MEDICAL BACKGROUND.............................................................................13
1.1
DRUG PROFILE................................................................................................14
1.2
1.2.1
Nintedanib............................................................................................................14
1.2.2
Sildenafil ..............................................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....18
RATIONALE FOR PERFORMING THE TRIAL.........................................18
2.1
TRIAL OBJECTIVES........................................................................................19
2.2
BENEFIT - RISK ASSESSMENT.....................................................................19
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................21
OVERALL TRIAL DESIGN AND PLAN .......................................................21
3.1
3.1.1
Administrative structure of the trial .................................................................21
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................23
SELECTION OF TRIAL POPULATION .......................................................23
3.3
3.3.1
Main diagnosis for trial entry ............................................................................23
3.3.2
Inclusion criteria .................................................................................................24
3.3.3
Exclusion criteria ................................................................................................24
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................28
3.3.4.2
4.
TREATMENTS...................................................................................................29
TREATMENTS TO BE ADMINISTERED.....................................................29
4.1
4.1.1
Identity of BI investigational product and comparator product....................29
4.1.2
Method of assigning patients to treatment groups...........................................29
4.1.3
Selection of doses in the trial..............................................................................30
4.1.4
Drug assignment and administration of doses for each patient......................30
Nintedanib.............................................................................................................30
4.1.4.1
Sildenafil and matching placebo...........................................................................31
4.1.4.2
4.1.5
Blinding and procedures for unblinding...........................................................31
Blinding.................................................................................................................31
4.1.5.1
Unblinding and breaking the code ........................................................................32
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................32


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4.1.7
Storage conditions...............................................................................................33
4.1.8
Drug accountability.............................................................................................33
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................33
4.2.1
Rescue medication, emergency procedures, and additional treatment..........33
Recommendations for managing AEs (exceptions include diarrhoea and liver 
4.2.1.1
enzyme elevations)................................................................................................34
Recommendations for managing diarrhoea ..........................................................34
4.2.1.2
Recommendations for managing liver enzyme elevations ...................................36
4.2.1.3
4.2.2
Restrictions ..........................................................................................................37
Restrictions regarding concomitant treatment ......................................................37
4.2.2.1
Restrictions on diet and life style..........................................................................39
4.2.2.2
Restrictions regarding women of childbearing potential......................................39
4.2.2.3
TREATMENT COMPLIANCE........................................................................39
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................40
TRIAL ENDPOINTS..........................................................................................40
5.1
5.1.1
Primary Endpoint ...............................................................................................40
5.1.2
Secondary Endpoints..........................................................................................40
............................................................................................40
ASSESSMENT OF EFFICACY........................................................................41
5.2
5.2.1
Patient Reported Outcomes ...............................................................................41
5.2.2
Forced Vital Capacity, Carbon Monoxide Diffusion Capacity, Alveolar 
Volume, Oxygen Saturation and Arterialised Blood Gases............................41
5.2.3
Acute IPF exacerbations.....................................................................................42
ASSESSMENT OF SAFETY.............................................................................43
5.3
5.3.1
Physical examination ..........................................................................................43
5.3.2
Vital Signs............................................................................................................43
5.3.3
Safety laboratory parameters ............................................................................43
5.3.4
Electrocardiogram ..............................................................................................44
5.3.5
Other safety parameters.....................................................................................44
5.3.6
Assessment of adverse events.............................................................................44
Definitions of AEs ................................................................................................44
5.3.6.1
5.3.7
Adverse event collection and reporting.............................................................48
 


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OTHER ASSESSMENTS...................................................................................53
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................53
5.7
6.
INVESTIGATIONAL PLAN.............................................................................54
VISIT SCHEDULE.............................................................................................54
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................54
6.2
6.2.1
Screening and run-in period(s)..........................................................................54
6.2.2
Treatment period(s)............................................................................................55
6.2.3
Follow Up Period and Trial Completion...........................................................55
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................57
STATISTICAL DESIGN - MODEL.................................................................57
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................57
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................59
7.3.2
Secondary endpoint analyses .............................................................................60
................................................................................60
7.3.4
Safety analyses.....................................................................................................61
INTERIM ANALYSES ......................................................................................62
7.4
HANDLING OF MISSING DATA ...................................................................62
7.5
RANDOMISATION ...........................................................................................62
7.6
DETERMINATION OF SAMPLE SIZE .........................................................63
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........65
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................65
DATA QUALITY ASSURANCE ......................................................................66
8.2
RECORDS...........................................................................................................66
8.3
8.3.1
Source documents ...............................................................................................66
8.3.2
Direct access to source data and documents.....................................................66
8.3.3
Storage period of records ...................................................................................67
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS67
8.4
8.4.1
Listedness.............................................................................................................67
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................67
STATEMENT OF CONFIDENTIALITY........................................................67
8.5
END OF TRIAL..................................................................................................67
8.6
PROTOCOL VIOLATIONS .............................................................................68
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................68
9.
REFERENCES....................................................................................................69
PUBLISHED REFERENCES............................................................................69
9.1
UNPUBLISHED REFERENCES......................................................................72
9.2
10.
APPENDICES.....................................................................................................73


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CRITERIA FOR HRCT/BIOPSY REVIEW...................................................73
10.1
CREATININE CLEARANCE...........................................................................73
10.2
ST GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ)....................74
10.3
THE UCSD SHORTNESS OF BREATH QUESTIONNAIRE (UCSD-
10.4
SOBQ) ..................................................................................................................80
EUROQOL-5D  (EQ-5D) ...................................................................................84
10.5
DLCO...................................................................................................................86
10.6
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................87


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ABBREVIATIONS
AC
Adjudication Committee
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
aPTT
AS
Alanine Transaminase
Activated Partial Thromboplastin Time
Aortic Stenosis
AST
Aspartate Transaminase
AUC
Area under the Curve
AV
Atrioventricular
BI
bid
BNP
Boehringer Ingelheim
bis in die (twice daily dosing)
Brain Natriuretic Peptide
cGMP
Cyclic Guanosine Monophosphate
CI
Confidence Interval
Cmax
Maximum Plasma Concentration
CML
Local Clinical Monitor 
Cpre,ss
CRA
Steady State Pre-dose Plasma Concentrations
Clinical Research Associate
CRF
CRO
Case Report Form
Clinical Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
DBP
DDI
DILI
DLCO
Clinical Trial Report
Diastolic Blood Pressure
Drug-drug Interaction
Drug Induced Liver Injury
Carbon Monoxide Diffusion Capacity
DMC
DNA
Data Monitoring Committee
Desoxyribose Nucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
EOT
EudraCT
Ejection Fraction
End of Treatment
European Clinical Trials Database
FEV1
Forced Expiratory Volume in 1 second
FGF(R)
Fibroblast Growth Factor (Receptor)
FVC
Forced Vital Capacity
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GI
HRCT
IB
ICH
Gastrointestinal
High-resolution Computed Tomography
Investigator’s Brochure
International Conference on Harmonization


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IEC
IHSS
Independent Ethics Committee
Idiopathic Hypertrophic Subaortic Stenosis
INR
International Normalised Ratio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
IU
Investigator Site File
International Units
i.v.
Hb
Intra venous
Haemoglobin
Kco
Carbon Monoxide Transfer Coefficient
MACE
Major Adverse Cardiovascular Events
LDH
MedDRA
Lactate Dehydrogenase
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Effects Model for Repeated Measures
NAC
N-acetylcysteine
nRTK
Non-receptor Tyrosine Kinase
PaCO2
PAH
PaO2
Partial Pressure of Carbon Dioxide
Pulmonary Arterial Hypertension
Partial Pressure of Oxygen
PDGF(R)
Platelet Derived Growth Factor (Receptor)
PDE5
Phosphodiesterase Type-5
PK
Pharmacokinetics
p.o.
PRO
per os (oral)
Patient Reported Outcomes
PT
Prothrombin Time
REML
REP
Restricted Maximum Likelihood
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
RTK
Ribonucleic Acid
Receptor Tyrosine Kinase
SAE
Serious Adverse Event
SBP
s.c.
Systolic Blood Pressure
Subcutaneous
SGRQ
St. George’s Respiratory Questionnaire
SpO2
Oxygen Saturation
SUSAR
tid
Suspected Unexpected Serious Adverse Reactions
ter in die (3 times a day)
TSAP
TSH
Trial Statistical Analysis Plan
Thyroid Stimulating Hormone
ULN
UCSD SOBQ
VA
Upper Limit of Normal
University of California San Diego Shortness of Breath Questionnaire
Alveolar Volume
VEGF(R)
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 fibrosis of the interstitium of the lung, leading to decreasing 
lung volume and 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 latest update on clinical practice guideline for the treatment of IPF, jointly issued in 2015
by the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese 
Respiratory Society (JRS) and Latin American Thoracic Association (ALAT) has provided a 
conditional recommendation for treatment with nintedanib or pirfenidone for the majority of 
IPF patients, taking into account individual patient values and preferences [P15-07362]. 
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 [P15-07362; 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 has been shown to positively impact survival in patients with IPF
[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].
Pirfenidone, a compound which demonstrated anti-fibrotic activity in non-clinical models, 
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 ASCEND Phase III trial met the primary endpoint of change from baseline 
FVC % predicted [R14-2103]. Pirfenidone is now licensed since February 2011 for the 
treatment of mild to moderate IPF in the EU and since October 2014 for the treatment of IPF 
in USA. 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 


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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 USA in October 2014, in the EU in January 2015
and in Japan in July 2015. It has been submitted for marketing authorization in other 
countries across the world.
Although nintedanib and pirfenidone can be considered a standard of care for patients 
diagnosed with IPF, there is an additional need to further characterize their profile, including 
their use in special populations not previously studied or in potential combination treatment 
regimens to enhance efficacy.
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 gelatin capsule formulation of nintedanib is used in humans. Maximum plasma 
concentrations occur between 2 - 4 hours after oral administration. 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 is 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 and the 
terminal half-life found in healthy volunteers is in the range of 7 to 19 h. The absolute 
bioavailability of nintedanib is slightly below 5%. Nintedanib is mainly eliminated via faeces.
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 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. 
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 


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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. Also weight decrease and decreased appetite have frequently been 
reported in studies with nintedanib. 
Risks of nintedanib treatment also include arterial hypertension, gastrointestinal perforations, 
thromboembolism, pancreatitis, thrombocytopenia 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 AEs were balanced between the nintedanib and placebo groups, a higher 
proportion of patients in the nintedanib groups had myocardial infarctions. Conversely, a 
lower proportion of patients in the nintedanib groups had other ischemic heart disease. ‘Other 
ischemic heart disease’ was a pre-defined category including terms such as coronary artery 
disease, angina pectoris, coronary angioplasty, coronary artery stenosis, myocardial ischemia, 
coronary artery stent insertion, electrocardiogram (ECG) ST segment depression. 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 confirms the safety profile 
observed in the phase II and III trials [P15-09876].
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).


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1.2.2
Sildenafil
Sildenafil is an inhibitor of cyclic guanosine monophosphate (cGMP) specific 
phosphodiesterase type-5 (PDE5) in the smooth muscle of the pulmonary vasculature, where 
PDE5 is responsible for degradation of cGMP. Sildenafil, therefore, increases cGMP within 
pulmonary vascular smooth muscle cells resulting in relaxation. This can lead to vasodilation 
of the pulmonary vascular bed and, to a lesser degree, vasodilatation in the systemic 
circulation.
Sildenafil is rapidly absorbed after oral administration, with a mean absolute bioavailability 
of 41% (25–63%). Maximum observed plasma concentrations are reached within 30 to 120 
minutes (median 60 minutes) of oral dosing in the fasted state. Sildenafil and its major 
circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. 
Protein binding is independent of total drug concentrations. N-desmethyl metabolite has a 
phosphodiesterase selectivity profile similar to sildenafil and an in vitro potency for PDE5 
approximately 50% of the parent drug. Both sildenafil and the active metabolite have 
terminal half-lives of about 4 hours. After oral administration, sildenafil is excreted as 
metabolites predominantly in the faeces (approximately 80% of the administered oral dose) 
and to a lesser extent in the urine (approximately 13% of the administered oral dose).
Sildenafil metabolism is principally mediated by the CYP3A (major route) and CYP2C9 
(minor route) cytochrome P450 isoforms. Therefore, inhibitors of these isoenzymes may 
reduce sildenafil clearance and inducers of these isoenzymes may increase sildenafil 
clearance. Concomitant use of sildenafil with ritonavir and other potent CYP3A inhibitors is 
not recommended.
Sildenafil is indicated for the treatment of Pulmonary Arterial Hypertension (PAH) in adults 
to improve exercise ability and delay clinical worsening. The efficacy of sildenafil was 
evaluated in four phase 3 short term studies (12 to 16 weeks), and included predominately 
patients with New York Heart Association (NYHA) Functional Class II–III symptoms. 
Etiologies were idiopathic (71%) or associated with connective tissue disease (25%). Based 
on the identification of different mechanistic pathways involved in the pathogenesis of 
pulmonary arterial hypertension, i.e. the nitric oxid, endothelin and prostaglandin pathways,
increasing evidence suggests a role for sequential or upfront combination treatment in 
patients with PAH [R15-5447]. However, the effects of combination treatment of sildenafil 
with endothelin antagonists like macicentan or bosentan on morbidity and mortality are 
mixed [R15-5445; R15-5446].
Sildenafil (20 mg tid) has also been studied in a 12 week double-blind placebo-controlled
randomized trial followed by a 12 week period of open-label treatment which enrolled 180 
IPF patients with advanced lung function impairment (STEP-IPF). Although this study met 
significant differences in some secondary endpoints such as quality of life, it failed to meet its 
primary outcome of change in 6-minute walk distance of ≥ 20% at week 12 [R12-3686].
Safety data of sildenafil in adults were obtained from a 12-week, placebo-controlled clinical 
study and an open-label extension study in 277 patients with PAH, WHO Group I. The 
overall frequency of discontinuation in patients treated with sildenafil on 20 mg three times a 
day was 3% and was the same for the placebo group. Most common adverse reactions greater 
than or equal to 3% and more frequent than placebo were epistaxis, headache, dyspepsia, 


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flushing, insomnia, erythema, dyspnea, and rhinitis. Adverse reactions were generally 
transient and mild to moderate in nature.
Potential risks of treatment with sildenafil include hypotension, worsening of pulmonary 
veno-occlusive disease, epistaxis, visual loss, hearing loss, priapism and vaso-occlusive crisis 
in patients with pulmonary hypertension secondary to sickle cell disease.
In the STEP-IPF study approximately 90% of patients in each group (sildenafil or placebo) 
had at least one adverse event with the most common being dyspnoea, cough and progression 
of IPF during the double-blind 12 weeks period. The proportion of serious adverse events 
was also similar between groups (15% in sildenafil vs. 16% in placebo) without significant 
between-group differences in the occurrence of specific serious adverse events [R12-3686].
Sildenafil is also indicated in adult men with erectile dysfunction with a recommended dose 
of 50 mg taken as needed approximately one hour before sexual activity. This dose will not 
be used in this study.
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
Until recently, IPF was essentially an untreatable disease. With the availability of specific 
antifibrotic drugs like nintedanib and pirfenidone, a major advance in the management of IPF 
has been achieved. Although both drugs are approved for the treatment of all IPF patients 
(with the exception of pirfenidone in Europe and other countries where it is approved only for 
“mild to moderate IPF”), patients with advanced lung function impairment have been 
typically excluded from the most recent clinical trials in IPF.
In contrast to patients with more preserved lung function, abnormalities of the pulmonary 
vasculature due to continuous destruction of the vasculature by fibrosis and aberrant vascular 
remodeling, leading to decreased levels of resting and exercise-induced production of nitric 
oxide, are more common in patients with advanced lung function impairment, specifically in 
patients with advanced impairment in diffusion capacity. Since nitric oxide is a potent 
pulmonary vasodilator, reduced levels are associated with pulmonary vasoconstriction and 
impaired gas exchange.
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 of IPF
[P08-08684; P14-02860]. The phase II and III clinical studies showed that nintedanib slowed 
IPF disease progression by reducing the annual lung function decline and potentially the risk 
for acute exacerbations, however no clinically relevant beneficial effect on health related 
quality of life or other patient-related outcomes measures was observed [P14-07514; P11-
11216].
Sildenafil, a PDE5 inhibitor approved for the treatment of PAH, stabilizes the second 
messenger of nitric oxide (cGMP) which leads to pulmonary vasodilation. Although the 
STEP-IPF trial failed to meet its primary outcome of change in 6-minute walk distance of ≥ 
20% at week 12, it showed promising results in secondary endpoints with clinically 
significant differences in the degree of dyspnea and quality of life, as well as in gas exchange 
parameters [R12-3686].
Combining these two drugs with different molecular targets might ultimately provide 
additional benefits to patients with IPF and advanced lung function and gas exchange 
impairment: nintedanib by slowing the disease progression and sildenafil by impacting 
patient relevant outcomes such as quality of life and dyspnea.
Given the limitations of the STEP-IPF study, including the low number of patients, further 
data is required in order to confirm the symptomatic benefits of sildenafil. In addition, this 
trial will allow the collection of safety and tolerability data of the combined treatment of 
nintedanib and sildenafil as well as of nintedanib alone in a population with advanced disease 
which has been typically excluded from the most recent clinical trials in IPF.


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TRIAL OBJECTIVES
2.2
The primary objective is to assess efficacy and safety of concomitant treatment with 
nintedanib and sildenafil in IPF patients with advanced lung function impairment.
A further important objective of the trial is to enlarge the existing nintedanib mono-therapy
database with safety and tolerability data in this population.
In addition, the effect of nintedanib and sildenafil on biomarkers related to IPF 
pathophysiology will be assessed to increase understanding of the mode of action of both 
compounds.
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 a first acute exacerbation in 2 out of 3 clinical trials [P11-11216, P14-
07514].
Half of the patients in this trial will be treated with sildenafil in addition to nintedanib. In the 
STEP-IPF trial, sildenafil showed promising results in symptomatic or patient-related
endpoints such as dyspnea and health-related quality of life [R12-3686].
Although currently unknown, concomitant treatment of both drugs may ultimately be found 
to add further benefits to patients. 
The safety profile of nintedanib and sildenafil is described in section 1.2.
The most common side effects of nintedanib are of gastrointestinal nature (diarrhoea, nausea, 
vomiting, abdominal pain), as well as liver enzyme elevations. Side effects are generally mild 
to moderate in nature. In case of side effects, symptomatic treatment, dose adjustments and/or 
interruptions of nintedanib should be considered to allow for resolution of the symptoms 
(section 4.2.1).
Risks of nintedanib treatment also include arterial hypertension, gastrointestinal perforations, 
thromboembolism, pancreatitis, thrombocytopenia 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.
The most common side effects of sildenafil are epistaxis, headache, dyspepsia, flushing, 
insomnia, erythema, dyspnea and rhinitis. Side effects are generally mild to moderate in 
nature. In case of side effects, symptomatic treatment and/or interruption of sildenafil should 
be considered to allow for resolution of the symptoms (section 4.2.1).
Potential risks of treatment with sildenafil include hypotension, worsening of pulmonary 
veno-occlusive disease, epistaxis, visual loss, hearing loss, priapism and vaso-occlusive crisis 


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in patients with pulmonary hypertension secondary to sickle cell disease. Patients at higher 
risk for these conditions are excluded from this trial.
Clinical data on the pharmacokinetics of nintedanib and sildenafil when given in combination 
is not available. Based on the known metabolic properties of both compounds, the likelihood 
of a pharmacokinetic drug-drug interaction is considered to be low. Nintedanib and its
metabolites, BIBF 1202 and BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes 
in vitro.
It is currently unknown if the co-administration of both drugs will result in additional side 
effects. To minimize this risk, 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 elevation. In addition, an independent data-monitoring committee 
(DMC) will review the safety data at specified intervals during the study conduct (refer to 
section 3.1.1).
Overall, the clinical safety profile of both nintedanib and sildenafil as established during the 
previous clinical trials 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, multi-national, prospective, randomised, double-blind, parallel-group 
clinical trial to investigate the efficacy and safety of nintedanib when co-administered with 
sildenafil, compared to treatment with nintedanib alone, in patients with IPF and advanced 
lung function impairment.
A total of approximately 250 patients will be randomised in a blinded fashion to nintedanib
150 mg bid co-administered with sildenafil 20 mg tid or to nintedanib 150 mg bid co-
administered with placebo matching sildenafil. Patients will be stratified at randomization by 
the presence of any echocardiographic signs indicative of right heart dysfunction including 
right ventricular hypertrophy and right ventricular or atrial dilatation (as described in sections 
6.2.1 and 7.6). Randomized treatment will last 24 weeks. During the randomized treatment 
period, dose reductions and/or temporary interruptions of nintedanib, as well as drug 
interruption of sildenafil/matching placebo, are allowed to manage adverse events (section 
4.2.1). The planned follow-up period for patients after study treatment completion will be 
four weeks. Patients who prematurely discontinue all study drugs, will be invited to attend all 
visits as planned until week 24 (visit 7).
Each patient’s participation in the trial is estimated to last approximately 32 weeks (from visit 
1).
Figure 3.1:1 Trial design scheme
3.1.1
Administrative structure of the trial
The sponsor of this trial is Boehringer Ingelheim (BI).


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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,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management, Pharmacokinetic 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.
Additional information for Japan only: A list of responsible persons and relevant local 
information (as protocol reference, if applicable) 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 the ISF.
Sites selected for participation will consist of specialized referral centres experienced in the 
management of IPF.
A DMC, independent of the sponsor, will be established to assess the progress of the clinical 
trial, including an unblinded safety assessment at specified intervals, and to recommend to 
the sponsor whether to continue, modify, or stop the trial. Measures are in place to ensure 
blinding of the sponsor and all other trial participants. 
All death cases will be assessed (to evaluate the primary cause of death), as well as all 
adverse events categorized as major adverse cardiovascular events (MACE) and all acute IPF 
exacerbations (based on written clinical reports, for diagnostic confirmation) by an 
independent Adjudication Committee (AC), in a blinded manner before data base lock. The 
tasks and responsibilities of the DMC and the AC will be specified in a charter. 
The DMC and the AC will maintain written records of all its meetings.
A central laboratory will perform all protocol specified blood analysis of the trial. 
An IRT will perform randomization of patients and ensure appropriate distribution of trial 
medication to sites during the trial. 
A central vendor will provide spirometers for the complete duration of the trial. 


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
In the STEP-IPF trial sildenafil has been shown to improve patient-relevant outcomes such as 
dyspnea and quality of life in patients with advanced lung function impairment at 12 weeks
[R12-3686]. In order to confirm these findings and a potential added benefit of sildenafil 
when added to current standard of care, a double-blind, parallel group trial design was 
selected where half of the patients will be treated with sildenafil and half of the patients will 
be treated with placebo matching sildenafil. All patients will be treated with nintedanib as 
background therapy considered usual care in patients with IPF. 
The randomized treatment period duration of 24 weeks is thought to be adequate to evaluate 
if the efficacy is maintained after the primary endpoint assessment at 12 weeks. In addition it
is considered an appropriate treatment duration to allow the collection of safety and 
tolerability data of concomitant treatment of nintedanib and sildenafil, as well as collection of 
additional safety data for nintedanib monotherapy in a population with a more advanced lung 
function impairment in comparison to the population enrolled in the Phase II and III 
TOMORROW and INPULSIS® trials.
The frequency of visits will allow close monitoring of emergent adverse events as well as 
control of liver enzyme values consistent with the recommendations of the prescribing 
information of nintedanib.
To obtain further efficacy and safety information on the concomitant treatment of nintedanib 
and sildenafil, lung function tests, clinical laboratory tests and electrocardiograms will be 
performed. Data on discontinuations and death will be recorded.
SELECTION OF TRIAL POPULATION
3.3
A total of approximately 250 patients with an IPF diagnosis and advanced lung function 
impairment will be randomized. Approximately 80 sites are each expected to include 
approximately 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.
3.3.1
Main diagnosis for trial entry
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.


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3.3.2
Inclusion criteria
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. A clinical diagnosis of IPF within the last 6 years before visit 1, based upon the 
ATS/ERS/JRS/ALAT 2011 guideline [P11-07084];
4. Combination of high-resolution computed tomography (HRCT) pattern, and if 
available, surgical lung biopsy pattern consistent with a diagnosis of IPF (see 
appendix 10.1) as assessed by the investigator based on a HRCT scan performed 
within 18 months of visit 1;
5. DLCO (corrected for Hb) ≤ 35% predicted of normal at visit 11.
3.3.3
Exclusion criteria
1. Previous enrolment in this trial;
2. ALT, AST > 1.5 fold upper limit of normal (ULN) at visit 11;
3. Total bilirubin > 1.5 fold ULN at visit 11;
4. Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC <0.7 at visit 11);
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;

Patients who require fibrinolysis, full-dose therapeutic anticoagulation (e.g. 
vitamin K antagonists, direct thrombin inhibitors, 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 11;

Prothrombin time (PT) and activated partial thromboplastin time (aPTT) > 
150% of institutional ULN at visit 11;
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;


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9. Creatinine clearance < 30 mL/min calculated by Cockcroft–Gault formula (appendix 
10.2) at visit 11;
10. Presence of aortic stenosis (AS) per investigator judgement at visit 1;
11. Severe chronic heart failure: defined by left ventricular ejection fraction (EF) < 25%
per investigator judgement at visit 1;
12. Presence of idiopathic hypertrophic subaortic stenosis (IHSS) per investigator 
judgement at visit 1;
13. Second-degree or third-degree atrioventricular (AV) block on electrocardiogram
(ECG) per investigator judgement at visit 1;
14. Hypotension (systolic blood pressure [SBP] < 100 mm Hg or diastolic blood pressure
[DBP] < 50 mm Hg) (symptomatic orthostatic hypotension) at visit 1;
15. Uncontrolled systemic hypertension (SBP > 180 mmHg or DBP > 100 mmHg) at visit 
11;
16. Known penile deformities or conditions (e.g., sickle cell anemia, multiple myeloma, 
leukemia) that may predispose to priapism;
17. Retinitis pigmentosa;
18. History of vision loss;
19. History of nonarteritic ischemic optic neuropathy;
20. Veno-occlusive disease;
21. History of acute IPF exacerbation or respiratory infection within 8 weeks of visit 2.
22. Treatment with nitrates, n-acetylcysteine, pirfenidone, azathioprine,
cyclophosphamide, cyclosporine, prednisone >15 mg daily or >30 mg every 2 days 
OR equivalent dose of other oral corticosteroids as well as any investigational drug 
within 4 weeks of visit 2;
23. Treatment with prostaglandins (e.g., epoprostenol, treprostinil), endothelin-1 
antagonists (e.g., bosentan, sitaxsentan, ambrisentan), phosphodiesterase inhibitors
(e.g., sildenafil, tadalafil, vardenafil) or a stimulator of guanylatcyclase (e.g., 
riociguat) within 4 weeks of visit 2;
24. Treatment with potent CYP3A4 inhibitors such as ketoconazole, itraconazole and 
ritonavir within 4 weeks of visit 2;
25. Supplementation with L-arginine and concurrent use of grapefruit juice or St John’s 
wort within 4 weeks of visit 2;
26. Treatment with the reduced dose of nintedanib (100 mg bid) within 4 weeks of visit 
24;
27. Permanent discontinuation of nintedanib in the past due to adverse events considered 
drug-related;
28. Known hypersensitivity or intolerance to nintedanib, sildenafil, galactose, peanut or 
soya or any other components of the study medication;


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29. 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;
30. Alcohol or drug abuse which in the opinion of the treating physician would interfere 
with treatment;
31. Women who are pregnant, nursing, or who plan to become pregnant while in the trial;
32. Women of childbearing potential5 not willing or able to use highly effective methods 
of birth control per ICH M3 (R2) that result in a low failure rate of less than 1% per 
year when used consistently and correctly6;
33. Patients not able to understand and follow study procedures including completion of 
self-administered questionnaires without help.
34. Patients with underlying chronic liver disease (Child Pugh A, B or C hepatic 
impairment)
1 Laboratory parameters, blood pressure and lung function tests 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.
2 Exceptions: prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g., enoxaparin 4000 IU 
subcutaneous (s.c.) per day) and prophylactic use of antiplatelet therapy (e.g., acetyl 
salicylic acid up to 325 mg/d, and/or clopidogrel at 75 mg/d, and/or equivalent doses 
of other antiplatelet therapy).
3 Definition of major is per investigator judgement.
4 Patients on treatment with nintedanib 150 mg bid during the screening period are 
eligible. However if an interruption or reduction of dose is required during the 
screening period or at time of randomization, the patient will no longer be eligible.
5 Women 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).
6 A list of contraception methods meeting these criteria is provided in the patient 
information.


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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial participation if the patient withdraws 
consent for trial participation, without the need to justify the decision.
An individual patient is to be withdrawn from all trial drugs (nintedanib and 
sildenafil/matching placebo) if:

The patient withdraws consent for study treatment, without the need to justify the 
decision;

The patient needs to take concomitant drugs that interfere with the investigational 
products (section 4.2.2);

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy);
If a patient becomes pregnant or pregnancy is suspected during the trial, the patient will 
be permanently discontinued from study treatment and will be followed up until birth or 
otherwise termination of pregnancy, please see section 5.3.7.

The patient experiences signs or symptoms of acute myocardial ischemia or stroke;

The patient experiences signs of hepatic injury, defined as one of the following:

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.
For potential drug induced liver injury (DILI) follow up requirements please see sections
4.2.1.3 and 5.3.6.1. 
Treatment with nintedanib must be permanently discontinued in the following situations:

In the opinion of the investigator, the patient experiences unacceptable toxicity due to 
nintedanib despite dose adjustments and supportive care;

Gastrointestinal perforation;

Major surgery including abdominal or intestinal surgery;

Signs or symptoms of deep vein thrombosis or pulmonary embolism;

Treatment interruption longer than 4 weeks (continuous).


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In addition, permanent discontinuation of nintedanib should be considered in the following 
situations:

Patient who requires 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, continuation of nintedanib should be discussed with the patient and the 
decision based on an individual benefit-risk assessment documented in the source data. 
Treatment with sildenafil/matching placebo must be permanently discontinued in the 
following situations:

In the opinion of the investigator, the patient experiences unacceptable toxicity due to 
sildenafil despite supportive care;

Hypotension (SBP < 100 mmHg or DBP < 50 mmHg) accompanied by symptoms;

In the event of any sudden visual defect;

Prolonged erections and priapism;

Treatment interruption longer than 4 weeks (continuous).
If a patient discontinues all study drugs (nintedanib and sildenafil/matching placebo), he/she 
will undergo the procedures for early treatment discontinuation and will be invited to attend 
all planned study visits until week 24 as outlined in the flow chart.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
electronic case report form (eCRF). These data will be included in the trial database and 
reported.
Discontinuation of the trial by the sponsor
3.3.4.2
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 good clinical practice (GCP), the clinical trial protocol (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 and comparator product
Table 4.1.1:1
Nintedanib 
Substance:
Nintedanib (Ofev®)
Pharmaceutical formulation:
Soft gelatine capsule
Source:
BI Pharma GmbH & Co.KG
Unit strength:
150 mg, 100 mg
Posology
1 capsule, bid
Route of administration:
Oral (swallowed)
Table 4.1.1:2
Sildenafil and placebo matching sildenafil
Substance:
Sildenafil
Placebo
Pharmaceutical formulation:
Capsules
Capsules
Source:
BI Pharma GmbH & 
Co.KG tablets for 
overencapsulation 
sourced from Pfizer
BI Pharma GmbH & 
Co.KG
Unit strength:
20 mg
Not applicable
Posology
1 capsule, tid
1 capsule, tid
Route of administration:
Oral (swallowed)
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups
Patient randomization to treatment groups will be determined by an IRT system. Access to
the randomization code will be controlled and documented. All necessary instructions for


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using the IRT system will be described in a user guide/manual, a copy of which will be
available in the ISF.
At visit 2, eligible patients will be randomised via IRT to one of the two treatment groups.
Patients will have an equal chance of being randomised to nintedanib co-administered with 
sildenafil or to nintedanib co-administered with placebo matching sildenafil.
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 participating countries.  
Dose adjustments are permitted as per section 4.1.4.1 and section 4.2.1.
Sildenafil: A dose of 20 mg tid (total daily dose of 60 mg) was selected for this trial as this is 
the recommended dose for the approved indication of PAH based on the prescribing 
information in participating countries. This was also the dose studied in IPF patients in the 
STEP-IPF study [R12-3686]. No dose adjustment is allowed during this study.
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. IRT will be used to assign appropriate treatment kits to each patient. 
To ensure patients receive adequate supply of study medication, kits will be dispensed at 
clinic visits in quantities outlined in table 4.1.4:1
Table 4.1.4:1
Quantity of medication kits dispensed:
Visit
Nintedanib Kit
Sildenafil / Matching 
Placebo Kit
2
1
1
3
1
1
4
1
1
5
3
3
Nintedanib
4.1.4.1

Treatment with nintedanib will consist of 1 capsule twice daily (bid). 

The first administration of nintedanib will be taken in the clinic at visit 2. 

The patients should swallow nintedanib unchewed with a glass of water (250mL) and 
should observe a dosing interval of 12 hours.

Nintedanib should be taken at the same time every day between 06:00 and 11:00 in 
the morning and between 18:00 and 23:00 in the evening.


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
Because nintedanib may cause stomach discomfort, it is recommended to be taken at 
the end of a meal. 

If a dose of 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. 
Dose adjustment of nintedanib is allowed to manage adverse events: 300 mg daily (150 mg 
bid) may be reduced to 200 mg daily (100 mg bid). For additional details please refer to 
section 4.2.1.
Dose reductions or re-escalation of nintedanib must be done in the clinic at a dose adjustment 
visit (refer to the flow chart), as a new medication kit will need to be assigned through IRT. 
The amount of study drug dispensed at the time of dose reduction and dose re-escalation is 
dependent upon the amount of time between the dose adjustment visit and the next planned 
study visit. IRT will assign only the number of study medication kits needed until the next 
planned patient visit.
Sildenafil and matching placebo
4.1.4.2

Treatment with sildenafil (or matching placebo) will consist of 1 capsule three times 
daily (tid). 

The first administration of sildenafil (or matching placebo) will be taken in the clinic 
at visit 2. 

Sildenafil capsules should be taken approximately 6 to 8 hours apart.

It is recommended that nintedanib and sildenafil are administered together at the same 
time in the morning and evening at the end of a meal, with the third sildenafil dose 
administered at the midpoint. 

If a dose of sildenafil 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. 

No dose adjustments are allowed for sildenafil within this study.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial (apart from the DMC) will remain blinded with regard to the 
randomized treatment assignments until after database lock.
The randomization code will be kept secret by Clinical Trial Support up to database lock.


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The DMC may review unblinded data upon request, and only under conditions that ensure 
that patients, investigators and everyone involved in trial conduct or analysis or with any 
other interest in this double-blind trial will remain blinded.
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s
Pharmacovigilance group to access the randomisation code for individual patients during trial
conduct. The access to the code will only be given to authorised Pharmacovigilance
representatives and not be shared further.
For Japan only: In this blinded trial, an emergency code break will be available to the 
Investigator / the sub-Investigators via the IRT system. This code break may only be accessed 
in emergency situations when the identity of the trial drug must be known to the Investigator 
/the sub-Investigators in order to provide appropriate medical treatment or if required to 
assure the safety of trial participants. Each site receives a manual from the IRT provider that 
contains instructions on how to unblind the treatment of a patient via the IRT (via 24-hour 
Emergency helpline). If the code break for a patient is accessed, the sponsor must be 
informed immediately. The reason for accessing the code break, together with the date, must
be documented on the appropriate eCRF page. In case third party needs to break the code,
however, when the Investigator cannot be reached, the code can be opened by calling
emergency code manager.
4.1.6
Packaging, labelling, and re-supply
Nintedanib will be packaged in blisters (containing either nintedanib 100 mg or nintedanib 
150 mg). Each blister will contain 10 capsules. Seven blisters will be packaged into one 
child-resistant tamper-evident wallet (i.e. 70 capsules/wallet). 
Sildenafil / matching placebo will be packaged in blisters. Each blister will contain 15
capsules. Seven blisters will be packaged into one child-resistant tamper-evident wallet (i.e. 
105 capsules/wallet). 
For details of packaging and the description of the label, refer to the ISF.
Re-supplies of study medication are planned due to the long duration of the study. The 
medication for re-supply will be packaged in an identical manner as the medication for initial 
supply.


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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.
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

If applicable, availability of the proof of a medical license for the principal 
Investigator

In the USA, availability of Form 1572
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 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.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment
Rescue medications to reverse the action of nintedanib or sildenafil are not available.


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Recommendations for managing AEs (exceptions include diarrhoea and liver 
4.2.1.1
enzyme elevations)

If a patient experiences adverse events considered related to the trial medication,
symptomatic treatment should be initiated (e.g. anti-emetic treatment such as 
dimenhydrinate, if appropriate). 

Patients experiencing adverse events considered related to nintedanib may require 
drug interruption (up to a maximum of 4 weeks) or reduction of dose (at the discretion 
of the investigator) to allow for resolution of symptoms. 

After resolution of AE, nintedanib may be reintroduced and/or re-escalated to the 
higher dose (at the discretion of the investigator):
a.
If dose has been reduced, consider re-escalation to 150 mg bid  
b. If treatment was temporarily interrupted, resume treatment at the full dose 
(150 mg bid), or at the reduced dose (100 mg bid), which subsequently may be 
re-escalated to the full dose (150 mg bid).

Patients experiencing adverse events considered related to sildenafil may require drug 
interruption (up to a maximum of 4 weeks) to allow for resolution of symptoms. No 
dose adjustments are allowed for sildenafil within this study. In the event of an 
erection that persists longer than 4 hours, the patient should seek immediate medical
assistance.

For adverse events not related to the trial medications, treatment interruptions for a 
maximum of 4 weeks are allowed. Nintedanib and sildenafil should then be resumed 
at the same dose taken prior to interruption.  

In the occurrence of acute IPF exacerbations all treatment options considered 
adequate by the investigator are allowed.  
Recommendations for managing diarrhoea
4.2.1.2
In general, diarrhoea should be managed as early as possible after onset of first symptoms 
with standard antidiarrheal symptomatic treatment, e.g. loperamide.
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption (for a 
maximum of 4 weeks) and dose reduction of nintedanib should be considered based on the 
recommendations described in Table 4.2.1.2: 1.
If diarrhoea is not manageable after dose reduction and/or nintedanib interruption,
interruption of sildenafil should also be considered.


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Table 4.2.1.2: 1 Recommendations for managing diarrhoea
CTCAE 
Grade
Description
Symptomatic Treatment
Action with Nintedanib
1
Increase of <4 
stools per day 
over baseline
Initiate anti-diarrheal 
medicines at first signs of 
symptoms (e.g., 4 mg 
loperamide followed by 2 mg 
after each loose stool or every 
2-4 hours to a maximum of 
16 mg/day1) until bowel 
movements cease for 12 
hours
Continue same nintedanib dose
2
Increase of 4-6 
stools per day 
over baseline
Initiate/continue anti-
diarrheal medicines;
If diarrhoea grade 2 persists 
for ≥48-72 hours assess for 
dehydration and electrolyte 
imbalance; 
In addition, consider i.v.
fluids and electrolyte 
replacement as clinically 
indicated.
If diarrhoea grade 2 persists for 
≥48-72 hours despite optimal 
symptomatic care: 
Interrupt nintedanib until 
recovery2
Reduce dose to 100 mg bid 
after recovery 
Re-escalate to 150 mg bid if 
deemed clinically appropriate
3
Or
4
Increase of ≥ 7 
stools per day 
over baseline; 
incontinence; 
Or
Life threatening 
consequences
Follow recommendations 
above.
In addition, consider stool 
work-up to exclude infectious 
colitis; aggressive i.v. fluid 
replacement ≥24 hours, 
hospitalisation as clinically 
indicated; consider referral to 
a GI specialist to rule out 
potential differential 
diagnoses.
Interrupt nintedanib until 
recovery2
Reduce dose to 100 mg bid 
after recovery
Consider re-escalation to 150 
mg bid if deemed clinically 
appropriate
In case of recurrence of 
diarrhoea grades 3 or 4 despite 
optimal symptomatic treatment 
and dose reduction, treatment 
with nintedanib should be 
permanently discontinued.
1  Refer to national prescribing information
2 Treatment interruptions are allowed up to a maximum of 4 weeks.


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Recommendations for managing liver enzyme elevations
4.2.1.3
For a detailed guidance on how to manage liver enzyme elevations, please refer to table 4.2.1.3: 1
Table 4.2.1.3: 1
Recommendations for managing liver enzyme elevations
AST /ALT ≥3 but <5 x ULN
AST /ALT ≥5 but <8 x ULN
Signs of hepatic 
injury 3
Reduce nintedanib to 100 mg bid or interrupt2 (at the 
discretion of the investigator) 
Lab tests1 at 48/72 hours, at 1 week and at 2 weeks
Interrupt2 nintedanib
Lab tests1 at 48/72 hours, at 1 week and at 2 weeks
Permanently 
discontinue all 
study drugs
If AST /ALT < 3 x ULN
within 2 weeks
If AST /ALT ≥3 ULN       
at 2 weeks
If AST /ALT < 3 x ULN
within 2 weeks
If AST /ALT ≥3 ULN       
at 2 weeks
Re-escalate nintedanib to 
150 mg bid if reduced; 
restart at 100 mg bid if 
interrupted
Lab tests1 at weeks 2 and 4
Interrupt2 both drugs
Lab tests1 at weeks 1 and 2
Reintroduce nintedanib at 
100 mg bid
Lab tests1 at weeks 1, 2 
and 4
Interrupt2 sildenafil
Lab tests1 at weeks 1 and 2
If AST / ALT ≥ 3 x ULN
permanently discontinue 
nintedanib
If AST / ALT < 3 x ULN
reintroduce drugs in a 
stepwise approach; lab tests1
every week as needed
If AST / ALT ≥ 3 x ULN
permanently discontinue all 
study drugs
If AST / ALT ≥ 3 x ULN
permanently discontinue 
nintedanib
If AST / ALT < 3 x ULN
reintroduce drugs in a 
stepwise approach; lab tests1
every week as needed
If AST / ALT ≥ 3 x ULN
permanently discontinue all 
study drugs


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1 Laboratory tests include ALT, AST, total bilirubin, eosinophils, INR
2 Treatment interruptions are allowed up to a maximum of 4 weeks.
3 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.
For potential drug induced liver injury (DILI) follow up requirements please see section 
5.3.6.1.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Concomitant medications (or therapy) to provide adequate care may be given as clinically 
necessary. If restricted concomitant therapy is necessary, treatment with study medication 
should be permanently discontinued (except in case of acute IPF exacerbations – refer to 
section 4.2.1.1). 
Table 4.2.2.1:1
Permitted and Restricted Concomitant therapy 
Prior to 
randomisation
During 
treatment 
period
After Visit 7 
(Follow-up 
Period)
After early
EOT9
Nintedanib
Permitted (150 mg 
bid dose only)
Study 
medication
Permitted
Not permitted
Sildenafil
Not permitted in 
the 4 weeks prior 
to visit 2 1
Study 
medication
Permitted
Not permitted
Pirfenidone, N-
acetylcysteine, 
Azathioprine, 
Cyclophosphamide,  
Cyclosporine
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted
Prednisone and  other 
oral corticosteroid2
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted


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Table 4.2.2.1:1
(continued) Permitted and Restricted Concomitant therapy 
Investigational 
Medication
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not 
permitted10
Not permitted
Nitrates
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted
Prostaglandins3, 
endothelin-1 
antagonists4 or 
phosphodiesterase 
inhibitors5 or a 
stimulator of 
guanylatcyclase 6
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Not permitted
Potent CYP3A4 
inhibitors such as 
ketoconazole, 
itraconazole and 
ritonavir
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted
L-arginine, grapefruit 
juice or St John’s wort
Not permitted in 
the 4 weeks prior 
to visit 2 1
Not permitted
Not permitted
Permitted
Anticoagulation at full 
dose7, antiplatelet 
therapy at high dose 8,
fibrinolysis
Permitted
Not permitted
Not permitted
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.
3.
e.g., epoprostenol, treprostinil
4.
e.g., bosentan, sitaxsentan, ambrisentan
5.
e.g., sildenafil, tadalafil, vardenafil
6.
e.g., riociguat
7.
Anticoagulation at full dose (vitamin K antagonists, direct thrombin inhibitors, heparin, 
hirudin, etc.). Exceptions: 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)
8.
Antiplatelet therapy at high dose. Exceptions: prophylactic use of antiplatelet therapy 
(e.g. acetylsalicylic acid up to 325 mg/day and/or clopidogrel at 75 mg/day and/or 
equivalent doses of other antiplatelet therapy) is allowed 


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9.
For patients who withdrew all study medications before the planned EOT date and decide 
to attend all remaining study planned visits.
10. Nintedanib as investigational product is allowed during the follow-up period in case the 
patient transitions to an extension trial or compassionate use program.
Wash-out periods for concomitant therapy which might influence the spirometry results are 
described in section 5.2.2.
Restrictions on diet and life style
4.2.2.2
There are no restrictions on diet and life style.
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, 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 capsule actually taken 100
     Number of capsules which should have been 
taken
If the number of doses taken is not between 80-120% (inclusive) 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 accordingly (section 5.3.5).
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 Endpoint
The primary endpoint is the change from baseline in St George’s Respiratory Questionnaire 
(SGRQ) total score at week 12.
5.1.2
Secondary Endpoints

Change from baseline in dyspnea using the University of California San Diego 
Shortness of Breath Questionnaire (UCSD SOBQ) at week 12;

Change from baseline in SGRQ total score at week 24;

Change from baseline in dyspnea using UCSD SOBQ at week 24;

Percentage of patients with on-treatment Serious Adverse Events (SAE) from baseline 
to week 24.


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ASSESSMENT OF EFFICACY
5.2
5.2.1
Patient Reported Outcomes 
Three different PRO questionnaires will be used:

St George’s Respiratory Questionnaire (SGRQ – See Appendix 10.3)

The UCSD Shortness of Breath Questionnaire (UCSD-SOBQ – See Appendix 10.4)

EuroQoL-5D  (EQ-5D – See Appendix 10.5)
The PRO questionnaires will be assessed at timepoints as indicated in the flow chart. It 
should be completed at the start of each applicable visit, prior to performing any other trial 
procedures and in the following order: SGRQ, UCSD-SOBQ, EQ-5D.
5.2.2
Forced Vital Capacity, Carbon Monoxide Diffusion Capacity, Alveolar Volume, 
Oxygen Saturation and Arterialised Blood Gases
FVC will be assessed using identical spirometry devices which will be supplied to all 
participating sites at trial initiation and spirometry performance will be centrally reviewed. 
Spirometers and usage of spirometers must meet ATS/ERS criteria [P05-12782], including 
daily calibration of the spirometer, and regular calibration of the calibration pump (according 
to the instructions provided in the ISF). Spirometry will be conducted while the patient is in 
a seated position. The test will be done in triplicate and the best result selected according to 
the guidelines. Spirometry results captured by spirometers provided by the sponsor will be 
electronically transmitted and confirmed by central reading. The best of three efforts will be 


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defined as the highest FVC, obtained on any of the three blows meeting the ATS/ERS 
criteria, preferably with a maximum of five manoeuvres.
The site will use its own equipment to assess carbon monoxide diffusion capacity (DLCO) 
and alveolar volume (VA) during the single breath diffusion test and conduct all 
measurements with the same equipment (e.g. if several devices would be available at the 
site). Single-breath diffusion test will be carried out according to the ATS / ERS guidelines
[R06-2002]. Before beginning the test, the manoeuvres should be demonstrated and the 
subject carefully instructed. The mean value between at least two acceptable tests should be 
reported. Please refer to Appendix 10.6 for additional information.
For each patient, pulmonary function testing and single-breath diffusion test will always start 
at approximately the same time of day. The DLCO/VA assessment should always be 
performed after the FVC assessment.
On days of clinic visits, patients must refrain from strenuous activity at least 12 hours prior to 
pulmonary function testing. 
Smoking should be discouraged throughout the study day (clinic visit) and will not be 
permitted in the 30-minute period prior to spirometry. Patients should also avoid cold 
temperatures, environmental smoke, dust, or areas with strong odours (e.g., perfumes).
Washout of bronchodilators therapies (betamimetic drugs, anticholinergic drugs) has to be 
observed before spirometry (24 hours for long acting and 8 hours for short acting 
bronchodilators). 
Oxygen saturation (SpO2) will be measured at rest by standard pulse oximetry (unaffected 
skin of earlobe or fingertip). Arterialised blood gases (PaO2 and PaCO2) will be measured in 
selected sites experienced in earlobe capillary blood gas sampling. Values will be entered in
the eCRF.
5.2.3
Acute IPF exacerbations
Acute IPF exacerbations will be collected as adverse events.
Acute IPF exacerbation is defined as an acute, clinically significant, respiratory deterioration 
characterized by evidence of new widespread alveolar abnormality [P16-06899]. 
Extra-parenchymal causes (e.g. pneumothorax, pleural effusion, pulmonary embolism) 
should be excluded and the following 3 diagnostic criteria need to be met:

Acute worsening or development of dyspnea typically of less than one month 
duration;

Computed tomography with new bilateral ground-glass opacity and/or consolidation 
superimposed on a background pattern consistent with usual interstitial pneumonia 
pattern;

Deterioration not fully explained by cardiac failure or fluid overload.


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Events that are clinically considered to meet the definition of acute exacerbation of IPF but 
fail to meet the three diagnostic criteria due to missing computed tomography data will be 
termed “suspected acute exacerbations” by the Adjudication Committee.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Physical examination includes assessment of heart, lung, abdomen and measurement of 
weight. Height will also be measured at visit 1. Abnormal findings 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 the 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 including platelet count 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, brain 
natriuretic peptide (BNP) and thyroid stimulating hormone (TSH).

Coagulation: International normalized ratio (INR) and partial thromboplastin time (PTT).

Urine: pregnancy testing (for all women of childbearing potential).
If laboratory values indicate toxicity, adequate and more frequent blood sampling will be 
performed at the discretion of the investigator.
Laboratory analysis 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 elevations, close monitoring must be ensured by the investigator
(section 4.2.1.3).


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5.3.4
Electrocardiogram
ECGs are to be conducted with site equipment as specified in the flow chart. Changes should 
be examined, compared to the 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
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. The diary will be used to prompt patient recollection during AE and 
medication compliance discussions at clinic visits. Instructions for use of the diary will be 
provided in the ISF.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended.  Response in this context means that a causal relationship between medicinal 
product and an adverse event is at least a reasonable possibility.  Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure.  Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors. 
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,


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
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. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse. Any suspected transmission via a medicinal product of an infectious agent is 
considered a serious adverse reaction.
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.
For Japan only: The following events will be handled as “deemed serious for any other 
reason”. An AE which possibly leads to disability will be reported as a SAE.
Other significant adverse event (according to ICH E3)
An “other significant adverse event” is defined as any non-serious adverse event which 

represents a marked haematological or other laboratory abnormality;

led to an intervention, including withdrawal of drug treatment, dose reduction or 
significant additional concomitant therapy.
AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further 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 system. 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 


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need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAEs, see section 5.3.7.
The following are considered 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.
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 in the ISF.
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 adverse events should in addition be classified and recorded in the 
(e)CRF according to the Common Terminology Criteria for Adverse Events (CTCAE)
version 4 [R10-4848].


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Table 5.3.6: 1 
CTCAE Categorization for diarrhoea
CTCAE Grade
1
Increase of <4 stools per day over baseline
2
Increase of 4 to 6 stools per day over baseline
3
Increase of ≥7 stools per day over baseline; incontinence
4
Life threatening consequences
5
Death
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks
of drug administration; an allergic reaction weeks after discontinuation of the drug
concerned)


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
Continuation of the event despite the withdrawal of the medication, taking into
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
For Japan only: The reason for the decision on causal relationship for unlisted AEs needs to 
be provided in the eCRF.
5.3.7
Adverse event collection and reporting
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
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 individual patient’s end of trial: all AEs (serious and non-serious) and all AESIs.
However, if an individual patient discontinues trial medication prematurely but stays 
in the trial (i.e. if further visits incl. telephone visits, or vital status assessments are 
planned) from then on and until the individual patient’s end of the trial the 
Investigator must report related SAEs and related 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 5.3.7:1 AE Collection


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The Residual Effect Period (REP) is defined as 28 days after the last trial medication 
administration. All AEs which occurred through the treatment phase and throughout the REP 
will be considered as 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.
For Japan only: All SAEs must be reported immediately to the head of the trial site. 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. The Investigator should determine the causal relationship 
to the trial medication.
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 may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s
unique entry point (country-specific contact details will be provided in the ISF). The
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.


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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). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE 
form must be completed in addition. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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. 


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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 any washout of restricted medications (refer to table 4.2.2.1:1). 
The study will consist of a screening period up to 28 days, a randomised treatment period of 
24 weeks and a follow up period lasting a minimum of four weeks (28 days). 
All patients are to adhere to the visit schedule as outlined in the flow chart. Some flexibility is 
allowed in scheduling the visits according to the visit time windows as specified. The trial 
medication kits contain sufficient medication to allow for these time windows. All deviations 
from the planned visit schedule will be documented.  If any visit is to be re-scheduled, 
subsequent visits should follow the original visit date schedule (calculated from visit 2). 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 and run-in period(s)
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.  
Please refer to the flow chart for complete procedures at visit 1. 
An echocardiogram will be performed with site equipment at visit 1 to evaluate cardiac 
function and assess exclusion criteria 10, 11 and 12 (section 3.3.3). In addition, this test will 
be used for the stratification of patients during randomization (as described in section 7.6).
The following questions will be captured in the eCRF based on the investigator’s judgement:

Presence of right ventricular systolic dysfunction (yes/no)

Presence of right ventricular hypertrophy (yes/no)

Presence of right ventricular dilatation (yes/no)

Presence of paradoxical septum motion (yes/no)

Presence of right atrium enlargement (yes/no)
Clinically relevant findings will be recorded as baseline conditions.
Patients who have a laboratory test, blood pressure or lung function test value outside the 
range specified by the exclusion criteria and thought to be a measurement error or the result 
of a temporary and reversible medical condition may have the test repeated once to determine 


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eligibility; however, the result must be available prior to visit 2. The period between visit 1 
and visit 2 should last a maximum of 28 days. If visit 2 could not be performed within this 
timeframe the patient will be considered as screen failed. 
All patients who have signed consent must be entered in the enrolment log and documented 
in the eCRF. Patients found to be ineligible at or prior to visit 2 and do not initiate treatment 
will be considered a screen failure.
6.2.2
Treatment period(s)
If the patient has been determined eligible by the investigator to enter the trial (refer to
section 3.3), the investigator will assign medication numbers to the patient through the IRT 
system at visit 2. First dose of trial drugs will be administered at visit 2 in the clinic (day 1).
Additional clinic visits will be scheduled after 4, 8, 12, 18 and 24 weeks of treatment (visits 
3-7). For detailed description of the trial procedures at each visit and dispensing schedule, 
please refer to the flow chart.
Dose Adjustment Visit
The dose of nintedanib can be reduced and increased as described in section 4.2.1. In this 
case, the patient will be required to return to the clinic for an unscheduled visit where new 
medication will be assigned via the IRT system. Please refer to the flow chart for complete 
procedures in this visit.
6.2.3
Follow Up Period and Trial Completion
A follow-up (FUP) visit should be planned for 28 days after last trial drug administration. For 
detailed description of the trial procedures at the FUP visit, please refer to the flow chart.
Trial completion
The trial completion eCRF page has to be filled-in when the patient has terminated the trial. 
The end of the trial is:

At the end of the follow-up visit for patients who have completed the trial on 
treatment as planned;

After the early end of treatment (EOT) and follow-up visits, if a patient did not agreed
to come to the remaining planned study visits;

At the end of visit 7 for patients who discontinued drug early but agreed to come to 
the remaining planned study visits.


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Patients who prematurely discontinued trial medication
Patients who prematurely discontinue all study drugs (refer to section 3.3.4) before the 
planned end of treatment at visit 7, should come to the clinic as soon as possible after last 
drug intake for an early EOT visit. Reason for discontinuation must be documented in the 
eCRF. For detailed description of the trial procedures at this visit, please refer to the flow
chart. 
In addition patients will be invited to attend all planned visits despite not being under 
treatment anymore and perform all study procedures except the laboratory tests (optional), 
biomarker sampling, pharmacokinetic sampling and the ECG. If patients don’t accept to 
attend all remaining study visits, they will be contacted for vital status collection at week 24.
The need for coming to future visits in case of premature discontinuation of trial medication 
will be explained to patients prior to their participation in the trial. 
Vital status information
In case of early discontinuation of all study drugs, if the patient does not agree to come to 
future visits as planned, every attempt will be made to get information on vital status at week 
24 after his/her randomization.
Patients will be asked to agree to be contacted by the site personnel, which could be by 
telephone calls, to allow collection of this information.
If death occurs, the investigator will review the circumstances, including the relevant medical 
records to ascertain the most likely primary and secondary causes of death.
Collection of vital status will be performed in accordance with national ethical and regulatory 
guidelines. The need for vital status information will be explained to patients prior to their 
participation in the trial.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a double-blind, randomized, parallel-group study stratified by presence of any 
echocardiographic signs indicative of right heart dysfunction to evaluate the efficacy and 
safety of nintedanib when co-administered with sildenafil, compared to treatment with 
nintedanib alone, in patients with idiopathic pulmonary fibrosis (IPF) and advanced lung 
function impairment.
The primary endpoint is the change from baseline in SGRQ total score at week 12.
The primary endpoint will be analysed using a Mixed Effects Model for Repeated Measures 
(MMRM). The details are provided in section 7.3.1.
The secondary endpoints related to SGRQ and UCSD SOBQ will be analysed using MMRM. 
Details are provided in section 7.3.2.
The secondary endpoint percentage of patients with on-treatment SAEs from baseline to 
week 24 will be analysed using the Cochran-Mantel-Haenszel test exploratorily.
Analysis of further endpoints is described in section 7.3.3.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The objective of this study, demonstrating an additional treatment effect of nintedanib co-
administered with sildenafil compared to treatment with nintedanib alone, in patients with 
idiopathic pulmonary fibrosis (IPF) and advanced lung function impairment will be tested 
using the following null hypothesis:
H0: There is no difference in the mean change from baseline in SGRQ total score at 
week 12 between nintedanib co-administered with sildenafil compared to treatment 
with nintedanib.
The alternative hypothesis is
Ha: There is a difference in the mean change from baseline in SGRQ total score at 
week 12 between nintedanib co-administered with sildenafil compared to treatment 
with nintedanib.
A hierarchical testing procedure will be applied in order to allow for confirmative testing of 
the secondary endpoints related to SGRQ and UCSD SOBQ also. This procedure is specified in 
Table 7.2:1.


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Table 7.2:1 
Flow of hypothesis testing
Step 1
If H0 is rejected at 5% level (two-sided test) then go to the next step otherwise 
procedure is stopped and subsequent tests will be done only for exploratory 
purposes.
Step 2
H01: There is no difference in the mean change from baseline in UCSD SOBQ 
at week 12 between nintedanib co-administered with sildenafil compared to 
treatment with nintedanib.
Ha1: There is a difference in the mean change from baseline in UCSD SOBQ at 
week 12 between nintedanib co-administered with sildenafil compared to 
treatment with nintedanib.
If H01 is rejected at 5% level (two-sided test) then go to the next step otherwise 
procedure is stopped and subsequent tests will be done only for exploratory 
purposes.
Step 3
H02: There is no difference in the mean change from baseline in SGRQ total 
score at week 24 between nintedanib co-administered with sildenafil compared 
to treatment with nintedanib.
Ha2: There is a difference in the mean change from baseline in SGRQ total 
score at week 24 between nintedanib co-administered with sildenafil compared 
to treatment with nintedanib.
If H02 is rejected at 5% level (two-sided test) then go to the next step otherwise 
procedure is stopped and subsequent tests will be done only for exploratory 
purposes.
Step 4
H03: There is no difference in the mean change from baseline in UCSD SOBQ 
at week 24 between nintedanib co-administered with sildenafil compared to 
treatment with nintedanib.
Ha3: There is a difference in the mean change from baseline in UCSD SOBQ at 
week 24 between nintedanib co-administered with sildenafil compared to 
treatment with nintedanib. 
The hypotheses will be tested using 5% level of significance (two-sided test). Global type I 
error will be not exceed 5% within this procedure, thus no adjustment for multiplicity is 
required. 
Statistical tests performed for any other endpoints not included in the above defined testing 
procedure will also be done only for exploratory purposes.
PLANNED ANALYSES
7.3
The statistical analysis will be based on the Treated Set (TS), which consists of patients who
are randomised to a treatment group and receive at least one dose of randomised study
medication. 


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Most analyses will be based on the treatment group (nintedanib only or nintedanib co-
administered with sildenafil) as randomized. Safety parameters will be analyzed from an as 
treated perspective.
Although there is no per protocol set in the study, reasons for important protocol violations
will be specified in the Trial Statistical Analysis Plan (TSAP). Patients with potential
important protocol violations (those that relate to patient safety) will be identified at Blinded 
Review Planning Meetings and listed in the CTR and their impact will be evaluated.
7.3.1
Primary endpoint analyses
Change from baseline in SGRQ total score at week 12 will be analysed using REML based
MMRM. The model will include fixed effect for treatment, visit and presence of any 
echocardiographic signs indicative of right heart dysfunction including right ventricular 
hypertrophy and right ventricular or atrial dilatation (as described in section 6.2.1), baseline 
SGRQ total score as a covariate and treatment-by-visit and baseline-by visit as interaction 
terms. Baseline SGRQ total score will be measured at visit 2. No imputation is planned if this 
assessment is not available for a patient. An unstructured (co)variance matrix will be used to 
model the within-patient measurements. In case there is a lack of convergence, a Compound 
Symmetry (co)variance matrix will be used. The Roger-Kenward approximation will be used 
to estimate denominator degrees of freedom. Data collected after visit 5 (planned 12 weeks 
after start of study treatment) will not be used for this analysis. Analyses will be implemented 
using SAS® Version 9.4 or higher. The primary treatment comparisons will be the contrast 
between treatments at 12 weeks.
Sensitivity analysis: The effect of missing data will also be investigated using tipping point
sensitivity analyses. The technique will be detailed in the TSAP. The effect on the following 
subgroups will be explored:

sex (female/male)

age (<65, ≥65 years)

race (White, Asian, Other)

baseline FVC % predicted (<50%, ≥50%)

baseline St. George’s Respiratory Questionnaire (SGRQ) total score (≤40, >40)

presence of any echocardiographic signs indicative of right heart dysfunction (yes/no)
Within subgroup analyses, subgroup (if not already included in the primary analysis model) 
and treatment subgroup interaction effect will be added to the primary analysis model. The 
treatment subgroup interaction effect will be of primary interest for subgroup analyses. 
As needed, further details and/or further subgroups will be defined and described in the Trial 
Statistical Analysis Plan.


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7.3.2
Secondary endpoint analyses
Change from baseline in UCSD SOBQ at week 12 will be analysed using the same method as 
the primary endpoint, but with baseline UCSD SOBQ instead of SGRQ total score as 
covariate. Data collected after visit 5 (planned 12 weeks after start of study treatment) will 
not be used for this analysis.
Both changes from baseline in SGRQ and UCSD SOBQ at week 24 will be analysed as in the 
respective week 12 analysis. For these analyses, data collected from the complete 24 weeks 
treatment period will be used.
Percentages of patients with on-treatment SAEs from baseline to week 24 will be compared 
using the Cochran-Mantel-Haenszel test adjusting for the categorical covariate presence of 
any echocardiographic signs indicative of right heart dysfunction (yes/no). Adjusted Mantel-
Haenszel type risk ratios and risk differences with 95% confidence intervals will be used to 
quantify the treatment effect for the comparison between treatment groups.


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7.3.4
Safety analyses
Analysis of key safety endpoints is described in sections 7.3.2 and 7.3.3.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment 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.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  The residual effect 
period is defined as 28 days. Adverse events that start before first drug intake and deteriorate 
under treatment will also be considered as ‘treatment-emergent’.
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 Drug 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. Treatment groups will be compared descriptively 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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INTERIM ANALYSES
7.4
No interim analysis is planned but the conduct of the trial will be monitored by a DMC.
HANDLING OF MISSING DATA
7.5
In efficacy analyses of continuous endpoints missing data will not be imputed. In the analyses
of the time-to-event endpoints, missing or incomplete data are managed by standard survival
analysis techniques. These will be described in detail in the TSAP.
Missing or incomplete AE dates will be imputed according to BI standards. With respect to 
other safety evaluations, it is not planned to impute missing values.
In pharmacokinetic analyses, missing data will not be imputed. 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 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, and NOA are included). 
Descriptive statistics of parameters are also 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.
RANDOMISATION
7.6
Patients will be stratified by the presence of any echocardiographic signs indicative of right 
heart dysfunction including right ventricular hypertrophy and right ventricular or atrial 
dilatation (as described in section 6.2.1) and will be randomized in blocks to double-blind 
treatment. Approximately equal numbers of patients will be randomized to each treatment 


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group. BI will arrange for the randomization and the packaging and labelling of trial
medication. The randomization lists will be generated using a validated system, which 
involves a pseudo-random number generator so that the resulting treatment will be both 
reproducible and non-predictable. The block size will be documented in the CTR. Access to 
the codes will be controlled and documented.
DETERMINATION OF SAMPLE SIZE
7.7
The hypothesis for expected difference in the change from baseline in SGRQ total score at 
week 12 is -4.5 units between nintedanib co-administered with sildenafil compared to 
treatment with nintedanib alone using a two group t-test with a 0.025 one-sided significance 
level.
The assumed difference is based on observations made in the INPULSIS® trials, where the 
observed mean change from baseline to week 12 in SGRQ total score when treated with 
nintedanib alone was 0.75/0.05 units with a standard deviation of 12.93/11.64 (INPULSIS®-
1/INPULSIS®-2).
Based on the STEP-IPF trial [R12-3686], the mean change from baseline to week 12 in 
SGRQ total score when treated with sildenafil alone was -4.08 units with an estimated 
standard deviation of 11.02 units. It is assumed that the observed treatment effect remains 
stable when nintedanib is co-administered with sildenafil.
Therefore, power calculations are made based on the assumption of equal standard deviations 
among groups and an expected difference of -4.5 units.
Table 7.7: 1 presents the different scenarios for the sample size calculation.
Table 7.7: 1 Sample size calculations for difference in the change from baseline in SGRQ 
total score at week 12 assuming a group difference of -4.5 units for several 
standard deviations and a 1:1 randomisation ratio using a two group t-test with a 
0.025 one-sided significance level. 
Standard deviation
N per group
Total sample size
80% power
11
95
190
12
113
226
13
132
264
90% power
11
127
254
12
150
300
13
177
354
So, a sample size of 125 patients in both groups will have about 90% power to detect a
difference in means of -4.5 units in change from baseline in SQRG total score assuming that 


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the common standard deviation is 11 units using a two group t-test with a 0,025 one-sided 
significance level.
As we use a mixed model, including adjustment for several variable, this sample size based 
on t-test should provide at least 90% power.
Calculations were performed using nQuery Advisor® 6.1 statistical package by Statistical 
Solutions Ltd.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
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 and the Japanese GCP regulations (Ministry of Health and Welfare 
Ordinance No. 28, March 27, 1997) only for Japan.
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.
For Japan only: 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.
For Japan only: The Investigator must give a full explanation to trial patients including the 
items listed below in association with the use of the patient information form, which is 
prepared avoiding the use of technical terms and expressions. The patient is given sufficient 


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time to consider participation in the trial. The Investigator obtains written consent of the 
patient’s own free will with the informed consent form after confirming that the patient 
understands the contents. The Investigator must sign (or place a seal on) and date the 
informed consent form. If a trial collaborator has given a supplementary explanation, the trial 
collaborator also signs (or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
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
Electronic Case Report Forms (e)CRF 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.
8.3.2
Direct access to source data and documents
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 
medical 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.


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8.3.3
Storage period of records
For Japan only:
Trial site(s): The trial site(s) must retain the source documents and essential documents for a 
period defined by the Japanese GCP regulation and trial site’s contract with the sponsor.
Sponsor: The sponsor must retain the essential documents according to the sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the sponsor must notify the head of trial site.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
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 the nintedanib this is the current version of the Investigator’s Brochure [U07-1248].
For sildenafil the EU SmPC (Revatio®) serves as reference document.
The current versions of these reference documents are provided in the ISF. No AEs are 
classified as listed for matching placebo, trial design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IEC / IRB
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
8.5
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
8.6
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”). 


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The IEC / competent authority in each participating EU member state will be notified about 
the end or early termination of the trial.
For Japan only: When the trial is completed, the Investigator should inform the head of the 
trial site of the completion in writing, and the head of the trial site should promptly inform the 
IRB and sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
For Japan only: The investigator should document any deviation from the protocol regardless 
of their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal investigator 
should prepare and submit the records explaining the reasons thereof to the sponsor, and 
retain a copy of the records.
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
For Japan only: In the event of health injury associated with this trial, the sponsor is 
responsible for compensation based on the contract signed by the trial site.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
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Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
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Crestani B, Ogura T, Pelling K, Coeck C, Quaresma M, Kreuter M, Kaye M 
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R06-2002
Macintyre N, Crapo RO, Viegi G, Johnson DC, Grinten CPM van der, 
Brusasco V, Burgos F, Casaburi R, Coates A, Enright P, Gustafsson P, 
Hankinson J, Jensen R, McKay R, Miller MR, Navajas D, Pedersen OF, 
Pellegrino R, Wanger J Standardisation of the single-breath determination of 
carbon monoxide uptake in the lung. Eur Respir J 26 (4), 720 - 735 (2005)


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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)
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.pd f (2010)
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)
R12-3686 
Idiopathic Pulmonary Fibrosis Clinical Research Network. A controlled trial 
of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 363 (7), 
620 - 628 (2010)


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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)
R15-5445
Pulido T, Adzerikho I, Channick RN, Delcroix M, Galie N, Ghofrani HA, 
Jansa P, Jing ZC, Brun FO Le, Mehta S, Mittelholzer CM, Perchenet L, Sastry 
BKS, Sitbon O, Souza R, Torbicki A, Zeng X, Rubin LJ, Simonneau G, 
SERAPHIN Investigators Macitentan and morbidity and mortality in 
pulmonary arterial hypertension. N Engl J Med 369 (9), 809 - 818 (2013)
R15-5446
McLaughlin V, Channick RN, Ghofrani HA, Lemarie JC, Naeije R, Packer M, 
Souza R, Tapson VF, Tolson J, Hiti H al, Meyer G, Hoeper MM Bosentan 
added to sildenafil therapy in patients with pulmonary arterial hypertension. 
Eur Respir J 46, 405 - 413 (2015)
R15-5447
Ghofrani HA, Humbert M The role of combination therapy in managing 
pulmonary arterial hypertension. Eur Respir Rev 23, 469 - 475 (2014)
R96-0690
Cockcroft DW, Gault MH Prediction of creatinine clearance from serum 
creatinine. Nephron 16 (1), 31 - 41 (1976)
UNPUBLISHED REFERENCES
9.2
U07-1248
 Investigator’s brochure: Nintedanib (BIBF1120), Indication: 
Idiopathic Pulmonary Fibrosis. 1199.P3. Version 10. 23 Sep 2015.


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10.
APPENDICES
CRITERIA FOR HRCT/BIOPSY REVIEW
10.1
The following criteria should be assessed at screening for all patients based on a HRCT scan 
performed within 18 months of visit 1:
A)      Definite honeycomb lung destruction with basal and peripheral predominance.
B)      Presence of reticular abnormality AND traction bronchiectasis consistent with 
fibrosis with basal and peripheral predominance. 
C)      Atypical features are ABSENT, specifically: nodules and consolidation. Ground 
glass opacity, if present, is less extensive than reticular opacity pattern.
Patients with HRCT meeting either criteria A, B and C, or criteria A and C, or criteria B and 
C are eligible for this trial without the need of a surgical lung biopsy.
In the presence of a surgical lung biopsy, the histology should be reviewed based on the 
ATS/ERS/JRS/ALAT guidelines [P11-07084]. An HRCT pattern "possible UIP" coupled 
with a surgical biopsy pattern “definite UIP” or "probable UIP", upon multidisciplinary team 
discussion, could qualify for inclusion as “consistent with a diagnosis of IPF”.
CREATININE CLEARANCE
10.2
Creatinine clearance calculation is done according to Cockroft and Gault [R96-0690].
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum creatinine 
in mg/dL)


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ST GEORGE’S RESPIRATORY QUESTIONNAIRE (SGRQ)
10.3


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THE UCSD SHORTNESS OF BREATH QUESTIONNAIRE (UCSD-
10.4
SOBQ)


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EUROQOL-5D  (EQ-5D)
10.5
By placing a checkmark in one box in each group below, please indicate which
statements best describe your own health state today.
Mobility
I have no problems in walking about

I have some problems in walking about

I am confined to bed

Self-Care
I have no problems with self-care

I have some problems washing or dressing myself

I am unable to wash or dress myself

Usual Activities (e.g. work, study, housework, family or
leisure activities)
I have no problems with performing my usual activities

I have some problems with performing my usual activities

I am unable to perform my usual activities

Pain/Discomfort
I have no pain or discomfort

I have moderate pain or discomfort

I have extreme pain or discomfort

Anxiety/Depression
I am not anxious or depressed

I am moderately anxious or depressed

I am extremely anxious or depressed



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DLCO
10.6
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.
Predicted DLCO corrected for haemoglobin (Hb) expressed in g x dL-1 (R06-2002) can be 
calculated as:

Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(10.22+Hb)) for males 

Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(9.38+Hb)) for 
females 
For decision on inclusion / exclusion, DLCO results from Visit 1 will be corrected for 
haemoglobin (value obtained at visit 1) by the site. 
For analysis of the trial data, DLCO results will be corrected for haemoglobin by central data 
management. This means that the site has to enter the DLCO results without haemoglobin 
correction in the eCRF, at all visits.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
04 March 2016
EudraCT number
2015-002619-14
BI Trial number
1199.36
BI Investigational Product(s)
nintedanib
Title of protocol
A 24-week, double-blind, randomized, parallel-
group study evaluating the efficacy and safety of 
oral nintedanib co-administered with oral 
sildenafil, compared to treatment with nintedanib 
alone, in patients with idiopathic pulmonary 
fibrosis (IPF) and advanced lung function 
impairment
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
Yes
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
No
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
No
Section to be changed
Section 1.2.2 Sildenafil
Description of change
Potential risks of treatment with sildenafil include 
hypotension, worsening of pulmonary vascular 
occlusive disease, epistaxis, visual loss, hearing 
loss, priapism and vaso-occlusive crisis in patients 
with pulmonary hypertension secondary to sickle 
cell disease.
Was changed to:


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Potential risks of treatment with sildenafil include 
hypotension, worsening of pulmonary veno-
occlusive disease, epistaxis, visual loss, hearing 
loss, priapism and vaso-occlusive crisis in patients 
with pulmonary hypertension secondary to sickle 
cell disease.
Rationale for change
Rewording.
Section to be changed
Section 2.3 Benefit – Risk assessment
Description of change
Potential risks of treatment with sildenafil include 
hypotension, worsening of pulmonary vascular 
occlusive disease, epistaxis, visual loss, hearing 
loss, priapism and vaso-occlusive crisis in patients 
with pulmonary hypertension secondary to sickle 
cell disease. Patients at higher risk for these 
conditions are excluded from this trial.
Was changed to:
Potential risks of treatment with sildenafil include 
hypotension, worsening of pulmonary veno-
occlusive disease, epistaxis, visual loss, hearing 
loss, priapism and vaso-occlusive crisis in patients 
with pulmonary hypertension secondary to sickle 
cell disease. Patients at higher risk for these 
conditions are excluded from this trial.
Rationale for change
Rewording
Section to be changed
Section 3.3 Selection of trial population
Description of change
A total of approximately 250 patients with an IPF 
diagnosis and advanced lung function impairment 
will be randomized. Approximately 60 sites are 
each expected to include approximately 4 patients.
Was changed to:
A total of approximately 250 patients with an IPF 
diagnosis and advanced lung function impairment 
will be randomized. Approximately 80 sites are 
each expected to include approximately 3 patients. 
Rationale for change
Number of participating sites (increase) and 
average number of patients per site (decrease) 
adjusted following site feasibility.


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Section to be changed
Section 3.3.3 Exclusion criterion and 
abbreviations
Description of change
In exclusion criterion #6 Partial Thromboplastin 
Time (PTT) was replaced by Activated Partial 
Thromboplastin Time. The same has been 
corrected in the Abbreviations section.
Rationale for change
Correction / rewording 
Section to be changed
Section 3.3.3 Exclusion criterion
Description of change
Exclusion criterion #34 has been added:
Patients with underlying chronic liver disease 
(Child Pugh A, B or C hepatic impairment)
Rationale for change
Based on interactions with regulatory authorities 
including the FDA, the recommended dosage of 
nintedanib for patients with Child Pugh A hepatic 
impairment is 100 mg bid which has been recently 
included into the US Prescribing Information. As 
in the current protocol all patients should initiate 
treatment with the same starting dose of 
nintedanib 150 mg bid, patients with Child Pugh A 
will be excluded. In addition, patients with Child 
Pugh B and C hepatic impairment will also be 
excluded to again be in line with the information 
stated in the US Prescribing Information that 
treatment with nintedanib in these patients is not 
recommended.
Section to be changed
Section 5.4.1 Assessment of Pharmacokinetics; 
Section 5.4.2 Methods of sample collection and 
Section 5.4.3 Analytical determinations
Description of change
5.4.1 Assessment of Pharmacokinetics


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Pre-dose plasma samples of nintedanib and its 
metabolites, BIBF 1202 and BIBF 1202
glucuronide, will be taken according to the flow 
chart.
Was changed to:
Pre-dose plasma samples of nintedanib will be 
taken according to the flow chart.
5.4.2 Methods of sample collection
A detailed description of sample collection and 
handling is provided in the ISF/lab manual. For 
quantification of drug plasma concentrations of 
nintedanib (BIBF 1120) and its metabolites BIBF 
1202 and BIBF 1202- glucuronide, 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 1 vial (at least 0.5 
mL plasma). After completion of the study, the 
plasma samples may be used for further 
methodological investigations, e.g. stability 
testing. However, only data related to nintedanib 
and/or its metabolite(s) will be generated by these 
additional investigations.
Was changed to:
A detailed description of sample collection and 
handling is provided in the ISF/lab manual. For 
quantification of drug plasma concentrations of 
nintedanib, 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 1 vial (at 
least 0.5 mL plasma).
After completion of the study, the plasma samples 
may be used for further methodological 
investigations, e.g. stability testing. However, only 
data related to nintedanib will be generated by 
these additional investigations.
5.4.3 Analytical determinations
Nintedanib (in form of its free base BIBF 1120 
BS), its metabolites BIBF 1202 (in form of the 


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free zwitterion BIBF 1202 ZW) and the 
acylglucuronid thereof (BIBF 1202 glucuronide)
plasma concentrations will be determined by a 
validated assay based on liquid chromatography-
tandem mass spectrometry (LC-MS/MS).
Was changed to:
Nintedanib (in form of its free base BIBF 1120 
BS) plasma concentrations will be determined by a 
validated assay based on liquid chromatography-
tandem mass spectrometry (LC-MS/MS). 
Rationale for change
As none of the measured metabolites is active, 
metabolite assessment is not necessary and does 
not add any important additional information to 
the study. Following validation of a BIBF 1120 
only bioanalytical assay, it is now possible to 
measure just one analyte. Only pre-dose plasma 
concentration of nintedanib will be measured.
Section to be changed
Section 5.5.1 Blood, serum and RNA samples for 
pre-specified biomarker analyses.
Description of change
Overall, approximately 72.5 mL blood will be 
taken for exploratory biomarker assessment and 
banking during the course of the trial.
Was changed to:
Overall, approximately 114 mL blood will be 
taken for exploratory biomarker assessment and 
banking during the course of the trial.
Rationale for change
Correction of blood volume to be collected for the 
analysis of biomarkers.


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Number of global amendment
2
Date of CTP revision
18 Aug 2016
EudraCT number
2015-002619-14
BI Trial number
1199.36
BI Investigational Product(s)
nintedanib
Title of protocol
A 24-week, double-blind, randomized, parallel-
group study evaluating the efficacy and safety of 
oral nintedanib co-administered with oral 
sildenafil, compared to treatment with nintedanib 
alone, in patients with idiopathic pulmonary 
fibrosis (IPF) and advanced lung function 
impairment
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
No
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
No
Section to be changed
Title
Description of change
A 24-week, double-blind, randomized, parallel-
group study evaluating the efficacy and safety of 
oral nintedanib co-administered with oral 
sildenafil, compared to treatment with nintedanib 
alone, in patients with idiopathic pulmonary 
fibrosis (IPF) and advanced lung function 
impairment
Was changed to :
INSTAGETM: A 24-week, double-blind, 
randomized, parallel-group study evaluating the 
efficacy and safety of oral nintedanib co-
administered with oral sildenafil, compared to 


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treatment with nintedanib alone, in patients with 
idiopathic pulmonary fibrosis (IPF) and advanced 
lung function impairment
Rationale for change
A trade name is now assigned for this study.
Section to be changed
ABBREVIATIONS
Description of change
Was added:
FEV1 Forced Expiratory Volume in 1 second
MACE Major Adverse Cardiovascular Events
Rationale for change
First definition was missing, second one was 
added.
Section to be changed
Section 1.2.1 Nintedanib
Description of change
Potential risks of nintedanib treatment also include 
arterial hypertension, gastrointestinal perforations, 
thromboembolism and bleeding. 
Was changed to :
Risks of nintedanib treatment also include arterial 
hypertension, gastrointestinal perforations, 
thromboembolism, pancreatitis, thrombocytopenia
and bleeding. 
Rationale for change
Addition of pancreatits and thrombocytopenia as 
risks of treatment with nintedanib in line with the 
new information provided in the Investigators 
Brochure (version 11, dated 21 Jul 2016).
Section to be changed
Section 2.3 Benefit – Risk assessment
Description of change
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.
Was changed to :
Risks of nintedanib treatment also include arterial 
hypertension, gastrointestinal perforations, 
thromboembolism, pancreatitis, thrombocytopenia
and bleeding. Therefore, patients requiring full 
dose concomitant anticoagulation, fibrinolysis or 
high-dose antiplatelet therapy will be excluded 
from this trial.
Rationale for change
Addition of pancreatitis and thrombocytopenia as 
risks of treatment with nintedanib in line with the 


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new information provided in the Investigators 
Brochure (version 11, dated 21 Jul 2016).
Section to be changed
Section 3.1.1 Administrative structure of the trial
Description of change
All death cases will be assessed (to evaluate the 
primary cause of death), as well as all acute IPF 
exacerbations (based on written clinical reports, for 
diagnostic confirmation) by an independent 
Adjudication Committee (AC), in a blinded 
manner before data base lock. The tasks and 
responsibilities of the DMC and the AC will be 
specified in a charter. 
Was changed to :
All death cases will be assessed (to evaluate the 
primary cause of death), as well as all adverse 
events categorized as major adverse cardiovascular 
events (MACE) and all acute IPF exacerbations 
(based on written clinical reports, for diagnostic 
confirmation) by an independent Adjudication 
Committee (AC), in a blinded manner before data 
base lock. The tasks and responsibilities of the 
DMC and the AC will be specified in a charter. 
Rationale for change
MACE events will also be assessed by the 
Adjudication Committee
Section to be changed
Section 3.3.2 Inclusion criteria 
Section 3.3.3 Exclusion criteria
Description of change
3.3.2 Inclusion criteria
5. DLCO (corrected for Hb) ≤ 35% predicted of 
normal at visit 1
Was changed to :
5. DLCO (corrected for Hb) ≤ 35% predicted of 
normal at visit 11
3.3.3 Exclusion criteria
4. Relevant airways obstruction (i.e. pre-
bronchodilator FEV1/FVC <0.7 at visit 1);
Was changed to :
4. Relevant airways obstruction (i.e. pre-
bronchodilator FEV1/FVC <0.7 at visit 1)1;
3.3.3 Exclusion criteria


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9. Creatinine clearance < 30 mL/min calculated by 
Cockcroft–Gault formula (appendix 10.2) at visit 
1;
Was changed to :
9. Creatinine clearance < 30 mL/min calculated by 
Cockcroft–Gault formula (appendix 10.2) at visit 
11;
3.3.3 Exclusion criteria
15. Uncontrolled systemic hypertension (SBP > 
180 mmHg; DBP > 100 mmHg) at visit 1
Was changed to :
15. Uncontrolled systemic hypertension (SBP > 
180 mmHg or DBP > 100 mmHg) at visit 11
3.3.3 Exclusion criteria
23. Treatment for pulmonary hypertension with 
prostaglandins (e.g., epoprostenol, treprostinil), 
endothelin-1 antagonists (e.g., bosentan, 
sitaxsentan, ambrisentan), phosphodiesterase 
inhibitors (e.g., sildenafil, tadalafil, vardenafil) or a 
stimulator of guanylatcyclase (e.g., riociguat) 
within 4 weeks of visit 2;
Was changed to :
23. Treatment with prostaglandins (e.g., 
epoprostenol, treprostinil), endothelin-1 
antagonists (e.g., bosentan, sitaxsentan, 
ambrisentan), phosphodiesterase inhibitors (e.g., 
sildenafil, tadalafil, vardenafil) or a stimulator of 
guanylatcyclase (e.g., riociguat) within 4 weeks of 
visit 2;
1Laboratory parameters 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.
Was changed to :
1Laboratory parameters, blood pressure and lung 


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function tests 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.
Rationale for change
To allow retest within the screening period of 
examinations required to assess inclusion criterion
#5 and exclusion criteria 4, 9 and 15. Clarification 
of exclusion criterion #15 and #23.
Section to be changed
Section 4.2.2 Restrictions
Table 4.2.2.1:1
Description of change
Prior 
to 
rando
misatio
n
During 
treatm
ent 
period
After 
Visit 7 
(Follow
-up 
Period)
After 
early 
EOT9
Treatment for 
PAH with 
prostaglandins
3, endothelin-1 
antagonists4 or 
phosphodieste
rase 
inhibitors5 or a 
stimulator of 
guanylatcyclas
e 6
Not 
permitt
ed in 
the 4 
weeks 
prior to 
visit 2 1
Not 
permitt
ed
Not 
permitte
d
Not 
permit
ted
Was changed to:
Prior 
to 
rando
misati
on
During 
treatm
ent 
period
After 
Visit 7 
(Follo
w-up 
Period
)
After 
early 
EOT9
Prostaglandins
3, endothelin-1 
antagonists4 or 
phosphodiester
ase inhibitors5
or a stimulator 
of 
guanylatcyclas
e 6
Not 
permitt
ed in 
the 4 
weeks 
prior to 
visit 2 1
Not 
permitt
ed
Not 
permitt
ed
Not 
permitt
ed
Rationale for change
Clarification of restricted concomitant therapy
Section to be changed
Section 5.2.2 Forced Vital Capacity, Carbon 
Monoxide Diffusion Capacity, Alveolar Volume, 
Oxygen Saturation and Arterialised Blood Gases
Description of change
Oxygen saturation (SpO2) will be measured at rest 
by standard pulse oximetry (unaffected skin of 
earlobe or forehead). Arterialised blood gases 


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(PaO2 and PaCO2) will be measured in selected 
sites experienced in earlobe capillary blood gas 
sampling. Values will be entered in the eCRF.
Was changed to :
Oxygen saturation (SpO2) will be measured at rest 
by standard pulse oximetry (unaffected skin of 
earlobe or fingertip). Arterialised blood gases 
(PaO2 and PaCO2) will be measured in selected 
sites experienced in earlobe capillary blood gas 
sampling. Values will be entered in the eCRF.
Rationale for change
Correction of the site for measurement of oxygen 
saturation.
Section to be changed
Section 5.2.3 Acute IPF exacerbations
Description of change
Acute IPF exacerbations are defined as otherwise 
unexplained clinical features within one
month, including all of the following:
Unexplained worsening or development of 
dyspnoea within 30 days;
New diffuse pulmonary infiltrates on chest X-
ray, and/or new HRCT parenchymal
abnormalities with no pneumothorax or pleural 
effusion (new ground-glass opacities) since the 
last visit;
Exclusion of infection as per routine clinical 
practice and microbiological studies;
Exclusion of alternative causes as per routine 
clinical practice, including left heart failure, 
pulmonary embolism or any identifiable cause 
of acute lung injury.
Was changed to :
Acute IPF exacerbation is defined as an acute, 
clinically significant, respiratory deterioration 
characterized by evidence of new widespread 
alveolar abnormality [P16-06899]. 
Extra-parenchymal causes (e.g. pneumothorax, 
pleural effusion, pulmonary embolism) should be 
excluded and the following 3 diagnostic criteria 
need to be met:
Acute worsening or development of dyspnea 
typically of less than one month duration;
Computed tomography with new bilateral 
ground-glass opacity and/or consolidation 
superimposed on a background pattern 


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consistent with usual interstitial pneumonia 
pattern;
Deterioration not fully explained by cardiac 
failure or fluid overload.
Events that are clinically considered to meet the 
definition of acute exacerbation of IPF but fail to 
meet the three diagnostic criteria due to missing 
computed tomography data will be termed 
“suspected acute exacerbations” by the 
Adjudication Committee.
Rationale for change
Update of the definition of acute IPF exacerbation 
in line with new definition recently published by 
an international working group (Collard et. al. 
2016)
Section to be changed
Section 5.5.2 Biobanking (optional)
Description of change
Was added:
If not authorized by a local IRB / IEC / Competent 
Authority, biobanking will not be performed for 
patients of the respective site / country (as 
applicable).
Rationale for change
Clarification that biobanking is an optional 
procedure and requires local approval.
Section to be changed
Section 6.2.1 Screening and run-in period(s)
Description of change
Patients who have a laboratory test value that is 
outside the range specified by the exclusion criteria 
may have the test repeated once to determine 
eligibility; however, the result must be available 
prior to visit 2.
Was changed to :
Patients who have a laboratory test, blood pressure 
or lung function test value outside the range 
specified by the exclusion criteria and thought to 
be a measurement error or the result of a temporary 
and reversible medical condition may have the test 
repeated once to determine eligibility; however, 
the result must be available prior to visit 2.
Rationale for change
To allow retest within the screening period of 
examinations required to assess inclusion criterion 
#5 and exclusion criteria 4, 9 and 15.
Section to be changed
Description of change


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Rationale for change
Section to be changed
Section 9.1
Description of change
Was added :
P16-06899 Collard HR, Ryerson CJ, Corte TJ, 
Jenkins G, Kondoh Y, Lederer DJ, et al
Acute exacerbation of idiopathic pulmonary 
fibrosis: an international working group report. Am 
J Respir Crit Care Med, (2016)
Rationale for change
Reference added
Section to be changed
Section 10.2
Description of change
In the presence of a surgical lung biopsy, the 
histology should be reviewed based on the
ATS/ERS/JRS/ALAT guidelines [P11-07084]. An 
HRCT "possible IPF" coupled with a
surgical biopsy of “definite UIP” or "probable 


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UIP", upon multidisciplinary team discussion,
could qualify for inclusion as “consistent with 
IPF”.
Was changed to :
In the presence of a surgical lung biopsy, the 
histology should be reviewed based on the 
ATS/ERS/JRS/ALAT guidelines [P11-07084]. An 
HRCT pattern "possible UIP" coupled with a 
surgical biopsy pattern “definite UIP” or "probable 
UIP", upon multidisciplinary team discussion, 
could qualify for inclusion as “consistent with a 
diagnosis of IPF”.
Rationale for change
Correction/rewording according to the guidelines.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03484701
3.0
clinical-trial-protocol-version-03
INSTAGE: A 24-week, double-blind, randomized, parallel-group study evaluating
the efficacy and safety of oral nintedanib co-administered with oral sildenafil,
compared to treatment with nintedanib alone, in patients with idiopathic pulmonary
fibrosis (IPF) and advanced lung function impairment
Author-Trial Clinical Monitor
18 Aug 2016 13:15 CEST
Approval-Team Member Medical
Affairs
18 Aug 2016 13:28 CEST
Approval-Project Statistician
18 Aug 2016 13:51 CEST
Approval-Team Member Medical
Affairs
18 Aug 2016 14:12 CEST
Approval-Therapeutic Area 
18 Aug 2016 14:21 CEST
Author-Trial Clinical
Pharmacokineticist
22 Aug 2016 08:21 CEST
Verification-Paper Signature
Completion
22 Aug 2016 21:01 CEST


Boehringer Ingelheim 
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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03484701
3.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c11290811-03
BI Trial No.:
1199.36
Title:
INSTAGETM: A 24-week, double-blind, randomized, parallelgroup 
study evaluating the efficacy and safety of oral nintedanib co-
administered with oral sildenafil, compared to treatment with
nintedanib alone, in patients with idiopathic pulmonary fibrosis
(IPF) and advanced lung function impairment
Including Protocol Amendment 2 [c03484701-03]
Investigational
Product(s):
Nintedanib (Ofev®)
Responsible trial 
statistician(s):
Phone :
Fax : 
Date of statistical 
analysis plan:
24 MAY 2018 SIGNED
Version:
Final version 
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................7
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
....................................................9
....................................................9
..................................................11
..................................................11
..................................................11
..................................................11
..................................................12
..................................................13
..................................................13
..................................................13
..................................................13
..................................................14
..................................................14
..................................................15
..................................................15
..................................................16
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................17
6.1
TREATMENTS...................................................................................................17
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................18
6.3
PATIENT SETS ANALYSED...........................................................................23
....................................................................................................24
6.5
POOLING OF CENTRES .................................................................................24
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................24
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................26
7.
PLANNED ANALYSIS......................................................................................31
7.4
PRIMARY ENDPOINT .....................................................................................32
7.4.1
Primary analysis..................................................................................................33


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7.5
SECONDARY ENDPOINTS.............................................................................35
7.5.1
Key secondary endpoints....................................................................................35
7.5.2
Secondary endpoints...........................................................................................35
7.8
SAFETY ANALYSIS..........................................................................................38
7.8.1
Adverse events.....................................................................................................39
7.8.2
Laboratory data ..................................................................................................45
7.8.3
Vital signs.............................................................................................................46
7.8.4
ECG......................................................................................................................46
7.8.5
Others...................................................................................................................46
.....................................47
.....................................47
.....................................49
8.
REFERENCES....................................................................................................49
.........................................................................50
10.
HISTORY TABLE..............................................................................................50


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................18
Table 6.3: 1
Patient sets analyzed.........................................................................................23
Table 6.7: 2
Time windowing rules for SGRQ, UCSD SOBQ, EQ-5D, Resting SpO2 .......28
Table 7.8.1: 1 Adverse events by system using aggregated terms...........................................41
............................48
Table 10: 1
History table .....................................................................................................50
2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine Transaminase
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Transaminase
ATC
Anatomical Therapeutic Chemical classification system
bid
bis in die (twice daily dosing)
BRPM
Blinded report planning meeting
BMS
Biomarker analysis set
cpm
counts per million
CT
Concomitant Therapies
CTC
Common Terminology Criteria
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBP
Diastolic Blood Pressure
DLCO
Carbon Monoxide Diffusion Capacity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual


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Term
Definition / description
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
ECG
Electrocardiogram
ECHO
Echocardiogram
EF
Ejection Fraction
EMA
European Medicines Agency
EOT
End of Treatment
FAS
Full analysis set
FDR
False Discovery Rate
FVC
Forced Vital Capacity
FUP
Follow-Up
Hb
Hemoglobin
HGNC
HUGO Gene Nomenclature Committee
HRCT
High-resolution Computed Tomography
HUGO
Human Genome Organisation
ICH
International Conference on Harmonisation
IHSS
Idiopathic Hypertrophic Subaortic Stenosis
INR
International Normalised Ratio
IPF
Idiopathic Pulmonary Fibrosis
IU
International Units
Kco
Carbon Monoxide Transfer Coefficient
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MAR
Missing at Random
MI
Multiple Imputation
MMRM
Mixed Effects Model for Repeated Measures
MQRM
Medical Quality Review Meeting
O*C
Oracle Clinical
PaCO2
Partial Pressure of Carbon Dioxide
PAH
Pulmonary Arterial Hypertension
PK
Pharmacokinetics
PKS
Pharmacokinetics set


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Term
Definition / description
PN
Preferred name
PPS
Per protocol set
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
REP
Residual effect period
RPKM
Read counts per million
SA
Statistical analysis
SAE
Serious Adverse Event
SBP
Systolic Blood Pressure
SD
Standard deviation
SGRQ
St. George’s Respiratory Questionnaire
SMQ
Standardised MedDRA query
SpO2
Oxygen Saturation
SOC
System organ class
SSC
Special Search Category
TCM
Trial Clinical Monitor
TESS
Treatment emergent signs and symptoms 
tid
ter in die (3 times a day)
TMW
Trial Medical Writer
ToC
Table of contents
TPM
Transcripts per million
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper Limit of Normal
UCSD SOBQ
University of California San Diego Shortness of Breath Questionnaire
VA
Alveolar Volume


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), 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, randomization.
SAS® Version 9.4 (or later version) will be used for all analyses.
Analyses of differential gene expression will be performed using R version 3.0.2 or later (R
Core Team (2013). R: A language and environment for statistical computing. R Foundation
for Statistical Computing, Vienna, Austria. weblink R-project.org) in conjunction with limma
package version 3.18.13 or later (Smyth GK, Limma: linear models for microarray data,
Bioinformatics and Computational Biology Solutions Using R and Bioconductor 397-420,
2005).


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5.
ENDPOINTS
Refer to Section 6.6 for missing baseline assessment.
Refer to Section 6.7 for baseline value definition. 
5.1
PRIMARY ENDPOINT
The primary endpoint is change from baseline in St George’s Respiratory Questionnaire 
(SGRQ) total score at week 12. Refer to the St George’s Respiratory Questionnaire (SGRQ) 
manual (2) for calculations of SGRQ scores.
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
The secondary endpoints are defined in Section 5.1.2 of the CTP and are:

Change from baseline in dyspnea using the University of California San Diego 
Shortness of Breath Questionnaire (UCSD SOBQ) at week 12.
The questionnaire should be scored as a simple sum of all items.

Change from baseline in SGRQ total score at week 24.

Change from baseline in dyspnea using UCSD SOBQ at week 24.
The questionnaire should be scored as a simple sum of all items.

Percentage of patients with on-treatment Serious Adverse Events (SAE) from baseline
to week 24.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
The following trial periods will be defined: screening, post-randomisation, 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 randomisation
•
Post-randomisation (optional): from randomisation to first randomised trial drug 
intake in treatment period
•
Treatment period: from first randomised trial drug intake (or re-start of treatment if 
interruption) to last randomised trial drug intake (or the day before start date of 
interruption, if interruption) plus one day
•
Off-treatment (optional): from start date of interruption to re-start of treatment
•
Residual effect period (optional): from the last trial drug intake plus one day to last 
trial drug intake plus 28 days plus one day
•
Follow-up (optional): 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, or for patients having prematurely discontinued 
the treatment and still continuing the trial


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•
Post-study: from the latest of last trial drug intake plus 29 days / date of trial 
completion / follow-up visit / early end of treatment visit plus 1 day to database lock
For safety analyses, data up to 28 days after last trial drug intake (included) will be considered 
on-treatment. For on-treatment efficacy analyses, data up to the day after last trial drug intake 
(included) will be considered.
For safety and efficacy analyses, patients will be assigned to the treatment group they were 
randomised to.
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 which analysis set(s).
Table 6.2: 1
Important protocol violations
Cate
gory
Description
Requirements / Classification
Excluded 
from
A
Entrance criteria not met
A1.1
Age < 40 years at Visit 1
Inclusion criterion 2 not met as specified in 
the protocol.
Automatic IPV
None
A1.2
No clinical diagnosis of IPF within 
the last 6 years before Visit 1,
based upon the
ATS/ERS/JRS/ALAT 2011 
guideline
Inclusion criterion 3 not met as specified in 
the protocol.
Automatic IPV
None
A1.3
Combination of HRCT pattern and 
surgical lung biopsy pattern (the 
latter if available) as assessed by 
the investigator is not consistent 
with the diagnosis of IPF as 
assessed by the investigator based 
on a HRCT scan performed within 
18 months of visit 1
Inclusion criterion 4 not met as specified in 
the protocol.
Automatic IPV
None
A1.4
DLCO (corrected for Hb) > 35% 
predicted of normal at visit 1
Inclusion criterion 5 not met as specified in 
the protocol.
Automatic IPV
None
A2.1
Previous enrolment in this trial
Exclusion criterion 1 met as specified in the
protocol 
Automatic IPV
None
A2.2
ALT, AST, Total bilirubin > 1.5 
fold upper limit of normal (ULN) 
at Visit 1
Exclusion criteria 2 or 3 met as specified in 
the protocol
Automatic IPV
None
A2.3
Relevant airways obstruction [i.e. 
pre-bronchodilator FEV1/FVC < 
0.7 at Visit 1]
Exclusion criterion 4 met as specified in the 
protocol
Automatic IPV
None
A2.4
History of myocardial infarction 
within 6 months of visit 1 or 
unstable angina within 1 month of 
Visit 1
Exclusion criterion 5 met as specified in the 
protocol (for more details refer to the 
protocol)
Automatic IPV
None


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Table 6.2: 1
Important protocol violations (cont’d)
Cate
gory
Description
Requirements / Classification
Excluded 
from
A
Entrance criteria not met
A2.5
Bleeding Risk
Exclusion criterion 6 met as specified in the 
protocol
Automatic IPV
None
A2.6
Planned major surgery during the 
trial participation, including lung
transplantation, major abdominal 
or major intestinal surgery
Exclusion criterion 7 met as specified in the 
protocol
Automatic IPV
None
A2.7
History of thrombotic event 
(including stroke and transient 
ischemic attack) within 12 months 
of Visit 1
Exclusion criterion 8 met as specified in the 
protocol
Automatic IPV
None
A2.8
Creatinine clearance < 30 mL/min 
calculated by Cockcroft–Gault 
formula at Visit 1
Exclusion criterion 9 met as specified in the 
protocol
Automatic IPV
None
A2.9
Presence of aortic stenosis (AS) 
per investigator judgement at visit 
1
Exclusion criterion 10 met as specified in the 
protocol
Automatic IPV
None
A2.10
Severe chronic heart failure: 
defined by left ventricular ejection 
fraction (EF) < 25% per 
investigator judgement at visit 1
Exclusion criterion 11 met as specified in the 
protocol
Automatic IPV
None
A2.11
Presence of idiopathic 
hypertrophic subaortic stenosis 
(IHSS) per investigator judgement 
at visit 1
Exclusion criterion 12 met as specified in the 
protocol
Automatic IPV
None
A2.12
Second-degree or third-degree 
atrioventricular (AV) block on 
electrocardiogram
(ECG) per investigator judgement 
at visit 1
Exclusion criterion 13 met as specified in the 
protocol
Automatic IPV
None
A2.13
Hypotension (systolic blood 
pressure [SBP] < 100 mm Hg or 
diastolic blood pressure [DBP] < 
50 mm Hg) (symptomatic
orthostatic hypotension) at visit 1
Exclusion criterion 14 met as specified in the 
protocol
Automatic IPV
None
A2.14
Uncontrolled systemic 
hypertension (SBP > 180 mmHg; 
DBP > 100 mmHg) at visit 1
Exclusion criterion 15 met as specified in the 
protocol
Automatic IPV
None
A2.15
Known penile deformities or 
conditions (e.g., sickle cell 
anemia, multiple myeloma,
leukemia) that may predispose to 
priapism
Exclusion criterion 16 met as specified in the 
protocol
Automatic IPV
None
A2.16
Retinitis pigmentosa
Exclusion criterion 17 met as specified in the 
protocol
Automatic IPV
None
A2.17
History of vision loss
Exclusion criterion 18 met as specified in the 
protocol
Automatic IPV
None
A2.18
History of nonarteritic ischemic 
optic neuropathy
Exclusion criterion 19 met as specified in the 
protocol
Automatic IPV
None


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Table 6.2: 1
Important protocol violations (cont’d)
Cate
gory
Description
Requirements / Classification
Excluded 
from
A
Entrance criteria not met
A2.19
Veno-occlusive disease
Exclusion criterion 20 met as specified in the 
protocol
Automatic IPV
None
A2.20
History of acute IPF exacerbation 
or respiratory infection within 8 
weeks of visit 2
Exclusion criterion 21 met as specified in the 
protocol
Automatic IPV
None
A2.21
Treatment with nitrates, n-
acetylcysteine, pirfenidone, 
azathioprine, cyclophosphamide, 
cyclosporine, prednisone >15 mg 
daily or >30 mg every 2 days OR 
equivalent dose of other oral 
corticosteroids as well as any 
investigational drug within 4
weeks of visit 2
Exclusion criterion 22 met as specified in the 
protocol
Automatic IPV
None
A2.22
Treatment with prostaglandins 
(e.g., epoprostenol, treprostinil), 
endothelin-1 antagonists (e.g., 
bosentan, sitaxsentan, 
ambrisentan), phosphodiesterase 
inhibitors (e.g., sildenafil, 
tadalafil, vardenafil) or a 
stimulator of
guanylatcyclase (e.g., riociguat) 
within 4 weeks of visit 2
Exclusion criterion 23 met as specified in the 
protocol
Automatic IPV
None
A2.23
Treatment with potent CYP3A4 
inhibitors such as ketoconazole, 
itraconazole and ritonavir within 4 
weeks of visit 2
Exclusion criterion 24 met as specified in the
protocol
Automatic IPV
None
A2.24
Supplementation with L-arginine 
and concurrent use of grapefruit 
juice or St John’s wort within 4 
weeks of visit 2
Exclusion criterion 25 met as specified in the 
protocol
Automatic IPV
None
A2.25
Treatment with the reduced dose 
of nintedanib (100 mg bid) within 
4 weeks of visit 2
Exclusion criterion 26 met as specified in the 
protocol
Automatic IPV
None
A2.26
Permanent discontinuation of 
nintedanib in the past due to 
adverse events considered
drug-related
Exclusion criterion 27 met as specified in the 
protocol
Automatic IPV
None
A2.27
Known hypersensitivity or 
intolerance to nintedanib, 
sildenafil, galactose, peanut or 
soya or any other components of 
the study medication
Exclusion criterion 28 met as specified in the 
protocol
Automatic IPV
None
A2.28
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
Exclusion criterion 29 met as specified in the 
protocol
Automatic IPV
None


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Table 6.2: 1
Important protocol violations (cont’d)
Cate
gory 
Description
Requirements / Classification
Excluded 
from
A
Entrance criteria not met
A2.29
Alcohol or drug abuse which in the 
opinion of the treating physician 
would interfere with the treatment 
Exclusion criterion 30 met as specified in the 
protocol
Automatic IPV
None
A2.30
Women who are pregnant, nursing, 
or who plan to become pregnant 
while in the trial, or who are of 
childbearing potential  and not 
willing or able to use highly 
effective methods of birth control
Exclusion criteria 31 and 32 met as specified 
in the protocol
Automatic IPV
None
A2.31
Inability to understand and follow 
any study procedures such as but
not limited to completion of self-
administered questionnaires 
without help
Exclusion criterion 33 met as specified in the 
protocol
Automatic IPV
None
A2.32
Underlying chronic liver disease 
(Child Pugh A, B or C hepatic
impairment)
Exclusion criterion 34 met as specified in the 
protocol
Automatic IPV
None
B
Informed consent
B1
Informed consent not available/not 
done
Inclusion criterion 1 met as specified in the 
protocol
Automatic IPV
None
B2
Informed consent too late
Inclusion criterion 1 not met as specified in 
the protocol.
Medical review during MQRM, BRPM or 
DBLM
None
B3
Informed consent not given for
pharmacogenetics samples 
(unspecified part) but 
pharmacogenetics sample collected 
and analyzed
According to pharmacogenetics database and 
CRF
Automatic IPV
None
B4
Informed consent too late for
pharmacogenetics samples 
(unspecified part) but 
pharmacogenetics sample collected 
and analyzed
Medical review during MQRM, BRPM or 
DBLM
None
B5
Informed consent not given for
serum banking samples 
(unspecified part) but serum 
banking sample collected and 
analyzed
According to serum banking database and 
CRF
Automatic IPV
None
B6
Informed consent too late for
serum banking samples 
(unspecified part) but serum 
banking sample collected and 
analyzed
Medical review during MQRM, BRPM or 
DBLM
None


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Table 6.2: 1
Important protocol violations (cont’d)
Cate
gory
Description
Requirements / Classification
Excluded 
from
C
Trial medication and 
randomization
C1
Incorrect trial medication taken
Wrong medication number use at any 
time (after Visit 2) during the trial. IPV 
only if medication error leads to an 
actual treatment switch (will be 
determined after unblinding). Medical
review of MQRM listings
None
C2
Randomization not followed
Wrong medication number given 
leading to the patient taking treatment 
different from the one randomized by 
IXRS at time of
randomization (Visit 2). IPV only if 
medication error leads to an actual
treatment switch. (to be determined 
after unblinding).
Medical review of MQRM listings
None
C3
Wrong stratum selected during 
randomization
Wrong stratum selected in IXRS during 
randomization (Visit 2)
Medical review of MQRM listings
None
C5
Medication code broken 
inappropriately
Except for emergency situation.
Medical review of MQRM listings
None
C6
Drug not permanently discontinued 
despite criteria of Section 3.3.4.1 of 
CTP met
Medical review of MQRM listings
None
D
Concomitant medication
D1
Patient received prohibited 
concomitant therapies during 
treatment with any of the trial drugs
Medical review of MQRM
listings
None
E
Missing data
E1
No possible to calculate post-
baseline SGRQ total score  up to 
Week 24 and patient not died or 
withdrew consent before scheduled 
visit 3
Automatic IPV
None
E2
Not possible to calculate baseline 
SGRQ total score
Automatic IPV
None
E3
Serious non-compliance potentially 
affecting primary endpoint
Review of  PVs escalated from Quality 
Management tool “GEM” during 
MQRM or BPRM
None


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6.3
PATIENT SETS ANALYSED
Patient sets will be used as defined in the CTP, Section 7.
Additionally the Biomarker analysis set (BMS) includes all subjects in the treated set who 
have analysable data (observed or imputed) in at least one serum/plasma derived protein
biomarker (see Section 5.3.4.1) and will be used for the respective analysis.
The following table shows which patient set will be used for which class of endpoints.
Table 6.3: 1
Patient sets analyzed
Patient Set
Class of endpoint
TS
BMS
Primary and key secondary 
endpoints 
X
Secondary endpoints 
X
Further endpoints
X
Safety endpoints 
X
Demographic/baseline 
characteristics
X
Biomarkers[1]
X
X
[1] Analyses of soluble biomarkers will be performed on the BMS.
Transcriptome profiling will be performed on the TS.
Note that the number of patients with available data for an endpoint may differ. For details, 
see Section 6.6 “Handling of missing data and outliers”.


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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
In general, the efficacy analyses as well as safety analyses will be evaluated by observed case
analysis, i.e. using only available data without imputation.
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.
For the SGRQ, the SGRQ manual (2) allows for 25% of missing data per component (i.e. 2
questions for symptoms, 6 questions for impacts and 4 questions for activities), the rules
defined in the SGRQ manual will be used to derive the SGRQ.
Additionally the responses to questions 5 and 6 will be made consistent to the extent that if
the answer to question 5 is 5 (none of the time) and the answer to question 6 is non-missing
(i.e., length of worst attack specified), then question 6 will be set to missing. 
Therefore scores will be calculated ignoring that item. In this case, the missing response to 
question 6 will not be included in the count of missing questions for the symptoms 
component.


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If SOBQ is not completely answered, the missing questions will not be imputed, and the
score will be set to missing.
 
 
 
 
 
 


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For an overview on planned visits refer to Flow Chart in the CTP.
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 table 6.7:1 to table 6.7: 6 in order to assign 
data to the relevant study visit based on the actual day of the assessment. Data will be 
analyzed 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.
All visits, regardless whether study treatment is ongoing or not, and EOT visit are classified 
according to the time windowing rules. EOT is the day of the last trial drug administration
(nintedanib and sildenalfil/placebo).
Visits recorded as FUP visits will be classified according to the time windowing as given in 
the table for time windowing and will not keep their labeling “FUP”, unless they fulfill the 
conditions for the last category in the table.
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.
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.
For visits of patients who continue to attend the scheduled study visits after early EOT visit 
the same rules apply as given above.
 


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Table 6.7: 2
Time windowing rules for SGRQ, UCSD SOBQ, EQ-5D, Resting SpO2
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
2
Baseline
1
2
57
56
3
4 weeks
29
58
127
69
5
12 weeks
85
128
No limit
7
24 weeks
169
         [1] First trial drug intake date is taken into account as a reference to calculate time windows


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7.
PLANNED ANALYSIS
For End of Text 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 treatment group (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed as the last category only if there are actually 
missing values.
 
 
 
 
 
 
 


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7.4
PRIMARY ENDPOINT
Please refer to Section 7.3.1 of the CTP.


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7.4.1
Primary analysis
The primary analysis will be done on the TS in observed cases including observations after 
premature discontinuation of treatment.
All visits from baseline to week 12 will be included in the primary analysis, after time-
windowing. Measurements after week 12 are not taken into consideration for this endpoint.
A patient is considered as having signs indicative of right heart dysfunction if at least one of 
the conditions presence of right ventricular dilatation, paradoxical septum motion, right 
atrium enlargement, right ventricular systolic dysfunction, or right ventricular hypertrophy is 
met.
If the null hypothesis of no difference in the mean change from baseline in SGRQ total score 
at week 12 between nintedanib co-administered with sildenafil compared to treatment with 
nintedanib alone is rejected at the two-sided alpha level of 5%, the secondary endpoints 
UCSD SOBQ at week 12, SGRQ total score at week 24, and UCSD SOBQ at week 24 are 
tested hierarchically as described in Section 7.2 of the CTP.
As defined in Section 7.3.1 of the CTP, change from baseline in SGRQ total score at week 12
will be analysed using REML based MMRM. The model will include fixed effect for 
treatment, visit and presence of any echocardiographic signs indicative of right heart 
dysfunction (as described in Section 5.4.1.4), baseline SGRQ total score as a covariate and 
treatment-by-visit and baseline-by visit as interaction terms. Baseline SGRQ total score will 
be measured at visit 2. No imputation is planned if this assessment is not available for a 
patient. An unstructured (co)variance matrix will be used to model the within-patient 
measurements. In case there is a lack of convergence, a Compound Symmetry (co)variance
matrix will be used. The Roger-Kenward approximation will be used to estimate denominator 
degrees of freedom. Data collected after visit 5 (planned 12 weeks after start of study 
treatment) will not be used for this analysis. Analyses will be implemented using SAS® 
Version 9.4 or higher. The primary treatment comparisons will be the contrast between 
treatments at 12 weeks.
 
 
 
 
 


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7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
Not applicable.
7.5.2
Secondary endpoints
The analysis will be performed as defined in Section 7.3.2 of the CTP.
The variable ‘signs indicative of right heart dysfunction’ (yes/no) is derived as described for 
the primary endpoint. 
For SGRQ total score and UCSD SOBQ, a graph of the mean total score change from 
baseline (± SEM) over time for each treatment group will be displayed. The same graph will 
be performed on adjusted mean changes from baseline.
Descriptive statistics for SGRQ total score and subscores as well as SOBQ over time and 
change from baseline will be displayed.
 
 
 


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 


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7.8.1
Adverse events
Unless otherwise specified, analyses of adverse events will be descriptive in nature and will 
be based on BI standards (6). No hypothesis testing is planned. 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 guideline “Analysis and 
Presentation of Adverse Event Data from Clinical Trials” (6).
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 until 28 days 
after last drug intake (end of the residual effect period) will be assigned to the randomised 
treatment. Adverse events that start before first drug intake and deteriorate under treatment 
will also be considered as ‘treatment-emergent’.
All adverse events occurring before first drug intake and do not deteriorate under treatment 
will be assigned to ‘screening’ or ‘post-randomisation’ and all adverse events occurring after 
last drug intake will be assigned to ‘residual effect period', ‘post-study’ or ‘follow-up’ (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 (7), AEs classified as ‘other significant’ will include those non-serious 
and non-significant adverse events which
•
represents a marked hematological or other laboratory abnormality;
•
led to an intervention, including withdrawal of drug treatment, dose reduction 
(‘action taken = discontinuation’ or ‘action taken = reduced’ for any of the study 
treatments), or significant additional concomitant therapy.
An overall summary of adverse events will be presented. 
Separate tables will be provided for 


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•
patients with adverse events occurring with an incidence in preferred term greater than 
5% (in at least one treatment arm)
•
patients with investigator defined drug related adverse events
•
patients with serious adverse events
•
patients with investigator defined drug related serious adverse events
•
patients with other significant adverse events according to ICH E3 (7)
•
patient with adverse events of special interest (AESI) (as defined in the CTP Section 
5.3.6.1).
•
patients with adverse events leading to death
•
patients with adverse events leading to temporary or permanent dose reduction of 
nintedanib
•
patients with adverse events leading to permanent dose reduction of nintedanib
•
patients with adverse events leading to interruption of nintedanib
•
patients with adverse events leading to interruption of sildenafil/placebo
•
patients with adverse events leading to premature discontinuation of nintedanib only,
•
patients with adverse events leading to premature discontinuation of sildenafil/placebo
only,
•
patients with adverse events leading to permanent discontinuation of nintendanib and 
sildenafil/placebo
These AE tables will be displayed in total and by subgroup presence (yes/no) of signs 
indicative of right heart dysfunction.
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency in oral nintedanib coadministered with oral 
sildenafil treatment arm (within system organ class).
Specific tables will be created in order to describe diarrhoea events:
•
Display of the diarrhoea specific page of the CRF
•
Summary of diarrhoea events including time to onset, number and duration of 
episodes
•
Summary of diarrhoea adverse events including seriousness, clinical consequences
(dose reduction, drug discontinuation or drug interruption) and outcome
Also, a Kaplan-Meier plot of time to first diarrhoea event will be drawn by treatment. 
Specific summary tables including seriousness, clinical consequences and outcome will also 
be presented to describe the bleeding adverse events. Depending on the number of patients 
having such adverse events, summary tables including time to onset, number of episodes and 
duration may also be produced.


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In addition, the number of treatment emergent MACE events will be displayed including 
result of adjudication overall and by presence (yes/no) of signs indicative of right heart 
dysfunction. 
The following adverse event groupings have been defined outside the trial protocol:
Table 7.8.1: 1 Adverse events by system using aggregated terms
System
Safety Topic 
Definition (selection criteria)
Gastro-
intestinal 
Diarrhoea
PT Diarrhoea
Nausea
PT Nausea
Vomiting
PT Vomiting
Abdominal pain
HLT ‘Gastrointestinal and abdominal 
pains (excl oral and throat)
Pancreatitis
SMQ Acute pancreatitis (narrow)
Gastrointestinal 
perforation
SMQ Gastrointestinal perforation (narrow)
Hepato-
biliary 
Drug-induced liver 
injury (DILI)
PT Drug-induced liver injury
Hepatic disorders 
combined
Table to show cumulative row for all 4 SMQs 
below, followed by a cumulative row for each 
subSMQ, followed by all PTs driving that 
subSMQ
SMQ Drug related hepatic disorders –
comprehensive search (narrow) OR
SMQ Liver related investigations, signs and 
symptoms (broad) OR
SMQ Cholestasis and jaundice of hepatic 
origin (narrow) OR
SMQ Hepatitis, non-infectious (narrow)
Hepatic failure
SMQ Hepatic failure, fibrosis and cirrhosis 
and other liver damage-related conditions 
(narrow) 
Cardio-
vascular
Arterial 
thromboembolism
SMQ Embolic and thrombotic events, arterial 
(narrow) 
Myocardial infarction
SMQ Myocardial infarction (narrow)


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Table 7.8.1: 1 Adverse events by system using aggregated terms (continued)
System
Safety Topic 
Definition (selection criteria)
Cardio-
vascular
Stroke
Haemorrhagic stroke
Ischaemic stroke
Stroke (broad)
Pharmacovigilance Endpoint Stroke PTs (see 
list in ADS Plan)
SMQ Haemorrhagic central nervous system 
vascular conditions (narrow)
SMQ Ischaemic central nervous system 
vascular conditions (narrow) 
SMQ Haemorrhagic central nervous system 
vascular conditions (narrow) OR
SMQ Ischaemic central nervous system 
vascular conditions (narrow) 
MACE
Fatal events in SOC Cardiac OR
Fatal events in SOC Vascular OR
Any fatal or nonfatal events in SMQ 
Myocardial infarction (narrow) OR
PTs Cardiac death, Sudden death, Sudden 
Cardiac death OR
Any fatal or nonfatal events as defined in PV 
Endpoint Stroke PTs
Cardiac failure
SMQ Cardiac failure (narrow)
QT prolongation
SMQ Torsade de pointes/QT prolongation 
(narrow)
Venous 
thromboembolism
SMQ Embolic and thrombotic events, venous 
(narrow)
Pulmonary embolism
PT Pulmonary embolism
DVT
PT Deep vein thrombosis 
Hypertension
SMQ Hypertension (narrow)
Metabolic
Decreased appetite
PT Decreased appetite
Weight decreased
PTs: Weight decreased, Abnormal loss of 
weight


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Table 7.8.1: 1 Adverse events by system using aggregated terms (continued)
System
Safety Topic 
Definition (selection criteria)
Blood
Bleeding
GI bleeding – oral
GI bleeding – upper
GI bleeding – lower
GI bleeding –
nonspecific
Skin bleeding
Respiratory bleeding
CNS bleeding
Urogenital bleeding
Other bleeding
SMQ Haemorrhage terms (excl. laboratory 
terms) (narrow) displayed in total and then 
according to categories (see list in ADS Plan):

Gastrointestinal – oral

Gastrointestinal – upper

Gastrointestinal – lower

Gastrointestinal – nonspecific

Skin

Respiratory

CNS

Urogenital

Other
Thrombocytopenia
PTs: Thrombocytopenia, Platelet count 
decreased, Immune thrombocytopenic purpura
Haematopoietic 
thrombocytopenia
SMQ Haematopoietic thrombocytopenia 
(broad)
Neutropenia
SMQ Agranulocytosis (narrow) OR
SMQ Haematopoietic leukopenia (narrow)
Renal 
Renal failure
SMQ Acute renal failure (narrow)
Proteinuria
SMQ Proteinuria (narrow)
Glomerulonephritis 
(broad)
Glomerulonephritis 
(narrow)
SMQ Chronic kidney disease (broad)
HLT Glomerulonephritis and nephrotic 
syndrome
Psychiatric 
Depression
SMQ Depression (excl suicide and self-injury) 
(narrow)
Suicide
SMQ Suicide/self-injury (narrow)


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Table 7.8.1: 1 Adverse events by system using aggregated terms (continued)
System
Safety Topic 
Definition (selection criteria)
Cutaneous
Rash
BIcMQ Skin rash (narrow):
Exfoliative rash
Mucocutaneous rash
Rash
Rash erythematous
Rash follicular
Rash generalized
Rash macular
Rash maculo-papular
Rash maculovesicular
Rash morbilliform
Rash neonatal
Rash papular
Rash papulosquamous
Rash pruritic
Rash pustular
Rash rubelliform
Rash scarlatiniform
Rash vesicular
Symmetrical drug-related itertriginous and 
flexural exanthema
Vascular access site bruising
Pruritus
PT Pruritus
Severe skin reactions
SMQ Severe cutaneous adverse reactions 
(narrow)
Liver 
laboratories
Hepatic enzyme 
increased
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
Hepatic enzyme abnormal
Hepatic enzyme increased
Hepatic function abnormal
Hypertransaminasaemia
Liver function test abnormal
Transaminases abnormal
Transaminases increased
Blood alkaline phosphatase abnormal
Blood alkaline phosphatase increased
Gamma-glutamyltransferase abnormal
Gamma-glutamyltransferase increased


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Table 7.8.1: 1 Adverse events by system using aggregated terms (continued)
System
Safety Topic 
Definition (selection criteria)
Liver 
laboratories
Hyperbilirubinaemia
Blood bilirubin abnormal
Blood bilirubin increased
Blood bilirubin unconjugated increased
Hyperbilirubinaemia
Icterus index increased
Jaundice
Jaundice hepatocellular
Bilirubin conjugated abnormal
Bilirubin conjugated increased
Alanine aminotransferase 
increased
Alanine aminotransferase increased
Alanine aminotransferase abnormal
Aspartate aminotransferase 
increased
Aspartate aminotransferase increased
Aspartate aminotransferase abnormal
Gamma-glutamyl-transferase 
increased 
Gamma-glutamyltransferase increased
Gamma-glutamyltransferase abnormal
Blood alkaline phosphatase 
increased
Blood alkaline phosphatase increased
Blood alkaline phosphatase abnormal
For definitons of Pharmacovigilance Endpoint Stroke PTs and for SMQ haemorrhage term 
categorization see ADS plan.
All these definitions are based on MedDRA version 20.1. Note that changes to these 
definitions due to MedDRA updates will not trigger a TSAP update. Updated definitions are 
maintained in BIRDS under Human Pharma/nintedanib/Clinical/substance level/Project Data 
Management and Statistics/Section 4 Database.
The most recent version effective at DBL date will be used for trial reporting.
Frequencies and percentages of patients with AEs within system and within safety topic 
according to aggregated terms will be presented by treatment arm. The data will be displayed
according to the order given in Table 7.8.1: 1.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(8).
Please refer to Section 7.3.4 of the CTP.
Kaplan-Meier plot for time to first liver enzyme elevation will be presented and displayed by 
treatment (if sufficient number of events).


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Specific tables will be presented to describe liver enzyme elevations as defined in Section 
5.4.4 by treatment group:
•
Summary table of liver enzyme elevation including time to first onset and number of 
patients with liver enzyme elevation.
•
Kaplan-Meier plot of time to first liver enzyme elevation (if sufficient number of 
events). No statistical test will be performed. The time to event will be censored at 
EOT + 28 days. The Kaplan-Meier plots will present the time period until 24 weeks + 
28 days.
•
Summary table of individual maximum liver enzyme and bilirubin elevations
•
Plot of time course profile of liver enzyme for patients having liver enzyme and 
bilirubin elevation
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


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH 
Guideline Topic E9, Note For Guidance on Statistical Principles for Clinical 
Trials, current version.
2
Jones PW, Forde Y. St George’s Respiratory Questionnaire Manual.
Version 2.3, 20.06.2009 [R12-2870]  
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON.
4
001-MCS-36-472_RD-01: Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses
5
001-MCS 36-472: "Standards and processes for analyses performed within 
Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
6
001-MCG-156: "Analysis and Presentation of Adverse Event Data from 
Clinical
Trials", current version; IDEA for CON.
7
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
8
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", 
current version; IDEA for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of 
change
Initial
17-OCT-16
None
This is the initial TSAP 
with necessary information 
for trial conduct.
Final
21 FEB 2018
None
This is the final TSAP
Final
24 MAY 2018
None
Updated TSAP after BRPM 
comments in April 2018.