Clinical trial NCT02597933
Conditions: Scleroderma, Systemic
Sponsor: Boehringer Ingelheim
Start date: 2015-11-12; Completion date: 2018-11-28
Enrollment: 580 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. Patients suffer from multiple organ fibrosis whereas lung fibrosis (interstitial lung disease, ILD) is one of the main driver for mortality. There is preclinical evidence for efficacy of nintedanib in SSc and associated ILD (SSc-ILD) and the anti-fibrotic efficacy of nintedanib was proven in idiopathic pulmonary fibrosis patients, who are presenting a similar pattern regarding lung fibrosis. Hence it is the purpose of the trial to confirm the efficacy and safety of nintedanib 150 mg bid in treating patients with SSc-ILD, compared with placebo. The trial will be conducted as a double blind, randomised, placebo-controlled trial with primary efficacy evaluation at week 52 and placebo-controlled treatment until last patient out (up to a maximum of 100 weeks). Respiratory function is globally accepted for assessment of treatment effects in patients with lung fibrosis. The chosen endpoint (Forced Vital Capacity (FVC) decline) is easy to obtain and is part of the usual examinations done in patients with SSc-ILD.

Detailed description:

Arms: arm 1: patient receives capsules containing nintedanib twice a day arm 2: patient receives capsules identical to those containing active drug
Interventions: intervention 1: Nintedanib intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (11.0) / Saved on: 24 Jul 2014
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03014699-05
EudraCT No.:
2015-000392-28
BI Trial No.:
1199.214 (SENSCISTM)
BI Investigational 
Product(s):
Nintedanib
Title:
A double blind, randomised, placebo-controlled trial evaluating 
efficacy and safety of oral nintedanib treatment for at least 52 
weeks in patients with ‘Systemic Sclerosis associated Interstitial 
Lung Disease’(SSc-ILD).
Brief Title:
A trial to compare nintedanib with placebo for patients with 
scleroderma related lung fibrosis.
Clinical Phase:
III
Trial Clinical 
Monitor:
Boehringer-Ingelheim Pharma GmbH & Co. KG
Birkendorfer Strasse 65, 88397 Biberach an der Riss (Germany)
Phone: 
Fax: 
Coordinating 
Investigators:
Division of Rheumatology, University Hospital Zurich
Gloriastrasse 25, 8091 Zurich (Switzerland)
  Phone
 Fax 
 and
 MD, MSCR
Cleveland Clinic Lerner College of Medicine
9500 Euclid Avenue, Desk A90, Cleveland, OH 44195 (USA)
  Phone
Fax
Status:
Final Protocol (Revised Protocol (based on Global Amendment 
No. 3))
Version and Date:
Version: 4.0
Date: 15 Feb 2018
Page 1 of 126
Proprietary confidential information.
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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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Nintedanib
Protocol date:
22 Jul 2015
Trial number:
1199.214
Revision date:
15 Feb 2018
Title of trial:
A double blind, randomised, placebo-controlled trial evaluating 
efficacy and safety of oral nintedanib treatment for at least 52 weeks 
in patients with ‘Systemic Sclerosis associated Interstitial Lung 
Disease’(SSc-ILD).
Coordinating
Investigators:
Division of Rheumatology, University Hospital Zurich
Gloriastrasse 25, 8091 Zurich (Switzerland)
Phone
Fax 
 MD, MSCR
Cleveland Clinic Lerner College of Medicine
9500 Euclid Avenue, Desk A90, Cleveland, OH 44195 (USA)
Phone
Fax
Trial site(s):
Multi-centre trial conducted in approximately 20 countries
Clinical phase:
III
Objective(s):
To investigate the efficacy and safety of 150 mg bid nintedanib in 
patients with Systemic Sclerosis associated Interstitial Lung Disease.
Methodology:
Parallel design, double blind, randomised, placebo-controlled trial 
with primary efficacy evaluation at week 52 and placebo-controlled 
treatment until last patient out (up to a maximum of 100 weeks).
No. of patients: 
total entered:
520 randomised
each treatment:
Nintedanib: 260
Placebo: 260


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Nintedanib
Protocol date:
22 Jul 2015
Trial number:
1199.214
Revision date:
15 Feb 2018
Diagnosis:
Patients diagnosed with Systemic Sclerosis associated Interstitial 
Lung Disease based upon classification according to the most recent 
ACR / EULAR criteria and HRCT (within previous 12 months), onset 
of Systemic Sclerosis (defined as first non-Raynaud symptom) not 
more than 5 years ago.
Main criteria
for inclusion:
≥18 years; extent of fibrotic disease in the lung ≥10%; FVC ≥40%
predicted; DLCO 30% to 89% predicted (corrected for Hb).
Test product(s):
Nintedanib
dose:
150 mg bid (300 mg daily) with possibility to interrupt or reduce to 
100 mg bid (200 mg daily) to manage adverse events (AE).
mode of 
administration:
p.o.
Comparator products:
Placebo matching nintedanib
dose:
Not applicable
mode of 
administration:
p.o.
Duration of treatment:
52 weeks (primary endpoint) with continuation of blinded treatment 
to a maximum of 100 weeks.
Endpoints:
Primary endpoint:
Annual rate of decline in FVC in mL over 52 weeks.
Key secondary endpoints (in the following order):
1) Absolute change from baseline in the modified Rodnan Skin 
Score (mRSS) at week 52.
2) Absolute change from baseline in SGRQ total score at Week 52.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Name of active ingredient:
Nintedanib
Protocol date:
22 Jul 2015
Trial number:
1199.214
Revision date:
15 Feb 2018
Endpoints (con´t):
Secondary endpoint(s):

Annual rate of decline in FVC in percent predicted over 52 
weeks.

Absolute change from baseline in FVC in mL at week 52.

Relative change from baseline (%) of mRSS at week 52.

Time to all-cause mortality.

Absolute change from baseline at week 52 in CRISS index score.

Absolute change from baseline in DLCO (percent predicted) at 
week 52.

Absolute change from baseline at week 52 in digital ulcer net
burden.

Absolute change from baseline in HAQ-DI score at week 52.

Absolute change from baseline in FACIT dyspnoea score at 
week 52.
Safety criteria:
Vital signs, physical examination, safety laboratory tests, 12-lead 
electrocardiogram, adverse events.
Statistical methods:
A random coefficient regression model (with random slopes and 
intercepts) for the primary endpoint and similar secondary endpoint, a 
Mixed Model Repeated Measures (MMRM) analysis for all other 
continuous secondary endpoints, and a Cox proportional hazards 
model as well as a Kaplan-Meier plot for the time to event endpoint.


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FLOWCHART - MAIN TRIAL
Visit
1
2
3
4
5
6
6a
7
7a
8
8a
9
Xa18
(9a, 10a, 
11a)
X18
(10, 11)
12/
EOT
FU19
Screening
Randomised Treatment Period*
FU
Weeks of treatment
0
2
4
6
12
18
24
30
36
44
52
60 + 
every 
16wk
68 + 
every 
16wk
100 
EOT 
+ 
4wk
Day
Time window
Before 
or at 
the 
latest 
at 
Visit 1
≥4d 
prior
Visit 2
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
309
±7
365
±7
±7
±7
701
±7
+28
+7
Informed Consent1
X
Send HRCT to central review2
X
Demographics
X
Medical history
X
X
Adverse events, conc. therapy
X
X
X
X
X
X
X
X
X
X
X
X
In-/exclusion criteria
X
X
Questionnaires (SGRQ, FACIT-
dyspnoea, SHAQ, EQ-5D-5L, 
patient global VAS)3
X
X
X
X
Review questionnaires for 
completeness
X
X
X
X
Physical examination, vital signs
X
X
X
X
X
X
X
X
X
X
X
X
Collect/review/dispense 
menstruation calendar
X
X
X
X
X
X
X
X
X
X
X
X


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Visit
1
2
3
4
5
6
6a
7
7a
8
8a
9
Xa18
(9a, 10a, 
11a)
X18
(10, 11)
12/
EOT
FU19
Screening
Randomised Treatment Period*
FU
Weeks of treatment
0
2
4
6
12
18
24
30
36
44
52
60 + 
every 
16wk
68 + 
every 
16wk
100 
EOT 
+ 
4wk
Day
Time window
Before 
or at 
the 
latest 
at 
Visit 1
≥4d 
prior
Visit 2
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
309
±7
365
±7
±7
±7
701
±7
+28
+7
HCRU
X
X
X
X
X
X
X
X
X
X
mRSS assessment
X
X
X
X
X
X
X
Digital ulcer assessment
X
X
X
X
X
X
X
Safety Laboratory (blood and 
urine)
X4
X
X
X
X
X
X5
X
X5
X
X5
X
X5
X
X
X
Pregnancy test6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK sample7
X
X
Autoantibody assessment8
(X)
X
X
X
Biomarker samples9
X
X
X
X
DNA banking sample10
X
SpO2 (earlobe or forehead, 
resting)
X
X
X
X
Spirometry (FVC)11
X
X
X
X
X
X
X
X
X
X
X
X
DLCO11
X
X
X
X
X
12-lead ECG
X
X12
X
X
X
Echocardiography13
X
X


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Visit
1
2
3
4
5
6
6a
7
7a
8
8a
9
Xa18
(9a, 10a, 
11a)
X18
(10, 11)
12/
EOT
FU19
Screening
Randomised Treatment Period*
FU
Weeks of treatment
0
2
4
6
12
18
24
30
36
44
52
60 + 
every 
16wk
68 + 
every 
16wk
100 
EOT 
+ 
4wk
Day
Time window
Before 
or at 
the 
latest 
at 
Visit 1
≥4d 
prior
Visit 2
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
309
±7
365
±7
±7
±7
701
±7
+28
+7
Randomization
X
IRT call/notification
X14
X
X
X
X
X
X
X
(X)
Dispense trial medication
X
X
X
X
X
X
X
Collect trial medication
X
X
X
X
X
X
X
Compliance/drug accountability
X20
X
X20
X
X
X
X
X
X
Physician global VAS
X
X
X
X
Termination of trial medication15
X
Vital status assessment16
X
X
Conclude subject participation17
X
Footnotes:
* In case of dose change (reduction or re-escalation) additional visits have to be included (refer to Section 6.2.4).

In case of prematurely trial medication discontinuation, the patient completes end of treatment Visit (EOT and follow-up Visit (FU) 4 weeks later), the patient should be 
asked to come to future visits as planned (refer to Section 6.2.3).

EOT assessments are the same as described for Visit 12. If EOT is performed at week 52, the Flowchart for Visit 9 is valid (i.e. Biomarker samples to be drawn).
1 Before or at the latest at Visit 1. Informed consent (IC) needs to be signed before any procedure related to the trial is performed. All adverse events (AEs) and concomitant 
therapies (CTs) from the day of signing informed consent have to be recorded. The screening period (informed consent to Visit 2) must not be longer than 12 weeks.
2 Review of high resolution computer tomography (HRCT) for extent of fibrotic disease in the lung (10% or more). Central review: a historical HRCT not older than 12 months 
should be sent; only if the patient does not have a HRCT within 12 months at Visit 1 but meets all other inclusion and no exclusion criteria, the HRCT can be performed for the 
purposes of participation in the trial (except for patients in Germany).


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3 Self-reported outcome questionnaires must always be done by the patients in a quiet place prior to any other visit procedure. Order of questionnaires: 1. SGRQ, 2. FACIT-
dyspnoea, 3. SHAQ, 4. EQ-5D-5L, 5. Patient’s global VAS.
4 The safety lab of Visit 1 must be repeated if screening is longer than 6 weeks.
5 Intermediate lab tests (a-Visit) do not necessarily need to be a site visit. Cautionary note: dependent on concomitant treatment additional safety monitoring should be considered 
at discretion of the investigator.
6 ß-HCG will be performed at Visit 2 only, at central lab. Urine dipstick pregnancy tests will be provided centrally and should be performed in all women of childbearing potential 
every 4-6 weeks: at least at every visit and if necessary, additionally at home or at a local doctor / laboratory. If urine test is not acceptable to local authorities, a blood test can be 
done at a local laboratory. Women of childbearing potential will be instructed accordingly.
7 PK samples will be taken at Visits 4 and 7 just before drug administration. Date and exact clock time of drug administration and blood sampling must be recorded on the eCRF.
patients will be provided (Visits 3 and 6) with a PK card to support the record of the exact clock time of medication intake three days preceding PK sampling.
8 anti-Topoisomerase antibodies (ATA) will be assessed at Visit 2, 7, and 9 (and at V1 if historically not available); anti-RNA polymerase III antibodies ((anti-)RNA Pol III) and
anti-centromere antibodies (ACA) will be assessed at Visit 2 only.
9 Biomarker samples will be taken just before drug administration. Date and exact clock time of drug administration and blood sampling must be recorded on the eCRF.

Samples for Protein Biomarkers will be taken at Visits 2, 4, 7, 9, just before drug administration.

One sample for prespecified DNA analyses will be taken at Visit 2.

Samples for RNA expression analyses will be taken at Visits 2, 7, and 9, just before drug administration.
10 DNA (Desoxyribo Nucleid Acid) banking sample: one blood sample will be taken from those eligible patients who signed a separate informed consent at Visit 2 (or on a 
subsequent visit); Participation is voluntary and is no prerequisite for participation in the trial.
11 Order of lung function measurements: same time each visit ± 90 min, reference time at Visit 2: 1. FVC followed by patients rest; 2. DLCO.
12 ECG will be performed (if possible prior to blood draw) at Visit 2 prior randomisation (only if abnormal at Visit 1).
13 Echocardiography will at least be performed in patients with a history of pulmonary hypertension at screening (time window Visit 1 to Visit 2) and after 1 year (time window
Visit 9 to Visit 9a).
14 IRT needs to be notified at time point of informed consent (at the latest at Visit 1) to trigger trial medication shipments; ATA status (historical) will be entered at randomisation
(Visit 2) at the latest.
15 Termination of trial medication data needs to be collected any time trial medication is permanently discontinued.
16 Vital status at 52 weeks and at 100 weeks or at the timepoint when patient’s last full visit (i.e. EOT or V9, V10, V11, V12) would have been scheduled, whatever occurs earlier
should be available for all patients. Permission to contact withdrawn patients for vital status assessment should be requested by site.
17 Trial completion:

At the end of the follow-up Visit for patients who have completed the trial on treatment as planned.

After early discontinuation (end of treatment [EOT]) and follow-up Visit), if a patient refuses to attend future visits as originally planned.

At the end of Visit 12 or at the global end of the trial for patients who discontinued trial medication early but came to future visits as planned.
18 Same scheme should be repeated as often as needed: Visit ‘X’ stands for Visit 10 and Visit 11; Visit ‘Xa’ stands for Visits 9a, 10a, and 11a.
19 The follow-up (FU) visit should be planned for 28 days (+7 days window) after last drug intake (end of treatment [EOT]).
20 Compliance / drug accountability only in case of dose reduction/increase


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FLOWCHART – OPTIONAL SUBSTUDIES
Substudies are optional and independent from each other (by site specialty / experience)
Visit
1
2
3
4
5
6
6a
7
7a
8
8a
9
Xa
(9a,
10a, 
11a)
X
(10, 11)
12/
EOT
FU
Screening
Randomised Treatment Period
FU
Weeks of treatment
0
2
4
6
12
18
24
30
36
44
52
60 + 
every 
16wk
68 + 
every 
16wk
100
EOT 
+ 
4wk
Day
Time window
Before 
or at 
the 
latest 
at Visit 
1
≥ 4d 
before 
Visit 2
1
15
±3
29
±3
43
±3
85
±3
127
±7
169
±7
211
±7
253
±7
309
±7
365
±7
±7
  ±7
701
±7
+ 28
+7
SUBSTUDY Informed Consent*
X
HRCT optional SUBSTUDY1
X
X
Skin Biopsy optional 
SUBSTUDY2
X
X
X
Nailfold capillary microscopy 
optional SUBSTUDY2
X
X
X
X
X
Footnotes:
* Substudies are optional and independent from each other. Substudy procedures should only be performed if a patient is eligible for the main trial and has signed a separate 
informed consent for the respective substudy. Informed consent for substudies is to be signed before performing substudy procedures (at the latest at Visit 2). Participation in 
either 1 or 2 or 3 substudies is possible.
The following rules apply for substudy assessments
1 Baseline HRCT between Visit 1 and Visit 2; post treatment HRCT earliest at Visit 9 and latest at Visit 9a. The HRCT at week 52 should be performed in patients that received 
trial medication at least until Visit 7. The HRCT substudy will not be performed in Germany.
2 Skin biopsy and nailfold capillary microscopy should be performed in patients on trial medication only.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOWCHART - MAIN TRIAL.............................................................................................5
FLOWCHART – OPTIONAL SUBSTUDIES......................................................................9
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................18
MEDICAL BACKGROUND.............................................................................18
1.1
DRUG PROFILE................................................................................................19
1.2
2.
RATIONALE, OBJECTIVES AND BENEFIT RISK ASSESSMENT.........22
RATIONALE FOR PERFORMING THE TRIAL.........................................22
2.1
TRIAL OBJECTIVES........................................................................................23
2.2
BENEFIT - RISK ASSESSMENT.....................................................................23
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................26
OVERALL TRIAL DESIGN AND PLAN .......................................................26
3.1
3.1.1
Administrative structure of the trial .................................................................27
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................28
SELECTION OF TRIAL POPULATION .......................................................29
3.3
3.3.1
Main diagnosis for trial entry ............................................................................29
3.3.2
Inclusion criteria .................................................................................................30
3.3.3
Exclusion criteria ................................................................................................30
3.3.4
Removal of patients from therapy or assessments...........................................33
Removal of individual patients from therapy .......................................................33
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................34
3.3.4.2
4.
TREATMENTS...................................................................................................36
TREATMENTS TO BE ADMINISTERED.....................................................36
4.1
4.1.1
Identity of BI investigational product(s)...........................................................36
4.1.2
Method of assigning patients to treatment groups...........................................36
4.1.3
Selection of doses in the trial..............................................................................36
4.1.4
Drug assignment and administration of doses for each patient......................36
4.1.5
Blinding and procedures for unblinding...........................................................37
Blinding.................................................................................................................37
4.1.5.1
Unblinding and breaking the code ........................................................................38
4.1.5.2
4.1.6
Packaging, labelling, and re-supply...................................................................38
4.1.7
Storage conditions...............................................................................................39


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4.1.8
Drug accountability.............................................................................................39
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................40
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....40
Management of diarrhoea .....................................................................................40
4.2.1.1
Management of liver enzyme elevation................................................................42
4.2.1.2
4.2.2
Restrictions ..........................................................................................................43
Restrictions regarding concomitant treatment ......................................................43
4.2.2.1
Cautionary notes ...................................................................................................45
4.2.2.2
Restrictions on diet and life style..........................................................................46
4.2.2.3
Restrictions regarding women of childbearing potential......................................46
4.2.2.4
TREATMENT COMPLIANCE........................................................................46
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................47
TRIAL ENDPOINTS..........................................................................................47
5.1
5.1.1
Primary endpoint(s)............................................................................................47
5.1.2
Secondary endpoint(s) ........................................................................................47
Key secondary endpoints ......................................................................................47
5.1.2.1
Secondary endpoints .............................................................................................47
5.1.2.2
5.1.3
Further endpoint(s).............................................................................................47
ASSESSMENT OF EFFICACY........................................................................48
5.2
5.2.1
Assessment of FVC..............................................................................................48
5.2.2
Assessment of mRSS...........................................................................................49
5.2.3
Assessment of DLCO ..........................................................................................49
5.2.4
Assessment of SpO2.............................................................................................49
5.2.5
Assessment of Digital Ulcers ..............................................................................49
5.2.6
Assessment of questionnaires and derived outcomes.......................................50
Saint George’s Respiratory Questionnaire (SGRQ) .............................................50
5.2.6.1
Functional Assessment of Chronic Illness Therapy-dyspnoea (FACIT- dyspnoea)
5.2.6.2
...............................................................................................................................50
Scleroderma Health Assessment Questionnaire (SHAQ).....................................51
5.2.6.3
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D-5L).....................51
5.2.6.4
Patient’s and physician’s global impression of health..........................................52
5.2.6.5
Combined Response Index in Systemic Sclerosis (CRISS)..................................52
5.2.6.6
5.2.7
Disease progression.............................................................................................52
5.2.8
Nailfold capillary microscopy (substudy at dedicated sites only)...................52
5.2.9
HRCT (substudy at dedicated sites only)..........................................................53
5.2.10
Skin biopsy (substudy at dedicated sites only) .................................................53
ASSESSMENT OF SAFETY.............................................................................54
5.3
5.3.1
Physical examination ..........................................................................................54
5.3.2
Vital signs.............................................................................................................54
5.3.3
Safety laboratory parameters ............................................................................55
5.3.4
Electrocardiogram ..............................................................................................56
5.3.5
Echocardiography...............................................................................................56
5.3.6
Other safety parameters.....................................................................................57
5.3.7
Assessment of adverse events.............................................................................57
Definitions of AEs ................................................................................................57
5.3.7.1


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5.3.8
Adverse event collection and reporting.............................................................60
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................62
5.4.1
Assessment of pharmacokinetics .......................................................................62
5.4.2
Methods of sample collection .............................................................................62
5.4.3
Analytical determinations ..................................................................................62
5.4.4
Pharmacokinetic / pharmacodynamic relationship.........................................62
ASSESSMENT OF EXPLORATORY BIOMARKER(S)..............................63
5.5
5.5.1
Methods and timing of sample collection..........................................................64
5.5.2
Analytical determinations ..................................................................................64
5.5.3
Biobanking...........................................................................................................65
OTHER ASSESSMENTS...................................................................................65
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................65
5.7
6.
INVESTIGATIONAL PLAN.............................................................................66
VISIT SCHEDULE.............................................................................................66
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................68
6.2
6.2.1
Screening..............................................................................................................68
6.2.2
Treatment phase..................................................................................................69
6.2.3
Follow-up Visit and trial completion.................................................................74
6.2.4
Dose reduction visit / dose increase visit...........................................................76
6.2.5
Optional substudies.............................................................................................76
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................78
STATISTICAL DESIGN - MODEL.................................................................78
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................78
7.2
PLANNED ANALYSES.....................................................................................79
7.3
7.3.1
Primary endpoint analyses.................................................................................79
7.3.2
Secondary endpoint analyses .............................................................................80
Analyses of the key secondary endpoints .............................................................80
7.3.2.1
Analyses of the other secondary endpoints...........................................................80
7.3.2.2
7.3.3
Further endpoint analyses..................................................................................81
7.3.4
Safety analyses.....................................................................................................81
7.3.5
Pharmacokinetic analyses ..................................................................................82
INTERIM ANALYSES ......................................................................................82
7.4
HANDLING OF MISSING DATA ...................................................................82
7.5
7.5.1
Efficacy endpoints...............................................................................................82
7.5.2
Safety endpoints ..................................................................................................84
7.5.3
Plasma concentrations........................................................................................84
RANDOMISATION ...........................................................................................84
7.6
DETERMINATION OF SAMPLE SIZE .........................................................84
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........87
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................87
DATA QUALITY ASSURANCE ......................................................................88
8.2


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RECORDS...........................................................................................................88
8.3
8.3.1
Source documents ...............................................................................................88
8.3.2
Direct access to source data and documents.....................................................88
8.3.3
Storage period of records ...................................................................................89
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS89
8.4
8.4.1
Listedness.............................................................................................................89
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................89
STATEMENT OF CONFIDENTIALITY........................................................89
8.5
END OF TRIAL..................................................................................................89
8.6
PROTOCOL VIOLATIONS .............................................................................90
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................90
9.
REFERENCES....................................................................................................91
PUBLISHED REFERENCES............................................................................91
9.1
UNPUBLISHED REFERENCES......................................................................93
9.2
10.
APPENDICES.....................................................................................................95
LUNG FUNCTION CRITERIA........................................................................95
10.1
CREATININE CLEARANCE...........................................................................95
10.2
PATIENT REPORTED OUTCOME QUESTIONNAIRES ..........................96
10.3
10.3.1
SGRQ ...................................................................................................................96
10.3.2
Functional Assessment of Chronic Illness Therapy (FACIT-dyspnoea) .....102
10.3.3
Scleroderma health assessment questionnaire (SHAQ) ................................108
10.3.4
EQ-5D-5L...........................................................................................................111
PATIENTS GLOBAL IMPRESSION OF HEALTH....................................114
10.4
PHYSICIAN’S GLOBAL IMPRESSION OF PATIENTS’S HEALTH.....115
10.5
HANDLING AND DERIVATION OF PHARMACOKINETIC 
10.6
PARAMETERS.................................................................................................116
10.6.1
Pharmacokinetic Methods................................................................................116
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................117


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ABBREVIATIONS
ACA
Anti-Centromere Antibodies
ACE
Angiotensin-Converting-Enzyme
ACR
American College of Rheumatology
AE(s)
Adverse Event(s)
AESI
Adverse Event of Special Interest
ALK
Alkaline Phosphatase
ALT
Alanine Aminotransferase
(anti-)RNA Pol 
III
Anti-RNA polymerase III Antibodies
AST
Aspartate Aminotransferase
ATA
Anti-Topoisomerase
ATS / ERS
American Thoracic Society / European Respiratory Society
AUC
Area Under the Curve
BGM
Specific fragment of MMP-9 and -12- mediated degradation of biglycan
BI
Boehringer Ingelheim
bid
Bis in die (twice daily dosing)
BLQ
Below Limit of Quantification
BNP
Brain Natriuretic Peptide
C1M
Specific fragment of MMP-2,9,13-mediated degradation of type I collagen
C3M
Specific fragment of MMP-9-mediated degradation of type III collagen
C5M
Specific fragment of MMP-2,9-mediated degradation of type V collagen
C6M
Specific fragment of MMP-2-mediated degradation of type VI collagen
CA
Competent Authority
CCL2/18
Chemokine (C-C Motif) Ligand 2/18
CI
Confidence Interval
CK
Creatine Kinase
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor 
CNS
Central Nervous System
CO
Carbon Monoxide
COHb
Carboxyhaemoglobin
COPD
Chronic Obstructive Pulmonary Disease
Cpre, ss 
Pre-dose plasma concentrations at steady state
CRA(s)
Clinical Research Associate(s)
CRISS
Combined Response Index in Systemic Sclerosis
CRO
Clinical Research Organisation
CRPM
Specific fragment of MMP-1, -3, -8, -9, CatS/K, ADAMTS1-mediated 
degradation of C-reactive protein
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTGF
Connective Tissue Growth Factor
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CXCL4
Chemokine (C-X-C motif) ligand 4


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CYP3A4
Cytochrome P450 3A4
DDI
Drug-Drug Interaction
DEDP
Drug Exposure during Pregnancy
DILI
Drug-Induced Liver Injury
dL
Decilitre
DLCO
Carbon Monoxide Diffusion Capacity
DMC
Data Monitoring Committee
DNA
Desoxyribo Nucleid Acid
DoH
Declaration of Helsinki
DU
Digital Ulcer
EC
Ethics Committee
ECG
Electrocardiogram
ECM
Extra Cellular Matrix
eCRF
Electronic Case Report Form
EDTA
Ethylendiamine Tetraacetic Acid
e.g.
Example given
EMA
European Medicines Agency
EOT
End of Treatment
EQ-5D-5L
EuroQol 5-Dimensional quality of life Questionnaire (five-level version)
EudraCT
European Clinical Trials Database
EULAR
European League against Rheumatism
EuroQol Group
European Quality of Life Group
FACIT
Functional Assessment of Chronic Illness Therapy
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 second
FGFR
Fibroblast Growth Factor Receptor
FU
Follow-up
FVC
Forced Vital Capacity
g
Gram
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transferase
GI
Gastrointestinal
GLI
Global Lung Initiative
GP
General Practitioner
h
Hour
HAQ
Health Assessment Questionnaire
HAQ-DI
Health Assessment Questionnaire Disability Index
Hb
Haemoglobin
HCG
Human chorionic gonadotropin
HCRU
Health Care Resource Utilisation
Hct
Haematrocrit
HRCT
High Resolution Computer Tomography
HSCT
Hematopoietic Stem Cell Transplantation
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
i.e.
id est


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IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
INR
International Normalised Ratio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
IRF5
Interferon Regulatory Factor 5
IRT
Interactive Response Technology
ISF
Investigator Site File
ITT
Intention-to-treat
I.U. s.c.
International Unit sub cutaneous
KL6
Krebs von den Lungen-6
kPA
Kilopascal
Lck
Lymphocyte-specific protein tyrosine kinase
LC-MS / MS
Liquid Chromatography-Mass Spectroscopy
LDH
Lactate Dehydrogenase
Lyn
Lymphocyte antigen receptor-associated tyrosine kinases
MedDRA
Medical Dictionary for Drug Regulatory Activities
mg
Milligram
min
Minute
miRNA
Micro Ribonucleid Acid
mL
Milliliter
mm
Millimeter
mmHg
Millimetres of mercury
mmol
Millimolar
MMRM
Mixed Model Repeated Measures
mRSS
Modified Rodnan Skin Score
NOA
Not Analyzed
NOR
No Valid Result
NOS
No Sample
nRTK
Non-Receptor Tyrosine Kinase
PAH
Pulmonary Arterial Hypertension
(p) c-abl
(polyclonal) Abelson´s tyrosine kinase
PD
Pharmacodynamic
(p) PDGF / R
(polyclonal) Platelet Derived Growth Factor / Receptor
PFT
Pulmonary Function Test
P-gp
P-glycoproteine (MDR1)
PH
Pulmonary Hypertension
PI / IC
Patient Information / Informed Consent
PK
Pharmacokinetic
p.o.
per os (oral)
PROMIS
Patient-Reported Outcomes Measurement Information System’s
PRO
Patient Reported Outcome
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
QT 
Interval in the electrocardiogram from the onset of the QRS complex
to the end of the T wave


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RBC
Red Blood Cells
RDC
Remote Data Capture
REML
Restricted Maximum Likelihood
REP
Residual Effect Period
(m)RNA
(messenger) Ribonucleid Acid
RTK
Receptor Tyrosine Kinase
SAE
Serious Adverse Event
SGRQ
St. George's Respiratory Questionnaire
SHAQ
Scleroderma Health Assessment Questionnaire
SMA
Smooth Muscle Actin
SOP
Standard Operating Procedure
SpO2
Saturation of oxygen
Src
Rous sarcoma viral oncogene
SSc
Systemic Sclerosis
STPD
Standard Temperature and Pressure, Dry
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TGF-ß1
Transforming Growth Factor ß1
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
UGT1A1
UDP-glucuronosyltransferase polypeptide A1
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale
VEGF / R
Vascular Endothelial Growth Factor / Receptor
wk
Week


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Systemic Sclerosis (SSc) is a devastating disease of unknown etiology. The pathogenesis of 
SSc is characterized by systemic (multi-organ) immunological, vascular and fibrotic 
abnormalities. It is a rare disorder, an orphan disease, with prevalence rate of approximately 
50 to 300 in US, 20 to 50 in Asia and 100 to 200 per million in Europe (R14-4918, R14-
4927).
Patients suffer from multiple organ fibrosis, leading to chronic disability and premature 
death. Aside from skin, the lung is most often involved, but the disease may also manifest as 
proliferative and obliterative vascular abnormalities, kidney disease, oesophageal and 
gastrointestinal involvement (hypomotility), cardiac disorders, and muscle disease. SSc-
related mortality is mainly driven by interstitial lung disease and pulmonary arterial 
hypertension. Median survival is 5–8 years in SSc associated Interstitial Lung Disease (ILD) 
(P14-07919).
No approved SSc treatment is available, and no treatment is considered to be the gold 
standard for chronic treatment of SSc-ILD. Immunosuppressive therapy has been proposed as 
a treatment of SSc with limited controlled data.
According to the EULAR treatment guidelines (P15-00879) there are no therapies mandated 
for SSc-ILD. Cyclophosphamide, a lymphocyte-modulating agent, may have some effect on 
forced vital capacity (FVC) (R14-5407). EULAR recommends considering 
cyclophosphamide for the treatment of SSc-ILD, but its use is limited in regard of treatment 
duration due to its toxicity. Methotrexate may be considered for treatment of skin 
manifestations of early diffuse SSc (P15-00879). Uncontrolled and retrospectively controlled 
studies suggest some immunosuppressive regimens (such as azathioprine, mycophenolate,
tocilizumab, ciclosporine A) may have effect in selected manifestations of SSc. However, 
larger placebo-controlled studies are lacking (P15-00879). Endothelin receptor antagonists 
failed to show significant effects on pulmonary fibrosis outcomes in several large studies.
Based on pre-clinical and clinical evidence of antifibrotic activity of nintedanib in Idiopathic 
Pulmonary Fibrosis (IPF) and preclinical evidence of potential effects in SSc, along with an
acceptable safety profile as demonstrated in clinical trials with nintedanib in IPF, 
investigation in a patient population with active SSc-ILD accompanied by varying degrees of 
skin and other organ fibrosis is medically rational. Nintedanib may offer a long term anti-
fibrotic maintenance treatment option for SSc, a medical indication with high unmet medical 
need.


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DRUG PROFILE
1.2
Nintedanib is a small molecule that inhibits a distinct spectrum of receptor tyrosine kinases 
(RTKs) and non-receptor tyrosine kinases (nRTKs) including VEGFR (vascular endothelial 
growth factor receptor), PDGFR (platelet-derived growth factor receptor), FGFR (fibroblast 
growth factor receptor), and Src family kinases (Src, Lck and Lyn belonging to a family of 
proto-oncogene tyrosine-protein kinases).
All of these growth factor pathways and their down-stream signal cascades have been 
demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling.
In experiments with dermal fibroblasts from patients with SSc, nintedanib inhibited migration 
and proliferation reduced the expression of extracellular matrix markers and attenuated 
transformation to myofibroblast. In four animal models of SSc with different features, 
nintedanib effectively attenuated skin and lung fibrosis, reduced extracellular matrix 
deposition in skin and lung, attenuated myofibroblast accumulation in skin and lung and 
reduced dermal thickening. Nintedanib also reduced dermal microvascular endothelial cell 
apoptosis and effectively attenuated pulmonary vascular remodelling by reducing the number 
of vascular smooth muscle cells and occluded pulmonary vessels.
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 latest 
reached within one week of dosing. After food intake, a trend towards an increased systemic 
exposure (around 20%) and a delayed absorption was observed compared to administration 
under fasted conditions. Nintedanib is preferentially distributed in plasma with a blood to 
plasma ratio of 0.87 and the terminal half-life is in the range of 7 to 19 h. The absolute 
bioavailability of nintedanib was slightly below 5%.
Nintedanib is mainly eliminated via faeces.
Coadministration 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) trial. 
In a DDI trial with the P-gp inducer rifampicin, exposure to nintedanib decreased to 50.3% 
based on AUC and to 60. 3% based on Cmax upon coadministration with rifampicin 
compared to administration of nintedanib alone. 
Based on results from a dedicated DDI study (1199.229, c09712613), there was no clinically 
relevant PK interaction between nintedanib and pirfenidone when co-administered in patients 
with IPF. 
In a dedicated DDI study in healthy volunteers (1199.239, c09412738), there was no 
clinically relevant pharmacokinetic effect of steady state bosentan treatment on nintedanib 
exposure.


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The clinical efficacy of nintedanib has been studied in over 1400 patients with IPF in one 
phase II dose finding trial (TOMORROW) including four different doses of nintedanib, and 
two replicate phase III (INPULSIS 1 and 2) trials. These were randomised, double-blind, 
placebo-controlled trials comparing treatment with nintedanib twice daily to placebo for 
52 weeks. A statistically significant reduction in the annual rate of decline of FVC (in mL) 
was demonstrated in patients receiving nintedanib 150 mg bid compared to patients receiving 
placebo. The treatment effect of nintedanib compared to placebo on FVC was consistent in 
all 3 studies, i.e. a relative reduction of decline of approximately 50%. Supporting the effect 
of nintedanib on slowing disease progression (P14-07514; P11-11216), 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  acute exacerbations
(adjudicated) by 68% in a pre-specified sensitivity analysis of  pooled data from the
INPULSIS trials.
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, pancreatitis) and to drug-
induced liver injury/increases in liver enzymes (aspartate aminotransferase [AST], alanine 
transaminase [ALT], alkaline phosphatase [ALK], gamma-glutamyl transferase [GGT] and 
bilirubin).
Based on data from clinical trials and post-marketing and supported by population 
pharmakokinetic models, patients with low body weight (<65 kg), Asian and female patients 
have a higher risk of liver enzyme elevations with nintedanib treatment.
The most frequently reported adverse event was diarrhoea, which was mild to moderate in 
intensity for the vast majority of patients and led to treatment discontinuation in less than five 
percent of patients treated with nintedanib. Weight decrease, decreased appetite and arterial 
hypertension have also been associated with nintedanib treatment.
Risks of nintedanib treatment also include hypertension, bleeding, thrombocytopenia, 
gastrointestinal perforations, thromboembolism and decreased appetite and decreased weight. 
Thus, 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 disorder adverse events were balanced 
between the nintedanib and placebo groups, a higher proportion of patients (1.6%) in the 
nintedanib groups had myocardial infarctions compared to the placebo groups (0.5%). 
Conversely, a lower proportion of patients in the nintedanib groups had other ischemic heart 
disease, which includes terms such as coronary artery disease, angina pectoris, coronary 
angioplasty, coronary artery stenosis, myocardial ischemia, coronary artery stent insertion, 


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electrocardiogram (ECG) ST segment depression. The clinical significance of this finding is 
unknown, and further observation is needed.
No evidence of QT prolongation was observed for nintedanib in the clinical trial program. As
some tyrosine kinase inhibitors are known to exert an effect on QT, caution should be 
exercised when administered nintedanib in patients who may develop QT prolongation.
For patients finalizing the 52 week trial 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 is confirming the safety profile 
observed in the phase II and III trials.
Nintedanib was developed in Idiopathic Pulmonary Fibrosis (IPF) and approved by Food and 
Drug Administration (FDA) and European Medicines Agency (EMA) in October 2014 and 
January 2015 respectively.
See also Investigator’s Brochure (IB) nintedanib in Idiopathic Pulmonary Fibrosis, Systemic 
Sclerosis, Progressive Fibrosing Interstitial Lung Disease (c01783972-11) for more details.


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2.
RATIONALE, OBJECTIVES AND BENEFIT RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
As no approved SSc-ILD treatment is available, and internal organ fibrosis, especially lung 
fibrosis, leads to severe loss of function and ultimately results in death, there is a high unmet 
medical need to stop the fibrotic remodeling and thus prevent loss of organ function.
As a common practice, immunosuppressive agents (e.g. mycophenolate mofetil, 
cyclophosphamide, methotrexate, azathioprine, prednisone) are widely used to address the 
organ-specific manifestations. Currently no approved treatment is available addressing the 
interstitial lung manifestation of the disease.
Based upon the mechanism of action and the similarities of pathophysiology resulting in the 
same pro-fibrotic cascade described in both SSc-ILD and IPF (P14-07919), the 
pharmacological rationale for multiple tyrosine kinase inhibition in SSc-ILD is sound and 
promising. Pre-clinical evidence of anti-fibrotic activity of nintedanib in SSc and clinical 
evidence in IPF with an acceptable safety profile support the rationale of performing a trial in 
patients with SSc-ILD.
SSc-ILD is expected to be a co-manifestation with varying degrees of involvement of skin 
and other organs. From a mechanistic point of view and based on preclinical data, an effect of 
nintedanib on manifestations of the disease outside of the lung, for example skin effects, is 
also expected.
The rationale to conduct this Phase III trial in SSc-ILD can be summarized as follows:

High unmet medical need

Preclinical evidence for efficacy in SSc and SSc-ILD

Anti-fibrotic efficacy of nintedanib proven in IPF patients (similar pattern regarding 
lung fibrosis)

From a mechanistic point of view, treatment with nintedanib may also be beneficial 
on the disease outside of the lung, for example skin.


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TRIAL OBJECTIVES 
2.2
The objective of the trial is to assess the efficacy and safety of nintedanib in the treatment of 
SSc with ILD at a dose of 150 mg bid compared to placebo.
The primary objective is to demonstrate a reduction in the annual rate of decline in FVC in 
mL over 52 weeks in the nintedanib treatment group compared to the placebo group.
The main secondary objectives are to demonstrate efficacy in regard to skin fibrosis as 
assessed by the modified Rodnan Skin Score at week 52 and to demonstrate an improvement 
of patient’s symptoms as measured by the SGRQ (Saint George’s Respiratory Questionnaire) 
total score at week 52.
Other objectives are to assess safety and tolerability, mortality, the effects on different 
systemic organ manifestations of SSc, pharmacokinetics and the effects of nintedanib on 
patient’s perception of his/her disease.
BENEFIT - RISK ASSESSMENT
2.3
Initiating and amplifying events in SSc-ILD and IPF are described to be different, but 
culminate in fibroblast activation and myofibroblast accumulation that represent the final 
common pathways of lung fibrosis in both SSc-associated ILD and IPF (P14-07919). 
Nintedanib inhibits migration, proliferation and transformation of fibroblasts and thereby 
addresses this common pathway.
As shown for IPF patients, patients with SSc-ILD may also benefit from lesser decline in 
lung function and hence slower disease progression as a result of treatment with nintedanib.
The safety profile and the tolerability of nintedanib are expected to be similar in patients with 
IPF and SSc-ILD. However, specific SSc-related sensitivities are considered by specific 
in/exclusion criteria for this trial.
Based on the efficacy and safety shown in IPF patients, and considering the similarity of the 
pharmacological rationale between IPF and SSc, the same dose regimen of 150 mg 
nintedanib bid is considered appropriate.
The risks of treatment with nintedanib have been well delineated in patients with the fibrotic 
lung disease IPF. These risks are primarily related to the gastrointestinal tract (nausea, 
vomiting, diarrhoea, abdominal pain), and are usually managed with supportive therapy and 
with temporary or permanent dose reduction to 100 mg bid. In some cases, temporary 
interruption or permanent drug discontinuation is necessary. A reduction in appetite and 
weight decrease has also been reported in patients treated with nintedanib. Patients with SSc
may already suffer from gastrointestinal symptoms and will be monitored for such events. 
Parenteral fed patients will be excluded from the trial.


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Increases in liver enzymes and bilirubin have been reported with the use of nintedanib. Cases 
of drug-induced liver injury (DILI) have been observed with nintedanib treatment. The 
majority of patients presented with mild to moderate liver enzyme elevation, which was in 
most cases transient upon dose reduction or treatment discontinuation. However, severe DILI 
with fatal outcome has also been reported. Liver enzymes must be followed closely during 
treatment (see also Section 4.2.1.2). Nintedanib must be dose-reduced, or interrupted in the 
event of hepatic toxicity and further treatment withheld until recovery of the abnormal 
laboratory parameters.
Concomitant therapies with a known overlap in side effects with nintedanib (e.g. 
gastrointestinal [GI] adverse events, increase of AST, ALT, bilirubin) or concomitant use of 
therapies that interact with metabolism of nintedanib (through UGT1A1 and P-gp) should be 
used with caution and patients should be closely monitored (see Section 4.2.2.2).
Potential risks of nintedanib treatment also include gastrointestinal perforations, 
thromboembolism and bleeding. Therefore, patients who have planned major elective 
surgery, suffer from severe peripheral vascular disease, requiring full dose therapeutic 
anticoagulation, fibrinolysis or high-dose antiplatelet therapy will be excluded from this trial.
Patients with severe pulmonary hypertension will be excluded. Echocardiography is used to 
monitor patients with mild to moderate pulmonary hypertension.
The mode of action of nintedanib indicates a high potential for teratogenicity and
embryotoxicity, including fetotoxicity and 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.
To address the organ-specific manifestations, immunosuppressive agents (e.g. mycophenolate 
mofetil, cyclophosphamide, methotrexate, azathioprine, prednisone) are commonly used and 
needs to be considered although appropriate randomised-controlled data for these therapies 
are lacking.
A placebo arm is needed to allow for a true assessment of the effects of nintedanib on the rate 
of decline in FVC. To address current practice, patients without immunosuppressive 
background therapy as well as patients on a stable background therapy either of 
mycophenolate mofetil /sodium or methotrexate will be eligible for the trial. Rescue 
treatment is allowed in case of clinical deterioration of SSc, either in the lungs (FVC decrease 
≥10% compared to baseline), in the skin (mRSS increase of >25% and >5 points compared to 
baseline) or at any other organ system (Section 4.2.2). By implementing these measures, the 
inclusion of a placebo arm is considered to be ethically justifiable.
Non-immunosupressant therapies for other SSc manifestations as for digital ulcers (e.g.
bosentan), GI symptoms (e.g. proton pump inhibitors, prokinetic drugs), renal crisis (e.g. 
angiotensin-converting-enzyme inhibitor [ACE inhibitors]), PH / PAH (e.g. bosentan, 
sildenafil, epoprostenol) are not restricted. Cautionary notes are included in the protocol 


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(Section 4.2.2.2) with regard to such therapies whose safety profile could interfere with that 
of nintedanib.
Safety will be monitored at site visits, including physical examinations, safety laboratory and 
specific monitoring procedures, to follow-up potential hepatic enzyme elevation, exclusion of 
pregnancy, electrocardiographic assessments, monitoring of renal function, hypertension and
digital ulcers. In patients who develop severe symptoms of gastrointestinal toxicity not 
amenable to symptomatic treatment with standard measures or severe liver enzyme elevations 
or other severe adverse events as specified in Section 3.3.4, treatment with nintedanib must 
be discontinued and appropriate therapeutic measures taken.
An independent Data Monitoring Committee (DMC) will be reviewing safety data on a 
regular basis and whenever necessary, as detailed in the DMC charter. The DMC will review 
data in a blinded or unblinded manner, as deemed necessary. After each meeting, the DMC 
will recommend to the sponsor whether to continue, modify, or to terminate the trial.
Overall, the extrapolated benefit-risk ratio of chronic treatment of patients with SSc-ILD with 
nintedanib 150 mg bid, to be reduced to nintedanib 100 mg bid, interrupted or discontinued 
during periods of intolerability, is judged positive.


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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, placebo-controlled, double 
blind clinical trial to investigate the efficacy and safety of nintedanib at a dose of 150 mg bid, 
in patients with SSc-ILD.
The main efficacy analysis will be assessed at week 52. Patients will stay on treatment up to a 
maximum of 100 weeks in order to collect follow-up safety and efficacy information (Figure 
3.1: 1).
Patients on treatment will have their end of treatment visit (EOT visit) at the same time or 
before the planned Visit 9 of the last randomised patient. The EOT visit will replace either 
Visit 9, 10, 11 or 12, whatever is the latest possible visit before or at the planned visit 9 of the 
last randomised patient. For these patients, the trial ends with the completion of the follow-
up visit 28 days after the EOT. All patients who have concluded the trial on treatment will be 
offered the opportunity to enter an open label extension trial.
Patients, who discontinued treatment but agreed to come to further visits, the last visit will be 
either Visit 9, 10, 11 or 12, whatever is the latest possible visit before or at the planned visit 9 
of the last patient randomized. A follow up visit is not needed for patients who discontinued 
trial drug earlier.
After signing informed consent (IC) before or at Visit 1, a HRCT will be collected and sent
for central eligibility review.
The initial screening Visit (Visit 1) will be performed and patients will enter a screening 
period of maximum 12 weeks. For detailed procedural assessments of patient’s eligibility, 
and refer to the Flowchart and Section 6.2.1.
After receiving the HRCT central review eligibility result, Visit 2 will be scheduled and
collection of clinical and safety laboratory, review of all In- and Exclusion Criteria and 
randomization will be performed by phone or Internet, using an Interactive phone/web 
Response System (IRT).
Patients with confirmed SSc-ILD diagnosis will be randomised to either nintedanib or 
placebo in a 1:1 stratified randomization and in addition stratified by ATA status (positive or 
negative).
Concomitant treatment rules, dose reduction procedures and short term drug interruptions in 
case of adverse events are described in Section 4.2.
Patients who permanently discontinue trial medication will be asked to come to future visits 
as planned. This request will be outlined in the patient information / informed consent
procedure prior to randomization. Patients who permanently discontinue trial medication will 
be asked for a vital status assessment 52 weeks and 100 weeks after their randomization or at 


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the timepoint when patient’s last full visit would have been scheduled, whatever occurs 
earlier.
Patients who discontinue trial medication early (i.e. before week 100 or the global end of the 
trial) will not be eligible to enter the open label extension trial.
For each individual patient the trial period is from the signature of informed consent until 
their last visit.
Figure 3.1: 1 Schedule of visits
3.1.1
Administrative structure of the trial
Two coordinating investigators, experts in the field of SSc, were assigned for the trial. The
trial will be conducted at specialized referral centres experienced in the management of 
SSc-ILD.
SSc will be classified by the american college of rheumatology/european league against 
rheumatism (ACR / EULAR) 2013 criteria (R14-5055). Associated ILD will be assessed on
chest HRCT by central review.
Central laboratory facilities will handle all laboratory analyses of the trial. Samples for 
intermediate measurements (liver enzymes, creatinine) and pregnancy tests may be collected 
at a local doctor by using trial specific lab kits that will be send to central laboratory for 
analyses.
Boehringer Ingelheim (BI) has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating all required activities, in order to manage the trial in accordance with applicable 
regulations and internal Standard Operation Procedures (SOPs), direct the clinical trial team 
in the preparation, conduct and reporting of the trial, order the materials as needed for the 
trial, ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries. Data Management 
and Statistical Evaluation will be done by BI according to BI SOPs. A list of responsible 
V2
0 wk
Active
V6a
V1 
≥ 4d prior 
V2
FU 
+28d
V3
2wk
V4
4wk
V5
6wk
V7
24 wk
V7a
V8
36 wk
V8a
V9
52 wk
V6
12 wk
Placebo
V10
68 wk
V9a
V10a
V11
84 wk
EOT/V12 
100 wk
V11a


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persons and relevant local information (as protocol reference, if applicable) can be found in 
the ISF.
An independent adjudication committee will review all fatal cases and adjudicate all deaths 
due to cardiac or respiratory causes. The adjudication committee will also review all adverse 
events categorized as major adverse cardiovascular events (MACE).
An independent data monitoring committee (DMC) will conduct regular reviews of the trial 
safety data as detailed in Section 2.3 and in the DMC charter. The DMC may review the data 
in an unblinded fashion. Measures are in place to ensure blinding of the Sponsor, 
investigators and all other trial participants. The procedures to assess data and the flow of 
information between the Sponsor and the DMC are described in the DMC charter. The DMC 
recommendations will be stored in the Trial Master File (TMF).
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Patients with SSc-ILD will be included in this trial.
Placebo-controlled randomised trials provide the most robust results and are thus considered 
the most appropriate design, especially in rare patient populations, where multiple trials are 
not possible due to lack of patients.
Based on the efficacy and safety data collected in the development program of nintedanib in 
IPF, an adequately powered placebo-controlled Phase III trial of nintedanib (with the dose 
strength recommended for the treatment of IPF) will allow for sufficient efficacy and safety 
assessment in the SSc-ILD patient population, which has similarities to IPF in the underlying 
pathophysiology.
In situations where effective therapies are available, a placebo-controlled trial could be 
considered not to be ethical. Importantly, there is currently no approved pharmacotherapy to 
prevent progression of the ILD component of SSc, which is one of the main causes of death 
in patients with Systemic Sclerosis. To address the organ-specific manifestations, 
immunosuppressive agents (e.g. mycophenolate, cyclophosphamide, methotrexate, 
prednisone) are commonly used although randomised-controlled data for these therapies are 
scarce.
Preferably patients should not have a chronic immunosuppressive therapy when entering the 
trial. As chronic immunosuppressive therapy reflects the current clinical practice for 
treatment of progressive SSc-ILD, patients on background stable dose of mycophenolate 
mofetil / sodium or methotrexate are allowed in this trial.
Rescue treatment is allowed in case of clinically relevant deterioration of SSc, defined as 
either a FVC decrease ≥ 10% compared to baseline or a mRSS score increase by >25% and
> 5 points or a relevant deterioration at any other organ system, see Section 4.2.2. By 
implementing these measures, the inclusion of a placebo arm is considered to be justified.


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As a positive ATA status is associated with progression of ILD (R14-5409), the 
randomization of patients will be stratified to two patients groups (ATA negative or ATA 
positive).
The annual rate of FVC decline, the primary endpoint in the trial, is an indicator for 
progression of ILD in IPF patients and in SSc-ILD patients as well. Even if progression in 
SSc-ILD patients is known to be slower than in IPF patients, a 52 weeks exposure is 
considered appropriate to demonstrate efficacy based upon FVC decline and allows 
assessment of safety, tolerability and possible effects on other systemic manifestations of the 
disease.
Efficacy beyond 52 weeks until last patient out (up to a maximum of 100 weeks) will be 
assessed in an exploratory way.
SELECTION OF TRIAL POPULATION
3.3
A sufficient number of patients of either sex, 18 years of age or older, with a diagnosis of 
SSc-ILD will be enrolled in the trial (see Section 7.7 for sample size details). All patients are 
expected to be randomised in about 18 months of overall trial initiation (i.e. initiation of the 
first site).
The enrolment will be competitive. 
No sufficient scientific data are currently available to either rule out or confirm efficacy of 
stable immunosuppressive treatment at baseline (mycophenolate or methotrexate), as allowed 
per protocol, for the enrolled study population. To be able to assess the treatment effect of 
nintedanib versus placebo in patients without mycophenolate or methotrexate background 
medication in the trial, recruitment of patients on stable dose of such background treatment 
may be restricted.
A maximum of 520 patients will be recruited by approximately 230 sites in about 33
countries worldwide. Sites will be experienced in the management of patient with SSc-ILD
and are each expected to include approximately 3 patients.
Additional sites may be initiated and ‘non-productive’ sites may be closed to ensure 
sponsor’s timelines.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator’s site file (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
Outpatients diagnosed with Systemic Sclerosis associated ILD (SSc-ILD) based upon
classification according to the ACR / EULAR 2013 criteria (R14-5055) and a chest HRCT 
demonstrating fibrotic/interstitial changes are eligible for inclusion if they fulfil all the


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inclusion criteria (Section 3.3.2) and do not present any of the exclusion criteria (Section
3.3.3).
Please refer to Section 8.3.1 (source documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Written informed consent consistent with ICH-GCP guidelines and local laws signed 
prior to entry into the trial and any trial related procedures.
2. Patient aged ≥18 years when signing his/her informed consent.
3. Patients must fulfil the 2013 ACR / EULAR classification criteria for SSc.
4. SSc disease onset (defined by first non-Raynaud symptom) must be within 7 years of 
Visit 1.
5. SSc related Interstitial Lung Disease pattern must be confirmed by HRCT performed
within 12 months of Visit 1. The extent of fibrotic disease in the lung must be ≥10% on 
HRCT, assessed by central review.
6. FVC ≥40% of predicted normal at Visit 2 (refer to Appendix 10.1).
7. DLCO (corrected for Hb [Visit 1]): 30 % to 89% of predicted at Visit 2 (refer to 
Appendix 10.1).
3.3.3
Exclusion criteria
Laboratory parameter thresholds (Visit 1)
1. AST, ALT >1.5 x ULN.
2. Bilirubin >1.5 x ULN.
3. Creatinine clearance <30 mL/min calculated by Cockcroft–Gault formula (Appendix 
10.2).
Laboratory parameters from Visit 1 have to satisfy the laboratory threshold values as shown 
above. Visit 2 laboratory results will be available only after randomization. In case at Visit 2 
the results do no longer satisfy the entry criteria, the Investigator has to decide whether it is 
justified that the patient remains in the trial. The justification for decision needs to be 
documented. Laboratory parameters that are found to be abnormal at Visit 1 are allowed to be 
re-tested (once) if it is thought to be a measurement error (i.e. there was no abnormal result of 
this test in the recent history of the patient and there is no related clinical sign) or the result of 
a temporary and reversible medical condition, once that condition is resolved.


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Lung diseases
4. Airway obstruction (pre-bronchodilator FEV1/FVC <0.7) at Visit 2.
5. In the opinion of the Investigator, other clinically significant pulmonary abnormalities.
Other diseases
6. Significant PH defined by any of the following:
a.
Previous clinical or echocardiographic evidence of significant right heart failure
b. History of right heart catheterisation showing a cardiac index ≤ 2 l/min/m²
c.
PH requiring parenteral therapy with epoprostenol/treprostinil
7. Cardiovascular diseases, any of the following
a.
Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 
6 month of Visit 1
b. Myocardial infarction within 6 months of Visit 1
c.
Unstable cardiac angina within 6 months of Visit 1
8. More than 3 digital fingertip ulcers at Visit 2 or a history of severe digital necrosis 
requiring hospitalization or severe other ulcers at discretion of the investigator.
9. Bleeding risk, any of the following
a.
Known genetic predisposition to bleeding.
b. Patients who require 
i. Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K 
antagonists, direct thrombin inhibitors, heparin, hirudin)
ii. High dose antiplatelet therapy.
[Note: Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 
I.U. s.c. per day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl 
salicylic acid up to 325 mg/day, or clopidogrel at 75 mg/day, or equivalent 
doses of other antiplatelet therapy) are not prohibited].
c.
History of hemorrhagic central nervous system (CNS) event within 12 months of 
Visit 1.
d. Any of the following within 3 months of Visit 1:
i. Haemoptysis or haematuria
ii. Active gastro-intestinal bleeding or GI – ulcers
iii. Major injury or surgery (investigators judgement).


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e.
Coagulation parameters: International normalised ratio (INR) >2, prolongation of 
prothrombin time (PT) and partial thromboplastin time (PTT) by >1.5 x ULN at 
Visit 1.
10. History of thrombotic event (including stroke and transient ischemic attack) within 
12 months of Visit 1.
11. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin).
12. Other disease or conditions that may interfere with testing procedures (e.g. inability to 
tolerate interruption of supplemental oxygen for pulmonary function testing) or in the 
judgment of the Investigator may interfere with trial participation or may put the patient 
at risk when participating in this trial (e.g. severe GI symptoms due to SSc).
13. Life expectancy of <2.5 years for disease other than SSc in investigator assessment.
14. Patients with clinical signs of malabsorption or needing parenteral nutrition.
General exclusion criteria
15. Previous treatment with nintedanib or pirfenidone.
16. Other investigational therapy received within 1 month or 6 half-lives (whichever was 
greater) prior to screening Visit (Visit 1).
17. Treatment with
a.
Prednisone >10 mg/day or equivalent received within 2 weeks prior Visit 2,
b. Azathioprine, hydroxychloroquine, colchizine, D-penicillamine, sulfasalazine, 
received within 8 weeks prior Visit 2,
c.
Cyclophosphamide, rituximab, tocilizumab, abatacept, leflunomide, tacrolimus, 
newer anti-arthritic treatments like tofacitinib and ciclosporine A, potassium para-
aminobenzoate, received within 6 months prior Visit 2.
18. Unstable background therapy with either mycophenolate mofetil / sodium or methotrexate
(combined therapy not allowed). Patients have to be either
a.
not on mycophenolate mofetil / sodium or methotrexate within at least 8 weeks 
prior Visit 2, or
b. on stable therapy with either mycophenolate mofetil / sodium or methotrexate for 
6 months prior Visit 2 and should stay stable on this background therapy for at 
least 6 months after randomization (for exclusion criterion 17 and 18, and pre-
cautionary notes on concomitant medication refer to Section 4.2.2).
19. Previous hematopoietic stem cell transplantation (HSCT), or HSCT planned within the 
next year.
20. Major surgical procedures planned to occur during trial period.


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21. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
22. Women of childbearing potential 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 correctly as well as one barrier method for 28 days prior to 
and 3 months after nintedanib administration1. A list of contraception methods meeting 
these criteria is provided in the patient information.
1Women 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.
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy).
23. In the opinion of the Investigator, active alcohol or drug abuse.
24. Patients not able to understand or follow trial procedures including completion of self-
administered questionnaires without help.
25. Patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment).
26. Patients with a history of Scleroderma Renal Crisis.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients from therapy
3.3.4.1
The trial medication has to be permanently discontinued in the following circumstances

The patient experiences signs of hepatic injury, defined in Section 5.3.7.1.

In the opinion of the investigator, the patient experiences unacceptable adverse events
despite dose adjustments and supportive care.

Use of concomitant treatment: as defined in Section 4.2.2 “restrictions”.

Parenteral feeding requirement.

Pregnancy (refer to Section 5.3.6).

If a patient becomes pregnant during the trial the investigational product needs to be 
stopped and the patient should be followed up until birth or otherwise termination of 
the pregnancy. The data of the patient will be collected and reported in the clinical 
trial report (CTR) until patient´s last visit and any events thereafter will be reported in 
the BI drug safety database. Refer to Section 5.3.6 for detailed information on event 
reporting in case of pregnancy.
In the following cases discontinuation of trial medication is highly recommended. Only in 
special circumstances, the Investigator, upon thorough assessment of all available clinical 
data and taking into consideration the potential risks associated with administration of 
nintedanib, may decide not to withdraw the trial medication, even though one or more of the 
below mentioned criteria are fulfilled. In such a case, continuation of treatment with trial 


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medication should be discussed with the patient, and the decision and reasoning documented 
in the source data.

Major surgery, including any abdominal or intestinal surgery.

Anti-coagulation. Patients who require full-dose therapeutic anticoagulation (e.g. 
vitamin K antagonists, heparin, hirudin, direct thrombin inhibitors, etc), or high-dose 
antiplatelet therapy. (Prophylactic low dose heparin or heparin flush as needed for 
maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per 
day), as well as prophylactic use of antiplatelet therapy (e.g. acetyl salicylic acid up to 
325 mg/day, or clopidogrel at 75 mg/day, or equivalent doses of other antiplatelet 
therapy is allowed.).

Major thrombo-embolic events e.g. stroke, deep vein thrombosis, pulmonary 
embolism, myocardial infarction.

Increased risk of bleeding e.g. hemorrhagic CNS event, gross / frank haemoptysis or 
haematuria, active gastro-intestinal bleeding or GI-ulcers.
For conditions that allow treatment interruption please refer to Section 4.2.1.
Permanent discontinuation of trial medication (prematurely): if a patient permanently 
discontinues the trial medication prematurely, it is of utmost importance for the robustness 
and integrity of the trial results that his/her lung function parameters, other efficacy endpoints 
and safety data are further recorded until the end of the trial. Patients, who prematurely
discontinue trial medication, will be asked to follow their original visit schedule (except the 
laboratory ‘a-Visits’. refer to Section 6.2.2).
Vital status should be collected for all patients at week 52 and at week 100 or at the timepoint 
when with their last full visit would have been scheduled, whatever occurs earlier. Removal
of individual patients from trial participation
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.
Given the patient’s agreement, the patient will undergo the procedures for trial 
discontinuation and follow up as outlined in the Flowchart and Section 6.2.3.
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
will be 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:

Failure to meet expected enrolment goals overall or at a particular trial site


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
Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial

Violation of Good Clinical Practice (GCP), the Clinical Trial Protocol (CTP), or the 
contract disturbing the appropriate conduct of the trial
 


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product(s)
Table 4.1.1: 1 Identity of BI investigational products
Nintedanib
Placebo 
Substance:
Nintedanib
-
Pharmaceutical formulation:
Soft gelatine capsule
Soft gelatine capsule
Source:
BI Pharma GmbH Co. KG
BI Pharma GmbH Co. KG
Unit strength:
150 mg, 100 mg
Placebo to 150 mg, 100 mg
Posology:
bid
bid
Route of administration:
Oral (swallowed)
Oral (swallowed)
4.1.2
Method of assigning patients to treatment groups
At Visit 1, patients who meet all entrance criteria will enter a screening period.
When a patient is qualified for entry into the randomised treatment period at Visit 2, 
treatment will be assigned via Interactive Response Technology (IRT). To facilitate the use of 
the IRT, the Investigator will receive all necessary instructions for using the IRT.
4.1.3
Selection of doses in the trial
Based on the efficacy, safety and dose-finding from trials investigating nintedanib in IPF, 
TOMORROW (P11-11216), INPULSIS I and INPULSIS II (P14-07514), a dose of 150 mg 
bid was selected. With 150 mg bid, acceptable tolerability in Systemic Sclerosis patients is 
expected based on the risk profile seen in IPF patients. Lower starting doses may not be 
expected to demonstrate efficacy based on the dose ranging trial (TOMORROW) in IPF. 
However, to manage adverse events, the dose may be reduced to 100 mg bid temporarily or 
permanently (refer to Section 4.2.1 and Section 6.2.4).
4.1.4
Drug assignment and administration of doses for each patient
The treatment for an individual patient will be assigned by means of an IRT contact during 
Visits 2, 4, 6, 7, 8, 9, 10, and 11. Patient will receive either active drug at a dosage of 
150 mg bid or placebo bid.
Trial medication will consist of 1 capsule twice daily throughout the trial. Wallets covering 4 
30 days + 5 days reserve treatment (1 wallet = 6 blisters with 10 capsules each, plus 1 blister 
reserve) will be dispensed to the patient:

1 wallet at day 1 (randomization = Visit 2) (30 days plus 5 days reserve).


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
2 wallets at Visit 4 (60 days plus 10 days reserve).

3 wallets at Visit 6 and Visit 7 (90 days plus 15 days reserve).

4 wallets at Visit 8 (120 days plus 20 days reserve).

4 wallets at Visit 9, 10 and 11 respectively (120 days plus 20 days reserve).
Trial medication will be administered orally on a twice daily basis (bid). The patients should 
swallow the trial medication unchewed together with a glass of water (~250 mL), and should 
observe a dose interval of 12 hours. Trial medication needs to 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). 
Because nintedanib may cause stomach discomfort, it is recommended to take the trial 
medication with food intake.
A forgotten dose should be skipped if the time window to the next dose is less than 8 hours.
The next dose should be taken as scheduled. 
The investigational product should only be dispensed to participating patients according to 
the protocol by authorised personnel as documented in the form “Investigator’s Trial Staff”.
In case of adverse events requiring dose reduction between planned visits, an additional site 
visit is required. 100 mg bid (or matching placebo) will be assigned by means of an IRT call 
from the Investigator (refer to Section 6.2.4). The color of capsules (100 mg capsule or 
corresponding placebo) will be slightly different but the packaging will remain the same 
(same number of capsules per blister and same number of blisters per wallet).
The dose can be reduced without prior interruption, i.e., immediately stepping down from 
150 mg bid to 100 mg bid if necessary due to adverse events which requires a special trial 
visit according to procedures described in Section 4.2.1.
If the reduced dose is well tolerated, re-escalation is possible within 4 weeks (after the dose 
reduction visit), which if it occurs between scheduled trial visits will also require a special 
trial visit according to procedures described in Section 4.2.1.
Patients experiencing adverse events requiring temporary interruption of trial medication may 
re-start trial medication according to procedures described in Section 4.2.1.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This trial is a double-blind trial.
Trial medication is identified by a medication code number. Packaging and labelling will be
otherwise identical. The booklet cover page for 150 mg and 100 mg nintedanib and the 
respective corresponding placebo is differently coloured. Colour, size and shape of 


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nintedanib and placebo capsules are indistinguishable within dose strength, but are different 
between dose strengths.
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 
randomised treatment assignments until after database lock.
The randomization code will be kept secret by the sponsor’s clinical trial support up to 
database lock.
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 store manager via IRT. It must 
only be used in an emergency situation when the identity of the trial medication 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 along with the date and the initials of the person who broke the code and 
information needs to be entered on the appropriate eCRF page.
For Japan:
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 medication 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
Primary trial material will be capsules containing 150 mg of nintedanib (or 100 mg of 
nintedanib if dose is reduced), and matching placebo. All trial medication will be packaged in 
blister cards. Each blister card will contain 10 capsules. Seven blisters cards will be packaged 
into one child-resistant tamper-evident wallet (i.e. 70 capsules/wallet). Each wallet will be 
labelled with a multi-language booklet according to the requirements of the participating 
countries.


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One wallet covers for one month of treatment.
Details of packaging and the description of the label will be provided in the ISF.
Initial supply and further re-supplies will be managed by an IRT. The IRT will assign an 
appropriate kit to each patient according to the randomization list that are generated by the 
Sponsor and not known by the trial personnel.
Re-supplies of trial medication are planned due to the short expiry date and the long duration 
of the trial. The medication for re-supply will be packaged in an identical manner as the 
medication for initial supply.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A 
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
All unused trial medication must be returned to the Sponsor or appointed CRO. Receipt, 
usage and return must be documented on the respective forms. Account must be given for any 
discrepancies.
4.1.8
Drug accountability
The Investigator will receive the investigational drugs delivered by a clinical research 
organisation (CRO) appointed by the Sponsor, when the following requirements are fulfilled:

Approval of the trial protocol by the institutional review board (IRB) / ethics 
committee (EC).

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.

In countries where it is required, availability of the proof of a medical license for the 
Principal Investigator.

In the US, availability of Form 1572.
The Investigator 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 appointed CRO.


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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 will maintain records that document adequately that the patients were provided 
the doses specified in Section 4.1.4 and reconcile all investigational products received from 
the Sponsor. At the time of return to the Sponsor or appointed CRO, the Investigator 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(s)
Rescue medications to reverse the action of nintedanib are not available.
Dose reduction (from 150 mg bid to 100 mg bid) or treatment interruption should be 
considered to manage adverse events. No further dose reduction is possible for patients on the 
100 mg bid regimen. In case of persistent adverse events observed at this dose, or severe 
effects at 150 mg bid, permanent treatment discontinuation should be considered.
Treatment interruption and reduction and reescalation are repeatedly possible.
Table 4.2.1: 1 Allowed treatment reduction / interruption periods:
AEs considered drug related
AEs not considered drug related
Maximum interruption
4 weeks
8 weeks
Recommended restart
with reduced dose (100 mg bid)
with the same dose (100 mg bid or 
150 mg bid)
Re-escalation
within 4 weeks to 150 mg bid
----
Management of diarrhoea
4.2.1.1
Other causes for diarrhoea should always be considered and treated accordingly (e.g. viral 
infections, SSc related diarrhoea, bacterial overgrowth, antibiotic treatment).
Diarrhoea should be managed as early as possible after onset of first symptoms with standard 
antidiarrhoeal symptomatic treatment, e.g. loperamide.
If diarrhoea persists despite optimal symptomatic treatment, treatment interruption and dose 
reduction of nintedanib should be considered based on the recommendations described in 
Table 4.2.1.1: 1.


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Table 4.2.1.1: 1 Management of diarrhoea (considered related to trial medication)
Description
Symptomatic Treatment*
Action with trial medication
Diarrhoea with 
increase of <4 stools 
per day over baseline1.
Initiate anti-diarrhoeal 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/day) until bowel 
movements cease for 12 hours.
Continue same trial medication 
dose.
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline1.
Initiate/continue anti-diarrhoeal 
medicines;
If diarrhoea of this severity 
persists for ≥48 to 72 hours assess 
for dehydration and electrolyte 
imbalance; 
In addition, consider IV fluids and 
electrolyte replacement as 
clinically indicated.
If diarrhoea persists for ≥48 to 72 
hours despite optimal symptomatic 
care:
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid 
after recovery.
3.
Re-escalate to 150 mg bid 
within 4 weeks if deemed 
clinically appropriate.
Diarrhoea with 
increase of ≥7 stools 
per day over baseline1; 
stool incontinence,
or
life threatening 
consequences.
Follow recommendations above.
In addition, consider stool work-
up to exclude infectious colitis; 
adequate IV fluid replacement 
≥24 hours, hospitalisation as 
clinically indicated; consider 
referral to a GI specialist to rule 
out potential differential 
diagnoses.
1.
Interrupt trial medication until 
recovery.
2.
Reduce dose to 100 mg bid 
after recovery.
3.
Consider re-escalation within 4 
weeks to 150 mg bid if deemed 
clinically appropriate.
In case of reoccurrence of diarrhoea 
of this severity despite optimal 
symptomatic treatment and dose 
reduction, treatment with trial 
medication should be permanently 
discontinued.
Footnotes:
* Other causes for diarrhoea should always be considered and treated accordingly (e.g. viral infections, SSc related 
diarrhoea, bacterial overgrowth, antibiotic treatment)
1 Baseline defined as usual stools/day prior randomisation.


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Management of liver enzyme elevation
4.2.1.2
Evaluate the concomitant use of other drugs known to cause liver enzyme elevations. For a 
detailed guidance on how to manage liver enzyme elevations, please refer to Table 4.2.1.2: 1.
Table 4.2.1.2: 1: Recommendations for managing liver enzyme elevations
AST or ALT increase to
Signs of hepatic injury*
(Section 5.3.6)
>1.5x to <3x
ULN
≥3x to <5x
ULN and no 
signs of  hepatic 
injury
(Section 5.3.6)
≥5x to <8x
ULN and no 
signs of  hepatic 
injury
(Section 5.3.6)
Visit 2
(randomization)
Withdraw trial 
medication or
justify 
continuation1
Withdraw trial 
medication 
Withdraw trial 
medication 
Withdraw trial medication 
Any other Visit
Continue as 
planned2
Reduce dose or 
interrupt trial 
medication 3
Interrupt trial 
medication 
Withdraw trial medication
CLINICAL 
EVALUATION OF 
HEPATIC INJURY
(Section 5.3.6) 
Close 
observation4
After 2 weeks or 
any time later
Close 
observation4
After 2 weeks 
or any time later
<3x ULN
≥3x ULN
<3x ULN
≥3x ULN
Reduced: 
return to initial 
dose.
Interrupted: 
restart at 
reduced dose.
Monitor bi-
weekly for at 
least 8 weeks
Permanently 
discontinue trial 
medication
Close 
observation4
Restart at 
reduced dose
Monitor weekly
for 4 weeks, 
then bi-weekly 
for at least 8 
weeks
Permanently discontinue 
trial medication.
Close observation4
Footnotes:
*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
1 Investigator to confirm in writing that continuation is justified (e.g. intermittent fluctuation of transaminases).
2 According to visit schedule. Consider additional control visits as adequate.
3 To be decided by Investigator, based on individual risk assessment.
4 Close observation: Re-test ALT and AST, alkaline
phosphatase, total bilirubin, and eosinophils within 48 to 72 hours, then approximately 7 days, then approximately 2 weeks
by using intermediate visit lab kit.


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Initial assessment of liver enzyme elevation should be performed at the investigational site. 
Blood samples for additional monitoring may be collected at the investigational site, primary 
care physician or external laboratory with specific trial lab kits and sent to the central 
laboratory for analysis.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Medication as individually indicated per discretion of the investigator is allowed unless 
covered by medication restrictions in Table 4.2.2.1:1.
In case of a clinically significant deterioration of SSc, initiation of additional therapy is 
allowed as described in Table 4.2.2.1:1. Detailed (S)AE information following such events 
should be recorded in the eCRF.
Clinically significant deterioration is defined as:

An absolute decline since baseline in FVC percent predicted >10% (for example, if 
FVC percent predicted changes from 70% at baseline to less than 60%), or

A relative change from baseline in mRSS of  >25% and an absolute change from 
baseline of >5 points, or

Clinically significant deterioration in other organ systems or clinical parameters at the
discretion of the investigator.
Other causes for FVC decline (i.e. respiratory tract infection) should be excluded.
Please also refer to cautionary notes (Section 4.2.2.2).


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Table 4.2.2.1:1. Medication restrictions and requirements
Prior to 
randomisation
During treatment 
period
After EOT 
attending future 
visits
Anticoagulant and antiplatelet therapies
Full dose therapeutic 
anticoagulation
permitted
note: coagulation 
parameters will be 
measured at Visit 1
NOT permitted
discontinuation of 
trial medication is 
highly recommended
permitted
High-dose antiplatelet 
therapy1
permitted
NOT permitted
discontinuation of 
trial medication is 
highly recommended
permitted
Low dose antiplatelet 
therapy2
permitted
permitted
permitted
Prophylactic low dose 
heparin or heparin flush3
permitted
permitted
permitted
Immunosuppressive agents
Stable therapy with 
mycophenolate mofetil /
sodium 
permitted if stable 
for at least 6 months 
prior V2 (otherwise 
washout for 8 weeks 
prior V2) 
pre-trial dose to be 
continued4
permitted
Stable therapy with 
methotrexate
permitted if stable 
for at least 6 months 
prior V2 (otherwise 
washout for 8 weeks 
prior V2)  
pre-trial dose to be 
continued4
permitted
Azathioprine
NOT permitted
8 weeks prior Visit 2
NOT permitted
except for 
deterioration4
permitted
Cyclophosphamide
NOT permitted
6 month prior Visit 2
NOT permitted
except for 
deterioration4
permitted
Ciclosporine A
NOT permitted 6 
month prior Visit 2
NOT permitted 
except for 
deterioration4
permitted
Corticosteroids
Prednisone ≤10 mg or 
equivalent 
permitted
permitted
permitted


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Table 4.2.2.1:1. Medication restrictions and requirements (con’t)
Prior to 
Randomisation
During Treatment 
Period
After End of 
Treatment 
attending future 
visits
Prednisone >10 mg/day
NOT permitted
2 weeks prior Visit 2
NOT permitted
except for 
deterioration4
permitted
Other restricted medications
Hydroxychloroquine
Colchizine, D-
penicillamine, 
sulfasalazine
NOT permitted
8 weeks prior Visit 2
NOT permitted
except for 
deterioration4
permitted
Rituximab, tocilizumab, 
abatacept, leflunomide, 
tacrolimus, newer anti-
arthritic treatments like 
tofacitinib, potassium 
para-aminobenzoate
NOT permitted 6
month prior Visit 2
NOT permitted
except for 
deterioration4
Permitted
Pirfenidone
NOT permitted
NOT permitted
NOT permitted
Nintedanib
(outside of the trial)
NOT permitted
NOT permitted
NOT permitted
Other investigational 
drugs
washout 1 month or 
6 half-lives 
(whichever is 
greater) prior Visit 1
NOT permitted
NOT permitted
Footnotes:
*it is not allowed to switch between mycophenolate mofetil and mycophenolate sodium
1 e.g. acetyl salicylic acid >325 mg/day, or clopidogrel >75 mg/day, or equivalent doses of other antiplatelet therapy.
2 e.g. acetyl salicylic acid up to 325 mg/day, or clopidogrel up to 75 mg/day, or equivalent doses of other antiplatelet
therapy.
3 As needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 I.U. s.c. per day)
4 Initiation / change in dose permitted in case of clinically significant deterioration, defined as:

Absolute decline since baseline in FVC percent predicted >10% (for example, if FVC percent predicted changes 
from 70% at baseline to less than 60%), or

Relative change from baseline in mRSS of >25% and an absolute change from baseline of >5 points, or 

Clinically significant deterioration in other organ systems or clinical parameters at the discretion of the 
investigator.
Cautionary notes
4.2.2.2
As nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4, concomitant use of 
P-gp and CYP3A4 inhibitors (e.g. erythromycin) with nintedanib may increase exposure to 
nintedanib. Patients taking potent P-gp inhibitors (e.g. ketoconazole, erythromycin or 
ciclosporine) should be monitored closely for tolerability of nintedanib.


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Concomitant use of P-gp and CYP3A4 inducers (e.g. carbamazepine, phenytoin, and St. 
John’s wort) with nintedanib may decrease exposure to nintedanib. For patients taking potent 
P-gp inducers, selection of alternatative treatment with no or minimal P-gp induction should 
be considered.
As the most common side effects known for nintedanib are GI effects, the concomitant use of 
medication with an overlapping safety profile (e.g. mycophenolate mofetil/ sodium) should 
be carefully considered.
Nintedanib is also associated with increases in liver enzymes and bilirubin. If in addition to 
the trial medication, a treatment is introduced that is known to induce AST/ALT elevations 
(e.g. methotrexate, bosentan), adequate measures should be taken to ensure patients safety:
perform additional measurement of liver enzymes (ALT and AST, alkaline phosphatase, total 
bilirubin, and eosinophils) every 2 weeks for approximately 6 weeks, by using intermediated 
(a-visit) trial lab kit.
Restrictions on diet and life style
4.2.2.3
There are no restrictions on diet and life style.
Restrictions regarding women of childbearing potential
4.2.2.4
The anti-angiogenic properties of nintedanib indicate a high potential for teratogenicity and
embryotoxicity, including fetotoxicity and 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. Compliance will be verified by the on-site monitor 
authorized by the Sponsor.
Treatment compliance (%) =
Number of capsules actually taken 100
Number of capsules which should have been taken
If the number of doses taken is not between 80-120%, site personnel will explain the patient 
the importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
5.1.1
Primary endpoint(s)
The primary efficacy endpoint is the annual rate of decline in FVC in mL over 52 weeks.
5.1.2
Secondary endpoint(s)
Key secondary endpoints
5.1.2.1
The key secondary endpoints are:
1. Absolute change from baseline in the mRSS at week 52.
2. Absolute change from baseline in SGRQ total score at week 52.
Secondary endpoints
5.1.2.2

Annual rate of decline in FVC in percent predicted over 52 weeks.

Absolute change from baseline in FVC in mL at week 52.

Relative change from baseline (%) of mRSS at week 52.

Time to all-cause mortality.

Absolute change from baseline at week 52 in CRISS index score.

Absolute change from baseline in DLCO in percent predicted at week 52.

Absolute change from baseline in digital ulcer net burden at week 52.

Absolute change from baseline in HAQ-DI score at week 52.

Absolute change from baseline in FACIT dyspnoea score at week 52.
5.1.3
Further endpoint(s)

Proportion of patients with a relative decline since baseline in FVC (mL) at week 52
of >5%.

Proportion of patients with a relative decline since baseline in FVC (mL) at week 52 
of >10%.

Absolute change from baseline in SpO2 (oxygen saturation, expressed in percent) at 
rest evaluated at week 52.

Proportion of patients with an absolute change from baseline in mRSS at week 52 of 
≥5 points.

Absolute change from baseline at week 52 in SHAQ domain scores (individual visual 
analogue scale [VAS] scores).


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
Absolute change from baseline at week 52 in FACIT functional limitation score.

Absolute change from baseline at week 52 in SGRQ domain scores.

Absolute change from baseline at week 52 in EQ-5D-5L VAS score.

Absolute change from baseline at week 52 in patient global VAS score.

Absolute change from baseline at week 52 in physician global VAS score.

Proportion of patients with disease progression at week 52 as defined in Section 5.2.7.
Additional explorative measures derived from further endpoint assessments will be described 
in detail in the trial statistical analysis plan (TSAP).
Efficacy data collected beyond week 52 will be analysed in a descriptive manner only (see 
TSAP for details).
PK endpoints will include pre-dose concentration of BIBF 1120, BIBF 1202 and BIBF 1202-
glucuronide as specified in Section 5.4.
ASSESSMENT OF EFFICACY
5.2
5.2.1
Assessment of FVC
FVC will be assessed with the FlowScreen® spirometer which will be supplied to all 
participating sites. Central reading will be conducted along the 2005 ATS/ERS Guideline. 
Spirometry measurements must be performed according to ATS/ERS 2005 guideline (P05-
12782), including daily calibration of the spirometer, and regular calibration of the calibration 
pump. Spirometry will be conducted while the patient is in a seated position. The test will be 
done in triplicate (three curves to be provided), 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.
Feedback will be provided to Investigators about unacceptable readings.
The best of three efforts will be defined as the highest FVC, obtained on any of the three 
blows meeting the ATS/ERS criteria with preferably a maximum of five maneuvers.
For each patient, the spirometric measurements will always start at approximately the same 
time of the day (with ±90 minutes maximum difference, time will be recorded), with 
reference to baseline measurement (Visit 2).
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 visit days (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). If treated with bronchodilators, washout of 24 hours for long acting and 8 hours 
for short acting bronchodilators should be observed before spirometry.


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Further instructions regarding FVC measurements will be provided in the site’s ISF.
5.2.2
Assessment of mRSS
The modified Rodnan Skin Score (mRSS) consists of an evaluation of patient’s skin 
thickness rated by clinical palpation using a 0–3 scale (0=normal skin; 1=mild thickness; 
2=moderate thickness; 3=severe thickness with inability to pinch the skin into a fold) for each 
of 17 surface anatomic areas of the body: face, anterior chest, abdomen, (right and left 
separately) fingers, forearms, upper arms, thighs, lower legs, dorsum of hands and feet. These 
individual values are added and the sum is defined as the total skin score (R15-1205).
Further instructions regarding mRSS assessment will be provided in the ISF.
5.2.3
Assessment of DLCO
The site will use its own carbon monoxide diffusion capacity (DLCO) equipment and 
conduct all measurements with the same DLCO equipment (e.g. if several devices would be 
available at the site). Single-breath DLCO will be carried out according to the ATS / ERS 
guideline on DLCO measurements (R06-2002). DLCO and the corresponding alveolar 
volume will be measured at time points given in the Flowchart. Before beginning the test, the 
maneuvers should be demonstrated and the subject carefully instructed.
DLCO values will be adjusted for the most recent haemoglobin value (Appendix 10.1). For 
predicted normal values, different sites may use different prediction formulas, based on the 
method used to measure DLCO. In any case, the calculation 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.
The DLCO assessment should always be performed after the FVC assessment and should 
always be started approximately the same time a day i.e. with ±90 minutes maximum 
difference between start of the tests at baseline (Visit 2).
Further instructions regarding DLCO measurements will be provided in the ISF.
5.2.4
Assessment of SpO2
Oxygen saturation (SPO2) will be measured at rest by standard pulse oximetry (unaffected 
skin of earlobe or forehead) and the recorded value will be entered in eCRF.
5.2.5
Assessment of Digital Ulcers
Net ulcer burden is defined as the number of new digital ulcers (DU) plus the number of DUs 
that have been verified at any earlier assessment during the trial.


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A DU is defined as an area of loss of continuity of both epithelial coverage and of part of the 
dermal tissue. If covered by a scab and there is no debridement performed, the decision 
whether there is an ulcer with loss of continuity of both epithelial coverage and part of the 
dermal tissue is by investigator’s clinical judgement. Only DUs distal to the proximal 
interphalangeal joints and vascular in origin are assessed.
Digital ulcer net burden will be assessed by counting total number of digital ulcers at the time
points indicated in the Flowchart. The absolute change is calculated by counting of ulcers at 
time point minus number of ulcers at baseline.
Further instructions regarding Digital Ulcers assessment will be provided in the ISF.
5.2.6
Assessment of questionnaires and derived outcomes
The patient should complete patient reported outcome (PROs) questionnaires on his/her own 
in the pre-specified order defined in the Flowchart in a quiet area/room prior to any other 
trial-related examination. Site personnel will check the answers of the patients in the 
questionnaires for completeness prior to the patient leaving the site, but the response to each 
item should not be scrutinized. In instances where a patient cannot give or decide upon a 
response, no response should be recorded. The scores will then be transcribed into the eCRF 
by designated site-personnel.
The PRO questionnaires should be presented and filled out in the following order:
1. Saint George’s Respiratory Questionnaire (SGRQ)
2. Functional Assessment of Chronic Illness Therapy (FACIT-dyspnoea)
3. Scleroderma Health Assessment Questionnaire (SHAQ)
4. EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D-5L) 
5. Patient global impression of health VAS.
Saint George’s Respiratory Questionnaire (SGRQ)
5.2.6.1
The St George´s Respiratory Questionnaire (SGRQ, R98-0966) measures health status in 
patients with chronic airflow limitation. It comprises 2 parts which cover three domains 
(symptoms, activities and impacts) with scores ranging from 0 (no impairment) to 100 (worst
possible).
The SGRQ (Appendix 10.3.1) will be self-administered by the patient at visits indicated in 
indicated in the Flowchart and Section 6. 
Functional Assessment of Chronic Illness Therapy-dyspnoea (FACIT- dyspnoea)
5.2.6.2
The FACIT-dyspnoea is a questionnaire that was developed using the National Institutes of 
Health’s Patient-Reported Outcomes Measurement Information System’s (PROMIS) 


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databank (R11-1366). Originally developed with patients with Chronic Obstructive 
Pulmonary Disease (COPD), it assesses shortness of breath and its impact on 10 different 
activities of daily living. Recent evidence suggests that the FACIT-dyspnoea may have good 
measurement properties in patients with Systemic Sclerosis (R14-5056; R14-5045).
Patients should be instructed to read the brief directions at the top of the page. After the 
patient's correct understanding has been confirmed, he/she should be encouraged to complete 
every item in order without skipping any. Patients should be encouraged to circle the 
response that is most applicable. If, for example, a patient is not currently receiving any 
treatment, the patient should circle “not at all” to the question “I am bothered by side effects 
of treatment.”
The FACIT-dyspnoea (Appendix 10.3.2) will be self-administered by the patient at visits 
indicated in the Flowchart and Section 6. 
Scleroderma Health Assessment Questionnaire (SHAQ)
5.2.6.3
The SHAQ includes the Health Assessment Questionnaire Disability Index (HAQ-DI) and 6
additional visual analog scales of relevance to patients with Systemic Sclerosis (P14-16917).
The Health Assessment Questionnaire (HAQ) is a questionnaire that has been used frequently 
in rheumatological disorders including Systemic Sclerosis, assessing function/activities of 
daily living with 20 items in 8 categories, namely dressing and grooming, hygiene, arising, 
reach, eating, grip, walking, and common daily activities (P14-16916; R14-5058).
Each category has at least two sub-category questions. Within each category, patients report 
the amount of difficulty they have in performing the specific sub-category items. There are 
four response options ranging from No Difficulty to Unable to Do, scored 0-3. A global score
(the HAQ disability index, or HAQ-DI) will be calculated from the category scores.
The 6 additional visual analog scales of relevance to patients with Systemic Sclerosis are 
pain, a patient global assessment of limitation, vascular involvement, digital ulcers, lung 
involvement and gastrointestinal involvement. Scores from these scales are not incorporated 
into the overall score of the HAQ-DI.
The SHAQ (Appendix 10.3.3) will be self-administered by the patient at visits indicated in 
the Flowchart and Section 6. Detailed Further instructions regarding the SHAQ 
administration to the patient and scoring is provided in the ISF.
EuroQol 5-Dimensional quality of life Questionnaire (EQ-5D-5L)
5.2.6.4
The EQ-5D-5L was developed by the European Quality of Life Group (EuroQol Group) and 
is a standardised instrument for use as a measure of health outcome (R96-2382). The version 
used in this trial is the new five-level version (EQ-5D-5L). 


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The questionnaire essentially consists of 2 pages. The first page is the descriptive system with 
5 questions to the patient´s health state today. Each question captures one dimension of health 
(e.g. mobility, self-care) and has five levels to answer. The second page records the patient´s 
self-rated health status of today on a vertical graduated (0 to 100) visual analogue scale. 
The EQ-5D-5L (Appendix 10.3.4) will be self-administered by the patient at visits indicated 
in the Flowchart and Section 6. 
Patient’s and physician’s global impression of health
5.2.6.5
The patient’s global impression of health visual analog scale (VAS; Appendix 10.4) will be 
self-administered by the patient at visits indicated in the Flowchart and Section 6.
The physician’s global impression of health VAS (Appendix 10.5) will be filled out by the 
patient’s physician at visits outlined in the Flowchart after all other trial procedures have been 
completed.
The global impression of health VAS is a scale comprised of a horizontal line, about 10 
centimetres (100 mm) in length, anchored by verbal descriptors. The respondent places a
vertical line to the VAS line at the point that represents the intensity of the effect in question. 
The length of the VAS is imperative on paper, as the score is determined using a ruler and 
measuring the distance between the anchors (range from about 0 to 100 mm) (R15-2010).
Combined Response Index in Systemic Sclerosis (CRISS)
5.2.6.6
The Combined Response Index in Systemic Sclerosis (CRISS) is based on the mRSS, FVC 
percent predicted, HAQ-DI, patient’s global impression of overall health VAS and 
physician’s global impression of patient’s overall health VAS, as well as the absence of 
significant worsening of interstitial lung disease, a new scleroderma renal crisis, left 
ventricular failure or pulmonary arterial hypertension (R15-1207).
5.2.7
Disease progression
For the assessment of the proportion of patients with disease progression, any the following 
definition will apply:

An absolute decline since baseline in FVC percent predicted >10%

A relative change from baseline in mRSS of  >25% and an absolute change from 
baseline of >5 points

Death
5.2.8
Nailfold capillary microscopy (substudy at dedicated sites only)
Scleroderma pattern and changes will be assessed by nailfold capillaroscopy using the site’s 
own equipment, more specifically with a nailfold videocapillaroscope which allows digital 


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storage of the images with magnification (x 200). The software should allow a grid of one 
linear mm to be placed on the images that have been stored in order to count the number of 
capillaries in each picture. All measures will be conducted preferably by the same person.
Nailfold videocapillaroscopy will be performed as indicated in the Substudy Flowchart.
Images will be sent to central reading. Change from baseline in number of capillaries 
(density) will be assessed centrally by counting capillaries per linear mm. Further 
assessments might include abnormal shapes e.g. (neo) angiogenesis.
Detailed instructions for the nailfold capillary microscopy substudy will be provided in the 
site’s ISF. Results may be included into the clinical trial report or reported separately.
5.2.9
HRCT (substudy at dedicated sites only)
High resolution CT (HRCT) in the substudy will be performed as indicated in the Substudy 
Flowchart and according to the specifications provided in the ISF. All scans on each patient 
will be completed on the same scanner used for the baseline CT and accredited for use by the 
Central Imaging Vendor.
Whenever possible the same technician will complete the scans.
All scans will be digitally transferred for central review. Central review will be completed by 
the same reference radiologist where possible as for all previous scans for that patient.
The following assessments of structural change in the lungs will be determined on each scan:

Quantitative lung fibrosis score and quantitative total ILD score

Mean lung attenuation, skewness, and kurtosis on density histograms
The following assessments of structural change on HRCT may be determined on each scan:

Gastrointestinal Assessment / Assessment of the oesophagus
HRCTs should be performed only if ≥ 3 months have elapsed since the previous HRCT.
The HRCT substudy results may be included into the CTR or reported separately.
5.2.10
Skin biopsy (substudy at dedicated sites only)
Skin biopsy assessment will evaluate changes of certain protein and ribonucleid acid (RNA)
markers pre- and post-treatment. Therefore two 3 mm punch biopsies will be taken at visits 
indicated in the Substudy Flowchart (one for protein/immunhistochemistry and one for RNA 
analysis). Further details are provided in Section 5.5 and the ISF. Results may be included 
into the clinical trial report or reported separately.


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ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
Complete physical examination will be performed at timepoints indicated in the Flowchart. 
All abnormal findings at baseline will be recorded on the Baseline Condition 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
Systolic and diastolic blood pressure and pulse rate will be measured with the patient seated 
after having rested. All abnormal findings at baseline will be recorded on the baseline 
condition 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.


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5.3.3
Safety laboratory parameters
The laboratory tests at regular site visits will include:
Category
Laboratory test 
Haematology
Red blood cell count (RBC)
Haemoglobin (Hb)
Haematocrit (Hct)
Mean corpuscular volume
White blood cell count including differential
Platelet count
Biochemistry
Aspartate aminotransferase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transferase  (GGT)
Alkaline phosphatase (ALK)
Creatine kinase (CK)
Lactate dehydrogenase (LDH)
Total protein
Total bilirubin
Brain natriuretic peptide (BNP, only at V2, 7, 9,V12/EOT)
Creatinine
Glucose (non fasting)
Uric acid
Thyroid stimulating hormone (only at V2, 7, 9, V12/EOT)
ß-HCG (at Visit 2 only)
Electrolytes
Sodium
Potassium
Calcium
Chloride
Inorganic phosphorus
Coagulation
International normalized ratio (INR)
Partial thromboplastin time (PTT)
Prothrombin time  (PT)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semiquantitative 
measurements; -, +, ++, +++)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.


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The laboratory tests at intermediate ‘a’ visits will include:
Category
Laboratory test 
Biochemistry
Total protein, creatinine, electrolytes and liver function (AST, ALT, GGT, 
alkaline phosphatase, and total bilirubin)
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite (semiquantitative 
measurements; -, +, ++, +++)
Local Urine dipstick pregnancy test in all women of childbearing potential. If urine test is not 
acceptable to local authorities, a blood test must be done at a local laboratory.
Overall about 230 mL blood will be taken for standard safety laboratory during the course of 
the trial.
Creatinine clearance will be calculated based on serum creatinine according to Cockcroft and 
Gault (R96-0690, Appendix 10.2).
If laboratory values indicate abnormality, adequate and more frequent blood sampling may be 
performed at the discretion of the Investigator.
In case of liver function value elevations, close monitoring must be ensured by the 
Investigator. Refer to Section 4.2.1.2 for monitoring elevations and Section 3.3.4 for 
withdrawal criteria.
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 lab and detailed documentation will be included in 
the ISF.
5.3.4
Electrocardiogram
Regular 12 lead Electrocardiograms (ECGs) are conducted during the trial with site’s own 
equipment. Rate, rhythm and repolarisation changes have to be evaluated, compared to 
previous tracings, and assessed for clinical relevance.
Clinically relevant findings must be entered as adverse events.
5.3.5
Echocardiography
Doppler echocardiography will at least be performed in patients with a prior history of 
pulmonary hypertension at time of screening (note: severe PH patients are excluded 
according to Section 3.3.3).


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Each site will use their own equipment to evaluate e.g. right and left ventricular function, 
atrial size, ventricular morphology and the presence of valvular abnormalities and/or 
pericardial effusion.
Patients with a known history of PH that refuse or are not able to have echocardiograms will 
be excluded from the trial.
Clinically relevant findings must be entered as adverse events.
5.3.6
Other safety parameters
Worsening or new onset of SSc organ involvement (e.g. renal, cardiac, GI, vasculopathy) will 
be assessed via evaluation of adverse events / serious adverse events.
5.3.7
Assessment of adverse events
Definitions of AEs
5.3.7.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily has to 
have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

Results in death,

Is life-threatening,

Requires inpatient hospitalisation or prolongation of existing hospitalisation,

Results in persistent or significant disability or incapacity,

Is a congenital anomaly/birth defect
or

Is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.


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Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
For Japan, the following events will be handled as “deemed serious for any other reason”. 
An AE which possibly leads to disability will be reported as an SAE:
AEs considered “always serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “always serious AEs” can be found in the Remote Data Capture (RDC)
system (list of implied serious adverse events). These events should always be reported as 
SAEs as described in Section 5.3.7.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
Adverse events relating to gastrointestinal perforation and hepatic injury will be considered 
AESIs.
Hepatic injury
In this trial 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 immediately stop the trial medication and need to be followed up 
according to the “DILI checklist” provided in the ISF.


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In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST and 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
In addition the intensity of diarrhoea adverse events should be classified and recorded in the 
eCRF according to the Common Terminology Criteria for adverse events (CTCAE) version 4 
(R10-4848, Table 5.3.7:1).
Table 5.3.7:1
CTCAE Categorisation for diarrhoea
CTCAE Grade
Diarrhoea
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
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE.
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.


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5.3.8
Adverse event collection and reporting
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
From signing the informed consent through to the end of the residual effect period (REP) of 
at least 28 days after the date of last dose, all AEs (serious and non-serious) will be collected.
If a patient discontinues trial medication but continues to attend future visits, all AEs (serious 
and non-serious) should be collected until the patient completes the trial. AEs starting on or 
after the date of first dose of trial medication, and up to 28 days after the date of last dose will 
be considered as on-treatment.
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.
AE reporting to sponsor and timelines
The Investigator must report SAEs, and non-serious AEs which are relevant for the reported 
SAE 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.
For Japan:
All SAEs and AESIs 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 (if applicable), e.g. onset, end date, intensity, treatment 
required, outcome, seriousness, and action taken with the investigational drug(s). The 
Investigator should determine the causal relationship to the trial medication and the trial 
procedures outlined under Section 6.2.
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.


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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 the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
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.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the pregnancy monitoring 
form for clinical trials (Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the pregnancy monitoring form for clinical trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition.
The ISF will contain the pregnancy monitoring form for clinical trials (Part A and B).
Safety monitoring and adverse events with additional information collection:

An independent data monitoring committee (DMC) will conduct regular reviews of 
the trial safety data as detailed in Section 2.3 and in the DMC charter.

An independent adjudication committee will review all fatal cases (to review the 
primary cause of death). The independent adjudication committee (AC) will also 
review all adverse events categorized as major adverse cardiovascular events 
(MACE).
Before providing any copy of patients’ source documents to the sponsor the 
investigator must ensure that all patient identifiers (e.g. patient’s name, initials, 
address, phone number, social security number) have properly been removed or 
redacted to ensure patient confidentiality.

Additional details (on top of standard AE and SAE reporting) will be collected in the 
eCRF for the adverse event ‘Diarrhea’ and the adverse events in the subordinate
Standard MedDRA Query (SMQ) ‘Haemorrhage terms, excluding laboratory terms’.


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DRUG CONCENTRATION MEASUREMENTS AND
5.4
PHARMACOKINETICS
5.4.1
Assessment of pharmacokinetics
Plasma concentration monitoring of nintedanib (BIBF 1120) and its two main metabolites 
BIBF 1202 and BIBF 1202-glucuronide will be performed in order to assess drug exposure in 
the SSc-ILD patient population. PK plasma sampling will be conducted at Visit 4 and 7 just 
before drug administration and hence the pharmacokinetic parameter Cpre, ss will be 
determined. The pharmacokinetic parameter will be included in the clinical trial report.
5.4.2
Methods of sample collection
A detailed description of sample collection and handling is provided in the ISF. 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.
Overall about 7 mL blood will be taken for pharmacokinetic measurement during the course 
of the trial.
Date and exact clock time of drug administration and blood sampling at Visit 4 and 7 must be 
recorded on the eCRF. Additionally, the date and exact clock time of drug administration for 
the three days preceding the visit where blood sampling for PK is performed must be 
recorded.
5.4.3
Analytical determinations
Nintedanib (in form of its free base BIBF 1120 BS), its metabolites BIBF 1202 (in form of 
the 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).
The procedures and specifications of the analytical method are available at the bioanalytical 
site (
5.4.4
Pharmacokinetic / pharmacodynamic relationship
It is planned to investigate via modeling the relationship between nintedanib exposure and 
efficacy (primary efficacy endpoint) and safety (gastro-intestinal side effects and liver 
enzyme increase). In addition, pharmacokinetic / pharmacodynamic (PK / PD) relationships 
might be explored with selected exploratory biomarkers. The results will be reported 
separately.


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ASSESSMENT OF EXPLORATORY BIOMARKER(S)
5.5
In order to better understand the effects of nintedanib on local and systemic aspects of SSc
disease, mechanistic and disease related biomarkers will be assessed in the skin and 
peripheral blood of randomised patients.
Biomarkers related to SSc pathology will be explored pre and post treatment with nintedanib 
in serum, plasma, and whole blood RNA and will be correlated with the clinical endpoints.
Skin biopsies will be evaluated pre and post treatment for (epi)dermal thickness and the 
presence of proteins such as SMA, PDGFR, p-PDGFR, c-abl, and p-c-abl using 
histology/immunohistochemistry methods. RNA expression will also be assessed in skin 
biopsies pre and post treatment.
Note: Participation in the skin biopsy sampling is voluntary and not a prerequisite for 
participation in the trial.
Biomarkers that might be evaluated

Protein biomarker: VEGF, PDGF, CCL2, CCL18, CXCL4, KL6, TGF-ß1, CTGF, IL-
6, CRP, CA 125, CA 19-9, Cyfra 25.1, ECM turnover (BGM, C1M, C3M,  C5M, 
C6M, CRPM, Pro-C3, Pro-C6, C4M2, P4NP7S, VICM), miRNAs related to SSc such 
as miR-30b (Visit 2, 4, 7 and 9)

Autoantibodies: anti-topoisomerase antibodies (ATA) (Visit 2, 7 and 9), anti-RNA 
polymerase III antibodies ((anti-)RNA Pol III) (only at Visit 2), anti-Centromere 
antibodies (ACA) (only at Visit 2)

mRNA expression levels in whole blood (Visit 2, 7 and 9)

Skin biopsy substudy: mRNA expression levels, (epi)dermal thickness and histology 
analysis (optional after separate informed consent at Visits 2, 6 and 9)

pre-specified genetic markers for SSc, such as IRF5

Metabolome profile 
Overall about 118 mL blood will be taken for explorative biomarker assessment and banking 
during the course of the trial.
Remaining serum, plasma and RNA samples may be used for method development and 
evaluation and will be stored for a maximum of 3 years upon signature of the clinical trial 
report.


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5.5.1
Methods and timing of sample collection
Whole blood will be collected for the preparation of serum, plasma and RNA expression 
analysis. For substudy participants, skin biopsies will be collected for RNA expression 
analysis.
Collection time points are outlined in the Flowchart and respective footnotes.
Correct, complete and legible documentation of drug administration and blood sampling 
times is mandatory to obtain data of adequate quality for biomarker analysis.
A detailed description of biomarker sample collection and sample handling is provided in the 
ISF.
5.5.2
Analytical determinations
All biomarkers assessed in this trial are considered exploratory and assays, qualified 
according to sponsor’s procedures, will be used for analyses.
Protein biomarkers will be analysed in EDTA plasma or serum using qualified assays.
Characteristics of the analytical methods for the analysis of plasma and serum biomarkers 
will be given in detail in the analytical report.
Autoantibody analysis from serum samples will be processed at a central laboratory. 
Characteristics of the analytical method for the analysis will be given in detail in the 
analytical report.
The first biopsy collected in 10% neutral buffered formalin will be used for histology / 
immunohistochemistry assessment. Characteristics of the analytical method for the analysis
will be given in detail in the analytical report.
The second biopsy collected in a RNA later microtube will be used to gene expression 
analysis. Therefore the RNA is first homogenized using a Precellys Tissue RNA Kit and then 
RNA is purified using a Qiagen RNeasy Kit. For RNA expression analysis from whole blood 
samples RNA is directly purified by using a Qiagen RNeasy Kit. RNA quantity and quality of 
samples will additionally be checked using the Agilent RNA 6000 Nano Assay Protocol. 
Genome-wide expression profiling will be performed by RNA sequencing including 
bioinformatics analysis. Further characteristics of the analytical method for the analysis will 
be given in detail in the analytical report.
Changes in serum, plasma, histology / immunohistochemistry and gene expression (RNA) 
levels will be summarized over time pre and post treatment with nintedanib.
All assessed Biomarkers will either be analysed at the sponsor or at a CRO. The results of 
biomarker analyses may be included into the clinical trial report, or reported separately.


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5.5.3
Biobanking
DNA banking:
For countries participating in the optional DNA banking, one blood sample will be used for
desoxyribo nucleid acid (DNA) banking if participation and the separate informed consent is 
agreed upon by the patient as noted below. 
 
 
 
 
.
Note: Participation in the DNA banking is voluntary and not a prerequisite for participation in 
the trial. The DNA banking sample will be stored after separate informed consent is given in 
accordance with local ethical and regulatory requirements.
One 8.5 mL blood sample for DNA banking will be collected in PAXgene blood DNA tube 
at or after Visit 2 for those patients who signed a separate informed consent for DNA 
banking. Blood samples collected in PAXgene blood DNA tubes should be stored and 
shipped at a temperature of about -20°C or below.
OTHER ASSESSMENTS
5.6
For the purpose of a separate health economic analysis (such as cost-utility analysis), health
care resource utilisation (HCRU) data will be collected throughout the trial. Resource use 
data collected for calculating direct costs will include unscheduled hospitalisations, 
healthcare provider visits, and emergency room/intensive care unit use. Non-medical resource 
use data will include changes in work productivity.
The economic evaluation of the HCRU data will not be part of the clinical trial report but 
reported separately.
APPROPRIATENESS OF MEASUREMENTS
5.7
The measures conducted for primary, key secondary and secondary endpoints are using 
standard methods. Measures conducted for exploratory further endpoints might be new 
methodologies already used in clinical trials in SSc but not yet validated for this rare disease.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
There is one screening visit (which may be preceded by a separate informed consent visit) 
and up to 11 visits planned within the 100 weeks treatment period (52 weeks until primary 
endpoint and additional 48 weeks on treatment), plus intermediate blood analyses and one 
follow-up Visit. The trial will last until:

Follow-up visit of the last randomized patient if he/she completed 52 weeks of 
treatment, or

Visit 9 of the last randomized patient if he/she discontinued treatment early but agreed 
to come to future visits as planned, or

Follow-up visit of the last randomized patient if he/she discontinued treatment 
prematurely and did not agree to come to future visits
Approximately at this timepoint all ongoing patients will have their last trial visits and trial 
completion (patients on treatment will have an EOT and follow-up visit; patients who 
discontinue treatment early will have their next scheduled visit immediately).
After giving his/her informed consent, the patient will be screened for inclusion and 
exclusion criteria for the trial at Visit 1.
Visit 2 can be performed once the results from central laboratory of Visit 1 and central HRCT 
review are obtained. If for any reason the screening phase for an individual patient lasts for 
more than 6 weeks, then the laboratory examination for Visit 1 has to be repeated before 
randomization. The screening phase should not be longer than 12 weeks. 
Rescreening is possible, rescreened patients will be assigned a new patient number.
The patient will be randomised at Visit 2 if all inclusion and none of the exclusion criteria are 
fulfilled.
The results of laboratory parameters from Visit 2 will become available only after Visit 2. 
Therefore, laboratory results from Visit 2 cannot qualify as exclusion criteria; laboratory 
results from Visit 1 will be used instead. In case laboratory results of Visit 2 would 
retrospectively fulfill an exclusion criterion, the patient should not continue receiving trial 
medication unless continuation is justified in writing by the Investigator.
Visits 2, 3, 4 and 5 will occur every 2 weeks. Visit 6 will be scheduled 6 weeks later, Visits 7 
and 8 are planned every 12 weeks and further Visits (9, 10, 11 and 12/EOT) are planned 
every 16 weeks. Visits 6a, 7a, 8a, 9a, 10a and 11a (a-Visits) are intermediate laboratory 
control visits.
The samples for the ‘a-Visits’ may be drawn locally (i.e. local general practitioner [GP]). The 
Investigator would in that case give the required documentation to the patient, with the 


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corresponding trial kit for the respective ‘a-Visit’ to be sent to the central lab even if not at 
the trial site. Information, agreement and training of the respective local GP for blood draw
will be ensured on an individual site basis consulting the sponsor’s local monitor.
Pregnancy test will be performed in women of childbearing potential every 4-6 weeks. Urine 
dipstick test will be done at every visit and will be provided for at home pregnancy testing as 
soon as visit intervals are > 6 weeks (2 to 3 pregnancy test dipsticks to take home. Women of 
childbearing potential will be instructed accordingly. 
The primary endpoint Visit 9 is scheduled 52 weeks after randomization, occurring 16 weeks 
after Visit 8. Visit 10, 11 and 12/EOT are scheduled every 16 weeks from Visit 9.
A window of ±3 days for the Visits 3 to 6, ±7 days for Visits 6a to 12 is allowed to 
accommodate scheduling problems. If a delay is observed for a particular visit, the original 
calendar schedule should be kept for subsequent visits (delays should not accumulate).
If treatment is discontinued, regardless if prematurely, after 100 weeks, or at the global end of 
the trial, an end of treatment visit (EOT) will be performed.
A follow-up visit has to be organized 28 days (+ 7 days) after the end of treatment visit.
Patients who have been treated until the predefined end of the trial will have the possibility to 
participate in an extension trial to receive nintedanib open label.


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening
All trial procedures at selected visits will be done according to Flowchart and footnotes and 
the CTP.
Informed consent (before or at the latest at Visit1)

Informed consent will be obtained prior to patient participation in the trial, which 
includes any medication washout procedures or restrictions as well as HRCT transfer 
to central review. Upon obtaining informed consent, the patient will be instructed on 
the medication washout and other restrictions needed.

At selected sites performing one or more substudies, patients should be invited during 
the informed consent process to participate in the respective substudy(ies).

Patients will be asked to give informed consent to the DNA banking sample (please 
note: the DNA banking sample must not be taken prior to Visit 2). Participation is
voluntary and is not a prerequisite for participation in the trial.

A preliminary check of in-/exclusion criteria is recommended at time of informed 
consent to avoid unnecessary washout procedures in non-eligible patients.

A historical HRCT not older than 12 months will be sent for central review after 
investigator’s evaluation of fibrosis extent to be in accordance to inclusion criterion 5 
(Section 3.3.2). Only if the patient will not have a HRCT within 12 months at 
scheduled Visit 1 timepoint but meets all other inclusion and no exclusion criteria, the 
HRCT can be performed for the purposes of participation in the trial (exception: in 
Germany, no HRCT will be performed for the purposes of participation in the trial).

Site personnel will perform a screening call in IRT to ensure in-time trial medication 
shipment.

Upon obtaining informed consent the patient will receive:
o
A trial identification card.
o
Women of childbearing potential will receive a menstruation calendar.
Patient material templates will be provided by the sponsor.
Observations and procedures at Visit 1

If a separate informed consent Visit was not done, obtaining informed consent and the
above mentioned procedures will be done prior to any further procedure at this visit.

Demographics will be recorded.


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
Medical history including pre-existing conditions will be recorded.

Concomitant therapy including previous medications will be recorded.

Any adverse events (since consent, if applicable) will be recorded.

Local urine pregnancy test (dipstick) if applicable.

Complete physical examination including vital signs will be performed.

Patient’s menstruation calendar will be reviewed (if applicable).

A resting 12-lead electrocardiogram using site’s own equipment will be performed 
and evaluated (if possible prior to blood draw).

Echocardiography (at least to be performed in patients with a history of pulmonary 
hypertension (time window V1 to V2) and after 1 year (time window V9 to V9a).

FVC measurement will be conducted with the FlowScreen® spirometer.

DLCO measurement will be conducted. Order of lung function and DLCO will 
always be 1. FVC measurement followed by patient’s rest, followed by 2. DLCO 
measurement.

Blood and urine samples (safety lab) will be collected and submitted to the central
laboratory (for details refer to Section 5.3.3). Prior to blood draw, a pre-assessment of 
all in/exclusion criteria is highly recommended.

Site personnel will check if a historical ATA status is available. If no ATA status is 
available, an additional blood sample will be taken and sent to central lab for 
determination.

Local urine pregnancy test (dipstick) if applicable.

Site personnel will send HRCT to central review (if not already done at time of 
informed consent).

For patients qualified to enter the screening period, Visit 2 will be scheduled.

Site personnel will perform a screening call in IRT (if not already done at time of 
informed consent).
6.2.2
Treatment phase
At the beginning of each visit during treatment phase, investigator and site personnel should 
ensure the well-being of the patient as well as prepare all requirements for conduct of the 
visits that are necessary.


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The order of the different trial procedures should be planned taking into account the specific 
structure of the investigational site and following the mandatory needs outlined in the clinical 
trial protocol.
Mandatory needs / the following must be ensured during trial visits:

Patient reported outcome questionnaires have to be filled out always prior to any 
other procedures by the patient in a quiet area and in the following order:
1. SGRQ
2. FACIT
3. SHAQ
4. EQ-5D-5L
5. Patient’s visual analogue scale (VAS) on global impression of health

Urine pregnancy test and any laboratory sample collection must be performed prior 
trial medication administration.

Timing of FVC and DLCO measurement at the visits must be performed 
approximately the same time of the day with ± 90 min maximum difference to 
reference time point at Visit 2.

Order of pulmonary function tests must always be 
1.  FlowScreen® spirometry (FVC) followed by patient’s rest
2.  DLCO with site’s own equipment.
Timing of FVC and DLCO measurement at Visit 2 is critical as this will be the reference 
measurement for future visits (approximately the same time of the day with ± 90 min 
maximum difference). It is therefore highly recommended to discuss with the performing unit 
and the patient and plan for future visits upfront to ensure that the allowed time window can 
be met in all following visits.
For Visit 2 (randomization), the following prerequisites must be available

Eligibility confirmation of central HRCT review.

ATA status (positive or negative).

Safety laboratory results including haemoglobine and creatinine from Visit 1.


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Baseline Visit 2 (randomization) procedures

All patients will be asked to fill out the patient reported outcome questionnaires prior 
to any other visit procedure. The order of the questionnaires will always be: 1. SGRQ, 
2. FACIT, 3. SHAQ, 4. EQ-5D-5L, 5. Patient’s global impression of health visual 
analogue scale (VAS).

Site personnel will review questionnaires for completeness.

Physical examination including vital signs and HCRU interview will be performed.

Patient’s menstruation calendar will be reviewed (if applicable).

Adverse events and concomitant therapy since last visit will be reviewed and 
recorded.

Medical history will be reviewed.

Repeated resting 12-lead electrocardiogram using site’s own equipment will be 
performed and evaluated if ECG was abnormal at Visit 1 (if possible prior to blood 
draw).

Echocardiography will be performed (if applicable and not already performed during 
screening period).

The modified Rodnan Skin Score (mRSS) and digital ulcers will be assessed.

SPO2 (unaffected skin at earlobe or forehead) at rest will be recorded.

FVC measurement will be conducted with the FlowScreen® spirometer.

DLCO measurement with site’s own equipment will be conducted.

All in/exclusion criteria will be assessed based on Visit 1 laboratory and Visit 2 
measures.

Safety blood and urine samples will be collected and submitted to the central 
laboratory.

Biomarker samples will be collected and submitted to the central laboratory.

The time of blood collection for biomarker samples will be recorded in the eCRF.
Note: blood samples will always be collected prior to drug administration.

One blood sample for DNA banking will be collected in eligible patients and only 
after obtaining a separate informed consent.

Local urine dipstick pregnancy test (if applicable).

If a patient is eligible for the trial, randomization will be performed by using the IRT 
system (and entering the ATA status if not already done at Visit 1).


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
Treatment will be dispensed.

The next visit will be scheduled and prepared.

Patient’s menstruation calendar will be dispensed (if applicable).

Physician will complete his/her physician’s global impression of patient’s overall 
health visual analogue scale (VAS).
Visit 7, Visit 9, and Visit 12/EOT (‘big visits’) procedures
At Visit 7, Visit 9 (primary endpoint visit) and Visit 12/EOT, the same procedures will be 
performed as done at baseline Visit 2. Exceptions are the typical randomisation measures, 
e.g. eligibility review, medical history assessment and randomization as well as DNA 
banking sample which is only taken once. For Visit 7, 9 and 12/EOT always refer to the
Flowchart.
General rules

Treatment compliance will be reviewed by site personal.

Trial medication will be collected and/or dispensed according to Flowchart.

Visit 12 and end of treatment visit (EOT) are identical visits. EOT is to be used in 
eCRF at any time a patient ends trial medication (scheduled or prematurely).

Visit 12 is to be used if a patient prematurely discontinued trial medication but agreed 
and came to future visits as planned (e.g. patient discontinues trial medication 
prematurely at Visit 10, then he/she would complete Visit 11 and 12. If a patient does 
continue on trial medication until the end of the trial he/she would complete EOT 
instead).

IRT should always be notified on end of treatment (EOT).

Vital status will be collected for all patients at week 52 and 100 or at the timepoint 
when patient’s last full visit would have been scheduled, whatever occurs earlier.

PROs / Questionnaires will always be scheduled prior any other procedure and in the 
above described order and will be reviewed for completeness by site personal.

Drug intake at visit days should always be performed at site and after blood and urine 
sample collection and pregnancy test.

FlowScreen® spirometry (FVC) and DLCO measurements will always be in the 
allowed time window and the described order (reference visit = Visit 2).


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Some measures are not scheduled for every ‘big visit’, these are:

Resting 12-lead electrocardiogram using site’s own equipment will be performed and 
evaluated at Visit 7 and 9 and V12/EOT (if possible prior to blood draw).

Echocardiography (Visit 1 to 2 and Visit 9 to 9a, and not at Visit 7 and Visit 12/EOT).

ATA assessment (Visit 2, 7, 9, and not at Visit 12/EOT).

Biomarker blood sampling (Visit 2, 7, 9, and not at Visit 12/EOT).

At Visit 7 (and ‘medium Visit 4’ see below), a pharmacokinetic (PK) sample will be 
collected. The patient needs to record exact date and clock time of medication intake 
the preceding three days (via PK card dispensed the visit before). The date and time of 
blood collection and drug administration at the site will be recorded in the eCRF.

2 to 3 take home pregnancy tests (dipsticks) at Visit 7 and 9
‘Randomization’ and ‘big visit’ procedures may be performed on more than one calendar
days, adhering to the following rules:

Patients Questionnaires are to be completed before any other procedure.

FVC & DLCO are to be completed the same day

PK and Biomarker samples are to be taken before drug administration
Visit 3, 4, 5, 6, 8, 10, and 11 (‘medium visits’) procedures
Please note that not all medium visits are drug dispensation visits (please always refer to 
Flowchart). However, compliance of patients regarding drug intake should always be 
reviewed (see also treatment compliance in Section 4.3).

Physical examination including vital signs and HCRU interview will be performed.

Patient’s menstruation calendar will be reviewed (if applicable).

Adverse events and concomitant therapy since last visit will be reviewed and 
recorded.

Local dipstick pregnancy test (if applicable).

Safety blood and urine samples will be collected and submitted to the central 
laboratory.

At medium Visit 4, a PK sample and biomarker samples will be collected. The patient 
needs to record exact date and clock time of medication intake the preceding three 
days.


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
At Visit 3 and 6 the patient will be provided with the PK card to support the record of 
the exact date and clock time of medication intake three days preceding Visits 4 and 
7.

The date and time of blood collection and drug administration at the site will be 
recorded.

FlowScreen® spirometry (FVC) in the allowed time window will be performed.

mRSS and digital ulcer assessment will be done at Visits  6, 8, 10 and 11. 

Patient’s menstruation calendar will be dispensed (if applicable).

2 to 3 take home pregnancy tests (dipsticks) at Visit 8, 10 and 11

Treatment compliance will be reviewed by site personal at every visit (except at 
randomisation visit and at ‘a-Visits’).

Trial medication will be collected and/or dispensed according to Flowchart.
Intermediate ‘a-Visit’ procedures

Safety blood and urine samples will be collected and submitted to the central 
laboratory.

Local dipstick pregnancy test will be performed (if applicable).
6.2.3
Follow-up Visit and trial completion
A follow-up Visit has to be scheduled 28 days after End of treatment Visit (28 days safety 
follow-up after treatment discontinuation)

Physical examination including vital signs.

Adverse events and concomitant therapy will be assessment since last visit.

Patient’s menstruation calendar will be reviewed (if applicable).

Local dipstick pregnancy test (if applicable).

Safety blood and urine samples will be collected and submitted to the central 
laboratory.

FlowScreen® spirometry (FVC) in the allowed time window will be performed.

Patient’s participation will be concluded (trial completion).
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:


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
At the end of the follow-up Visit for patients who have completed the trial on 
treatment as planned.

After early discontinuation end of treatment (EOT) and follow-up Visit, if a patient 
did not accept to come to future visits planned.

At the end of Visit 12 or at the end of the trial for patients who discontinued drug 
early but came to future visits as planned.
Patients who prematurely discontinued trial medication
In case a patient has to permanently discontinue trial medication, for whatever reason, he/she 
will be encouraged to attend all future visits up to Visit 12 as originally planned (except for 
the laboratory ‘a-Visits’).

During these visits, the patient will undergo all planned examinations and especially 
FlowScreen® spirometry (FVC); however he/she will not have to do the ECG, safety 
laboratory, biomarker laboratory and PK blood draw. 

These visits will be regarded as part of the trial despite the patient having
discontinued trial medication.

For the substudy assessments after early discontinuation of trial medication refer to
Substudy Flowchart and respective footnotes.
The need for coming to future visits in case of prematurely discontinuation of trial medication 
will be explained to patients prior to their participation in the trial.
If the patient refuses to attend all future visits as originally planned, but agrees with vital 
status assessment, the latter will be conducted twice; 52 weeks and 100 weeks after 
randomization or at the timepoint when patient’s last full visit would have been scheduled, 
whatever occurs earlier. Details are described below.
Vital status information
In case of early discontinuation of trial medication, if the patient does not agree to come to 
future visits as originally planned, every attempt will be made to get information on vital 
status at 52 weeks and at 100 weeks after his/her randomization or at the timepoint when 
patient’s last full visit would have been scheduled, whatever occurs earlier.
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.


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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.
Extension trial
All patients who have completed the trial on trial medication will be offered to enter an open 
label extension trial. The main objective of the open label extension trial is to follow up long 
term safety and lung function parameters.
A maximum of 12 weeks drug-free interval before rolling over will be allowed. The 
extension trial is a separate trial and a specific consent will be sought before participation. A 
separate ISF and clinical trial protocol will be issued.
Procedures will be put in place so that the blind of the parent trial will be maintained for the 
trial team, investigator and patient (until database lock of the parent trial).
6.2.4
Dose reduction visit / dose increase visit
If a patient experiences a drug related adverse event, the dose can be reduced and the dose 
can be re-increased after recovery as described in Section 4.2.1. In both cases, the patient will 
have to come back to a visit where the following will be performed:

Physical examination including vital signs.

Adverse events and concomitant therapy will be assessment since last visit.

Local dipstick pregnancy test (if applicable).

Safety blood and urine samples will be collected and submitted to the central 
laboratory.

FlowScreen® spirometry (FVC) in the allowed time window will be performed.

Trial medication will be collected and treatment compliance will be reviewed.

IRT call for reduction or increase of the dose and trial medication dispensation.
6.2.5
Optional substudies
Substudies will be performed at selected, highly specialized and experienced sites. Patients at 
these dedicated sites will be invited to optionally participate in one or several substudies and 
give their consent by a separate patient information / informed consent (PI / IC). Participation 
in the main trial must not be affected if a patient withdraws from a substudy participation.
Participation in the substudies is voluntary and not a prerequisite for participation in the main 
trial.


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Scheduling of optional substudy procedures is specified in the Substudy Flowchart and 
corresponding footnotes.
Substudy information for respective sites will be provided in the ISF.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is a multi-centre, multi-national, prospective, randomised, placebo-controlled, double 
blind clinical trial to investigate the efficacy and safety of nintedanib at a dose of 150 mg bid, 
in patients with Systemic Sclerosis associated Interstitial Lung Disease.
The primary endpoint is the annual rate of decline in FVC in mL, estimated from readings 
taken over 52 weeks. The primary endpoint will be analysed using a random coefficient 
regression model (i.e. a random slope and intercept) as detailed in Section 7.3.1.
The key secondary endpoints are the absolute change from baseline in the mRSS at week 52, 
and the absolute change from baseline in the SGRQ total score at week 52. These will be 
analysed using a Mixed Model Repeated Measures (MMRM) approach as detailed in Section
7.3.2.
NULL AND ALTERNATIVE HYPOTHESES
7.2
A hierarchical testing procedure will be used to test the primary and key secondary endpoints 
in order to protect the type I error rate. The primary objective is to establish the superiority of 
nintedanib over placebo. The following hypotheses for the primary endpoint will be tested 
first (based on a two-sided test):
H01: There is no difference in the annual rate of decline in FVC in mL between 
nintedanib 150 mg bid and placebo.
Ha1: There is a difference in the annual rate of decline in mean FVC in mL between
nintedanib 150 mg bid and placebo.
If the null hypothesis H01 is rejected at the 5% significance level in favour of nintedanib 
150 mg bid, then the following hypotheses for the first key secondary endpoint will be tested
(based on a two-sided test):
H02: There is no difference in the mean absolute change from baseline in the mRSS at 
week 52 between nintedanib 150 mg bid and placebo.
Ha2: There is a difference in the mean absolute change from baseline in the mRSS at 
week 52 between nintedanib 150 mg bid and placebo.
If the null hypothesis H02 is rejected at the 5% significance level in favour of nintedanib 
150 mg bid, then the following hypotheses for the second key secondary endpoint will be 
tested:
H03: There is no difference in the mean absolute change from baseline in the SGRQ 
total score at week 52 between nintedanib 150 mg bid and placebo.


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Ha3: There is a difference in the mean absolute change from baseline in the SGRQ 
total score at week 52 between nintedanib 150 mg bid and placebo.
Each step will only be considered confirmatory providing all the previous steps were 
successful. If any of the previous steps were not successful (i.e. the null hypothesis was not 
rejected), then the procedure stops and the current endpoint (and any subsequent endpoints) 
will be analysed for exploratory purposes only.
PLANNED ANALYSES
7.3
The efficacy and safety analyses will be conducted on the treated set, which consists of 
patients who are randomised to a treatment group and receive at least one dose of trial
medication. For efficacy analyses, all measurements performed within the first 52 weeks will 
be used, even if a patient prematurely discontinues treatment (i.e. using an intent-to-treat 
principle).
For efficacy and safety analyses, patients will be analysed according to their planned
treatment group.
7.3.1
Primary endpoint analyses
The primary endpoint is the annual rate of decline in FVC in mL estimated from 
measurements taken over 52 weeks. ATA status (positive or negative), age, height, gender 
and baseline FVC in mL will be included as explanatory variables in the model. Baseline 
FVC is defined as the FVC result recorded at Visit 2, unless missing in which case the 
screening result will be used. The decrease in FVC is assumed to be linear within each 
subject over the 52 weeks; this was also assumed in the idiopathic pulmonary fibrosis trials 
INPULSIS-1 and INPULSIS-2 (P14-07514). The intercepts and slopes will be assumed to be 
normally distributed with arbitrary covariance matrix. The within patient error will be 
assumed to be independent and normally distributed with mean zero and a common variance. 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 
Significance tests will be based on least-squares means using a two-sided α = 0.05, and an 
intent-to-treat principle will be used (i.e. all available data up to 52 weeks will be used, 
including baseline and data for patients who prematurely discontinue randomised treatment). 
Analyses will be implemented using SAS® version 9.4 or higher.
The assumptions for the primary analysis of decline in FVC will be tested as described in the 
trial statistical analysis plan (TSAP). The primary analysis will be based on observed data
and will assume data are missing at random. The effect of missing data will be investigated 
using multiple imputation methods which assume that patients who discontinue treatment 
will no longer benefit from it in the future. See Section 7.5.1 for further details of these 
sensitivity analyses.


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Subgroup analyses (for example, by gender, age, ATA status, SSc subtype and subgroups 
reflecting disease severity) will be specified in the TSAP.
A cumulative distribution plot will be provided, showing the percentage of patients by the 
change from baseline in FVC in mL at week 52.
FVC data collected beyond week 52 will be analysed in a descriptive manner only. Data will 
be summarised graphically and using summary statistics.
7.3.2
Secondary endpoint analyses
Analyses of the key secondary endpoints
7.3.2.1
The key secondary endpoints of the absolute change from baseline in mRSS at week 52, and 
the absolute change from baseline in the SGRQ total score at week 52, will be analysed using 
a restricted maximum likelihood (REML) based repeated measures approach. Analyses will 
include the fixed, categorical effects of treatment, ATA status, visit, and treatment-by-visit 
interaction, as well as the continuous, fixed covariates of baseline and baseline-by-visit 
interaction. An unstructured (co)variance structure will be used to model the within patient 
measurements.
If this analysis fails to converge, the following covariance structures will be tested in order: 
heterogenous toeplitz, toeplitz and autoregressive 1 (AR[1]). The first model to converge will 
be used. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. Significance tests will be based on least-squares means using a two-sided α = 0.05 
(two-sided 95% confidence intervals [CIs]). In case the model fails to converge under PROC 
MIXED, the “singular” option will be considered. The treatment comparisons will be the 
contrast between treatments at week 52. An intent-to-treat principle will be used (i.e. all 
available data up to 52 weeks will be used, including data for patients who prematurely 
discontinue randomised treatment).
The effect of missing data will be investigated using multiple imputation methods which 
assume that patients who discontinue treatment will no longer benefit from it in the future. 
See Section 7.5.1 for further details. Additional sensitivity analyses and subgroup analyses 
may be done and will be described in the TSAP.
A cumulative distribution plot will be provided, showing the percentage of patients by the 
change from baseline in mRSS at week 52.
Analyses of the other secondary endpoints
7.3.2.2
The rate of decline in FVC in percent predicted will be analysed in the same way as the 
primary endpoint including ATA status and baseline FVC% predicted as covariates. All other
continuous secondary endpoints will be analysed in the same way as the key secondary 
endpoints using a MMRM approach.


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If the percentage of deaths during the trial is less than 2% in total, then the number and 
percentage of deaths will be presented by treatment group. Otherwise, a Cox proportional 
hazards model stratified by ATA status will be used to estimate and test (based on a Wald 
test) the hazard ratio of nintedanib vs placebo for the time to all-cause mortality endpoint. A 
Kaplan-Meier plot by treatment group will also be presented. Note that the endpoint will be 
based on all available data collected up to trial completion.
Any p-values presented for the secondary endpoints (with the exception of the key secondary 
endpoints) will be considered nominal in nature and no adjustment for multiplicity will be 
made.
7.3.3
Further endpoint analyses
All further endpoints will be summarized descriptively and will be considered exploratory in 
nature.
Baseline levels and changes from baseline in serum and plasma protein biomarkers will be 
summarized descriptively over time by treatment group. Correlations between change from 
baseline in clinical measures (FVC, mRSS) and serum/plasma and RNA biomarker levels 
will be explored. In addition, the relationships between drug concentrations, clinical efficacy
and selected biomarkers will be explored. The results may be included in a separate 
biomarker analysis plan and report.
7.3.4
Safety analyses
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 
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 the 28 days after the date of the last dose of trial medication. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’. Based on the half-life of the study drug, adverse events that occur 
between the start of treatment and up to 7 days after the date of the last dose of trial 
medication will be analysed in addition.
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 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 


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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.
7.3.5
Pharmacokinetic analyses
In the CTR, pre-dose plasma concentrations (Cpre,ss) of nintedanib and its two metabolites 
(BIBF 1202 and BIBF 1202-glucuronide) will be tabulated with descriptive statistics.
For pharmacokinetic analysis and displays, concentrations will be used in the same format as 
reported in the bio-analytical report. Only concentrations within the validated concentration 
range and actual sampling times will be used. See Appendix 10.6.1 for further details.
INTERIM ANALYSES
7.4
Safety data will be reviewed on a regular basis by a DMC (see the DMC charter for further 
details). A blinded assessment of variability and/or rate of FVC decline may be performed in 
order to check and re-estimate the sample size assumptions. More details regarding the timing 
and the recalculation strategy will be provided in the TSAP and will be available by the time 
of first patient in. No unblinded interim analyses are planned.
HANDLING OF MISSING DATA
7.5
7.5.1
Efficacy endpoints
The effect of missing data on the primary endpoint will be investigated using multiple 
imputation techniques.
For the primary endpoint, the following subsets of patients will be defined:
1) Patients with an FVC result at week 52 who received trial medication until week 52.
2) Patients with an FVC result at week 52 who prematurely discontinued trial medication 
prior to week 52.
3) Patients without an FVC result at week 52 who were alive at week 52.
4) Patients without an FVC result at week 52 who died prior to week 52.
These four subsets of patients will be used in sensitivity analyses to estimate the treatment 
effect under differing assumptions around the persistence of efficacy after withdrawal of trial 
medication. Table 7.5.1: 1 describes the planned sensitivity analyses for handling missing 
primary endpoint data. Sensitivity analyses 1 and 2 will only be performed if there are at least 
10 patients included in patient subset 2 in each treatment group.


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Table 7.5.1: 1 Sensitivity analyses for handling missing primary endpoint data
Analysis
Patient subset 3: No FVC result but 
alive at Week 52
Patient subset 4: No FVC result and 
died prior to Week 52
Handling of 
missing 
FVC result
Underlying 
assumption
Handling of 
missing 
FVC result
Underlying assumption
Primary 
analysis
Missing data 
handled by 
model.
Assumes missing at 
random. Discontinued 
patients would have 
behaved similarly to 
patients who did not 
discontinue.
Missing data 
handled by 
model.
Assumes missing at 
random. Discontinued 
patients would have 
behaved similarly to 
patients who did not 
discontinue.
Sensitivity 
analysis 1
Based on the 
slope 
estimates for 
drug and 
placebo in 
patient 
subset 2.
Patients without a result 
would have behaved 
similarly to 
discontinued patients 
with a result who are in 
the same treatment 
group.
Based on the 
slope 
estimates for 
placebo 
patients in 
patient 
subset 2, but 
truncated so 
that those 
who died are 
more severe.
Patients who died before 
week 52 would have 
behaved in a similar or 
worse way to a placebo 
patient who prematurely 
discontinued.
Sensitivity 
analysis 2
Based on the 
slope 
estimates for 
placebo in 
patient 
subset 2.
Patients without a result 
would have behaved 
similarly to 
discontinued placebo 
patients with a result.
Sensitivity 
analysis 3
Based on the 
slope 
estimates for 
placebo in 
patient 
subsets 1 and 
2.
Patients without a result 
would have behaved 
similarly to placebo 
patients with a result 
regardless of whether 
they prematurely 
discontinued treatment 
or not.
Based on 
slope 
estimates for 
placebo 
patients in 
subsets 1 and 
2, but 
truncated so 
those who 
died are 
more severe.
Patients who died before 
week 52 would have 
behaved in a similar or 
worse way to a placebo 
patient regardless of 
whether they prematurely 
discontinued treatment or 
not.


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Further sensitivity analyses will be described in detail in the TSAP. Similar sensitivity 
analyses will be performed for the key secondary endpoints. In the analysis of all other 
continuous secondary endpoints, missing data will not be imputed. The mixed effect model 
will handle missing data based on a likelihood method under the "missing at random 
assumption". Following the intention-to-treat (ITT) principle, every randomised patient with 
at least one data point (at baseline or after randomization) will be included in this analysis. In 
the analysis of time to all-cause mortality, missing or incomplete data will be handled using 
censoring as detailed in the TSAP.
7.5.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards. Other missing 
safety data will not be imputed.
7.5.3
Plasma concentrations
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, NOA are 
included).
RANDOMISATION
7.6
Patients will be randomised in blocks to double-blind treatment. The randomization will be 
stratified by ATA status (positive or negative) within the IRT system. Approximately equal 
numbers of patients will be randomised to each treatment group (i.e. a 1:1 randomisation will 
be used). BI will arrange for the randomization and the packaging and labelling of trial 
medication. The randomisation list 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 clinical trial 
report. Access to the codes will be controlled and documented. All members of the clinical 
trial team will remain blinded to the randomization schedule until the final database is locked. 
The independent DMC will at any time have the possibility to look at unblinded data 
according to the DMC charter.
DETERMINATION OF SAMPLE SIZE
7.7
The estimated treatment difference in the absolute change in FVC in mL over 52 weeks is 
assumed to be between 70 and 110 mL, based on the cyclophosphamide trial in scleroderma 
lung disease (R14-5407), and on the idiopathic pulmonary fibrosis (IPF) trials INPULSIS-1 
and INPULSIS-2 (P14-07514). Note that FVC percent predicted has been converted to mL 
using the approximate relationship of 1% = 35 mL based on the IPF results which were 


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presented in both percent predicted and mL. An equal standard deviation across treatment 
groups of 245 mL (based on the cyclophosphamide trial) and a 1:1 randomization is assumed. 
The sample size calculations in Table 7.7:1 have been performed based on a two-sided, two-
sample superiority t-test, with a significance level of 5% and power of either 80% or 90%.
Table 7.7: 1
Primary endpoint: Sample size calculations based on a two-sided, two-sample 
t-test with a significance level of 5% and various assumptions
Mean treatment difference in 
absolute change in FVC in mL
50
50
70
70
110
110
Standard deviation of FVC in mL
245
245
245
245
245
245
Power (%)
90
80
90
80
90
80
Sample size per treatment group
506
378
259
194
106
79
The first key secondary endpoint of the absolute change from baseline in the mRSS at week 
52 is also considered. Based on skin thickness results from the cyclophosphamide trial in 
scleroderma lung disease (R14-5407), the estimated treatment difference is assumed to be 
between 2 and 3 points. An equal standard deviation across treatment groups of 9 (based on 
the same reference) and a 1:1 randomization is assumed. The sample size calculations in 
Table 7.7: 2 have been performed based on a two-sided, two-sample superiority t-test, with a 
significance level of 5% and power of either 80% or 90%.
Table 7.7: 2
First key secondary endpoint: Sample size calculations based on a two-sided, 
two-sample t-test with a significance level of 5% and various assumptions
Mean treatment difference in 
absolute change in mRSS
3
3
2
2
2.2
2.6
Standard deviation of mRSS
9
9
9
9
9
9
Power (%)
90
80
90
80
80
90
Sample size per treatment group
191
143
427
319
260
260
Finally, the second key secondary endpoint of the absolute change from baseline in the 
SGRQ total score at week 52 is considered. As a minimum clinically important difference is 
yet to be established in SSc-ILD, the minimum clinically important difference in COPD 
patients of 4 points will be assumed (P12-11232). An equal standard deviation across 
treatment groups of 13 will be assumed based on the pooled analysis of the IPF trials 
INPULSIS-1 and INPULSIS-2 (P14-07514). The sample size calculations in Table 7.7: 3


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have been performed based on a two-sided, two-sample superiority t-test, with a significance 
level of 5% and power of either 80% or 90%.
Table 7.7: 3
Second key secondary endpoint: Sample size calculations based on a two-
sided, two-sample t-test with a significance level of 5% and various 
assumptions
Mean treatment difference in absolute 
change in SGRQ total score
-4
-4
-3
-3
-3.2
-3.7
Standard deviation of SGRQ total score
13
13
13
13
13
13
Power (%)
80
90
80
90
80
90
Power (%)
167
223
296
396
260
260
A hierarchical testing procedure will be used to test the primary and key secondary endpoints, 
as discussed in Section 7.2.
Assuming a small number of non-analysable patients (i.e. patients who do not provide at least 
one post-baseline result), a sample size of 260 patients per treatment group will achieve 90% 
power when detecting a treatment difference of 70 mL in the primary endpoint. There is also 
sufficient power to test the key secondary endpoints if the hierarchy testing procedure allows.
It should be noted that the sample size calculation for the primary endpoint is based on the 
treatment difference at 52 weeks using a two-sample t-test, although this endpoint will be 
analysed using a rate of decline model. This model is more powerful. Basing the sample size 
calculations on simulations of such a rate of decline model (applying the method by Chen et 
al., R15-3192) provides reassurance that a sample size of 260 will achieve at least 90% power 
and is robust to small changes in assumptions.
Calculations for the sample sizes shown in the tables were performed using nQuery Advisor® 
7.0 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) and relevant BI Standard Operating Procedures (SOPs) and 
the Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997).
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 and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
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.
Additional information for Japan:
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 


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informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
Additional information for Japan:
The Investigator must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions. The patient is 
given sufficient 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.
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
eCRF for individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
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. 
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 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:
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.
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 nintedanib this is the current version of the Investigator’s Brochure for more details.
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 last patient out.
For EU member states.
The IEC / competent authority in each participating EU member state needs to be notified 
about the end of the trial or early termination of the trial.


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For Japan:
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:
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:
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
P05-12782
Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
Crapo R, Enright P, Grinten CPM van der, Gustafsson P, Jensen R, 
Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, 
Pellegrino R, Viegi G, Wanger J. Standardisation of spirometry. Eur 
Respir J 2005. 26(2):319-338.
P11-11216
Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson 
AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, 
Juhel N, Klueglich M, Bois RM du. Efficacy of a tyrosine kinase 
inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011. 
365(12):1079-1087.
P12-11232
Jones PW. St.George's Respiratory Questionnaire: MCID. COPD J 
Chronic Obstruct Pulm Dis 2005. 2:75-79.
P14-07514
Richeldi L, et al, INPULSIS Trial Investigators. Efficacy and safety of 
nintedanib in idiopathic pulmonary fibrosis. New England Journal of 
Medicine, published on May 18, 2014, doi: 10.1056/NEJMoa1402584 N 
Engl J Med 2014. 370(22):2071-2082.
P14-07919
Herzog EL, Mathur A, Tager AM, Feghali-Bostwick C, Schneider F, 
Varga J. Interstitial lung disease associated with systemic sclerosis and 
idiopathic pulmonary fibrosis: how similar and distinct? Arthritis and 
Rheumatology, Accepted Article, Accepted: May 08, 2014, doi: 
10.1002/art.38702 Arthritis Rheumatol 2014. 66(8):1967-1978.
P14-16916
Pope J. Measures of systemic sclerosis (scleroderma): Health 
Assessment Questionnaire (HAQ) and Scleroderma HAQ (SHAQ), 
physician- and patient-rated global assessments, Symptom Burden Index 
(SBI), University of California, Los Angeles, Scleroderma Clinical Trials 
Consortium Gastrointestinal Scale (UCLA SCTC GIT) 2.0, Baseline 
Dyspnea Index (BDI) and Transition Dyspnea Index (TDI) (Mahler's 
Index), Cambridge Pulmonary Hypertension Outcome Review 
(CAMPHOR), and Raynaud's Condition Score (RCS). Arthritis Care Res 
(Hoboken) 2011. 63(Suppl 11):S98-S111.
P14-16917
Steen VD, Medsger TA. The value of the Health Assessment 
Questionnaire and special patient-generated scales to demonstrate change 
in systemic sclerosis patients over time. Arthritis Rheum 1997. 
40(11):1984-1991.
P15-00879
Kowal-Bielecka O, et al, EUSTAR Co-Authors. EULAR 
recommendations for the treatment of systemic sclerosis: a report from 
the EULAR Scleroderma Trials and Research group (EUSTAR). Ann 
Rheum Dis 2009. 68(5):620-628.


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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 2005. 
26(4):720-735.
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.
R11-1366
Choi SW, Victorson DE, Yount S, Anton S, Cella D. Development of a 
conceptual framework and calibrated item banks to measure patient-
reported dyspnea severity and related functional limitations. Value 
Health 2011. 14:291-306.
R14-4918
Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, 
prevalence, survival, risk factors, malignancy, and environmental 
triggers. Curr Opin Rheumatol 2012. 24(2):165-170.
R14-4927
Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med 
2009. 360(19):1989-2003.
R14-5045
Hinchcliff ME, Beaumont JL, Carns MA, Podlusky S, Thavarajah K, 
Varga J, Cella D, Chang RW. Longitudinal evaluation of PROMIS-29 
and FACIT-dyspnea short forms in systemic sclerosis. Journal of 
Rheumatology, Published online before print November 1, 2014, doi: 
10.3899/jrheum.140143 J Rheumatol 2014.
R14-5055
Hoogen F van den, et al. 2013 classification criteria for systemic 
sclerosis: an American College of Rheumatology/European League 
against Rheumatism collaborative initiative. Arthritis Rheum 2013. 
65(11):2737-2747.
R14-5056
Hinchcliff M, Beaumont JL, Thavarajah K, Varga J, Chung A, Podlusky 
S, Carns M, Chang RW, Cella D. Validity of two new patient-reported 
outcome measures in systemic sclerosis: Patient-Reported Outcomes 
Measurement Information System 29-item Health Profile and Functional 
Assessment of Chronic Illness Therapy-Dyspnea short form. Arthritis 
Care Res (Hoboken) 2011. 63(11):1620-1628.
R14-5058
Bruce B, Fries JF. The Health Assessment Questionnaire (HAQ). Clin 
Exp Rheumatol 2005. 23(Suppl 39):S14-S18.
R14-5407
Tashkin DP, et al. Cyclophosphamide versus placebo in scleroderma 
lung disease. N Engl J Med 2006. 354(25):2655-2666.
R14-5409
Assassi S, Sharif R, Lasky RE, McNearney TA, Estrada-Y-Martin RM, 
Draeger H, Nair DK, Fritzler MJ, Reveille JD, Arnett FC, Mayes MD, 
GENISOS Study Group. Predictors of interstitial lung disease in early 


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systemic sclerosis: a prospective longitudinal study of the GENISOS 
cohort. Arthritis Res Ther 2010. 12(5):R166.
R15-0845
Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, 
Enright PL, Hankinson JL, Ip MSM, Zheng J, Janet Stocks on behalf of 
the ERS Global Lung Function Initiative. Multi-ethnic reference values 
for spirometry for the 3 - 95 year age range: the global lung function 
2012 equations: report of the Global Lung Function Initiative (GLI), 
ERS task force to establish improved lung function reference values. Eur 
Respir J 2012. 40(6):1324-1343.
R15-1205
Clements PJ, et al. Skin thickness score in systemic sclerosis: an 
assessment of interobserver variability in 3 independent studies. J 
Rheumatol 1993. 20(11):1892-1896.
R15-1207
Khana D, et al, Investigators in CRISS and EPOSS. Measures of 
response in clinical trials of systemic sclerosis: the combined response 
index for systemic sclerosis (CRISS) and outcome measures in 
pulmonary arterial hypertension related to systemic sclerosis (EPOSS). J 
Rheumatol 2009. 36(10):2356-2361.
R15-2010
Ferraz MB, Quaresma MR, Aquino LRL, Atra E, Tugwell P, Goldsmith 
CH. Reliability of pain scales in the assessment of literate and illiterate 
patients with rheumatoid arthritis. J Rheumatol 1990. 17(8):1022-1024.
R15-2073
Kubota M, Kobayashi H, Quanjer PH, Omori H, Tatsumi K, Kanazawa 
M, Clinical Pulmonary Functions Committee of the Japanese Respiratory 
Society. Reference values for spirometry, including vital capacity, in 
Japanese adults calculated with the LMS method and compared with 
previous values. Respir Invest 2014. 52(4):242-250.
R15-3192
Chen J, Stock S, Deng C. Sample size estimation through simulation of a 
random coefficient model by using SAS. 
http://www.lexjansen.com/pharmasug/2008/sp/SP03.pdf (access date: 22 
June 2015) ; PharmaSUG 2008.
R96-0690
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976. 16(1):31-41.
R96-2382
EuroQol - a new facility for the measurement of health-related quality of 
life. Health Policy 1990. 16:199-208.
R98-0966
Jones PW, Quirk FH, Baveystock CM. The St.George's respiratory 
questionnaire. Respir Med 1991. 85(Suppl B):25-31.
UNPUBLISHED REFERENCES
9.2
c01783972-11
Investigator’s Brochure nintedanib (BIBF 1120)
c09412738
Influence of bosentan on the pharmacokinetics of nintedanib in healthy 
male
subjects, Study 1199.239, 10 November 2016


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c09712613
Investigation of drug-drug interaction between nintedanib and 
pirfenidone in patients with IPF (an open label, multiple-dose, Study 
1199.229, 31 July 2017 two group study)


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10.
APPENDICES
LUNG FUNCTION CRITERIA 
10.1
At Visit 2, FVC must fulfil the following criteria:

≥ 40% of predicted normal
Predicted normal values will be calculated according to GLI (Global Lung Initiative) (R15-
0845, R15-2073) at the site level, using the Flowscreen. FVC percent predicted is a key 
inclusion criterion and a secondary endpoint using the following demographic information:
race, age, gender and height.
At Visit 2, DLCO must fulfil the following criteria:

Within range 30% - 89% predicted of normal; corrected for Hb
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·dL-1 (R06-2002) can be 
calculated as:

Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(10.22+Hb)) for males 
aged 15 years or above

Predicted DLCO corrected for Hb = Predicted DLCO x (1.7Hb/(9.38+Hb)) for 
females and children aged less than 15 years
For decision on inclusion / exclusion, DLCO results from Visit 2 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.
There should be at least two acceptable tests that meet the repeatability requirement of either 
being within 3 mL CO (Standard Temperature and Pressure, Dry - STPD)•min-1 •mmHg-1
(or 1 mmol•min-1•kPa-1) of each other or within 10% of the highest value.
CREATININE CLEARANCE
10.2
Creatinine clearance calculation is done according to Cockroft and Gault (R96-0690).


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
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum 
creatinine in mg/dL)
PATIENT REPORTED OUTCOME QUESTIONNAIRES
10.3
10.3.1
SGRQ


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10.3.2
Functional Assessment of Chronic Illness Therapy (FACIT-dyspnoea)


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10.3.3
Scleroderma health assessment questionnaire (SHAQ)


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10.3.4
EQ-5D-5L


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PATIENTS GLOBAL IMPRESSION OF HEALTH
10.4


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PHYSICIAN’S GLOBAL IMPRESSION OF PATIENTS’S HEALTH
10.5


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HANDLING AND DERIVATION OF PHARMACOKINETIC 
10.6
PARAMETERS
10.6.1
Pharmacokinetic Methods
Concentrations will be used for calculations in the format that is reported in the bioanalytical
report. The data format for descriptive statistics of concentrations will be identical with the
data format of the respective concentrations. For the calculation of PK parameters, only
concentrations within the validated concentration range will be used. The descriptive
statistics of PK parameters will be calculated using the individual values with the number of
decimal places as provided by the evaluation program. Then the individual values as well as
the descriptive statistics will be reported with three significant digits in the clinical trial
report. The actual sampling times will be used. For pre-dose samples, the actual sampling
time will be set to zero. Noncompartmental PK parameters will be determined using
WinNonlin or another validated program.
Analyte plasma concentrations will be plotted graphically versus time for all subjects as listed
in the analyte plasma concentration-time tables. For the presentation of the mean profiles, the
geometric mean and the planned blood sampling times will be used.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1.0
Date of CTP revision
02 Mar 2016
EudraCT number
2015-000392-28
BI Trial number
1199.214 (SENSCISTM)
BI Investigational Product(s)
Nintedanib
Title of protocol
A double blind, randomised, placebo-controlled 
trial evaluating efficacy and safety of oral 
nintedanib treatment for at least 52 weeks in 
patients with ‘Systemic Sclerosis associated 
Interstitial Lung Disease’(SSc-ILD).
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
x
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis
Description of change
Administrative changes, corrections and 
clarification.
Rationale for change
Add clarification and correction, add trial name 
‘SENSCISTM’.
Section to be changed
I
II
Flowchart (Footnotes)
Section 6 (Investigational Plan)
Description of change
Women of childbearing potential will have to 
perform a pregnancy test every 4-6 weeks. Once 
intervals between site visits are > 6 weeks, these 
will be centrally provided and performed at home.
Rationale for change
To ensure regular pregnancy testing as requested 
by health authorities.
Section to be changed
Flowchart – optional substudies


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Description of change
Administrative changes, corrections and 
clarification.
Rationale for change
Clarification that the informed consent forms for 
substudy participation are to be signed before 
performing the respective substudy procedure. 
Depending on the substudy, the latest possibility 
would be at Visit 2.
Section to be changed
Abbreviations
Description of change
Administrative changes, corrections and 
clarifications.
Rationale for change
Abbreviation for ‘QT’ added
Section to be changed
I
II
III
IV
V
Section 1.1 (Medical Background)
Section 2.3 (Benefit Risk Assessment)
Section 3.2 (Discussion of Trial Design)
Section 3.3.3 (Exclusion Criteria)
Section 4.2.2 (Restrictions)
Description of change
Administrative changes, corrections and 
clarification
Rationale for change
Addition of mycophenolate sodium for 
clarification as for ‘mycophenolate’ two possible 
salt forms are available.
Section to be changed
Section 1.2 (Drug Profile)
Description of change
Addition of a cautionary statement for patients at 
risk to develop QT prolongation according to the 
IB.
Rationale for change
Clarification of inconsistency between IB and 
CTP.
Section to be changed
Section 3.1 (Overall Trial Design and Plan)
Description of change
Administrative changes, corrections and 
clarification.
Rationale for change
Clarification of ‘early discontinuation of trial 
medication’ through rewording.
Section to be changed
Section 3.3.2 (Inclusion Criteria)
Description of change
Change reference time point for historical HRCT 
within 12 month to Visit 1. 
Rationale for change
Visit 1 is presenting the better predictable time 
point compared to Visit 2.
Section to be changed
Section 3.3.3 (Exclusion Criteria)
Description of change
At discretion of the investigator, not only digital 
ulcers but also severe other ulcers could lead to 


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exclusion of a patient. The same holds true for 
severe GI symptoms due to SSc.
As described in the patient information, double 
contraception is a requirement for women of 
childbearing potential participating in the trial. 
Rationale for change
The respective wording was added to increase 
awareness for investigators for safety reasons.
Section to be changed
Section 3.3.3 (Exclusion Criteria)
Description of change
Patients with underlying chronic liver disease 
(Child Pugh A, B, C hepatic impairment) are to be 
excluded
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 4.2.2 (Restrictions regarding concomitant 
treatment)
Description of change
Low dose prednisone stabilization requirement 
removed
Rationale for change
Corrected for consistency with Exclusion 
Criterion No. 17
Section to be changed
Section 5.2.3 (Assessment of DLCO)
Description of change
DLCO adjustment for altitude and COHb 
removed
Rationale for change
Corrected for consistency with section 10.1


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Number of global amendment
2.0
Date of CTP revision
26 Jan 2017
EudraCT number
2015-000392-28
BI Trial number
1199.214 (SENSCISTM)
BI Investigational Product(s)
Nintedanib
Title of protocol
A double blind, randomised, placebo-controlled 
trial evaluating efficacy and safety of oral 
nintedanib treatment for at least 52 weeks in 
patients with ‘Systemic Sclerosis associated 
Interstitial Lung Disease’(SSc-ILD).
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
x
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve l3ogistical or 
administrative aspects only
Section to be changed
Flowchart – Main Trial
Description of change
Administrative changes, corrections and 
clarification.
Rationale for change
Add clarification and correction
Section to be changed
I
Flowchart – Main Trial (Footnotes)
Description of change
Compliance / drug accountability at Visit 3 and 
Visit 5 to be performed only in case of dose 
reduction/increase
Rationale for change
Clarification what needs to be documented at 
Visit 3 and Visit 5 in regards of compliance / drug 
accountability
Section to be changed
I
II
III
Flowchart – Main Trial (Footnotes),  
Abbreviations
5.5 (Assessment of exploratory biomarker(s))
Description of change
Administrative changes, corrections and 
clarification.


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Rationale for change
Clarification that the Abbreviation for anti-RNA 
polymerase III antibodies is (anti-)RNA Pol III.
Section to be changed
Section 1.2 Drug Profile
Description of change
According to the changes in the recent IB Version
2.0 and Version 3.0 it was added pancreatitis and 
thrombocytopenia as well as drug-induced liver 
injury were infrequently reported in the IPF 
clinical trials and in the post-marketing period and 
are considered adverse drug reactions of 
nintedanib treatment in IPF. Patients with low 
body weight (<65 kg), Asian and female patients 
have a higher risk of elevations in liver enzymes.
Rationale for change
Clarification of inconsistency between IB and 
CTP.
Section to be changed
I
Section 3.3
Description of change
Added that enrolment will be generally 
competitive but restriction of recruitment of 
patients on stable dose of mycophenolate or 
methotrexate background medications may occur.
Rationale for change
To be able to adequately assess the treatment 
effect of nintedanib versus placebo in patients 
without background medication.
Section to be changed
I
Section 3.3
Description of change
Update of numbers of global country and site 
contribution
Rationale for change
Clarification and correction
Section to be changed
I
Section 3.3.2 Inclusion criteria
Description of change
Change the requested SSc disease onset (defined 
by first non-Raynaud symptom) from 5 years to 7 
years of Visit 1.
Rationale for change
Ensure trial conduct feasibility without 
compromising characterization of study 
population.
Section to be changed
I
Section 3.3.3 (Exclusion Criteria)
Description of change
Change reference time point to assess eligibility in 
regards of airway obstruction (pre-bronchodilator 
FEV1/FVC <0.7) to Visit 2.
Rationale for change
Ensure consistency with all other Lung function 
criteria eligibility timepoints.


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Section to be changed
I
II
Section 3.3.3 (Exclusion Criteria)
Section 4.2.2.1 (Restrictions regarding 
concomitant treatment)
Description of change
Add of washout requirements for mycophenolate 
mofetil / sodium or methotrexate.
Rationale for change
Clarification of washout requirements for 
mycophenolate mofetil / sodium or methotrexate.
Section to be changed
I
Section 3.3.3 (Exclusion Criteria)
Description of change
Deletion of tubal occlusion as an example for 
method of permanent sterilization.
Rationale for change
According to Clinical Trial Facilitation Group 
recommendations (2014), woman who underwent 
a tubal ligation are still to be considered ‘of 
childbearing potential’.
Section to be changed
I
Section 3.3.3 (Exclusion Criteria)
Description of change
Additional Exclusion Criterion added. Patients 
with a history of SSc renal crisis are to be 
excluded.
Rationale for change
SSc renal crisis is a major complication in patients 
with systemic sclerosis (SSc) characterized by 
malignant hypertension and acute renal failure 
with a high risk for deterioration. As these 
patients may not automatically be captured by Ex 
3, a new criterion was added.
Section to be changed
I
Section 4.1.4 (Drug assignment and 
administration of doses for each patient)
Description of change
Wording: 1 week treatment was changed to 5 days 
treatment following blister size.
Rationale for change
Correction for consistency.
Section to be changed
I
5.1 (Trial endpoints)
Description of change
Add absolute change from baseline at week 52 in 
CRISS index score to secondary endpoints and 
remove from further endpoints.
Rationale for change
As the Combined Response Index for Systemic 
Sclerosis is further evolving in use in clinical 
trials it should be elevated to secondary endpoints.  
Section to be changed
I
5.3.7 (Assessment of adverse events)
Description of change
Remove additional note for Japan: The reason for 
the decision on causal relationship for unlisted 


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AEs needs to be provided in the eCRF.
Rationale for change
Removed for consistency reasons.
Section to be changed
I
5.3.8 (Adverse event collection and reporting)
Description of change
Clarification that all primary causes of death will 
be reviewed by the independent adjudication. 
committee and process clarification regarding 
dataprotection measures
Rationale for change
Correction for clarification and consistency.
Section to be changed
I
5.5.2 (Analytical determinations)
Description of change
Clarification that autoantibody analysis from 
serum samples will be done in a central 
laboratory.
Rationale for change
Correction for clarification and consistency.
Section to be changed
I
5.5.3 (Biobanking)
Description of change
Clarification that DNA banking is not performed 
in all countries.
Rationale for change
Correction for clarification and consistency.
Section to be changed
I
6.1 (Screening)
Description of change
Clarification that rescreening is possible.
Rationale for change
Correction for clarification and consistency.
Section to be changed
I
6.1 (Screening)
Description of change
Referral to specific Visits removed
Rationale for change
Correction for clarification and consistency.
Section to be changed
I
6.2.1 (Screening)
Description of change
Correct reference time point for historical HRCT 
within 12 month to Visit 1. 
Rationale for change
Correction for clarification and consistency with 
Inclusion criteria.
Section to be changed
I
6.2.2 (Treatment phase)
Description of change
Clarification that visit procedures may be 
performed on more than one calendar days.
Rationale for change
Correction for clarification and consistency.
Section to be changed
I
7.3.2 (Secondary endpoint analyses)
Description of change
Change test order of covariance structures.
Rationale for change
Correction for clarification.
Section to be changed
I
7.3.2 Secondary endpoint analyses


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Description of change
Including ATA status and baseline FVC% 
predicted as covariates.
Rationale for change
Correction for clarification.
Section to be changed
I
10.1 (Lung function criteria)
Description of change
Clarification that at Visit 2 FVC % predicted will 
be calculated at the site level, by using the 
Flowscreen.
Rationale for change
Correction for clarification and consistency.
Number of global amendment
3.0
Date of CTP revision
15 Feb 2018
EudraCT number
2015-000392-28
BI Trial number
1199.214 (SENSCISTM)
BI Investigational Product(s)
Nintedanib
Title of protocol
A double blind, randomised, placebo-controlled 
trial evaluating efficacy and safety of oral 
nintedanib treatment for at least 52 weeks in 
patients with ‘Systemic Sclerosis associated 
Interstitial Lung Disease’(SSc-ILD).
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
x
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve l3ogistical or 
administrative aspects only
Section to be changed
I
II
III
IV
Flowchart – Main Trial (Footnotes)
3.1 (Overall trial design and plan)
3.3.4 (Removal of patients from therapy or 
assessments)
6.2.2 (Treatment phase)
Description of change
Clarification of vital status assessment time 
points.
Rationale for change
Correction


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Section to be changed
I
1.2. (Drug profile)
Description of change
It was added that based on results from a 
dedicated DDI study no clinically relevant PK 
interaction between nintedanib and pirfenidone 
when co-administered in patients with IPF was 
seen. In addition it was added that there was no 
clinically relevant pharmacokinetic effect of 
steady state bosentan treatment on nintedanib 
exposure detected in a dedicated DDI study in 
healthy volunteers.
The new IB reference was added (combined IB 
for nintedanib in Idiopathic Pulmonary Fibrosis, 
Systemic Sclerosis, Progressive Fibrosing 
Interstitial Lung Disease).
Rationale for change
Correction for consistency between IB and CTP.
Section to be changed
I
2.3 (Benefit risk assessment) 
Description of change
According to the changes in the recent IB it was 
clarified that cases of drug-induced liver injury 
(DILI) have been observed with nintedanib 
treatment. The majority of patients presented with 
mild to moderate liver enzyme elevation, which 
was in most cases transient upon dose reduction or 
treatment discontinuation. However, severe DILI 
with fatal outcome has also been reported
Rationale for change
Correction for consistency between IB and CTP.
Section to be changed
I
II
III
3.1 (Overall trial design and plan)
6.1 (Visit schedule)
6.2.2 (Treatment phase)
Description of change
Clarification that patients on treatment will have 
their end of treatment visit (EOT visit) at the same 
time or before the planned Visit 9 of the last 
randomised patient. The EOT visit will replace 
either Visit 9, 10, 11 or 12, whatever is the latest 
possible visit before or at the planned Visit 9 of 
the last randomised patient. For these patients, the 
trial ends with the completion of the follow-up 
visit 28 days after the EOT. All patients who have 
concluded the trial on treatment will be offered 
the opportunity to enter an open label extension 
trial.
Clarification that for patients who discontinued 


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treatment but agreed to come to further visits, the 
last visit will be either Visit 9, 10, 11 or 12, 
whatever is the latest possible visit before or at the 
planned Visit 9 of the last patient randomized. A 
follow up visit is not needed for patients who 
discontinued trial drug earlier.
Rationale for change
To clarify that not all patients will complete the 
trial at once and to specify the individual patient’s 
end of the trial.
Section to be changed
I
4.2.2 (Restrictions)
Description of change
Clarification of clinically significant deterioration 
definition which could be related to organ systems 
other than skin and lung or in other clinical 
parameters than mRSS and FVC, at the discretion 
of the investigator.
Rationale for change
Clarification on definition.
Section to be changed
I
5.2.9 (HRCT substudy at dedicated sites only)
Description of change
It was added that the following assessments of 
structural change on HRCT may be determined on 
each scan: Gastrointestinal assessment / 
assessment of the oesophagus
Rationale for change
To add a possible exploratory assessment.
Section to be changed
I
5.5 (Assessment of exploratory biomarker)
Description of change
The list of biomarkers that might be evaluated was 
completed
Rationale for change
To clarify on possible biomarker panel.
Section to be changed
I
7.3.4 (Safety analyses)
Description of change
Clarification that based on the half-life of the trial
drug, adverse events that occur between the start 
of treatment and up to 7 days after the date of the 
last dose of trial medication will be analysed in 
addition.
Rationale for change
Specification of an additional adverse event 
analyses to take the half-life of the trial drug into 
account.

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c08861098-02
BI Trial No.:
  1199.214
Title:
  A double blind, randomised, placebo-controlled trial evaluating
efficacy and safety of oral nintedanib treatment for at least 52
weeks in patients with ‘Systemic Sclerosis associated Interstitial
Lung Disease’(SSc-ILD).
Including Protocol Amendment 3 [c16778189], Protocol 
Amendment 4 [c03014699]
Investigational
Product(s):
Nintedanib
Responsible trial 
statistician(s):
For Boehringer-Ingelheim Germany
Birkendorfer Str. 65
88397 Biberach an der Riß
Germany
Phone: 
Fax: 
Date of statistical 
analysis plan:
26 July 2018 SIGNED
Version:
Final 
Page 1 of  88
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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...................................................................................................................5
2.
LIST OF ABBREVIATIONS ..............................................................................6
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINT(S).....................................................................................................10
5.1
PRIMARY ENDPOINT(S) ................................................................................10
5.2
SECONDARY ENDPOINT(S) ..........................................................................10
5.2.1
Key secondary endpoint(s).................................................................................10
5.2.2
(Other) Secondary endpoint(s) ..........................................................................10
5.2.2.1
Change from baseline endpoints...........................................................................10
5.2.2.2
Time to death ........................................................................................................12
5.3
FURTHER ENDPOINT(S)................................................................................13
5.3.1
Absolute change from baseline endpoints.........................................................13
5.3.2
Categorical endpoints .........................................................................................14
5.3.3
Biomarkers ..........................................................................................................14
5.4
OTHER VARIABLE(S) .....................................................................................14
5.4.1
Demographics and baseline characteristics......................................................14
5.4.1.1
Demographic data .................................................................................................14
5.4.1.2
Trial indication......................................................................................................14
5.4.1.3
Baseline characteristics for lung function and gas transfer characteristics...........15
5.4.1.4
Baseline characteristics for questionnaires and derived outcomes.......................15
5.4.2
Compliance ..........................................................................................................15
5.4.3
Exposure ..............................................................................................................16
5.4.3.1
Exposure over 52 weeks .......................................................................................16
5.4.3.2
Exposure over all the trial.....................................................................................17
5.4.4
Liver enzyme and bilirubin elevations..............................................................17
5.4.5
Marked changes in vital signs............................................................................18
5.4.6
Safety time-to-event analyses.............................................................................19
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................20
6.1
TREATMENT(S)................................................................................................20
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................23
6.3
PATIENT SETS ANALYSED...........................................................................26
6.4
SUBGROUPS ......................................................................................................26
6.5
POOLING OF CENTRES .................................................................................28
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................28
6.6.1
Primary endpoint................................................................................................28
6.6.2
Secondary endpoints...........................................................................................29
6.6.2.1
Change from baseline endpoints...........................................................................29
6.6.2.1.1
Modified Rodnan Skin Score...............................................................................29


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6.6.2.1.2
Saint George’s Respiratory Questionnaire...........................................................29
6.6.2.1.3
Digital ulcer net burden........................................................................................29
6.6.2.1.4
HAQ-DI ...............................................................................................................29
6.6.2.1.5
FACIT dyspnoea or functional limitations score.................................................30
6.6.2.1.6
EQ-5D-5L (EuroQol 5-Dimensionnal quality of life questionnaire)...................30
6.6.2.1.7
CRISS...................................................................................................................30
6.6.2.1.8
Disease progression..............................................................................................30
6.6.2.2
Categorical endpoints............................................................................................31
6.6.2.3
Time-to-event endpoints .......................................................................................31
6.6.3
Other endpoints...................................................................................................31
6.6.3.1
Concomitant therapies...........................................................................................31
6.6.3.2
Safety endpoints....................................................................................................32
6.6.3.3
Trial diagnosis date / Date of onset of Raynaud / Date of onset of first non-
Raynaud symptom.................................................................................................32
6.6.3.4
Pharmacokinetic endpoints ...................................................................................32
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................32
7.
PLANNED ANALYSIS......................................................................................38
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........38
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................38
7.2.1
Baseline conditions..............................................................................................38
7.2.2
Concomitant therapies........................................................................................38
7.3
TREATMENT COMPLIANCE........................................................................40
7.4
PRIMARY ENDPOINT(S) ................................................................................40
7.4.1
Primary analysis..................................................................................................40
7.4.2
Sensitivity analyses..............................................................................................42
7.4.2.1
Sensitivity to data handling assumptions..............................................................43
7.4.2.1.1
Statistical model using on-treatment measurements only.....................................43
7.4.2.1.2
Sensitivity to missing data handling .....................................................................43
7.4.2.2
Sensitivity to the analysis model...........................................................................46
7.4.2.2.1
Sensitivity to linearity assumption........................................................................46
7.4.2.2.2
Sensitivity to covariates ........................................................................................46
7.4.2.3
Overall summary of sensitivity analyses ..............................................................47
7.4.3
Subgroup analyses...............................................................................................47
7.5
SECONDARY ENDPOINT(S) ..........................................................................49
7.5.1
Key secondary endpoint(s).................................................................................50
7.5.1.1
Absolute change from baseline in the mRSS at week 52 .....................................50
7.5.1.2
Absolute change from baseline in SGRQ total score at week 52 .........................50
7.5.2
(Other) Secondary endpoint(s) ..........................................................................51
7.5.2.1
Annual rate of decline in FVC in percent predicted over 52 weeks .....................51
7.5.2.2
Absolute change from baseline in FVC in mL at week 52...................................51
7.5.2.3
Relative change from baseline (%) of mRSS at week 52 .....................................51
7.5.2.4
Time to death ........................................................................................................51
7.5.2.5
CRISS index score at week 52..............................................................................51
7.5.2.6
Absolute change from baseline in DLCO in percent predicted at week 52..........52
7.5.2.7
Absolute change from baseline in digital ulcer net burden at week 52 ................52
7.5.2.8
Absolute change from baseline in HAQ-DI score at week 52..............................52


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7.5.2.9
Absolute change from baseline in FACIT dyspnoea score at week 52 ................53
7.6
FURTHER ENDPOINT(S)................................................................................53
7.6.1
Categorical endpoints .........................................................................................53
7.6.2
Change from baseline endpoints........................................................................53
7.6.3
Analyses over the whole trial .............................................................................53
7.6.4
Pharmacokinetics................................................................................................53
7.6.5
Biomarkers ..........................................................................................................53
7.7
EXTENT OF EXPOSURE.................................................................................54
7.8
SAFETY ANALYSIS..........................................................................................54
7.8.1
Adverse events.....................................................................................................54
7.8.1.1
Pre-specified adverse events of special interest....................................................56
7.8.1.2
Adverse events with additional information collection ........................................56
7.8.1.3
Adjudicated adverse events...................................................................................56
7.8.1.4
Additional analysis of adverse event groupings by system ..................................57
7.8.1.5
Adverse events of particular note..........................................................................61
7.8.1.6
Adverse event analyses over the whole trial.........................................................62
7.8.2
Laboratory data ..................................................................................................63
7.8.3
Vital signs.............................................................................................................63
7.8.4
ECG......................................................................................................................63
7.8.5
Others...................................................................................................................63
8.
REFERENCES....................................................................................................64
9.
ADDITIONAL SECTIONS ...............................................................................65
9.1
HCRU (HEALTH CARE RESOURCE UTILISATION)...............................65
9.2
COMPLEMENTARY INFORMATION ON STATISTICAL MODEL 
AND SAS CODE.................................................................................................65
9.3
ADDITIONAL ANALYSIS FOR REGIONAL SUBMISSIONS...................69
9.4
LIST OF BI CUSTOMISED DRUG GROUPINGS OF INTEREST............70
9.5
SPECIFICATION OF RESTRICTED AND FORBIDDEN 
CONCOMITANT THERAPIES .......................................................................72
9.6
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY 
DERIVATION.....................................................................................................73
9.7
LIST OF TERMS INCLUDED IN STROKE PHARMACOVIGILANCE 
ENDPOINT..........................................................................................................74
9.8
PREFERRED TERMS SELECTED FOR BLEEDING 
SUBCATEGORIES ............................................................................................77
10.
HISTORY TABLE..............................................................................................88


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LIST OF TABLES
Table 6.1: 1
Summary of analysed periods according to the type of endpoint ....................21
Table 6.2: 1
Important protocol violations over 52 weeks...................................................23
Table 6.4: 1
Subgroup analyses – List of subgroups............................................................27
Table 6.6.2.1.8: 1
Handling of missing data for disease progression ...................................31
Table 6.7: 1
Time windowing rules for spirometry, physical exam, vital signs, HCRU, 
mRSS, Digital ulcer, menstruation calendar....................................................33
Table 6.7: 2
Time windowing rules for SGRQ, FACIT-dyspnoea, SHAQ, EQ-5D-5L, 
patient global VAS, DLCO, SpO2, antoantibody assessment, Physician 
global VAS.......................................................................................................35
Table 6.7: 3
Time windowing rules for laboratory measurements (and pregnancy test).....36
Table 7.2.2:1 Concomitant therapy outputs and position in the CTR....................................39
Table 7.4.2.1.2: 1
Primary and sensitivity analyses for handling of missing data................44
Table 7.4.2.3: 1
Summary of planned sensitivity analyses according to the endpoint ......47
Table 7.4.3: 1 Subgroup analyses – List of analyses...............................................................48
Table 7.8.1.4:1
Adverse events by system and safety topic using aggregated terms ...........57
Table 9.3: 1
Patient subsets definition for local regulatory submission in Asia ..................69
Table 9.4: 1
Customized drug grouping of interest..............................................................70
Table 9.5: 1
Restricted and forbidden concomitant therapies ..............................................72
Table 9.6: 1
List of potentially relevant MedDRA preferred terms .....................................73
Table 10: 1
History table .....................................................................................................88


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
ALKP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
BIcMQ
BI customised MedDRA Query
BRPM
Blinded report planning meeting
CDG
Customised Drug Grouping 
CI
Confidence Interval
CT
Concomitant Therapy
CTC
Common Terminology Criteria  
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CRISS
Combined Response Index in Systemic Sclerosis
DLCO
Carbon Monoxide Diffusion Capacity
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
DMG
Dictionary Maintenance Group
EMA
European Medicines Agency
EQ5D-5L
EuroQol 5-Dimensionnal quality of life questionnaire (five-level 
version)
GLI
Global Lungs Initiative
HAQ-DI
Health Assessment Questionnaire Disability Index
Hb
Haemoglobin
FACIT
Functional Assessment of Chronic Illness Therapy
FAS
Full analysis set
FVC
Forced Vital Capacity
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
INR
International Normalized Ratio
LLN
Lower Limit of Normal


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Term
Definition / description
LOCF
Last observation carried forward
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
mRSS
Modified Rodnan Skin Score
O*C
Oracle Clinical
PK
Pharmacokinetics
PPS
Per protocol set
PSTAT
Project Statistician
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
SA
Statistical analysis
SD
Standard deviation
SGRQ
Saint George Respiratory Questionnaire
SHAQ
Scleroderma Health Assessment Questionnaire
SMQ
Standardised MedDRA query
SpO2
Saturation of oxygen
SOC
System organ class
TCM
Trial Clinical Monitor
TESS
Treatment emergent signs and symptoms 
ToC
Table of contents
TMW
Trial Medical Writer
TSAP
Trial statistical analysis plan
ULN
Upper Limit of Normal
VAS
Visual Analogue Scale


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3.
INTRODUCTION
As per ICH E9 (3), 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, randomisation.
SAS® Version 9.4 or later will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The methodology used in case of non-convergence of the models on the primary or key 
secondary endpoints has been updated in the TSAP, in order avoid a possible biased and 
over-precise estimates when using a simplified covariance matrix (see Section 7.4.1).
The combined response index in systemic sclerosis (CRISS) will not be analysed using a
MMRM as the distribution of this endpoint is not normal (U-Shaped). It will be analysed as 
described in Section 7.5.2.5. For clarification, the wording of the endpoint related to CRISS 
was updated from “Absolute change from baseline at week 52 in CRISS to “CRISS at Week 
52”. 
In addition to the analyses planned in the CTP, for exploratory purposes, FVC rate of decline 
based on all data collected during the whole trial period will be analysed using a similar 
model as the primary model on the primary endpoint  (see Section 7.6.3).
The absolute declines since baseline in FVC (% predicted) at week 52 of >5% or >10% will 
be added as further endpoints in order complement other analyses.
The “Time to first dose reduction or treatment interruption [days]” will be analysed as well in 
order to have a thorough description of dose reductions / treatment interruptions.
“Time to all-cause mortality” endpoint will be renamed “Time to death” for clarification 
purposes.


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5.
ENDPOINT(S)
In this Section, more details are given regarding endpoints whenever necessary. Note that for 
all endpoints and analyses, Section 6.7 should be consulted for the baseline value definition.
Unless otherwise specified, all data up to 52 weeks (included – as defined in Section 6.7) will 
be taken into account, including follow-up visits (scheduled 4 weeks after End-Of-Treatment) 
before 52 weeks. 
5.1
PRIMARY ENDPOINT(S)
The primary efficacy endpoint is the annual rate of decline in Forced Vital Capacity (FVC) 
over 52 weeks (expressed in mL). 
5.2
SECONDARY ENDPOINT(S)
Endpoints will be used as defined in the CTP section 5.1.2. Additional specifications for 
some endpoints are given below.
5.2.1
Key secondary endpoint(s) 

Absolute change from baseline in the modified Rodnan Skin Score (mRSS) at week 
52. The mRSS will be calculated as a sum of all its 17 areas and will have a range
from 0 (no thickening) to 51 (severe thickening in all 17 areas). A high score 
corresponds to worse skin thickness.

Absolute change from baseline in St George’s Respiratory Questionnaire (SGRQ)
total score at week 52. Specific rules of handling of missing / inconsistent SGRQ 
questions are detailed in Section 6.6. Please also refer to the SGRQ manual (13) for 
calculations of SGRQ scores. A high score corresponds to worse health.
5.2.2
(Other) Secondary endpoint(s)
5.2.2.1
Change from baseline endpoints
Refer to Section 6.6 for missing baseline assessment.

FVC [%predicted]. The predicted values are calculated by the vendor using Global 
Lungs Initiative (GLI) 2012 equations (17).

Carbon Monoxide Diffusion Capacity (DLCO) [%predicted]. The DLCO % predicted
value will be calculated as the mean of the two valid measurements entered in the 
CRF (in case only one valid measurement is available then this one will be used).
Then DLCO %predicted will be corrected for Haemoglobin (Hb) and will always be 
presented after correction for Hb (see formulae in Appendix 10.1 of the CTP):
In males (aged 15 years and above):


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DLCO % predicted (corrected for Hb) =
 % ! ("# $! % !& '()) (*+.-- . /0)
*.1 /0
In females (aged 15 years and above):
DLCO % predicted (corrected for Hb) =
 % ! ("# $! % !& '()) (2.34 . /0)
*.1 /0
(Hb being in g/dL)

CRISS index score (18): It represents a probability of patient improvement and 
therefore ranges from 0 to 1.   
Step 1: For patients who are considered as not improved over 52 weeks [1], CRISS index 
score is set to 0.
Step 2: For patients who are considered as improved over 52 weeks [1], CRISS index score 
is calculated as follows:
where:
MRSS, FVC%, Pt-glob, MD-glob and HAQ-DI indicate respectively the absolute change from 
baseline to week 52 in mRSS, in FVC% predicted, in patient global assessment, in 
physician global assessment and in health assessment questionnaire disability index 
(HAQ-DI) score. Visual analogue scale VAS ranges from 0 to 10.
[1] Irrespective of improvements in other core items, a patient is considered as not improved 
over 52 weeks if he/she develops any of the following:
o
He/she experiences a new scleroderma renal crisis over 52 weeks (according 
to reporting of AE preferred term coded “Scleroderma Renal Crisis”)
o
Relative decline from baseline in FVC% predicted≥ 15% at week 52 and 
FVC% predicted <80% predicted at week 52 
o
New onset of left ventricular failure (based on reporting of AE preferred term 
coded “Left ventricular failure” or “Acute left ventricular failure”) or new 
onset of pulmonary arterial hypertension requiring treatment (based on 
reporting of AE preferred term coded “Pulmonary arterial hypertension” and 
with therapy required according to tick box in the AE page of the CRF)
   

Digital ulcer net burden (see CTP Section 5.2.5 for the definition). It is calculated at a 
visit by counting the total number of fingertips with ulcers (i.e. number of fingers with 
presence of digital ulcer ticked “Yes” on the CRF) at the corresponding visit 

HAQ-DI (disability index) score (16). The score is calculated as follows: 
Each question is scored 0–3 (where 0= “without difficulty” and 3= “unable to do”). 
There are 8 categories (Dressing and Grooming, Arising, Eating, Walking, Hygiene, 
Reach, Grip, Activities), each including 2 or 3 questions. The score for each category 
corresponds to the maximum question score within each category. In each category 
where devices and/or help from another person are checked as being used, the score
5678−5.54 −0.81 ∗∆ABCC + 0.21 ∗∆FGH% −0.40 ∗∆IJ−KLMN −0.44 ∗∆AO−KLMN −3.41 ∗∆QRS−OTU
1 + 5678−5.54 −0.81 ∗∆ABCC + 0.21 ∗∆FGH% −0.40 ∗∆IJ−KLMN −0.44 ∗∆AO−KLMN −3.41 ∗∆QRS−OTU


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of that category is set to 2, except if the score is already at 2 (corresponding to “with 
much difficulty”) or at 3 (corresponding to “unable to do”) then the score cannot 
increase further. Finally, HAQ-DI score corresponds to the sum of the sub-scores of
all 8 categories divided by the number of categories completed.
Please note that if there are fewer than 6 categories with responses, then a score 
cannot be calculated. The HAQ-DI score scale has 25 possible values (i.e., 0, 0.125, 
0.250, 0.375 … 3). A high score corresponds to worse impairment.

FACIT dyspnoea score. Two sub-scale scores are calculated from the FACIT-
dyspnoea questionnaire: FACIT dyspnoea or functional limitations score (which is a 
further endpoint – please refer to Section 5.3.1). Each of them is scored so that a 
higher score value means worse dyspnoea (shortness of breath) or increased 
functional limitations. 
o
All 10 dyspnoea items include a 4-point rating scale (no shortness of breath = 
0; mildly short of breath = 1; moderately short of breath = 2; severely short of 
breath = 3). Those who report not doing the task (i.e. they ticked “I did not do 
this in the past 7 days”) are asked to report whether it was attributable to 
dyspnoea or simply because they did not have an opportunity to do the task in 
the past week. If the response is because of dyspnoea (i.e., “stopped trying” or 
“knew could not do it because of shortness of breath”), the response is treated 
the same as the response “severely short of breath.” (=3). Otherwise, the 
response is treated as missing (i.e., not included for scoring).
o
All 10 functional limitations items include a 4-point rating scale (no difficulty
= 0; A little difficulty = 1; some difficulty = 2; much difficulty = 3).
For each sub-scale of the FACIT scale, a raw score is calculated as: Sum individual 
item scores * 10 / number of items answered. When there are missing data, the
calculation by sub-scale in this way is acceptable as long as more than 50% of the 
items were answered (i.e. a minimum of 5 out of 10 items) (15)
Raw scores are then converted to scale scores using the table included in the FACIT-
Dyspnoea Scale Short Form Scoring Guideline (14).
5.2.2.2
Time to death
Time to death (over the whole trial duration, including after 52 weeks) is defined with start 
date being the date of randomisation. Patients who did not die during the trial will be 
censored at the last contact date.
For this endpoint, the last contact date of a patient is defined as the latest date recorded in the 
Case Report Form (CRF) from the dates listed below:
Date of last visit, last reported Adverse Event (AE) (excluding censored dates), last reported 
concomitant treatment date, last laboratory sample date, last drug intake, last reported date in 
menstruation diary, last reported dose change / interruption date, date of trial completion, last 
known alive date or date of death.


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Refer to Table 6.1:1 for details of the analysis periods used for time-to-event endpoints.
5.3
FURTHER ENDPOINT(S)
Further endpoints will be used as defined in the CTP section 5.1.3. Additional specifications 
for some endpoints are given below.
5.3.1
Absolute change from baseline endpoints
Refer to Section 6.6 for missing baseline assessment.

SHAQ domain scores are the following six VAS:
o
Pain (How much pain have you had because of your illness in the past week?)
o
Gastrointestinal involvement (How much have your intestinal problems 
interfered with your daily activities in the past week?)
o
Lung involvement (How much have your breathing problems interfered with 
your daily activities in the past week?)
o
Vascular (How much has Raynaud’s interfered with your daily activities in the 
past week?)
o
Digital ulcers (How much have your finger ulcers interfered with your daily 
activities in the past week?)
o
Patient global assessment (Overall, considering how much pain, discomfort, 
limitations in your daily life and other changes in your body and life, how 
severe would you rate your disease today?)
For each of the six VAS (rated from 0 to 10), the score is calculated according to the 
following formulae: 
*+ V WXYZ[\]^ _^[Y`a^W bac_ Zd^ e^bZ d[\W YXW^ Zc Zd^ _[af
gcZ[e e^\hZd cb Zd^ Y][e^
Each VAS is scored separately and the scores are not added together. Higher scores 
indicate more severe limitation.

FACIT functional limitations scoring: please refer to Section 5.2.2.1.

SGRQ domain scores: Specific rules of handling of missing / inconsistent SGRQ 
questions are detailed in Section 6.6. Please also refer to the SGRQ manual (13) for
calculations of SGRQ scores.

EQ-5D-5L VAS score indicating the self-rated patient’s health state today (rated from 
0 to 100). This does not take into account the first 5 descriptive questions of the 
questionnaire. 

Patient and physician global-VAS scores (rated from 0 to 10) are calculated as: 
*+ V WXYZ[\]^ _^[Y`a^W bac_ Zd^ e^bZ d[\W YXW^ Zc Zd^ _[af
gcZ[e e^\hZd cb Zd^ Y][e^
Lower scores indicate worse overall health.


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5.3.2
Categorical endpoints

Proportion of patients with a relative decline since baseline in FVC (mL) at week 52
of >5% or >10%

Proportion of patients with an absolute decline since baseline in FVC (% predicted) at 
week 52 of >5% or >10%  

Disease progression is defined in Section 5.2.7 of the CTP. Please refer to Section 6.6
for handling of missing data
5.3.3
Biomarkers
Biomarkers endpoints will be described in separate Statistical Analysis Plans.
5.4
OTHER VARIABLE(S)
5.4.1
Demographics and baseline characteristics
Demographics and other baseline characteristics will include the following. 
5.4.1.1
Demographic data 

Gender

Race:
-
Single race respondents 
-
Multiple race respondents (all combinations ticked)
-
All race categories, regardless of how many other races were also ticked in the CRF

Ethnicity, overall and by race

Age [years] will be calculated as : year of informed consent - year of birth

Age in classes [years] (<30; >=30 and <45; >=45 and <60;>=60 and <75; >=75)

Weight [kg] as continuous variable and in classes (<30; ≥30 and <60; ≥60 and <90; 
≥90)

Height [cm]

Body mass index [kg/m2]: Weight[kg] / Height [m]*Height[m], as a continuous variable 
and in classes (< 18.5; >=18.5 and <25; >=25 and <30, >=30)
5.4.1.2 Trial indication

Time elapsed since the first onset of non-Raynaud symptom [years] will be calculated 
as: (date of randomisation – date of onset of first non-Raynaud symptom) / 365.25

Time elapsed since the first onset of non-Raynaud symptom will also be coded in classes 
(<= 1 year; > 1 year to ≤ 3 years; > 3 years to ≤ 5 years; > 5 years to ≤ 7 years; > 7 
years)

SSc Subtype (Diffuse cutaneous SSc, Limited cutaneous SSc)


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
SSc related medical history as collected on the specific SSC related Medical History 
page of the CRF: history (Yes, No), symptoms still present at screening (Yes, No)

Autoantibodies (as collected on the SSc related history page of the CRF):
-
Anti-topoisomerase antibodies (ATA) status (Positive, Negative)
-
Anti-Centromere antibodies (ACA) status (Positive, Negative)
-
Anti-RNA polymerase III antibodies ((anti-)RNA Pol III) status (Positive, Negative)
-
Antinuclear antibodies (ANA) status (Positive, Negative)

HRCT assessment results:
-
Extent of fibrotic disease in the lung [%]
-
Ground Glass Opacities (Yes, No)
-
Honeycombing (Yes, No)
-
Reticulation (Yes, No)
5.4.1.3
Baseline characteristics for lung function and gas transfer characteristics

FVC [mL]

FVC [% predicted]

Oxygen Saturation on Pulse Oximetry (SpO2) [%]

DLCO (corrected for Hb) [% predicted] as defined in Section 5.2.2.1
5.4.1.4
Baseline characteristics for questionnaires and derived outcomes

Modified Rodnan Skin Score (mRSS)

SGRQ Total, Symptoms, Activities and Impact scores

Digital Ulcers count

FACIT dyspnoea score and FACIT functional limitations score

HAQ-DI score and SHAQ VAS scores (VAS scores include pain, assessment of
limitation, vascular involvement, digital ulcers, lung involvement and gastrointestinal 
involvement).

EQ-5D-5L patient´s self-rated health status

Patient’s global VAS

Physician’s global VAS
5.4.2
Compliance
Compliance will be calculated from baseline to Week 52, and over the duration of the study
as:


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Number of capsules actually taken
over the treatment period
Compliance [%]
=
x 100
Number of capsules which should
have been taken over the treatment 
period
The number of capsules which should have been taken over the treatment period will be 
calculated as:
Number of capsules which should have been taken over the treatment period [capsules] = 
(date of last trial drug intake [1] – date of first trial drug intake + 1) [days] × 2 [2]
[1] For compliance over 52 weeks, the earliest of (Day 373 as defined in Section 6.7, or date of last trial drug 
intake) will be used.
[2]The time of first administration are taken into account, so only one capsule may be expected to be taken on 
some days (if time is after 14:30 then the calculation is then adapted accordingly).
In case of dose reduction to 100 mg bid, the number of capsules taken per day is still 2, so the 
calculation of compliance remains the same. Only treatment interruptions not due to AE will 
be considered as a compliance issue and will be taken into account in the calculation 
(duration of interruptions due to AE will be subtracted from the duration of the treatment 
period, as defined in Section 6.1).
Compliance will also be categorised into classes: <50%, >=50% to <80%, >=80% to <= 
120%, > 120%.
5.4.3
Exposure
The date of first trial drug intake is recorded at visit 2. 
5.4.3.1
Exposure over 52 weeks
Duration of exposure [months] = [Earliest of (date of last trial drug intake, Day 373 as 
defined in Section 6.7) – date of first trial drug intake +1 day] / 30.5
Duration of exposure in categories: <=3 months (91 days); >3 months (91 days) to <= 6 
months (182 days); > 6 months (182 days) to <=12 months (365 days); > 12 months (365 
days) to <= 14 months (426 days); > 14 months (426 days).
Treatment interruptions will not be subtracted from the duration of exposure. 
Duration on each actual dose (100 or 150 mg bid): For each dose, sum of each continuous 
duration of exposure to dose effectively taken [days] up to Day 373 /30.5. By definition, this 
duration of exposure will be adjusted for treatment interruptions, dose reductions and dose


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increases. This will be summarised in months and in categories (<= 2 months, > 2 months to 
<= 6 months, > 6 months)
Total dose [g]: Duration of exposure [days] * actual dose [g] (0.1 or 0.15 based on dose 
actually administered, twice a day)
Dose intensity [%]: amount of drug actually administered over the first 52 weeks (dose 
100mg and 150mg) divided by the amount of drug that would have been administered had 
dose 150mg bid been administered over the first 52 weeks (from date of first trial drug intake 
to Day 373 as defined as Section 6.7, whether or not trial drug was prematurely 
discontinued). Dose intensity will be summarised in percent and in categories (<= 30 %, 
>30% - <=50%, >50% - <=90%, >90% - <100%, >=100%)
5.4.3.2
Exposure over all the trial
Similarly, duration of exposure, duration on actual dose, total dose and dose intensity will be 
summarised over the whole trial period (as defined in Section 6.7). 
Dose intensity [%] over the whole trial period is defined as: amount of drug actually 
administered over the whole trial (dose 100mg and 150mg bid) divided by the amount of 
drug that would have been administered had dose 150mg bid been administered over the 
whole trial (from date of first trial drug intake to date of last trial drug intake).
Over this period, the categories for the duration of exposure will be: <=3 months (91 days); 
>3 months (91 days) to <= 6 months (182 days); > 6 months (182 days) to <=12 months (365 
days); > 12 months (365 days) to <= 18 months (547 days); > 18 months (547 days) to <=24 
months (730 days); > 24 months (730 days).
Treatment interruptions will not be subtracted from the duration of exposure. 
5.4.4
Liver enzyme and bilirubin elevations
Liver enzyme and bilirubin elevations will be reported using the three following definitions: 

(ALT and/or AST ≥3 fold ULN) AND bilirubin ≥2 fold ULN[1]
o
And ALKP >= 2xULN
o
And ALKP < 2xULN

ALT ≥ 5 fold ULN and/or AST ≥5 fold ULN

ALT ≥ 3 fold ULN and/or AST ≥ 3 fold ULN
[1] These elevations are defined within a time window of 30 days i.e. the elevation of bilirubin 
should appear within 30 days after the elevation of AST and/or ALT.
The proportion of patients presenting signs of hepatic injury will be summarised, based on 
the following definition for signs of hepatic injury:


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
ALT and/or AST ≥8 fold ULN

ALT and/or AST ≥ 3 fold ULN and total bilirubin ≥ 2 fold ULN in the same sample

ALT and/or AST ≥3 fold ULN and unexplained INR > 1.5 in the same sample

ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%) in the same 
sample

ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right 
upper abdominal quadrant pain or tenderness, fever and/or rash within +/- 7 days of 
the abnormal ALT and/or AST laboratory test result (please refer to Section 9.6 for 
the list of relevant MedDRA preferred terms to support the derivation of a potential 
hepatic injury)
In addition, maximum individual elevations based on worst value on treatment will be 
defined as:

≥3 fold ULN; ≥5 fold ULN; ≥8 fold ULN for AST and ALT

≥1.5 fold ULN; ≥2 fold ULN for bilirubin

≥1.5 fold ULN; ≥2 fold ULN for ALKP

≥ 1 fold ULN; ≥ 3 fold ULN for GGT
5.4.5
Marked changes in vital signs
A marked increase is defined as: 

Systolic Blood Pressure >150 mmHg and increase >=25 mmHg above baseline

Diastolic Blood Pressure >90 mmHg and increase >10 mmHg above baseline

Pulse Rate >100 bpm and increase >10 bpm above baseline
A marked decrease is defined as: 

Systolic Blood Pressure <100 mmHg and decrease >10 mmHg below baseline

Diastolic Blood Pressure <60 mmHg and decrease >10 mmHg below baseline

Pulse Rate <60 bpm and decrease >10 bpm below baseline


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5.4.6
Safety time-to-event analyses

Time to first dose reduction [days]

Time to first treatment interruption [days]

Time to premature treatment discontinuation [days]

Time to first dose reduction or treatment interruption [days]
The above variables will also be described in categories : <= 1 month (30 days), > 1 month 
(30 days) to <= 2 months (61 days), > 2 months (61days) to <= 3 months (91 days);   > 3 
months (91 days) to <= 6 months (182 days); > 6 months (182 days).

Time to first liver enzyme elevation (ALT and/or AST > =3xULN)
In addition, the following two variables will be reported in section 16.1.13.1 of the CTR.

Time to first liver enzyme elevation in conjunction with bilirubin elevation (ALT and/or 
AST > =3x ULN and bilirubin >= 2xULN)

Time to first liver enzyme elevation (ALT and/or AST > =5xULN)
Safety time-to-event variables are defined with start date of time at risk being randomisation 
date. Censoring will be applied at Day 373 for the analysis over 52 weeks and on the date of 
last trial drug intake + 28 days for the analysis over the entire trial period (as defined in Table 
6.7: 1).
Refer to Table 6.1:1 for details of the analysis periods used for time-to-event endpoints.
For these endpoints, the last contact date of a patient is defined as the latest date recorded in 
the Case Report Form (CRF) from the dates listed below:
Date of last visit, last reported Adverse Event (AE) (excluding censored dates), last reported
concomitant treatment date, last laboratory sample date, last drug intake, last reported date in
menstruation diary, last reported dose change / interruption date, date of trial completion.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT(S)
For the definition of treatment administered during the trial, see section 4 of CTP.
Note: the last day of each of the following periods is excluded from the respective period. It 
defines the first day of the subsequent period.

Screening:  from informed consent to randomisation

Post-randomisation (optional[a]):  from randomisation to first trial drug intake in 
treatment period.

Treatment period:  from first trial drug intake (or re-start of treatment if interruption) 
to last trial drug intake (or the day before start date of interruption if interruption)  
plus one day

Off-treatment (optional[a]):  from start date of interruption to re-start of treatment

Residual effect period([b]): from the last trial drug intake plus one day to last trial drug 
intake plus 28 days plus one day or to date of first trial drug intake in extension trial, 
whichever occurs earlier

Follow-up (optional[a] [b]): 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

Post-study(optional[a] [b]): from the latest between last trial drug intake plus 29 days, 
‘date of trial completion’ (from the trial completion part of the eCRF) plus one day, 
and ‘date of Informed Consent in extension trial’ (if applicable). This period is not 
created if date of first trial drug intake in extension trial is before last trial drug intake 
plus 28 days
[a] This period is optional insofar as it does not necessarily exist for all patients.
[b] In addition, a residual effect period of 7 days will be used for adverse event analyses to more closely reflect 
the period of time after the last trial drug intake when measureable drug levels or pharmacodynamics effects are 
still likely to be present.
As a summary:

For efficacy analyses, data from randomisation date up to week 52 data will be 
considered (please see Section 7.4, Section 7.5 and Section 7.6). For efficacy descriptive 
analyses over the whole trial period, all data collected after randomisation date will be 
considered. 


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
For safety analyses, data from the treatment period, possible off-treatment periods and 
residual effect period will be considered as on-treatment.
All analyses will be based on the planned treatment group (Placebo or Nintedanib 150mg bid) 
as randomised by IXRS. 
Table 6.1: 1
Summary of analysed periods according to the type of endpoint
Studied period
Type of 
analysis
Analyses / Endpoints
Start date
End date [1]
Efficacy 
analyses over 
52 Weeks
Analyses on all endpoints listed in Section 
5.1 of the CTP, except for time to death
Date of 
randomisation
Date of last measurement 
up to 52 Weeks (included -
Day 373 as defined in
Section 6.7)
On-treatment 
efficacy 
analyses over 
52 Weeks
- Annual rate of decline in FVC in mL over 
52 weeks, including only on-treatment 
data
- Absolute change from baseline in the 
mRSS at week 52, including only on-
treatment data
- Absolute change from baseline in SGRQ 
total score at week 52, including only 
on-treatment data
Date of 
randomisation
Last trial drug intake 
(included) OR Week 52 
time-point (Day 373 as 
defined in Section 6.7), 
whichever occurs first
Off-treatment periods not excluded
Descriptive 
analyses over 
the trial period
Absolute change from baseline in:
- FVC (mL)
- FVC (% of predicted)
- mRSS
- SGRQ (Total score and Symptoms, 
Activities and Impact scores)
- DLCO (% of predicted )
- Digital ulcer net burden
- HAQ-DI score 
- SHAQ domain scores (VAS scores)
- FACIT dyspnoea and functional 
limitations score
- EQ-5D-5L VAS score
- Patient global VAS score
- Physician global VAS score
- SpO2(%)
- Vital signs
Date of 
randomisation
Date of last measurement 
up to follow-up visit 
(included)


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Table 6.1: 1
Summary of analysed periods according to the type of endpoint 
(cont’d)
Studied period
Type of 
analysis
Analyses / Endpoints
Start date
End date [1]
Descriptive 
analyses over 
the trial period
Relative change from baseline in :
- FVC (mL)
- mRSS
Date of 
randomisation
Date of last measurement 
up to follow-up visit 
(included)
Efficacy 
survival 
analysis[2]
Time to death (over the trial period) 
Date of 
randomisation
Last contact date (as 
defined in Section 
5.2.2.2)
Extent of 
exposure
See Section 5.4.3
Date of first trial 
drug intake
Last drug intake
Safety survival 
analysis[2]
Time to first liver enzyme elevation (for all 
definitions mentioned in Section 5.4.4)
Date of 
randomisation
Last trial drug intake + 
28 days 
Time to
- first dose reduction
- first treatment interruption
- premature treatment discontinuation
Date of 
randomisation
Last trial drug intake + 
28 days
Safety survival 
analysis over 52 
weeks[2]
Time to
- first dose reduction
- first treatment interruption
- premature treatment discontinuation
Date of first trial 
drug intake
- If last drug intake < 
Day 373: Last drug 
intake
- Else, if last drug intake 
≥ Day 373: Day 373
On-treatment 
safety analyses 
over 52 weeks
- Adverse events 
- Laboratory data
- Vital signs
Date of first trial 
drug intake
- If last drug intake < 
Day 373: Last drug 
intake + 28 days
- Else, if last drug intake 
≥ Day 373: Day 373
On-treatment 
safety analyses 
(over the whole 
trial)
- Adverse events 
- Laboratory data
- Vital signs
Date of first trial 
drug intake
Last trial drug intake + 
28 days 
Off-treatment periods not excluded. 
However, for safety listings, anything 
happening during a treatment interruption 
will be flagged as occurring during the off-
treatment period 


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[1] End date is included. End date will always be checked against the date of first trial drug intake in 1199.225. 
For safety endpoints, if date of first trial drug intake in 1199.225 is earlier than end date calculated as mentioned 
in this table, then the end date of the studied period will be substituted by the date of first trial drug intake in 
1199.225
[2] For time-to-event endpoint, if a patient does not have an event during the studied period then 
 will be 
censored on the day corresponding to the end date of the studied period
6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important PVs (7). As there is no Per 
Protocol Set planned in this trial, none of the IPVs will lead to exclusion from a patient set.
However the proportion of patients with IPVs will be presented for completeness purposes 
and to demonstrate the adherence to the CTP.
Unless otherwise specified, the following IPVs in Table 6.2: 1 have been defined over 52 
weeks as this is the primary timepoint of interest in this trial. IPVs detected over the whole 
trial period will be reported in Section 16.1.13.1 of the CTR and the derivation will be 
adapted accordingly.
Table 6.2: 1
Important protocol violations over 52 weeks
Category/Code
Description
Requirements
Excluded 
from
A
Entrance Criteria Not Met
A1
Inclusion criteria not met
A1.1
Patient aged <18 years when 
signing his/her informed consent
Inclusion criteria 2 not met (Age <18 at 
the date of Informed Consent – Or other 
age restriction specified as per a local 
amendment)
Automatic IPV
None
A1.2
2013 ACR / EULAR classification 
criteria for SSc not fulfilled OR no 
chest HRCT performed
demonstrating SSc related 
Interstitial Lung Disease pattern or 
extent of fibrotic disease in the lung 
<10% on HRCT
Inclusion criteria 3 or 5 not met; or 
extent of fibrotic disease <10%
according to database
Automatic IPV
None
A1.3
SSc disease onset (defined by first 
non-Raynaud symptom) > 7 years 
of Visit 1.
CRF date of onset (defined by first non-
Raynaud symptom) > 7 years before 
date of Visit 1, according to database
Automatic IPV
None
A1.4
FVC < 40% of predicted value at 
Visit 2
FVC < 35%  (5% tolerance) at visit 2 
according to database Automatic IPV
None
A1.5
Single breath DLCO (corrected for 
Hb) < 30% of predicted value at 
Visit 2
DLCO <25% (5% tolerance) at visit 2 
according to database
Automatic IPV
None
A2
Exclusion criteria met
A2.1
Patient has laboratory values that 
indicate additional risk at Visit 1:
a) >1.5xULN for AST or ALT
b) >1.5xULN for Bilirubin
c) Creatinine clearance < 30 mL 
/min (Cockcroft-Gault formula)
Laboratory values out of range at visit 1 
according to the database 
Automatic IPV
None


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Table 6.2: 1
Important protocol violations over 52 weeks (cont’d)
Category/Code
Description
Requirements
Excluded 
from
A2.2
Patient with other disease(s) which 
are excluded as per exclusion 
criteria
Exclusion criteria 6-7-8-9-10-11-12-13-
14-20-25-26 met
Automatic IPV
None
A2.3
Forbidden previous therapy
Exclusion criteria  15-16-17-18-19 met
Manual IPV based on exclusion criteria 
and / or to be identified at the site level 
on the manual PV log / issue log
None
A2.4
Potential risk related to fetotoxicity
Exclusion criteria 21-22 met
Automatic IPV
None
B
Informed Consent
B1
Informed consent not given 
Inclusion criteria 1 not met 
Automatic IPV
None
B2
Informed consent given too late
CRF date of informed consent is after 
date of Visit 1. Signature of the wrong IC 
version, and later signature of the correct 
one will also be part of this IPV category
Manual IPV / issue log
None
B3
Informed consent not given or 
withdrawn for one of the substudies 
(HRCT, Skin Biopsy) but 
procedure done
To be identified at the site level on the 
manual PV log/ issue log
None 
C
Trial medication and 
randomisation
C1
Incorrect trial medication taken 
Medication kit taken (between Baseline -
excluded - and Week 52) which does not
match the treatment which the patient 
was randomised to (to be determined 
after unblinding).
Review of MQRM listings and / or to be 
identified at the site level on the manual 
PV log / issue log
None
C2
Randomisation not followed
Wrong stratification factor at time of 
randomisation.
OR
Wrong medication kit given leading to 
the patient taking treatment different 
from the one randomised by IXRS at 
time of randomisation (Visit 2). 
This is an IPV only if the medication 
error leads to an actual treatment switch 
(to be determined after unblinding).
Review of MQRM listings and / or to be 
identified at the site level on the manual 
PV log/ issue log
None


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Table 6.2: 1
Important protocol violations over 52 weeks (cont’d)
Category/Code
Description
Requirements
Excluded 
from
C3
Overall Compliance (between 
baseline and Week 52) not between 
80% and 120% inclusive (or non-
compliance based on investigator 
assessment)
In case calculated overall between 
baseline and Week 52 compliance is 
missing: If the answer to the question 
“Did the patient take trial medication as 
instructed?” of the CRF is “No” at at 
least one of the visits where the 
compliance cannot be calculated, then an 
IPV will be flagged. Otherwise no IPV 
although calculated overall compliance 
between baseline and Week 52 is 
missing.
Automatic IPV with review of MQRM 
listings
None
C4
Trial medication not interrupted 
when ALT or AST ≥5 fold ULN
Based on liver enzyme elevation and 
interruptions reported between baseline 
and Week 52
Automatic IPV
None
C5
Trial medication not permanently 
discontinued after signs of liver 
enzyme elevations were observed 
that 
a) are indicative of hepatic injury as
defined in Section 5.3.7.1 of the 
CTP
b) correspond to ALT or AST ≥3 
fold ULN despite dose reduction or 
treatment interruption for 2 weeks 
or more
All patients where signs of liver enzyme 
elevations (between baseline and Week 
52) are not dealt with according to the 
requirements of the CTP.
Manual IPV based on review of MQRM 
listings 
None
C6
Medication code broken 
inappropriately
Reason for medication code broken is 
inappropriate (e.g. not emergency) and 
data collected after unblinding between 
baseline and Week 52 
Review of MQRM listings and / or to be 
identified at the site level on the manual 
PV log / issue log. 
None
D
Concomitant Medication
D1
Patient received prohibited 
concomitant therapies between 
baseline and Week 52 (see Section 
4.2.2.1 of the CTP)
Based on concomitant therapies reported 
between baseline and Week 52
Review of MQRM listings and / or to be 
identified at the site level on the manual 
PV log/ issue log
None


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Table 6.2: 1
Important protocol violations over 52 weeks (cont’d)
Category/Code
Description
Requirements
Excluded 
from
E
Missing data
E1
Patient without any physical 
assessment for more than 6 months, 
although under study medication
Missing results for physical assessment 
for more than 6 months during the trial
Automatic IPV 
None
E2
No baseline or post-baseline FVC 
assessments up to Week 52
Automatic IPV
None
E3
No baseline or post-baseline mRSS 
up to Week 52
Automatic IPV
None
E4
No reliable[1] baseline or post-
baseline SGRQ total score up to 
Week 52
[1] As per exclusion criteria 24
No baseline or post-baseline value or 
exclusion criteria 24 met
Automatic IPV
None
Automatic PVs are those detected via an automated programming process using SAS. 
Note: IPVs E2, E3 and E4 will be not be reported over the whole trial period. 
A summary of IPV decisions will be provided in the final BRPM minutes.
6.3
PATIENT SETS ANALYSED

Screened set
This patient set includes all patients having signed informed consent and performed 
visit 1.

Randomised set (RS)
This patient set includes all randomised patients, whether treated or not.

Treated set (TS)
This patient set includes all randomised patients who received at least one dose of trial
medication.

PK set (PKS)
This patient set includes those in the Treated Set with at least one valid plasma
concentration available
6.4
SUBGROUPS
The subgroups listed in Table 6.4: 1 will be investigated. Selected variables as defined in 
Section 5.4 will be used to characterize the study population in all subgroups. Selected safety 
analyses as well as efficacy analyses on the primary and both key secondary endpoints will 
be done on some selected subgroups only (only in subgroups with more than 20 patients over 
both treatment groups within each category of the subgroup)
For more details on the planned analysis, please refer to Section 7.4.3.


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Table 6.4: 1
Subgroup analyses – List of subgroups
Description 
of study 
population[1]
Efficacy 
analyses on 
the primary 
and both key 
secondary 
endpoints[2]
Safety 
analyses[3]
Rationale for subgroup 
analysis
ATA status (Positive / 
Negative)
X
X
X
ATA is the stratification 
factor for randomisation in 
the trial
Gender (Male / Female)
X
X
X
SSc differences  in males vs 
females have been described 
(Clin Exp Rheumatol. 2017 
Sep-Oct;35 Suppl 
106(4):89-97)
Age (<65 / ≥65)
X
X
X
Regulatory requirement
Race (White / Asian / Black 
or African American)[4]
X
X
X
Regulatory requirement
Region (Asia / Europe / 
Canada and United States / 
Rest of the World)
X
X
X
Assessing the homogeneity 
of treatment effect across 
region
Mycophenolate mofetil 
/sodium use at baseline (Yes / 
No)
X
X
X
Evaluation of influence of 
effect of stable background 
immunosuppressive therapy 
to study treatment as 
allowed per CTP
Methotrexate use at baseline 
(Yes / No)
X
Evaluation of influence of 
effect of stable background 
immunosuppressive therapy 
to study treatment as 
allowed per CTP
SSc subtype (Diffuse 
cutaneous SSc / Limited 
cutaneous SSc)
X
X
X
Evaluation of efficacy and 
safety in different SSc
subtypes as manifestation 
and course of disease is 
described as being 
significantly different


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Table 6.4: 1
Subgroup analyses – List of subgroups (cont’d)
Description 
of study 
population[1]
Efficacy 
analyses on 
the primary 
and both key 
secondary 
endpoints[2]
Safety 
analyses[3]
Rationale for subgroup 
analysis
Baseline bodyweight (≤65kg, 
>65kg)
X
X
Based upon safety profile of 
Nintedanib- “Patients with 
low body weight (< 65 kg), 
Asian and female patients 
have a higher risk of 
elevations in liver 
enzymes.”
[1] [2] [3] For more details, please refer to Table 7.4.3:1
[4] Only single race respondents are taken into account. In case more than 20% of patients ticked multiple races 
in the CRF, then a category “Multiple or missing’ will be added for subgroup analyses by race 
In addition, US / non-US subgroup analyses will also be done and will be included in Section 
16.1.13.1 (efficacy and safety analyses).
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
Missing data will not be imputed, except for some sensitivity analyses on the primary and key 
secondary endpoints.
6.6.1
Primary endpoint
The statistical model used for primary analysis (see Section 7.4.1) allows for missing data, 
assuming they are missing at random. Even patients with only one post-baseline assessment 
can be included in the model and can therefore participate in variance estimation. The 
statistical model assumes that patients who dropout would have behaved similarly to those who 
remained in the study.
Several sensitivity analyses will be conducted to investigate the potential effect of missing 
data on the results of the primary analysis (see Section 7.4.2).


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6.6.2
Secondary endpoints
6.6.2.1
Change from baseline endpoints
The statistical model Mixed effect Model for Repeated Measures (MMRM) used for the 
analysis of continuous secondary endpoints allows for missing data, assuming they are 
missing at random. 
For the two key secondary endpoints, several sensitivity analyses will be conducted to 
investigate the potential effect of missing data on the results of the main analysis.
6.6.2.1.1
Modified Rodnan Skin Score
In case of missing score for an area, mRSS total score will be missing.
6.6.2.1.2
Saint George’s Respiratory Questionnaire
As the SGRQ manual (13) 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.
If the patient did not receive any respiratory treatment, then Part 2 Section 5 of the SGRQ 
should be skipped to go directly to Section 6. In this case, based on SGRQ manual 
instructions, responses will be considered as zero (and thus will not be included in the count 
of missing questions for the impact component). 
Missing questions from Part1 Section 1 (“If you ever held a job…”) will be left as missing 
(and counted as missing). 
6.6.2.1.3
Digital ulcer net burden
If the presence of a digital ulcer is missing for a finger, digital ulcer net burden will be set to 
missing. 
6.6.2.1.4
HAQ-DI 
According to HAQ-DI scaling and scoring manual, if there are fewer than 6 categories with 
responses, an index score cannot be calculated and will be set to missing (no imputation 
planned). 


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6.6.2.1.5
FACIT dyspnoea or functional limitations score 
If there are missing items, subscale scores can be calculated by multiplying the sum of the 
subscale by the number of items in the subscale, then dividing by the number of items 
actually answered. However this is only acceptable if more than 50% of the items were 
answered (FACIT Administration and Scoring Guidelines). No imputation planned in case of 
missing score. 
6.6.2.1.6
EQ-5D-5L (EuroQol 5-Dimensionnal quality of life questionnaire)
No imputation planned. No score will be derived.
6.6.2.1.7
CRISS
Index score calculation:
For patients who are considered as improved over 52 weeks, in case the absolute change from 
baseline to week 52 in mRSS, FVC %predicted, patient global assessment, physician global 
assessment or HAQ-DI score is missing, then CRISS index score will be considered as 
missing. 
In the multiple imputations step, after transformation into a binary responder variable, 
missing values will be imputed using the worst case (i.e. as Non-responder in all the 
imputations).
6.6.2.1.8
Disease progression
The handling of missing data is summarised in the table below:


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Table 6.6.2.1.8: 1
Handling of missing data for disease progression
Absolute change from 
baseline in FVC 
%predicted at 52 weeks
Change from baseline in 
mRSS (absolute and 
relative) at 52 weeks
Death
Disease 
progression
Missing data 
rule
Missing
Missing or no mRSS 
worsening
Alive
Yes
Worst case
Missing or no FVC 
worsening
Missing 
Alive
Yes
Worst case
Missing or FVC worsening 
or no FVC worsening
Missing or mRSS 
worsening or no mRSS 
worsening
Death
Yes
None
Missing or FVC worsening 
or no FVC worsening
mRSS worsening
Alive
Yes
None
FVC worsening
Missing or mRSS 
worsening or no mRSS 
worsening
Alive
Yes
None
No FVC worsening
No mRSS worsening
Alive
No
None
FVC worsening means absolute decline since baseline in FVC percent predicted >10%
mRSS worsening means relative change from baseline in mRSS of >25% and absolute change from baseline of 
>5 points. In case baseline mRSS is 0 (and relative change can therefore not be calculcated), then it will only be 
checked if the absolute change from baseline in mRSS is >5 points.
6.6.2.2
Categorical endpoints
In the analysis of the binary endpoints, patients with missing data will be considered as non-
responders (i.e. worst case analysis).
6.6.2.3
Time-to-event endpoints
In the analyses of the time-to-event endpoints, missing or incomplete data will be managed 
by standard survival analysis techniques (i.e. censoring).
6.6.3
Other endpoints
6.6.3.1
Concomitant therapies
In case of (partially) missing start and end dates of concomitant therapies, the dates will be 
imputed so that the extent of exposure to the concomitant therapy is maximal, i.e. the first 


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day (month) of the month (year) for incomplete start dates and the last day (month) of the 
month (year) for incomplete end dates.
6.6.3.2
Safety endpoints
Missing or incomplete AE dates will be imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”) (8).
6.6.3.3
Trial diagnosis date / Date of onset of Raynaud / Date of onset of first non-Raynaud 
symptom
In case of partially missing date of trial diagnosis or date of onset of Raynaud or date of onset 
of first non-Raynaud symptom, the following imputation will be done: 

If day is missing, then imputed day will be the 1st of the month

If day and month are missing, then imputed date will be the 1st of January of the (non-
missing) year

If year is missing, date will not be imputed
6.6.3.4
Pharmacokinetic endpoints
Handling of missing PK data will be performed according to the BI standard procedure
"Noncompartmental Pharmacokinetic / Pharmacodynamic Analyses of Clinical Studies"
(001-MCS-36-472_RD-01) (6).
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
As a general rule, the last assessment/measurement before the date of first trial drug intake 
(included) will be used as baseline (possibly last screening assessment if no further available 
value).
Endpoints which are censored at Week 52 will be cut on Day 373 which is calculated as: 
Date of first trial drug intake (i.e. Day 1) + 372 (=365+7 day window per the CTP flow 
chart). All references to Day 373 throughout this document refer to this date which is 372 
days after the date of first trial drug intake.
Visit windowing will be performed as described in Tables 6.7: 1, 6.7: 2 and 6.7: 3, in order to
assign data to the relevant study visit based on the actual day of the assessment. Data will be 
analysed using the re-calculated visits in the statistical tables. However, in the listings, all 


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visits performed will be displayed (even if outside time-window), along with the re-
calculated visit.
Table 6.7: 1
Time windowing rules for spirometry, physical exam, vital signs, 
HCRU, mRSS, Digital ulcer, menstruation calendar
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
Last 
assessment 
before the 
date of first 
trial drug 
intake
1
1
1 or 2[2]
Baseline
1
2
22
21
3
2 weeks
15
23
36
14
4
4 weeks
29
37
64
28
5
6 weeks
43
65
127
63
6
12 weeks
85


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Table 6.7: 1
Time windowing rules for spirometry, physical exam, vital signs, 
HCRU, mRSS, Digital ulcer, menstruation calendar (cont’d)
Time window of actual day [1]
Allocated to
128
211
84
7
24 weeks
169
212
309
98
8
36 weeks
253
310
373
63
9
52 weeks
365
374
533
161
10
68 weeks
477
534
645
112
11
84 weeks
589
646
708
63
12
100 weeks
701
709
Last trial drug
intake + 27 [3]
Variable
NA
Between 100 
weeks and 
follow-up visit
NA
Last trial 
drug intake + 
28
Last trial drug
intake + 35 [3]
7
FU
Follow-up
NA
Note: mRSS and Digital ulcer not measured at visits 3, 4, 5 and follow-up
[1] First trial drug intake date is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition
[3] These two periods only exist if follow-up visit occurs after 709 days (included)


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Table 6.7: 2
Time windowing rules for SGRQ, FACIT-dyspnoea, SHAQ, EQ-5D-
5L, patient global VAS, DLCO, SpO2, antoantibody assessment, 
Physician global VAS
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
Last 
assessment 
before the 
date of first 
trial drug 
intake
1
1
1 or 2[2]
Baseline
1
2
253
252
7
24 weeks
169
254
373
280
9
52 weeks
365
374
708
175
12
100 weeks
701
709
Last trial 
drug intake + 
27 [3]
Variable
NA
Between 100 
weeks and follow-
up visit
NA
Last trial 
drug intake 
+ 28
Last trial 
drug intake + 
35 [3]
7
FU
Follow-up
NA
[1] First trial drug intake date is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition
[3] These two periods only exist if follow-up visit occurs after 709 days (included)


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Table 6.7: 3
Time windowing rules for laboratory measurements (and pregnancy 
test)
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
Last 
assessment 
before the 
date of first 
trial drug 
intake
1
1
1 or 2[2]
Baseline
1
2
22
21
3
2 weeks
15
23
36
14
4
4 weeks
29
37
64
28
5
6 weeks
43
65
106
42
6
12 weeks
85
107
148
42
6a
18 weeks
127
149
190
42
7
24 weeks
169
191
232
42
7a
30 weeks
211
233
281
49
8
36 weeks
253
282
337
56
8a
44 weeks
309
338
373
56
9
52 weeks
365
374
449
56
9a
60 weeks
421
450
505
56
10
68 weeks
477
506
561
56
10a
76 weeks
533


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Table 6.7: 3
Time windowing rules for laboratory measurements (and pregnancy 
test) (cont’d)
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
562
617
56
11
84 weeks
589
618
673
56
11a
92 weeks
645
674
708
35
12
100 weeks
701
709
Last trial drug
intake + 27 [3]
Variable
NA
Between 100 
weeks and 
follow-up visit
NA
Last trial 
drug intake 
+ 28
Last trial drug
intake + 35 [3]
7
FU
Follow-up
NA
[1] First trial drug intake date is taken into account as a reference to calculate time windows
[2] Depending on the last assessment before first trial drug intake (included), refer to Section 6.7 for baseline 
definition
[3] These two periods only exist if follow-up visit occurs after 709 days (included)
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.


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7.
PLANNED ANALYSIS
For End-Of-Text (EoT) tables (1,2,5), the set of summary statistics is: N / Mean / SD / Min / 
Median / Max. In descriptive statistics tables, mean, SD and median will be rounded to one 
additional digit than the raw individual value. 
In case some endpoints show some extreme data, median, quartiles and percentiles will be 
presented additionally.
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 only if there are actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
7.2.1
Baseline conditions
A summary of baseline conditions will be provided by treatment group, System Organ Class 
(SOC) and Preferred Term (PT). SOC and PT will be sorted by descending frequency over 
both treatment arms. 
7.2.2
Concomitant therapies
Concomitant therapies will be described over several study periods:

Previous therapies will be defined as treatments with an end date before first trial drug 
intake. 

Baseline therapies will be defined as treatments with a start date before first trial drug 
intake and a stop date after or on the day of the first trial drug intake (or ongoing after 
first trial drug intake).

On-treatment concomitant therapies are defined as treatments with a start date after or 
on the day of first trial drug intake and before or on the day of last trial drug intake.

Post-study drug discontinuation therapies are defined as treatments with a start date 
after last trial drug intake and before trial completion. This aims at flagging 


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concomitant treatments taken by patients having prematurely discontinued study 
medication but followed-up up to the end of the study.
Concomitant therapies will be described over the first 52 weeks, as well as over the entire 
duration of the study. Concomitant therapies over 52 weeks will be defined as follows:

On-treatment concomitant therapies over 52 weeks are defined as treatments with a 
start date after or on the day of first trial drug intake and before or on either:
o
the day of last trial drug intake for patients having prematurely discontinued 
study medication before 52 weeks 
o
the Week 52 time-point (Day 373 as defined in Section 6.7) for other patients.

Post-study drug discontinuation concomitant therapies over 52 weeks are defined as 
treatments with a start date after last trial drug intake (for patients having prematurely 
discontinued study medication before 52 weeks) and before Week 52 time-point (Day 
373 as defined in Section 6.7). 
Table 7.2.2:1 summarises the concomitant therapy outputs which will be provided for each 
category of concomitant therapy created.
Summaries by ATC and preferred name (PN) will use the ATC3 code, and will be sorted by 
alphabetical ATC class and decreasing frequency of PN in the Nintedanib treatment arm 
within ATC class.
Summaries by Customised Drug Grouping (CDG) will be sorted alphabetically by the name 
of the CDG and by decreasing frequency of PN in the Nintedanib treatment arm within a 
CDG. CDGs are built using WHO-DD Standardised Drug Groupings (SDG), Sub-SDGs and 
ATC4 levels. CDGs are listed in Section 9.4.
Table 7.2.2:1
Concomitant therapy outputs and position in the CTR
By ATC and PN
By CDG and PN
Over 52 weeks
Entire trial 
duration
Over 52 weeks
Entire trial 
duration
Previous therapies
16.1.13.1
Not applicable
Not required
Not applicable
Baseline therapies
16.1.13.1
Not applicable
15.1
Not applicable
On-treatment concomitant 
therapies
16.1.13.1
16.1.13.1
16.1.13.1
16.1.13.1


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Table 7.2.2:1
Concomitant therapy outputs and position in the CT (cont’d)
By ATC and PN
By CDG and PN
Over 52 weeks
Entire trial 
duration
Over 52 weeks
Entire trial 
duration
All on-treatment concomitant 
therapies* with a frequency 
>2% in at least one treatment 
arm
16.1.13.1
Not required
Not required
Not required
All on-treatment concomitant 
therapies*
16.1.13.1
16.1.13.1
16.1.13.1
16.1.13.1
All concomitant therapies**
16.1.13.1
16.1.13.1
15.1
16.1.13.1
All concomitant therapies** in 
patients who prem. disc. 
treatment
Not required
Not required
16.1.13.1
Not required
Post-study drug discontinuation 
therapies
Not required
Not required
16.1.13.1
Not required
* including baseline therapies.
** including baseline, on-treatment and post-study drug discontinuation therapies.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINT(S)
All analyses will be performed on the Treated Set. 
Refer to Section 7.3.1 of the CTP.
7.4.1
Primary analysis
The primary analysis will be performed on the TS (according to randomised treatment), using 
all available data from baseline (excluded) up to Week 52 (after time-windowing), including 
visits done after premature treatment withdrawal, EOT visits and follow-up visits done before 
Week 52. Patients will be analysed according to the ATA status stratum to which they belong 
to (as reported in the CRF), regardless of any mis-assignment to treatment based on 
identification of the wrong stratum in IXRS.
The primary analysis is a restricted maximum likelihood (REML) based approach using a random 
slope and intercept model. 


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The analysis will include the fixed, categorical effects of treatment, ATA status and gender, fixed 
continuous effects of time and baseline FVC (mL), age and height as well as the treatment-by-
time and baseline-by-time interactions. Random effects will be included for patient response for 
both time and intercept.
The statistical model can be written as follows:
iXjf_h = kα + aX + n_ + oh + o[RK5X+ odQ5pKℎJX + r+CX + sft + (γ + gX + rYCX +
wf)tXj + 5Xj
(aX, gX) ~ z- ({, |)
5Xj
pp}
~ z (0, ~-)
The components of the model are as follows:
yijkmg = FVC value (mL) for patient i in ATA status stratum m with gender g at Week
j receiving treatment k,
α = mean patient intercept
ai = random intercept effect  for patient i, i=1,2,…
n= the effect of ATA status stratum m, m=1,2. ATA status is used as reported in the 
CRF (“Positive” as the class of reference, regardless of any mis-assignment to 
treatment based on identification of the wrong stratum in IXRS)
oK = intercept coefficient of Gender covariate (“Male” as the class of reference)
o = intercept coefficient of Age covariate 
RK5X = Age covariate value [years] for patient i
oℎ= intercept coefficient of Height covariate 
Q5pKℎJX = Height covariate value [cm] for patient i
r0= intercept coefficient of baseline effect
Cp= FVC baseline measurement [mL] of patient i
s= intercept coefficient of the effect of treatment k, k=1,2
γ = mean patient slope
gi = random slope effect for patient i
r= slope coefficient of baseline effect
w= slope coefficient of the effect of treatment k
tij = time of measurement j for patient i, j= 1,2,… J
eij = the random error associated with the jth Week of patient i. Measurement errors are 
independent and normally distributed with mean 0 and variance ~2, and uncorrelated 
with ai and gi.
| = a 2x2 unstructured covariance matrix
Within patient errors are assumed to follow a random coefficient regression model with 
random effect for intercept and slope. An unstructured variance-covariance structure will be 


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used to model these random slope and intercept. The variance-covariance matrix modeled to 
estimate the inter-individual variability is considered to have a Variance-Components 
structure. In the event of non-convergence, the following methods will be attempted (in 
order) to overcome it:
1. Add the ‘singular=1e-10’ option in the model statement – This raises the threshold 
at which columns are declared linearly dependent (from typically 1e-12). 
2. Set ‘maxiter=100’ in the Proc Mixed statement – This increases the number of 
convergence iterations used from a default of 50.
3. Set ‘scoring=4’ to specify use of the Fisher scoring algorithm in the first 4 
iterations.
4. Include the statement ‘performance nothread’ – this removes multi-threading from 
the calculations.
The first model to converge will be used as the primary analysis on the FVC rate of decline at 
week 52. If convergence does not achieved based on above approach, more simplified model 
can be used.
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom 
and adjust standard errors. Significance tests will be based on least-squares means using a 
two-sided α = 0.05 (two-sided 95% confidence intervals).The primary treatment comparison 
of slopes will be assessed through the treatment-by-time interaction coefficient. 
Please refer to Section 9.2 for more details concerning the statistical model and SAS code 
specifications.
7.4.2
Sensitivity analyses
Sensitivity analyses using different assumptions will be conducted to investigate the potential 
effect of data handling and the analysis model on the results of the main analysis.
For all sensitivity analyses to data handling assumptions the estimate, two-sided 95% 
Confidence Interval and p-value of the treatment effect will be represented on the same 
Forest plot. Tables presenting the results of the sensitivity analyses will be included in 
Section 16.1.13.1 of the CTR.
Interpretation of sensitivity analyses:
Separate Forest-plots will be produced for the primary and each key secondary endpoint (in 
Section 15 of the CTR). The consistency of the results of the sensitivity analyses with the 
primary analysis result will be assessed by checking if the treatment effect estimate of a 
sensitivity analysis lies inside the confidence interval of the treatment effect of the primary 
analysis.
The tables corresponding to the Forest-plots will also be performed as part of Section 
16.1.13.1 of the CTR.


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7.4.2.1 Sensitivity to data handling assumptions
7.4.2.1.1
Statistical model using on-treatment measurements only
A sensitivity analysis including only on-treatment measurements of FVC (mL) will be 
presented. The same model as for the primary analysis will be used (see Section 7.4.1). This 
model which implies that data are assumed to be missing at random and it is implicitly 
supposed that patients who dropout would have behaved similarly to those who remained in 
the study.
This analysis is considered of principal importance amongst the planned sensitivity analyses 
since it most closely reflects the expected biologic effect of nintedanib in the treatment of 
patients with SSc-ILD. 
7.4.2.1.2
Sensitivity to missing data handling
To investigate the potential impact of missing data on the treatment effect, patients will be 
classified into different patterns depending on the availability of data:

Patients with a 52 week FVC value (see Table 6.1: 1 for further information regarding the 
analysis period):
1. those who received trial drug until 52 weeks (defined as patients who did not 
prematurely discontinue the trial medication before 52 weeks as according to the 
“end of trial medication” page of the CRF) (pattern 1)
2. those who prematurely discontinued trial drug before 52 weeks (as per 
information given on the “end of trial medication” page of the CRF) but who were 
followed up until week 52 (pattern 2)

Patients without a 52 week FVC value:
3. those who were alive at 52 weeks (based on “vital status” page of the CRF, and no 
fatal AE recorded on the “adverse event” page of the CRF)  (pattern 3)
4. those who died before 52 weeks (based on “vital status” page of the CRF, or fatal 
AEs recorded on the “adverse event” page of the CRF)  (pattern 4)
These four patterns will be used in sensitivity analyses to estimate the treatment effect under 
differing assumptions regarding the persistence of efficacy post withdrawal of randomised 
treatment. As described hereafter, three resulting alternative analyses will be defined. 
Multiple imputation will be used to handle missing data at week 52. Non-monotone missing 
data and/or missing data at visits before week 52 will not be imputed. The imputation model 
will be similar to the statistical model of the primary analysis (see Section 7.4.1).


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The number of imputations will be set to 1000 in order to ensure adequate efficiency for the 
estimation of missing data. For each imputed dataset, the same statistical model as defined for 
the primary analysis will be used for the analysis. See Section 7.4.1 for a description of the 
primary analysis model. The results will be pooled following the standard multiple 
imputation procedure (20). See also Section 9.2 for further technical information on the 
implementation of the multiple imputation approach.
Table 7.4.2.1.2: 1
Primary and sensitivity analyses for handling of missing data 
Analysis
Pattern 3: Missing week 52 data in patients 
still alive at 52 weeks
Pattern 4: Missing week 52 data in patients 
who died before 52 weeks
Handling of missing 
week 52 data
Underlying 
assumption 
regarding 
persistence of 
efficacy post-
withdrawal 
Handling of missing 
week 52 data 
Underlying 
assumption 
regarding 
persistence of 
efficacy after death
Primary
no imputation
assumes MAR
no imputation
assumes MAR
Sensitivity 
1[1]
based upon the slope 
(SE) estimates in 
Drug and Placebo in 
patients of pattern 2, 
multiple imputation 
of missing week 52 
data in the respective 
treatment group
rate of decline in 
patients with missing 
week 52 data is 
similar to rate of 
decline in patients of  
pattern 2 in the 
respective treatment 
group (e.g. treatment 
effect persists in 
same manner as for 
pattern 2 patients 
after trial drug 
discontinuation)
multiple imputation 
of missing 52 week 
data due to death 
based on the same 
slope (SE) estimates 
in Placebo patients of 
pattern 2, but 
truncated[3] to force 
the slope in patients 
who died to be more 
severe than in those 
who survived 
Assuming that deaths 
observed in the trial 
will likely be related 
to worsening of SSc, 
it seems reasonable to 
assume that the 
unobserved FVC 
values should on 
average be lower than 
those in patients who 
did not die prior to 
week 52
Rate of decline in 
patients who died 
before week 52 is 
similar to rate of 
decline in the Placebo 
patients of pattern 2 
with most severe 
slopes
Sensitivity 
2[1]
based upon the slope 
(SE) estimates in 
Placebo patients of 
pattern 2: multiple 
imputation of missing 
week 52 data in all 
patients regardless of 
treatment group
rate of decline in all 
patients with missing 
week 52 data is 
similar to rate of 
decline in Placebo 
patients of pattern 2 
(e.g. treatment effect 
does not persist after 
trial drug 
discontinuation)


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Table 7.4.2.1.2: 1
Primary and sensitivity analyses for handling of missing data (cont’d)
Analysis
Pattern 3: Missing week 52 data in patients 
still alive at 52 weeks
Pattern 4: Missing week 52 data in patients 
who died before 52 weeks
Handling of missing 
week 52 data
Underlying 
assumption 
regarding 
persistence of 
efficacy post-
withdrawal 
Handling of missing 
week 52 data 
Underlying 
assumption 
regarding 
persistence of 
efficacy after death
Sensitivity 
3[2]
based upon the slope 
(SE) estimates in 
Placebo patients from 
the primary analysis 
model,  i.e. in
patients from pattern 
1 or 2: multiple 
imputation of missing
week 52 data in all 
patients regardless of 
treatment group
rate of decline in all 
patients with missing 
week 52 data is 
similar to rate of 
decline estimated in 
all Placebo patients 
(e.g. treatment effect 
does not persist after 
trial drug 
discontinuation)
multiple imputation 
of missing 52 week 
data due to death 
based on the same 
slope (SE) estimates 
in all Placebo patients
(i.e. in patients from 
pattern 1 or 2), but 
truncated[3]  to force 
the slope in patients 
who died to be more 
severe than in those 
who survived 
Assuming that deaths 
observed in the trial 
will likely be related 
to worsening of SSc, 
it seems reasonable to 
assume that the 
unobserved FVC 
values should on 
average be lower than 
those in patients who 
did not die prior to 
week 52
Rate of decline in 
patients who died 
before week 52 is 
similar to rate of 
decline in the Placebo 
patients with most 
severe slopes
[1] Sensitivity analyses 1 and 2 will only be performed if the number of patients in pattern 2 is greater than 10 
(from both Nintedanib and Placebo group together for sensitivity analysis 1 and from placebo group for 
sensitivity analysis 2)
[2] Patients falling into pattern 2 are used as the basis for multiple imputations in sensitivity analyses 1 and 2
but since the number of patients in that pattern may be small, a third sensitivity analysis will be performed to 
confirm the robustness of the primary analysis results.
[3] If represents the true slope with f() ~ N(β, σ-) where β and σ are the placebo slope and SE estimates from 
either patients in pattern 2 or all placebo patients, then sampling for patients who died prior to 52 weeks is 
restricted to the interval (−∞, β] of the truncated distribution f()/2.  In this way, it is guaranteed that, on 
average, the imputed FVC slope for patients who died is steeper than the average slope in patients who survived 
to week 52.
In addition to the patterns defined in the scope of the multiple imputation, the number (and 
percentage) of patients in each possible pattern of FVC data will be explored and presented in 
Appendix 16.1.13.1 of the CTR. Graphs showing FVC data over time in each pattern of 
monotonic missing data will also be provided in Appendix 16.1.13.1 of the CTR.


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7.4.2.2
Sensitivity to the analysis model
7.4.2.2.1
Sensitivity to linearity assumption
The linearity assumption for the decline in FVC [mL/yr] will be explored graphically. The 
following graphical displays will be provided:
-
the mean (± Standard Error of the Mean (SEM)) observed FVC [mL] for each 
treatment group over time 
-
the mean (± SEM) observed FVC change from baseline [mL] for each treatment 
group over time
-
the mean (± SEM) estimated FVC [mL] for each treatment group over time (as 
estimated in the primary analysis)
The following alternative models will also be performed and a graphical display only will be 
provided:
-
A polynomial time model (quadratic form in t) will be explored
-
An exponential model (of the form: a + b exp(-c*t)) will be explored as well
For each model, a plot will be provided representing both the mean (± SEM) estimated FVC 
[mL] over time and the mean (± SEM) estimated FVC [mL] over time using the linear form 
(by treatment group).
In these models, data are assumed to be missing at random, which implies that patients who 
dropout would have behaved similarly to those who remained in the study. 
7.4.2.2.2
Sensitivity to covariates
A statistical model similar to the primary analysis will be done, including the fixed, 
categorical effects of treatment, ATA status (Positive / Negative), fixed continuous effects of 
time and baseline FVC (mL), the treatment-by-time and baseline-by-time interactions. Random 
effects will be included for patient response for both time and intercept.
A statistical model similar to the primary analysis will be done, the fixed, categorical effects of 
treatment, ATA status (Positive / Negative), gender and mycophenolate mofetil /sodium
background therapy use (Yes / No), fixed continuous effects of time, age , height and baseline 
FVC (mL), the treatment-by-time and baseline-by-time interactions. Random effects will be 
included for patient response for both time and intercept.


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7.4.2.3
Overall summary of sensitivity analyses
Table 7.4.2.3: 1
Summary of planned sensitivity analyses according to the endpoint
Sensitivity 
analysis
Scope of sensitivity 
analysis
Primary 
endpoint
Key secondary 
endpoints
Rate of 
FVC 
decline
Change 
from 
baseline 
in mRSS 
score
Change 
from 
baseline in 
SGRQ total 
score
Sensitivity 
to data 
handling 
assumptions
Analysis including 
only on-treatment 
data
To assess the direct effect 
of the trial drug and the 
impact of data measured 
post trial drug 
discontinuation.
X
X
X
Multiple 
imputation 
approaches
To estimate the treatment 
effect under differing 
assumptions regarding the 
persistence of efficacy 
post withdrawal of 
randomised treatment
X
X
X
Sensitivity 
to the 
analysis 
model
Polynomial / 
Exponential time 
models
To verify the linear 
assumption of the primary 
model of the primary 
endpoint
X
Use of different 
covariates
To verify the impact of the 
choice of covariates in the 
primary model
X
7.4.3
Subgroup analyses
For each subgroup analysis (refer to Section 6.4) of the primary endpoint, the heterogeneity 
of the treatment effect on the slope across subgroups will be estimated: A random slope and 
intercept mixed model will be fitted based upon the statistical model for the primary analysis 
considering the treatment-by-subgroup and treatment-by-subgroup-by-time interaction terms. 
A contrast statement, with appropriate contrasts, will be used to conduct an F-test of 
heterogeneity across all levels of the subgrouping at Week 52. The level at which p-values 
will be considered nominally significant is 5%. Nominally significant results will be 
discussed and may be explored further.
It can be shown that the following simplified, saturated model is equivalent to the fully 
specified model and will therefore be used for the analysis of subgroups:
iXjf_h` = kα + aX + n_ + oh + o[RK5X+ odQ5pKℎJX + r+CX + sff`t
+ (γ + gX + rYCX + f`wf ∗KX)tXj + 5Xj


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5Xj
pp}
~ z (0, ~-)
The components of the model are identical to the primary model (see Section 7.4.1 for 
explanation of notions) only adding the subgroup covariate:
-
f`
= intercept coefficient for the effect of treatment k in subgroup category u for 
patient i and k = 1,2, u = 1,2,…
-
f`
= slope coefficient for the effect of treatment k in subgroup category u for 
patient i and k = 1,2, u = 1,2,…
In the event of non-convergence, the same methods than the ones described in Section 7.4.1
will be used to overcome the issue.
Table 7.4.3: 1
Subgroup analyses – List of analyses
Description of study 
population
-
Disposition of patients
-
Demographic data
-
Trial indication characteristics
-
Baseline pulmonary efficacy variables
-
Baseline SGRQ scores and mRSS
-
Baseline conditions
Efficacy analyses on 
the primary and both 
key secondary 
endpoints
Primary endpoint analyses
-
Forest-plot for rate of decline in FVC (mL/yr) over 52 weeks in all 
subgroups: representation on the same graph of the estimate, 95% 
Confidence Interval for each subgroup and subgroup interaction p-value 
value of F-test for heterogeneity across all levels of the subgrouping 
-
Rate of decline in FVC (mL/yr) over 52 weeks by subgroup
-
Graphical representation of the mean (SEM) observed FVC change from 
baseline (mL) over time by subgroup
-
Graphical representation of the mean  (SEM) estimated FVC change from 
baseline (mL) over time by subgroup


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Table 7.4.3: 1
Subgroup analyses – List of analyses (cont’d)
Efficacy analyses on 
the primary and both 
key secondary 
endpoints
Key secondary endpoint analyses
-
Forest-plot for adjusted mean (SE) for absolute change from baseline in 
mRSS at 52 weeks in all subgroups: representation on the same graph of 
the estimate, 95% Confidence Interval for each subgroup and subgroup 
interaction p-value of F-test for heterogeneity across all levels of the 
subgrouping 
-
Adjusted mean (SE) for absolute change from baseline in mRSS at 52 
weeks by subgroup
-
Graphical representation of the  mean (SEM) observed mRSS change 
from baseline over time by subgroup
-
Graphical representation of the  mean (SEM) estimated mRSS change 
from baseline over time by subgroup
-
Forest-plot for adjusted mean (SE) for absolute change from baseline in 
SGRQ total score at 52 weeks in all subgroups: representation on the same 
graph of the estimate, 95% Confidence Interval for each subgroup and 
subgroup interaction p-value of F-test for heterogeneity across all levels of 
the subgrouping  
-
Adjusted mean (SE) for absolute change from baseline in SGRQ total 
score at 52 weeks by subgroup
-
Graphical representation of the mean (SEM) observed SGRQ total score 
change from baseline over time by subgroup
-
Graphical representation of the mean (SEM) estimated SGRQ total score 
change from baseline over time by subgroup
Safety analyses
Over 52 weeks and over the whole trial: 
-
Exposure to study drug 
-
Exposure to actual treatment dose received 
-
Adverse event overall summary 
-
Frequency of patients with adverse events occurring with incidence in 
preferred term > 1% in at least one treatment arm by SOC and PT
-
Frequency of patients with adverse events by SOC and PT
-
Frequency of patients with serious adverse events by SOC and PT
-
Frequency of patients with adverse events leading to permanent drug 
discontinuation by SOC and PT
-
Frequency of patients with investigator defined drug-related adverse 
events by SOC and PT
-
Frequency of patients with adverse events by safety topic
-
Frequency of patients with serious adverse events by safety topic
7.5
SECONDARY ENDPOINT(S)
The statistical analyses for secondary endpoints will be based on the TS (according to 
randomised treatment), using data from baseline (excluded) up to Week 52 (after time-
windowing), including visits done after premature treatment withdrawal, EOT visits and 
follow-up visits done before Week 52.


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7.5.1
Key secondary endpoint(s)
7.5.1.1
Absolute change from baseline in the mRSS at week 52
Absolute change from baseline in the mRSS at week 52 will be analysed in the TS using a 
restricted maximum likelihood (REML) based repeated measures approach , as described in 
the CTP Section 7.3.2.1. Analyses will include the fixed, categorical effects of ATA status,  
and treatment-by-visit interaction, as well as the continuous fixed covariate of baseline-by-
visit interaction. Visit will be treated as the repeated measure with an unstructured covariance 
structure used to model the within-patient measurements.
In the event of non-convergence, the same methods than the ones described in Section 7.4.1
will be used to overcome the issue, including in addition the following one: 5. Provide 
starting values for covariance parameters using a ‘parms’ statement. Estimates will be 
obtained from a simpler covariance matrix.
A cumulative distribution plot of the absolute change from baseline in the mRSS at week 52
will be provided, showing the cumulated frequencies for all possible absolute change from 
baseline in the mRSS values.
Several sensitivity analysis will be lead in order to assess the potential effect of data handling 
and the analysis model on the results of the main analysis.
The thorough list of sensitivity analyses planned is listed in Table 7.4.2.3: 1.
Note that for the imputation of mRSS total score missing values, imputed values will be 
truncated if needed so that they are comprised between 0 and 51.
A graph of the mean mRSS absolute 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.
In the subgroup analysis of the key secondary endpoints using MMRM models, a similar 
approach as for the primary endpoint will be used: A single MMRM model will be fitted 
involving all model terms from the primary analysis model except replacing the treatment-by-
visit term by treatment-by-subgroup-by-visit. A Lsmestimate statement, with appropriate 
contrasts, will be used to conduct an F-test of heterogeneity across all levels of the 
subgrouping. The level at which p-values will be considered nominally significant is 5%. 
Nominally significant results will be discussed and may be explored further. 
7.5.1.2
Absolute change from baseline in SGRQ total score at week 52
Similar analyses as for the first key secondary endpoint (Absolute change from baseline in 
the mRSS) will be performed for the absolute change in SGRQ total score, in the TS. Please 
refer to Section 7.5.1.1.


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Note that for the imputation of SGRQ total score missing values, imputed values will be 
truncated if needed so that they are comprised between 0 and 100.
In addition, a cumulative distribution plot of the absolute change from baseline in SGRQ total 
score at week 52 will be provided.
7.5.2
(Other) Secondary endpoint(s)
No sensitivity or subgroup analyses will be performed on the following other secondary 
endpoints. These will be analysed on the TS.
7.5.2.1
Annual rate of decline in FVC in percent predicted over 52 weeks
A similar analysis as the primary model on the primary endpoint will be done, including
baseline FVC% predicted and ATA status as a covariate. Please refer to Section 7.4.1.
7.5.2.2
Absolute change from baseline in FVC in mL at week 52
A similar analysis based on MMRM as for the key secondary endpoints will be performed for 
the absolute change in FVC. Please refer to Section 7.5.1.1.
In addition, a cumulative distribution plot of the absolute change from baseline in FVC in mL 
at week 52 will be provided.
7.5.2.3
Relative change from baseline (%) of mRSS at week 52
A similar analysis based on MMRM as for the key secondary endpoints will be performed for 
the relative change in mRSS. Please refer to Section 7.5.1.1.
7.5.2.4
Time to death
Please refer to CTP Section 7.3.2.2 for the summary of analyses and Section 5.2.2.2 for the 
definition of the censoring.
A Kaplan-Meier plot of time to death over the whole trial duration will be displayed. Time to 
death at Week 52 will also be displayed as additional information. 
7.5.2.5
CRISS index score at week 52 
For all analyses, please note that CRISS index represents a probability of improvement and 
ranges between 0 and 1.
Descriptive statistics summarizing CRISS value at 52 weeks will be provided by treatment 
group.
The cumulative proportion of patients whose probability of improving at week 52 with regard 
to their CRISS index will be shown by using a broad range of cut-offs for the CRISS value at 
52 weeks (>=0, >=0.1, >=0.2,  ... , >=0.9,1), in a cumulative proportion of responder analysis 


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graph (19). The proportion of patients showing improvement for CRISS based on each cut-
off will also be tabulated.
In order to analyse CRISS index across both treatment groups, it will be transformed into a 
binary responder endpoint using multiple imputation. More specifically, the following steps 
will be applied: 
•
For each patient, 100 random uniform draws in the range from 0 to 1 will be taken
o
If the value of the draw > CRISS index value of the patient then the responder 
variable will be set to « No » for that patient
o
If the value of the draw ≤CRISS index value of the patient then the responder 
variable will be set to « Yes » for that patient
•
This results in 100 imputed datasets including a responder variable for each of the 
patients that indicates whether or not this patient is considered a responder or not, as 
derived from the actual CRISS index of the patient
•
For each complete dataset of patients obtained by imputation as described above, the 
comparison between both treatment groups regarding the newly obtained binary will be 
performed using a Cochran-Mantel-Haenszel (CMH) model adjusting for ATA status. 
Adjusted Mantel-Haenszel odds ratio (OR) with 95% confidence intervals (CI) will be 
used to quantify the treatment effect between the Nintedanib group and Placebo.
•
The OR and the 95% CI as obtained from all 100 imputations will then be combined 
using Rubin’s rule (20): First, they will be log-transformed so that they are approximately 
normally-distributed. The SE on the log-scale will then be estimated by dividing the range 
of the CI on the log-scale by 2*1.96. Rubin’s rules will then be applied to the log-scale 
point estimate and SE, and a nominal p-value calculated. The overall CI on the log-scale 
will be recalculated as the combined point estimate +/- 1.96 times the combined SE. For 
the purpose of interpretation and presentation, both the point estimate and 95% CI 
boundaries will be back transformed to the original scale.
7.5.2.6
Absolute change from baseline in DLCO in percent predicted at week 52
A similar analysis based on MMRM as for the key secondary endpoints will be performed for 
the absolute change in DLCO % predicted. Please refer to Section 7.5.1.1.
7.5.2.7
Absolute change from baseline in digital ulcer net burden at week 52
A similar analysis based on MMRM as for the key secondary endpoints will be performed for 
the absolute change in digital ulcer net burden. Please refer to Section 7.5.1.1.
7.5.2.8
Absolute change from baseline in HAQ-DI score at week 52
A similar analysis based on MMRM as for the key secondary endpoints will be performed for 
the absolute change in HAQ-DI score. Please refer to Section 7.5.1.1.


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7.5.2.9
Absolute change from baseline in FACIT dyspnoea score at week 52
A similar analysis based on MMRM as for the key secondary endpoints will be performed for 
the absolute change in FACIT dyspnoea. Please refer to Section 7.5.1.1.
7.6
FURTHER ENDPOINT(S)
Further endpoints are listed in CTP section 5.1.3.
7.6.1
Categorical endpoints
Categorical endpoints representing proportion of patients (as defined in Section 5.3.2) will be 
summarised descriptively. Wilson 95% confidence interval and a nominal p-value will be 
calculated for each proportion of patients specified in Section 5.3.2. 
The proportion of patients with an absolute change from baseline in SGRQ >= 4 points at 
week 52 will be analysed similarly.
The proportion of patients showing improvement based on CRISS will be summarised 
(improvement is defined based on CRISS value at 52 weeks and using a broad range of cut-
offs) ([18]).
7.6.2
Change from baseline endpoints
Change from baseline endpoints at Week 52 (as defined in Section 5.3.1) will be summarised
descriptively. 
7.6.3
Analyses over the whole trial 
Descriptive statistics by visit over the whole trial will be provided in the TS for endpoints 
listed in Table 6.1: 1. A graphical representation of the change from baseline over the whole 
trial may also be displayed. 
In addition, for exploratory purposes, a similar analysis as the primary model on the primary 
endpoint will be done, based on all data collected during the whole trial period (up to 100 
weeks). Only the treatment effect and associated confidence interval will be provided. 
7.6.4
Pharmacokinetics
For PK analyses, data will be summarised descriptively according to the BI Standard 
procedures (6).
7.6.5
Biomarkers 
Analyses on biomarkers will be described in a separate Statistical Analysis Plan and not 
included in the main CTR.


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7.7
EXTENT OF EXPOSURE
Extent of exposure data will be summarised on the TS both over 52 weeks and over the 
whole trial (refer to Section 5.4.3.1 and Section 5.4.3.2). 
A summary table showing the duration on treatment (both mean and frequency in classes, see 
Section 5.4.3) and dose intensity will be presented.
Besides, a summary table showing the duration on actual treatment dose (both mean and 
frequency in classes, see Section 5.4.3) and off-treatment duration will be performed. This 
will take into account the actual dose following dose reductions or increases.
A summary of treatment interruptions will be performed including number of patients with at 
least one interruption, number and reason of interruptions, as well as time to first interruption 
(both mean and frequency in classes, see Section 5.4.3). A similar summary will be 
performed for dose changes.
A table displaying the disposition of patients and the conclusion of patients’ participation,
and a table displaying the primary reason for non-inclusion/randomisation will be provided. 
A Kaplan-Meier plot of time to premature treatment discontinuation will be produced. 
Similarly, Kaplan-Meier plots will be performed for time to first dose reduction and for time 
to first treatment interruption. No statistical tests will be performed.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS. 
Safety analysis will primarily be based on data collected within the first 52 weeks. Additional
safety analysis will also be presented for safety data collected overall including data collected 
beyond 52 weeks. See Section 6.1 of this document for further details of the treatment period 
specifications and refer to Table 6.1: 1 for the start and end dates for these analyses.
7.8.1
Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of adverse events (AEs) will be based on the number of patients with AEs and NOT 
on the number of AEs (with the exception of AEs with additional information collection, see 
Section 7.8.1.3).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship [investigator defined drug-relatedness], 
outcome, AE of special interest)


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•
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)
For further details on summarization of AE data, please refer to (8, 10). 
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 last drug 
intake + 28 days will be assigned to the randomised treatment. 
In addition, selected adverse events analyses will also be done considering a residual effect 
period of 7 days.
All adverse events occurring before first drug intake will be assigned either to ‘screening’ or 
‘post-randomisation’ (for listings only). 
For analyses based on a residual effect period of 28 days, adverse events occurring after last 
drug intake + 28 days will be assigned to ‘follow-up’ or ‘post-study’ (for listings only). All 
adverse events occurring between the start of an interruption of trial medication and the end 
of interruption of trial medication will be assigned to ‘off-treatment’ period in the listings. 
For details on the treatment definition, see Section 6.1.
According to ICH E3 (11), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant (i.e. not defined as protocol-specified AEs of 
special interest) adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or lead to significant concomitant 
therapy 
Adverse events related to gastrointestinal perforation and hepatic injury will be considered as 
protocol pre-specified AEs of special interest (AESIs), and were collected as such in the 
eCRF.
An overall summary of adverse events will be presented.
The frequency of patients with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). This will also be presented restricted to incidence in 
preferred term > 5% (in at least one treatment arm).
Separate tables will be provided for patients with other significant AEs according to ICH E3 
(11), for patients with serious AEs (SAEs), for patients with severe AEs, for patients with 
AEs leading to permanent dose reduction, for patients with AEs leading to permanent drug
discontinuation, for patients with investigator defined drug-related AEs and for patients with 
AEs leading to death. The frequency of patients with SAEs will also be presented restricted to
incidence in preferred term > 1% (in at least one treatment arm).
In addition a table will be provided for patients with investigator defined drug-related SAEs. 
This will be based on the number of patients with AE that are both serious and investigator 


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defined drug-related. Similarly, a table will be provided for patients with investigator defined 
drug-related AEs leading to deaths.
The SOCs and PTs (within SOCs) will be sorted by descending frequency in Nintedanib 
treatment arm.
7.8.1.1
Pre-specified adverse events of special interest
Gastrointestinal perforations and hepatic injury are adverse events of special interest (AESI) 
pre-specified in the CTP Section 5.3.7.1. These are investigator reported on the eCRF and 
will be identified using this information for this analysis.
The frequency of patients with pre-specified AESI will be summarised by treatment, primary 
SOC and preferred term (PT).
7.8.1.2
Adverse events with additional information collection
Diarrhoea and bleeding are AEs with additional AE-specific information collected on the 
eCRF. These are investigator reported on the eCRF and will be identified using this 
information for this analysis. That is if the diarrhoea information has been completed for an 
adverse event then the adverse event will be considered as diarrhoea for this analysis 
regardless of subsequent MedDRA coding of the verbatim term. Likewise, if the bleeding 
information has been completed for an adverse event then the adverse event will be 
considered as bleeding for this analysis regardless of subsequent MedDRA coding of the 
verbatim term.
The frequency of patients with AEs with additional information collection will be 
summarised by treatment, primary SOC and PT separately for diarrhoea and bleeding. The 
additional information collected will also be summarised at the AE level rather than at the 
patient level separately for diarrhoea and bleeding.
7.8.1.3
Adjudicated adverse events
An independent adjudication committee will review all fatal cases and adjudicate cause of 
death to cardiovascular death, respiratory related death, non-cardiovascular/non-respiratory 
death, or undetermined cause of death on a per patient basis, e.g. one cause per patient. The 
adjudication committee will also review all AEs categorised as MACE according to the 
definition in the adjudication charter.
In addition to standard safety analyses, the frequency of patients with AEs leading to death 
will be summarised by treatment, adjudicated cause of death (Cardiac, Respiratory, Non-
cardiac/non-respiratory or Undetermined), and PT.
The frequency of patients with AEs categorised as MACE (that is all AEs with trigger terms 
for MACE and therefore sent for adjudication) will be summarised by treatment and outcome 
of adjudication (adjudicated as MACE or adjudicated as not MACE). The frequency of 
patients with AEs adjudicated as MACE will also be summarised by treatment and PT.


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7.8.1.4
Additional analysis of adverse event groupings by system
Further adverse event groupings by system have been defined outside the trial protocol as 
medically relevant to the clinical development program and are specified in Table 7.8.1.4: 1. 
The frequency of patients with AEs within these groupings will be summarised by treatment, 
safety topic and preferred term. Separate tables will be provided for patients with investigator 
defined drug-related AEs and serious AEs (SAEs).
Table 7.8.1.4:1
Adverse events by system and safety topic using aggregated terms
System
Safety Topic 
Definition (selection criteria)
Gastrointestinal 
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)
Hepatobiliary 
Drug-induced liver 
injury (DILI)
PT Drug-induced liver injury
Hepatic disorders 
combined
Sub-categories:
Drug related 
hepatic disorders –
comprehensive 
search (SMQ 
narrow)
Liver related 
investigations, 
signs and 
symptoms (SMQ 
broad)
Cholestasis and 
jaundice of hepatic 
origin (SMQ 
narrow)
Hepatitis, non-
infectious (SMQ 
narrow)
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) 


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Table 7.8.1.4:1
Adverse events by system and safety topic using aggregated terms 
(cont’d)
System
Safety Topic 
Definition (selection criteria)
Cardiovascular
Arterial 
thromboembolism
SMQ Embolic and thrombotic events, arterial (narrow) 
Myocardial infarction
SMQ Myocardial infarction (narrow)
Stroke
Stroke haemorrhagic 
Stroke ischaemic 
Stroke haemorrhagic 
and ischaemic
Pharmacovigilance Endpoint Stroke PTs (see Section 9.7)
for included Preferred Terms)
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
Sub-categories:
Fatal events in SOC 
Cardiac disorders
Fatal events in SOC 
Vascular disorders
Any fatal or non-
fatal events in SMQ 
Myocardial 
infarction (broad)
PTs Cardiac death, 
Sudden death, 
Sudden cardiac 
death
Any fatal or non-
fatal stroke events
Fatal events in SOC Cardiac OR
Fatal events in SOC Vascular OR
Any fatal or nonfatal events in SMQ Myocardial infarction 
(broad) OR
PTs Cardiac death, Sudden death, Sudden cardiac death OR
Any fatal or nonfatal events as defined in 
Pharmacovigilance Endpoint Stroke PTs – updated to 
MedDRA 21.0


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Table 7.8.1.4:1
Adverse events by system and safety topic using aggregated terms 
(cont’d)
System
Safety Topic
Definition (selection criteria)
Cardiovascular
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
Blood
Bleeding
Subcategories:
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 (attached 
spreadsheet):

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
Urinary tract infection
BIcMQ Urinary tract infection (broad)


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Table 7.8.1.4:1
Adverse events by system and safety topic using aggregated terms 
(cont’d)
System
Safety Topic 
Definition (selection criteria)
Psychiatric 
Depression
SMQ Depression (excl suicide and self-injury) (narrow)
Suicide
SMQ Suicide/self-injury (narrow)
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)


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Table 7.8.1.4:1
Adverse events by system and safety topic using aggregated terms 
(cont’d)
System
Safety Topic 
Definition (selection criteria)
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
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
These definitions are based on MedDRA Version 21.0. 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.
7.8.1.5
Adverse events of particular note 
Gastro-intestinal adverse events (diarrhoea, nausea, vomiting, dehydration, weight decrease 
and decreased appetite) are considered as AEs of particular note.


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Specific tables will be created in order to describe adverse events of particular note over 52 
weeks:
-
Summary of AEs including intensity, seriousness, clinical consequences (permanent 
dose reduction, drug discontinuation or drug interruption), drug relationship, therapy 
for event and outcome
-
Summary of AEs including time to onset, number and duration of episodes
Depending on the number of patients having such AEs, a Kaplan-Meier plot of time to first 
adverse event of particular note may be drawn by treatment.
In addition, for pairs of selected adverse events (from diarrhoea, nausea, vomiting, decreased 
appetite, dehydration, weight decreased as defined in Table 7.8.1.4: 1) , the frequency of 
patients with concurrent AEs will be summarised by treatment where concurrence is defined 
as an overlap of at least one day.
7.8.1.6
Adverse event analyses over the whole trial
Time at risk analyses of AEs will be presented for the overall timeframe. Time at risk and 
incidence rates per 100 patient years will be calculated based on the first onset of an AE.
An overall summary of adverse events will be presented.
A summary by treatment, primary system organ class (SOC) and preferred term (PT) will be 
presented. This will also be presented restricted to incidence in preferred term > 5% (in at 
least one treatment arm).
Separate tables will be provided for patients with other significant AEs according to ICH E3 
(11), for patients with serious AEs (SAEs), for patients with severe AEs, for patients with 
AEs leading to permanent dose reduction, for patients with AEs leading to permanent dose 
discontinuation, for patients with investigator defined drug-related AEs, for patients with AEs 
leading to death, for investigator defined drug-related SAEs, for investigator defined drug-
related AEs leading to death. The summary of patients with SAEs will also be presented 
restricted to incidence in preferred term > 1% (in at least one treatment arm).
Time at risk analyses of AEs pre-specified AESI will be summarised by treatment, primary 
SOC and preferred term.
Time at risk analyses of AEs, investigator defined drug-related AEs and SAEs within 
groupings by system will be summarised by treatment, safety topic and preferred term.
Adjudicated AEs will be analysed similarly as planned in Section 7.8.1.3, except based on 
time at risk analyses.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (12). This will be performed for the safety analysis over 52 weeks and overall.
Please refer to Section 7.3.4 of the CTP for further details.
In addition a thorough description of liver enzymes and bilirubin elevations over the whole 
study period will be given, according to the definitions in Section 5.4.4, including a display 
of maximum individual elevation and a Kaplan-Meier plot of time to first liver enzyme 
elevation (if sufficient number of events).
A similar summary table of liver enzymes and bilirubin elevations over the first 52 weeks 
will also be provided (please refer to Table 6.7: 3 for time windowing definition).
The time to onset of first liver enzyme and bilirubin elevation [days] will be summarised by 
categories (<=21; >21-<=42; >42-<=63; >63). 
For each patient having experienced a liver enzyme and bilirubin elevation, a graphical 
representation of AST, ALT and bilirubin over time will be provided.
7.8.3
Vital signs
Summary statistics will be presented for observed values and change from baseline by 
treatment and visit. This will be performed for the overall timeframe.
The frequency of patients with marked changes in vital signs over 52 weeks will also be 
summarised by treatment according to the definitions in Section 5.4.5 of this document.
7.8.4
ECG
Not applicable as ECG findings will be reported as adverse events.
7.8.5
Others
Clinically relevant findings after Doppler echocardiography will be reported as adverse 
events.
Any worsening of trial indication SSc-ILD will be reported and summarised as AEs.
In addition, information collected at Week 52 about relevant changes in echocardiography 
characteristics (based on Echocardiography eCRF page) will be summarised using descriptive 
statistics.


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8.
REFERENCES
1
001-MCG-159_RD-03: “Standard table shells for inferential and descriptive End-of-Text tables 
(EoT-Catalogue)”, current version; IDEA for CON.
2
001-MCG-410: "Structure, Derivation, and Documentation of Analysis Data Sets", current version; 
IDEA for CON.
3
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, Note For 
Guidance on Statistical Principles for Clinical Trials, current version.
4
001-MCG-741: "Clinical subgroup analyses for local and regional Populations in Asia - Clinical 
Bridging Study Waiver (BSW) and Descriptive Subgroup Analysis (SGA) Reports”, current version; 
IDEA for CON.
5
001-MCP-090: "BI Style Guide", current version; IDEA for CON. 
6
001 MCS 36-472: "Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
7
001-MCS-50-413: "Handling of Protocol Violations in Clinical Trials and Projects", current version; 
group: Study Conduct; IDEA for CON.
8
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; IDEA for 
CON.
9
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; IDEA for
CON.
10
001-MCG-156: "Handling and summarization of adverse event data for clinical trial reports and 
integrated summaries", current version; IDEA for CON.
11
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
12
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current version; IDEA for 
CON.
13
Jones PW, Forde Y. St George’s Respiratory Questionnaire Manual. Version 2.3, 20.06.2009 [R12-
2870]   
14
FACIT-Dyspnoea Scale Short Form Scoring Guideline [R16-0894]   
15
FACIT Administration and scoring guidelines [R10-5351]   
16
Mapi Research Trust, HAQ Scaling and Scoring, Version 4, July 2011 [R16-0893]     
17
Philip H. Quanjer, Multi-ethnic reference values for spirometry for the 3–95 year age range: The 
global lung function 2012 equations [R15-0845]     
18
Dinesh Khanna, et al, The American College of Rheumatology, Provisional Composite Response 
Index for Clinical Trials in Early Diffuse Cutaneous Systemic Sclerosis [R17-0095]     
19
Farrar J, Dworkin R, Max M. Use of Cumulative Proportion of Responders Analysis Graph to 
Present Pain Data Over a Range of Cut-Offs points: Making Clinical Trial Data More 
Understandable. Journal of Pain and Symptom Management, Vol. 31 No. 4, 2006 [R11-4172]     
20
Rubin, DB. Multiple Imputation for Nonresponse in Surveys. New
York: Wiley, 1987. [R12-2378]
21
Japanese Ministry of Health, Labour and Welfare, Format for Preparing the Common Technical 
Document for Submission of New Drug Applications to Reduce Total Review Time, 2011 [R18-
1356]


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9.
ADDITIONAL SECTIONS
9.1
HCRU (HEALTH CARE RESOURCE UTILISATION)
Descriptive statistics of HCRU over time will be provided in Section 16.1.13.1 of the CTR. 
Nevertheless, the economic modelling of the HCRU data will not be part of the clinical trial 
report but reported separately.
9.2
COMPLEMENTARY INFORMATION ON STATISTICAL MODEL AND 
SAS CODE
Primary endpoint model (and other rate of decline endpoints):  
The key code is given below.  Time is defined as duration since first trial drug intake divided 
by 365.25. Visit is the visit number.
Meanbase corresponds to the overall mean baseline for the endpoint.
proc MIXED data=FVC cl method=reml  order= formatted covtest;
      CLASS patient visit treatment gender ata;
MODEL endpoint= gender age height ata fvcbaseline fvcbaseline*time
treatment treatment*time /solution CL ddfm=KR;
  
RANDOM intercept time/ type=un subject=patient;
      ESTIMATE 'Nintedanib' fvcbaseline*time MEANBASE treatment*time 0 1 / 
e CL;       
      ESTIMATE 'Placebo' fvcbaseline*time MEANBASE treatment*time 1 0 / e 
CL;
  
ESTIMATE 'Nintedanib 150mg bid – Placebo’ treatment*time -1 1 / e CL;
RUN;
Primary endpoint subgroup analysis model:  
This is the case of subgroups wih 2 categories:
proc MIXED data=FVC cl method=reml  order= formatted covtest;
      CLASS patient visit treatment gender ata subgroup;
MODEL endpoint= gender age height ata fvcbaseline fvcbaseline*time
treatment*subgroup treatment*subgroup*time /solution CL ddfm=KR;
  
RANDOM intercept time/ type=un subject=patient;
ESTIMATE 'Nintedanib – Subgroup A'  fvcbaseline*time MEANBASE treatment *
subgroup *time 0 0 1 0 / cl e;
ESTIMATE 'Placebo - Subgroup A'   fvcbaseline*time MEANBASE treatment *
subgroup *time 1 0 0 0 / cl e;
ESTIMATE 'Nintedanib - Subgroup B'   fvcbaseline*time MEANBASE treatment *
subgroup *time 0 0 0 1 / cl e;
ESTIMATE 'Placebo - Subgroup B'   fvcbaseline*time MEANBASE treatment *
subgroup *time 0 1 0 0 / cl e;
ESTIMATE 'Nintedanib – Placebo Subgroup A'  subgroup * treatment *time  -1
0 1 0 / e CL;


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ESTIMATE 'Nintedanib – Placebo Subgroup B'   subgroup * treatment *time  0
-1 0 1 / e CL;
CONTRAST 'F-test of heterogeneity at 52 weeks' subgroup * treatment *time 
-1 1  1 -1 / e;  
RUN;
Model for key secondary endpoints (and other change from baseline endpoints):
The key code is given below.
proc MIXED data= MRSS cl order=internal covtest ;
      CLASS patient treatment visit ata;
MODEL endpoint= ata baseline*visit treatment*visit /solution ddfm=KR;
  
REPEATED visit/type=un subject =patient;
      LSMEANS treatment * visit / pdiff = control ("AM10PBO" "52")  om cl 
alpha=0.05;RUN;
Change from baseline endpoints analysis by subgroup:
The LSMESTIMATE code depends on the number visits where the parameter was 
measured and on the number of categories in the subgroup.
For FVC – in a subgroup with 4 categories: 
ods output contrasts=ftest lsmeans=lsmeans diffs=diffs;
proc MIXED data= FVC cl method=reml order=formatted covtest ;
    CLASS patient visit treatment subgroup ata ;
MODEL ept= ata baseline* visit visit*treatment*subgroup /solution 
ddfm=KR;
  
REPEATED visit/type=un subject =patient ;
/* Within subgroup estimates : adj mean and adj mean difference*/
    LSMEANS visit* treatment *subgroup / pdiff = all om cl alpha=0.05 ;
/* Overall heterogeneity (F-test) */
    LSMESTIMATE visit*treatment*subgroup
    'Week 52, Subgroup 1' 
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    -3 1 1 1 3 -1 -1 -1,
    'Week 52, Subgroup 2' 
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
   1 -3 1 1 -1 3 -1 -1,


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    'Week 52, Subgroup 3' 
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
   1 1 -3 1 -1 -1 3 -1,
    'Week 52, Subgroup 4' 
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
    0 0 0 0 0 0 0 0
   1 1 1 -3 -1 -1 -1 3
      /divisor=4  joint elsm cl alpha=0.05;
RUN;
For 2 subgroups, the LSMESTIMATE will write:
LSMESTIMATE visit*treatment*subgroup
    'Week 52, Subgroup 1' 
    0 0 0 0
    0 0 0 0
    0 0 0 0
    0 0 0 0
    0 0 0 0
    0 0 0 0
    -1 1 1 -1,
       
    'Week 52, Subgroup 2' 
    0 0 0 0
    0 0 0 0
    0 0 0 0
    0 0 0 0
    0 0 0 0
    0 0 0 0
    1 -1 -1 1
/divisor=2  joint elsm cl alpha=0.05;
Implementation of multiple imputation:
The following steps provide a guidance of how missing FVC data at week 52 will be
implemented in patients of pattern 3 and 4 using multiple imputation. Refer to Table 
7.4.2.1.2: 1 for the description of patterns and the different sensitivity analyses regarding 
handling of missing data.


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1. Run the MMRM of the primary analysis (either including patients of pattern 2 only 
for sensitivity analyses 1 and 2 or on all patients for sensitivity analysis 3) to get the 
slope estimates (SE) by treatment group. Let rDand ~D denote the slope (SE) 
estimates in Nintedanib 150 mg and rPand ~P the slope (SE) estimates in placebo.
2. Let D and P represent the true slopes in drug and placebo respectively with f(D) ~ 
N(r, ~-
) and with f(P) ~ N(r, ~-
), using the slope (SE) estimates obtained in 
step 1. 
3. Imputation of missing week 52 data in patients of pattern 3:
Multiple impute missing values (1000 imputations per patient). To do so, draw 
random slopes from the distributions defined in step 2. Considering that the 
withdrawal of a patient leading to missing data can occur at any time during the 
study, the timepoint of the last available FVC value has to be taken into account 
to impute the missing FVC value at 52 weeks. 
FVC week 52 imputedij = last FVC value availablei + rij(time between date of 
last FVC value availablei and planned 52 week timepoint [days])
where i denotes the indicator of the ith patient, j the indicator of the jth imputation 
and  rij denotes a random slope sampled from the distribution mentioned in step 
3a for the ith patient in the jth imputation. Depending on the sensitivity analysis, 
use either random slopes drawn from f(D) for patients randomised to Nintedanib 
150 mg in sensitivity analysis 1 or f(P) for all patients in sensitivity analyses 2 
and 3.
4. Imputation of missing week 52 data in patients of pattern 4:
Multiple impute missing values (1000 imputations per patient). To do so, draw 
random slopes from the truncated distribution f(P)/2 restricted to the interval 
(−∞, r] defined in step 2. 
See step 3 for further details on how to use these slopes to impute the missing 
values at week 52.
5. Run the MMRM of the primary analysis on each imputed dataset, using a "by 
_IMPUTATION_ " statement.
6. Combine the estimates obtained in step 5 using PROC MIANALYZE.


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9.3
ADDITIONAL ANALYSIS FOR REGIONAL SUBMISSIONS
For the Japanese submission, the analyses will be conducted according to “Format for 
Preparing the Common Technical Document for Submission of New Drug Applications to 
Reduce Total Review Time” (21). 
For the analysis due to local regulatory submission, the following subsets are defined (4).
Some outputs from CTR Section 15 will be selected for the subsets defined in Table 9.3: 1. 
Due to small sample size of some subsets, some tables might be skipped. The same analyses 
models as defined for the overall population will be used (please refer to Section 7.4.1). In 
the event of non-convergence, the same methods than the ones described in Section 7.4.1 will 
be used to overcome the issue.
Table 9.3: 1
Patient subsets definition for local regulatory submission in Asia
Category
Patient subset
Local

Japan

China
The patients in each local site and Asian race will be included (e.g. 
Japan: Site in Japan and single race is Asian). If Asian race will 
be ”Multiple” and multiple responder will be “Asian & xxx”, the patient 
will be handled as “Asian”. (e.g. Japan: Site in Japan and multiple race is 
Asian & White.)
East Asia

East Asian countries
The patients from East Asian countries or region (i.e. Japan and China) 
with Asian race. Asian race definition is same definition in local 
category.
India

India
The patients in any race from India sites will be included.
These subset analyses will not be produced as part of the CTR appendix and will not be 
described in the text of the CTR (9). The details will be handled in another document 
(cumulative SAP).


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9.4
LIST OF BI CUSTOMISED DRUG GROUPINGS OF INTEREST
Customized drug groupings of interest for this trial are listed in Table 9.4: 1.
Table 9.4: 1
Customized drug grouping of interest
CT grouping name
Type of grouping
Antiarrhythmics
SDG
Antidiarrheal
ATC4 ('A07DA')
Antiemetics and antinauseants
SDG, excluding drugs from the 
Corticosteroids SDG
Antihypertensives
SDG
Anti-infectives
SDG
Antithrombotic drugs
SDG
Corticosteroids
SDG
Drugs interacting with CYP3A
SDG
Disease-modifying antirheumatic drugs 
(DMARDs)
SDG
Diuretics
SDG
Drugs for gastric acid related disorders
SDG
Drugs for obstructive airway diseases
SDG
Drugs used in pain therapies
SDG
Hormone replacement therapy
SDG
Immunosuppressant drugs
Sub-SDG (from Immunomodulators 
SDG)
Monoclonal antibodies
SDG
Nonsteroidal anti-inflammatory drugs 
(NSAIDs)
SDG
Drugs interacting with P-glycoprotein 
(P-gp) 
SDG


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Table 9.4: 1 Customized drug grouping of interest (cont’d)
CT grouping name
Type of grouping
Phosphodiesterase (PDE) inhibitors
SDG
Statins
SDG
WHO−DD version used: 18.MAR


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9.5
SPECIFICATION OF RESTRICTED AND FORBIDDEN CONCOMITANT 
THERAPIES
Medications reviewed as potential IPVs were selected based on Table 9.5: 1
Table 9.5: 1
Restricted and forbidden concomitant therapies
Type of medication
Category of drugs
ATC/PN
Prohibited medications
Pirfenidone
PN=’Pirfenidone’
Nintedanib (outside of the 
trial)
L01XE
Other investigational 
drugs
PN=’Investigational drugs’
Restricted medications
Full dose therapeutic 
anticoagulation
B01AA, B01AB, B01AF, 
B01AE, B01AD, B01AX 
Antiplatelet therapies
B01AC, B01AX
Mycophenolate mofetil/
sodium / 
MYCOPHENOLIC ACID
PN=’ Mycophenolate mofetil’ 
or
PN=’ Mycophenolate sodium’ 
or
PN=’ MYCOPHENOLIC 
ACID’
Methotrexate
PN=’ Methotrexate’ or
PN=’ Methotrexate sodium’
Azathioprine, potassium 
para-aminobenzoate
L04AX
Cyclophosphamide
PN=’ Cyclophosphamide’


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Table 9.5: 1
Restricted and forbidden concomitant therapies (cont’d)
Type of medication
Category of drugs
ATC/PN
Prednisone > 10mg /day
H02AB
Hydroxychloroquine, 
colchizine, D-
penicillamine, 
sulfasalazine
PN=’ Hydroxychloroquine’ or
PN=’ colchizine’ or
PN=’ penicillamine’ or
PN=’ sulfasalazine
Rituximab, tocilizumab, 
abatacept,leflunomide, 
tacrolimus, newer anti-
arthritic treatment like 
tofacitinib
L04AC, L04AA, D11AH, 
L04AD, L04AA
9.6
LIST OF POTENTIAL TERMS FOR HEPATIC INJURY DERIVATION
Table 9.6: 1 shows the list of potentially relevant MedDRA preferred terms to support the 
derivation of a potential hepatic injury: 
Table 9.6: 1
List of potentially relevant MedDRA preferred terms
Symptom
MedDRA
Vomiting 
PT Vomiting
Fatigue
PT Fatigue
Nausea
PT Nausea
Right upper abdominal quadrant pain or 
tenderness
HLT “Gastrointestinal and abdominal pains 
(excl oral and throat)”
Fever
PT Fever
Rash
BIcMQ skin rash (narrow)


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9.7
LIST OF TERMS INCLUDED IN STROKE PHARMACOVIGILANCE 
ENDPOINT
This is list is based on MedDRA Version 21.0. Updates will be only maintained in BIRDS as 
specified in Section 7.8.1.4.
The following MedDRA Preferred Terms will be used to define stroke pharmacovigilance 
endpoint:
Amaurosis fugax
Amyloid related imaging abnormalities
Amyloid related imaging abnormality-microhaemorrhages and haemosiderin deposits
Amyloid related imaging abnormality-oedema/effusion
Basal ganglia haematoma
Basal ganglia haemorrhage
Basal ganglia stroke
Basilar artery occlusion
Basilar artery perforation
Basilar artery thrombosis
Brachiocephalic artery occlusion
Brain stem embolism
Brain stem haematoma
Brain stem haemorrhage
Brain stem infarction
Brain stem ischaemia
Brain stem stroke
Brain stem thrombosis
Brain stent insertion
Carotid aneurysm rupture
Carotid arterial embolus
Carotid artery occlusion
Carotid artery perforation
Carotid artery thrombosis
Central nervous system haemorrhage
Cerebellar artery occlusion
Cerebellar artery thrombosis
Cerebellar embolism
Cerebellar haematoma
Cerebellar haemorrhage
Cerebellar infarction
Cerebellar ischaemia
Cerebellar stroke
Cerebral aneurysm perforation
Cerebral arteriovenous malformation haemorrhagic
Cerebral artery embolism
Cerebral artery occlusion
Cerebral artery perforation
Cerebral artery restenosis


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Cerebral artery thrombosis
Cerebral haematoma
Cerebral haemorrhage
Cerebral haemorrhage foetal
Cerebral haemorrhage neonatal
Cerebral infarction
Cerebral infarction foetal
Cerebral ischaemia
Cerebral microembolism
Cerebral thrombosis
Cerebral vascular occlusion
Cerebrovascular accident
Delayed ischaemic neurological deficit
Embolic cerebral infarction
Embolic stroke
Haemorrhage intracranial
Haemorrhagic cerebral infarction
Haemorrhagic stroke
Haemorrhagic transformation stroke
Intracranial haematoma
Intracranial tumour haemorrhage
Intraoperative cerebral artery occlusion
Intraventricular haemorrhage
Intraventricular haemorrhage neonatal
Ischaemic cerebral infarction
Ischaemic stroke
Lacunar infarction
Lacunar stroke
Lateral medullary syndrome
Perfusion brain scan abnormal
Perinatal stroke
Periventricular haemorrhage neonatal 
Pituitary haemorrhage
Pituitary infarction
Post procedural stroke
Precerebral artery occlusion
Precerebral artery thrombosis
Pseudostroke
Putamen haemorrhage
Reversible ischaemic neurological deficit
Ruptured cerebral aneurysm
Stroke in evolution
Subarachnoid haematoma
Subarachnoid haemorrhage
Subarachnoid haemorrhage neonatal
Subdural haemorrhage neonatal 


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Thalamic infarction
Thalamus haemorrhage
Thrombotic cerebral infarction
Thrombotic stroke
Transient ischaemic attack
Vertebral artery occlusion
Vertebral artery perforation
Vertebral artery thrombosis


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9.8
PREFERRED TERMS SELECTED FOR BLEEDING SUBCATEGORIES
This is list is based on MedDRA Version 21.0. Updates will be only maintained in BIRDS as 
specified in Section 7.8.1.4.
The following MedDRA Preferred Terms will be used to define bleeding subcategories: 
CNS:
Acute haemorrhagic leukoencephalitis
Basal ganglia haematoma
Basal ganglia haemorrhage
Basilar artery perforation
Brain contusion
Brain stem haematoma
Brain stem haemorrhage
Brain stem microhaemorrhage
Carotid aneurysm rupture
Carotid artery perforation
Central nervous system haemorrhage
Cephalhaematoma
Cerebellar haematoma
Cerebellar haemorrhage
Cerebellar microhaemorrhage
Cerebral aneurysm perforation
Cerebral aneurysm ruptured syphilitic
Cerebral arteriovenous malformation haemorrhagic
Cerebral artery perforation
Cerebral haematoma
Cerebral haemorrhage
Cerebral haemorrhage foetal
Cerebral haemorrhage neonatal
Cerebral microhaemorrhage
Encephalitis haemorrhagic
Epidural haemorrhage
Extra-axial haemorrhage
Extradural haematoma
Haemorrhage intracranial
Haemorrhagic cerebral infarction
Haemorrhagic stroke
Haemorrhagic transformation stroke
Intracerebral haematoma evacuation
Intracranial haematoma
Intracranial tumour haemorrhage
Intraventricular haemorrhage
Intraventricular haemorrhage neonatal


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Meningorrhagia
Periventricular haemorrhage neonatal
Pituitary haemorrhage
Putamen haemorrhage
Ruptured cerebral aneurysm
Spinal cord haematoma
Spinal cord haemorrhage
Spinal epidural haematoma
Spinal epidural haemorrhage
Spinal subarachnoid haemorrhage
Spinal subdural haematoma
Spinal subdural haemorrhage
Subarachnoid haematoma
Subarachnoid haemorrhage
Subarachnoid haemorrhage neonatal
Subdural haematoma
Subdural haematoma evacuation
Subdural haemorrhage
Subdural haemorrhage neonatal
Thalamus haemorrhage
Traumatic intracranial haematoma
Traumatic intracranial haemorrhage
Vertebral artery perforation
GI Lower:
Acute haemorrhagic ulcerative colitis
Anal fissure haemorrhage
Anal haemorrhage
Anal ulcer haemorrhage
Anorectal varices haemorrhage
Colonic haematoma
Diarrhoea haemorrhagic
Diverticulitis intestinal haemorrhagic
Diverticulum intestinal haemorrhagic
Enterocolitis haemorrhagic
Haematochezia
Haemorrhoidal haemorrhage
Intra-abdominal haematoma
Intra-abdominal haemorrhage
Large intestinal haemorrhage
Large intestinal ulcer haemorrhage
Lower gastrointestinal haemorrhage
Melaena
Melaena neonatal
Proctitis haemorrhagic


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Rectal haemorrhage
Rectal ulcer haemorrhage
GI Nonspecific:
Anastomotic haemorrhage
Anastomotic ulcer haemorrhage
Bloody peritoneal effluent
Cullen's sign
Gastrointestinal vascular malformation haemorrhagic
Grey Turner's sign
Haemorrhagic ascites
Haemorrhagic hepatic cyst
Hepatic haematoma
Hepatic haemorrhage
Intestinal haematoma
Intestinal haemorrhage
Intestinal varices haemorrhage
Mesenteric haematoma
Mesenteric haemorrhage
Mucosal haemorrhage
Neonatal gastrointestinal haemorrhage
Peritoneal haematoma
Peritoneal haemorrhage
GI Oral:
Angina bullosa haemorrhagica
Gingival bleeding
Mouth haemorrhage
Oral contusion
Oral mucosa haematoma
Pharyngeal haematoma
Pharyngeal haemorrhage
Stomatitis haemorrhagic
Tongue haematoma
Tongue haemorrhage
Tonsillar haemorrhage
Tooth pulp haemorrhage
Tooth socket haemorrhage
GI Upper:
Chronic gastrointestinal bleeding


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Duodenal ulcer haemorrhage
Duodenitis haemorrhagic
Gastric haemorrhage
Gastric ulcer haemorrhage
Gastric ulcer haemorrhage, obstructive
Gastric varices haemorrhage
Gastritis alcoholic haemorrhagic
Gastritis haemorrhagic
Gastroduodenal haemorrhage
Gastroduodenitis haemorrhagic
Gastrointestinal angiodysplasia haemorrhagic
Gastrointestinal haemorrhage
Gastrointestinal polyp haemorrhage
Gastrointestinal ulcer haemorrhage
Haematemesis
Haemorrhagic erosive gastritis
Haemorrhagic necrotic pancreatitis
Mallory-Weiss syndrome
Oesophageal haemorrhage
Oesophageal intramural haematoma
Oesophageal ulcer haemorrhage
Oesophageal varices haemorrhage
Oesophagitis haemorrhagic
Pancreatic haemorrhage
Pancreatitis haemorrhagic
Peptic ulcer haemorrhage
Small intestinal haemorrhage
Small intestinal ulcer haemorrhage
Ulcer haemorrhage
Upper gastrointestinal haemorrhage
Respiratory:
Bronchial haemorrhage
Bronchial varices haemorrhage
Epistaxis
Haemoptysis
Haemothorax
Laryngeal haematoma
Laryngeal haemorrhage
Nasal septum haematoma
Paranasal sinus haematoma
Paranasal sinus haemorrhage
Pulmonary alveolar haemorrhage
Pulmonary contusion
Pulmonary haematoma


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Pulmonary haemorrhage
Respiratory tract haemorrhage
Respiratory tract haemorrhage neonatal
Thoracic haemorrhage
Tracheal haemorrhage
Traumatic haemothorax
Skin:
Abdominal wall haematoma
Abdominal wall haemorrhage
Achenbach syndrome
Administration site bruise
Administration site haematoma
Administration site haemorrhage
Application site bruise
Application site haematoma
Application site haemorrhage
Application site purpura
Bleeding varicose vein
Blood blister
Breast haematoma
Chest wall haematoma
Chronic pigmented purpura
Contusion
Ecchymosis
Eyelid bleeding
Eyelid contusion
Eyelid haematoma
Haemorrhage subcutaneous
Haemorrhage subepidermal
Haemorrhagic urticaria
Henoch-Schonlein purpura
Immune thrombocytopenic purpura
Implant site bruising
Implant site haematoma
Implant site haemorrhage
Incision site haematoma
Incision site haemorrhage
Increased tendency to bruise
Infusion site bruising
Infusion site haematoma
Infusion site haemorrhage
Injection site bruising
Injection site haematoma
Injection site haemorrhage


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Instillation site bruise
Instillation site haematoma
Instillation site haemorrhage
Lip haematoma
Lip haemorrhage
Medical device site bruise
Medical device site haematoma
Medical device site haemorrhage
Mucocutaneous haemorrhage
Muscle contusion
Muscle haemorrhage
Naevus haemorrhage
Nail bed bleeding
Palpable purpura
Petechiae
Post procedural contusion
Post procedural haematoma
Post procedural haematuria
Post procedural haemorrhage
Post transfusion purpura
Post-traumatic punctate intraepidermal haemorrhage
Puncture site haemorrhage
Purpura
Purpura fulminans
Purpura neonatal
Purpura non-thrombocytopenic
Purpura senile
Skin haemorrhage
Skin neoplasm bleeding
Skin ulcer haemorrhage
Splinter haemorrhages
Subcutaneous haematoma
Thrombocytopenic purpura
Thrombotic thrombocytopenic purpura
Traumatic haematoma
Traumatic haemorrhage
Umbilical haematoma
Umbilical haemorrhage
Vaccination site bruising
Vaccination site haematoma
Vaccination site haemorrhage
Varicose vein ruptured
Vascular access site bruising
Vascular access site haematoma
Vascular access site haemorrhage
Vascular access site rupture


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Vascular graft haemorrhage
Vascular pseudoaneurysm ruptured
Vascular purpura
Vessel puncture site bruise
Vessel puncture site haematoma
Vessel puncture site haemorrhage
Wound haematoma
Wound haemorrhage
Urogenital:
Bladder tamponade
Blood urine
Blood urine present
Broad ligament haematoma
Cervix haematoma uterine
Cervix haemorrhage uterine
Coital bleeding
Cystitis haemorrhagic
Dysfunctional uterine bleeding
Genital contusion
Genital haemorrhage
Haematosalpinx
Haematospermia
Haematuria
Haematuria traumatic
Haemorrhage urinary tract
Haemorrhagic ovarian cyst
Intrapartum haemorrhage
Kidney contusion
Menometrorrhagia
Menorrhagia
Metrorrhagia
Nephritis haemorrhagic
Ovarian haematoma
Ovarian haemorrhage
Pelvic haematoma
Pelvic haematoma obstetric
Pelvic haemorrhage
Penile contusion
Penile haematoma
Penile haemorrhage
Perineal haematoma
Peripartum haemorrhage
Perirenal haematoma
Polymenorrhagia


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Post abortion haemorrhage
Postmenopausal haemorrhage
Postpartum haemorrhage
Premature separation of placenta
Prostatic haemorrhage
Renal artery perforation
Renal cyst haemorrhage
Renal haematoma
Renal haemorrhage
Retroplacental haematoma
Scrotal haematocoele
Scrotal haematoma
Spermatic cord haemorrhage
Subchorionic haematoma
Subchorionic haemorrhage
Testicular haemorrhage
Third stage postpartum haemorrhage
Ureteric haemorrhage
Urethral haemorrhage
Urinary bladder haemorrhage
Urogenital haemorrhage
Uterine haematoma
Uterine haemorrhage
Vaginal haematoma
Vaginal haemorrhage
Vulval haematoma
Vulval haematoma evacuation
Vulval haemorrhage
Other:
Abnormal withdrawal bleeding
Adrenal haematoma
Adrenal haemorrhage
Aneurysm ruptured
Aortic aneurysm rupture
Aortic dissection rupture
Aortic intramural haematoma
Aortic perforation
Aortic rupture
Aponeurosis contusion
Arterial haemorrhage
Arterial intramural haematoma
Arterial perforation
Arterial rupture
Arteriovenous fistula site haematoma


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Arteriovenous fistula site haemorrhage
Arteriovenous graft site haematoma
Arteriovenous graft site haemorrhage
Astringent therapy
Atrial rupture
Auricular haematoma
Bloody discharge
Bone contusion
Bone marrow haemorrhage
Breast haemorrhage
Bursal haematoma
Cardiac contusion
Catheter site bruise
Catheter site haematoma
Catheter site haemorrhage
Choroidal haematoma
Choroidal haemorrhage
Ciliary body haemorrhage
Conjunctival haemorrhage
Corneal bleeding
Deep dissecting haematoma
Disseminated intravascular coagulation
Ear haemorrhage
Exsanguination
Extravasation blood
Eye contusion
Eye haematoma
Eye haemorrhage
Femoral artery perforation
Femoral vein perforation
Foetal-maternal haemorrhage
Graft haemorrhage
Haemarthrosis
Haematocoele
Haematoma
Haematoma evacuation
Haematoma infection
Haematotympanum
Haemobilia
Haemophilic arthropathy
Haemophilic pseudotumour
Haemorrhage
Haemorrhage coronary artery
Haemorrhage foetal
Haemorrhage in pregnancy
Haemorrhage neonatal


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Haemorrhagic adrenal infarction
Haemorrhagic anaemia
Haemorrhagic arteriovenous malformation
Haemorrhagic breast cyst
Haemorrhagic cyst
Haemorrhagic diathesis
Haemorrhagic disease of newborn
Haemorrhagic disorder
Haemorrhagic infarction
Haemorrhagic thyroid cyst
Haemorrhagic tumour necrosis
Haemorrhagic vasculitis
Haemostasis
Hepatic haemangioma rupture
Hereditary haemorrhagic telangiectasia
Hyperfibrinolysis
Hyphaema
Iliac artery perforation
Iliac artery rupture
Iliac vein perforation
Induced abortion haemorrhage
Inferior vena cava perforation
Internal haemorrhage
Intraocular haematoma
Iris haemorrhage
Joint microhaemorrhage
Lacrimal haemorrhage
Liver contusion
Lower limb artery perforation
Lymph node haemorrhage
Mediastinal haematoma
Mediastinal haemorrhage
Myocardial haemorrhage
Myocardial rupture
Nipple exudate bloody
Ocular retrobulbar haemorrhage
Optic disc haemorrhage
Optic nerve sheath haemorrhage
Osteorrhagia
Papillary muscle haemorrhage
Parathyroid haemorrhage
Parotid gland haemorrhage
Pericardial haemorrhage
Periorbital haematoma
Periorbital haemorrhage
Periosteal haematoma


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Peripheral artery aneurysm rupture
Peripheral artery haematoma
Placenta praevia haemorrhage
Procedural haemorrhage
Radiation associated haemorrhage
Retinal aneurysm rupture
Retinal haemorrhage
Retinopathy haemorrhagic
Retroperitoneal haematoma
Retroperitoneal haemorrhage
Scleral haemorrhage
Shock haemorrhagic
Soft tissue haemorrhage
Spleen contusion
Splenic artery perforation
Splenic haematoma
Splenic haemorrhage
Splenic varices haemorrhage
Spontaneous haematoma
Spontaneous haemorrhage
Stoma site haemorrhage
Subclavian artery perforation
Subclavian vein perforation
Subgaleal haematoma
Subgaleal haemorrhage
Subretinal haematoma
Superior vena cava perforation
Thyroid haemorrhage
Tumour haemorrhage
Umbilical cord haemorrhage
Vascular rupture
Vein rupture
Venous haemorrhage
Venous perforation
Ventricle rupture
Vitreous haematoma
Vitreous haemorrhage
Withdrawal bleed


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
Final 
version
26-JUL-18
None
This is the final TSAP.