Clinical trial NCT03675581
Conditions: Scleroderma, Systemic
Sponsor: Boehringer Ingelheim
Start date: 2018-11-08; Completion date: 2019-10-10
Enrollment: 17 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The main objective is to assess the potential influence of continuous intake of nintedanib on the systemic exposure of ethinylestradiol and levonorgestrel when administered in combination.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Microgynon intervention 2: Nintedanib
Intervention descriptions: intervention 1: fixed sequence trial intervention 2: fixed sequence trial

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (15.0) / Saved on: 30 Nov 2017
Clinical Trial Protocol
TITLE PAGE
Document Number:
c21847264-03
EudraCT No.
2018-001177-24
BI Trial No.
1199-0340
BI Investigational
Medicinal Product(s)
Nintedanib
Title
A Phase I trial to investigate the effect of nintedanib on the 
pharmacokinetics of a combination of ethinylestradiol and 
levonorgestrel in female patients with Systemic Sclerosis
associated Interstitial Lung Disease (SSc-ILD)
Lay Title
A study to test whether nintedanib influences the components of 
birth-control pills in women with Systemic Sclerosis associated 
Interstitial Lung Disease (SSc-ILD)
Clinical Phase
I
Trial Clinical 
Monitor
Phone:
Fax:
E-mail:
Coordinating 
Investigator
Phone:
Fax: 
E-mail:
Status
Final Protocol (Revised Protocol (based on global 
amendment 2))
Version and Date
Version: 3.0
Date: 29 Apr 2019
Page 1 of 108
Proprietary confidential information.
! 2019 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
Company name
Boehringer Ingelheim 
Protocol date
06 July 2018
Revision date
29 Apr 2019
BI trial number
1199-0340
Title of trial
A Phase I trial to investigate the effect of nintedanib on the 
pharmacokinetics of a combination of ethinylestradiol and 
levonorgestrel in female patients with Systemic Sclerosis associated 
Interstitial Lung Disease (SSc-ILD)
Coordinating 
Investigator
Trial site(s)
Multi-centre trial conducted in approximately 6 countries
Clinical phase
I
Trial rationale
Nintedanib is a potential human teratogen, which is intended for use 
in fertile women. In accordance to the European Medicines Agency 
(EMA) guideline on the investigation of drug interactions, this trial 
will investigate the in vivo effect of nintedanib on contraceptive 
steroids.
Trial objective(s)
To investigate the effect of multiple oral doses of nintedanib on the 
single dose kinetics of a combination of ethinylestradiol and 
levonorgestrel (Microgynon®)
Trial endpoints
Primary endpoints: 
∀
AUC0-tz and Cmax for ethinylestradiol and levonorgestrel
Secondary endpoints: 
∀
AUC0-# for ethinylestradiol and levonorgestrel
Trial design
Open-label, two-period, fixed sequence
Total number of patients
enrolled
Approximately 24 patients
Total number of patients
on treatment
14 patients who have completed the trial and are evaluable for both 
treatment periods
Diagnosis
Patients with Systemic Sclerosis associated Interstitial Lung Disease
(SSc-ILD)
Main inclusion criteria
Women ≥ 18 years, permanently sterilised or postmenopausal or 
using a highly effective non-hormonal method of birth control (i.e. 
intra-uterine device (IUD), bilateral tubal ligation) in combination 
with a barrier methods; Systemic Sclerosis associated Interstitial 
Lung Disease (SSc-ILD), fulfilling the 2013 ACR / EULAR 
classification criteria for SSc; extent of fibrotic lung disease ≥10% on 
high resolution computed tomography (HRCT); Forced Vital 
Capacity (FVC) ≥40% of predicted; carbon monoxide diffusion 
capacity of the lungs (DLCO) 30% to 89% predicted (corrected for 
Hb).


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Main exclusion criteria
Abnormal liver (alanine transaminase (ALT), asapartate transaminase 
(AST) and bilirubin > 1.5x upper level of normal (ULN)) and renal 
(creatinine clearance < 30 mL/min) parameters; significant 
pulmonary hypertension; cardiovascular disease within 6 months of 
Visit 1 (hypertension (≥160/100 mmHg); myocardial infarction, 
unstable angina pectoris); high bleeding risk; history of major 
thrombotic event within 12 months of Visit 1, concomitant use of P-
glycoprotein (P-gp)-, cytochrome P450 3A4 (CYP3A4) inhibitors or 
inducers medications, certain immunosuppressive agents.
Reference product
Microgynon® tablet
dose
One tablet containing 30 microgram ethinylestradiol (EE) and 150 
microgram levonorgestrel (LE) per tablet in each trial period
method and route of 
administration
Oral with 240 mL of water
Test product
Nintedanib soft gelatine capsule (containing 150 mg or 100 mg 
nintedanib) 
dose
150 mg b.i.d (300 mg daily) with possibility to interrupt and/ or
reduce to 100 mg b.i.d (200 mg daily) to manage adverse events 
(AE), if required
method and route of
administration
Oral with food and 240 mL of water
Duration of treatment
Period 1: 
∀
1 tablet of Microgynon® will be administered on the first 
pharmacokinetics (PK) profile day, after a standardised 
breakfast, at least 3 days before the first administration of 
nintedanib.
Period 2: 
∀
Nintedanib (150 mg b.i.d.) will be administered at Day 1. 
Nintedanib treatment will be continued for at least 14 days to 
approximately 28 days in this trial, depending on scheduling of 
the PK day, or nintedanib dose interruptions or dose reduction.
∀
After continuous intake of a stable dose of nintedanib for at least 
10 consecutive days, the PK day will be planned.
∀
On the PK-profile day, 1 tablet of Microgynon® will be given 
immediately after the morning dose of nintedanib, after a 
standardised breakfast. The evening dose of nintedanib will be 
administered approximately 12 hours after the morning dose of 
nintedanib.
∀
The PK-profile day should be followed by continuous intake of 
nintedanib for at least 2 further days.
Statistical methods
Relative exposure of ethinylestradiol and levonorgestrel will be 
estimated based on the ratios (test to reference treatment) of the 
geometric means (gMeans) of the primary and secondary endpoints. 
Additionally, their 2-sided 90% confidence intervals (CIs) will be 


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provided. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale, including effects for 'subject' and 
'treatment'. CIs will be calculated based on the residual error from 
ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Trial Periods
Screenin
g
Visit
*
Period 1
*
Period 2
**
End of 
Treat.
#
Follow 
Up
##
End of 
Study
#
Visit
1
2
*
3
4
5
5A

6
***
7
8
EOT
FU
EOS
Day
-14
-3
-2
-1
1
10
11
12
13
14
EOT+7
14 or
EOT+7
Time window (±Days)
±7
V2
+1
V2
+2
V6
-1
+14
V6
+1
V6
+2
V6
+3
+2
+2
Informed consent1
x
Demographics
x
Medical history
(SSc related2 and other 
baseline conditions)
x
Physical examination
and vital signs
x
x
x
x
x
In-/Exclusion criteria
x
x
HRCT3
x
Spirometry4
x
x
DLCO4
x
Echocardiogram5
x
mRSS assessment
x
Digital ulcer assessment
x
Questionnaires6: SGRQ, 
SHAQ, SCTC GIT, 
patient and physician 
global VAS
x
Laboratory tests
x
x
x7
x
x
x
Pregnancy test11
x
x
x
x
12-lead ECG
x
x
x
x
PK diary: instruction, 
handout and review
x
x
x
x
x
PK sampling pre-dose 
for nintedanib (trough)8
x
x
x
Dispense nintedanib + 
continuous (b.i.d.) intake 
of nintedanib
x
x
x9
x
x
PK sampling pre-dose 
Microgynon®
x
x
Standardized meal 
before Microgynon®
intake
x
x
Administration of 
Microgynon® 
x
x9
PK Sampling, after 
Microgynon® intake10
x
x
x
x
x
x
All AEs/SAEs/
AESIs
x
x
x
x
x
x
x
x
x
x
x
Compliance check 
x
x
x
x
x
x
x
Concomitant therapy
x
x
x
x
x
x
x
x
x
x
x
Completion of patient 
participation 
x


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Footnotes:
*
Screening Visit 1 may take place within Day -21 to Day -7, or earlier, depending on required washout of restricted 
medications prior to the 1st Microgynon® intake at Visit 2 (see Section 4.2.2.1)
Period 1/Visit 2: The 1st Microgynon® intake and start of pharmacokinetics (PK) profiling during Period 1 must take 
place at least 3 days (72 hours) prior to first intake of nintedanib (Visit 5/Day 1); results of Screening Visit 1 
examinations need to be awaited prior to proceeding with Period 1. In case of clinically significant electrocardiogram 
(ECG) or laboratory abnormalities at Visit 1, these examinations have to be repeated at an unscheduled Visit prior to 
Visit 2 in order to assess if the patient is still eligible and safe to continue the trial. 
**
Period 2 starts with Visit 5/Day 1 when the patient begins with the daily intake of nintedanib. During Period 2, the
nintedanib intake compliance will be checked with a Telephone Call one day prior to plan PK Visit 6. 
***
Visit 6 will take place at Day 11, but may be scheduled until Day 25 (a visit window of +14 days is allowed) and will
only be conducted when the patient has had at least 10 days of continuous nintedanib intake (b.i.d) at stable dose. If the 
patient is not able to continuously take nintedanib (150 mg b.i.d.) for at least 10 days* then Visit 6 (and the 2nd
Microgynon® administration and PK assessments) must be postponed until at least 10 days of continuous nintedanib on 
stable dose was taken by the patient (* e.g. in case of a temporary interruption or nintedanib dose reduction, 
additional bottles of nintedanib may have to be dispensed atVisit 6, or at an Unscheduled Visit and the V5-V6 visit 
window can be prolonged accordingly). The next Visits must be scheduled accordingly.
#
For patients that fully complete the trial and continue in the roll-on trial 1199-0225 (SENSCIS-ON), the End of 
Treatment (EOT) Visit and End of Study (EOS) Visit can be done simultaneously and must be done at the earliest 
3 days after last intake of Microgynon®. For patients that prematurely and permanently discontinue the Microgynon®
and/or nintedanib treatment in Periods 1 or 2, or patients that will not continue in the roll-on trial 1199-0225, the EOT
Visit must be done as soon as possible after stop of treatment, and a Follow-Up (FU) Visit must be scheduled 7 days 
(±2 days window) after last nintedanib intake.
##
The FU Visit must be done 7days ±2 days window) after last nintedanib intake, but only in the following cases: (a) 
If trial medication will be discontinued permanently due to adverse events, or (b) if the patient will not continue in the 
roll-over Trial 1199.225. No FU Visit will be doneif the patient is directly being rolled over into Trial 1199.225. For 
the patients (a) and (b) the FU Visit will be done simultaneously with the EOS Visit.
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. 
2
SSc related Medical History includes onset date of Raynaud symptom, onset of first non-Raynaud symptom, SSc 
subtypes, and check list of symptoms present at screening, e.g. digital ulcers, gastrointestinal and urinary symptoms, 
cardiovascular and pulmonary symptoms.
3
SSc related Interstitial Lung Disease pattern must be confirmed by by high resolution computed tomography (HRCT) 
of the lung performed within 12 months of Visit 1. If the patient does not have a HRCT within 12 month s of Visit 1, 
but meet all the other inclusion and no exclusion citeria , the HRCT scan can be performed for the purpose of 
participation in the trial, if accepted by local regulations (except for patients in Germany). The extent of fibrotic 
disease in the lung must be ≥10% on HRCT, assessed by local review.
4
Forced vital capacity (FVC) ≥40% of predicted normal at Visit 1. Lung function measurements at Visit 1 and at EOT
must be done at the approx. the same time ± 90 min. At screening visit 1, spirometry should be done prior to carbon 
monoxide diffusion capacity of the lungs (DLCO) and the patient should rest in between.
5
Echocardiography will at least be performed in patients with a history of pulmonary hypertension at Screening (time 
window: Visit 1 to Visit 2).
6
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. SHAQ, 3. SCTC GIT, 4. Patient’s global VAS (see Appendix 10.3). 
The SCTC GIT will only be done in countries if the locally required language version is available. 
7
Laboratory safety test at Visit 5, Day 1 should be done prior to intake of nintedanib in order to get baseline laboratory 
values without Microgynon® (past the Microgynon® residual effect period (REP) of 3 days) or nintedanib related 
effects.
8
PK sampling before intake of nintedanib in Period 2 (Visits 6-8) will be done as described in the PK overview on the 
following pages, which also contains detailed information about other assessments and timing of intake of meals and 
water.
9
In Period 2/Visit 6 Nintedanib will be administered first directly followed by Microgynon® and both have to be intaken 
within 1 minute on the PK day.


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10
Detailed information about timing and assesments during PK days in Periods 1 and 2 can be found in the overviews on 
the following pages. PK sampling after Microgynon® intake will be done at approximate timepoints t = +30 min to +12
h (9 times), at t = +24 h and t = +48 h. During PK day in Periods 1 and 2, at t = 20 h and 4 h, administration of 240 mL 
of water.
11
Pregnancy testing will only be done in women of childbearing potential: ß-HCG will be performed at Visit 1 only. 
Urine dipstick pregnancy tests will be performed at Visits 5 and EOT and FU visit if applicable. If urine test is not 
acceptable to local authorities, a blood test can be also done by local laboratory if needed. 


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Detailed overview and order of assessments on PK days in Period 1:
Period 1, Visits 2-4
Day
Relative. 
time to 
Microgynon®
intake
[h:min]
Approx. 
Clock 
Time*
[h:min]
Assessment/comment
PK blood for 
EE and LE
Visit 2, 
Day -3
Pre-dose
Physical examination
Pre-dose
Review in/exclusion criteria
Pre-dose
Vital signs
Pre-dose
12-lead ECG
Pre-dose
Safety Laboratory tests
(preferably after ECG)
Pre-dose
Adverse events
Pre-dose
Concomitant therapy
Pre-dose
Compliance check
-00:35
07:25
x
-00:30
07:30
Breakfast (standardized)**
00:00
08:00
Microgynon® intake*
00:30
08:30
x
01:00
09:00
x
01:30
09:30
x
02:00
10:00
240 mL water
x
03:00
11:00
x
04:00 
12:00
240 mL water + lunch
x
06:00
14:00
x
08:00
16:00
x
10:00
18:00
Snack
11:55
19:55
AE
x
Visit 3, 
Day -2
23:55
07:55
AE, CT, Compliance
x
Visit 4, 
Day -1
47:55
07:55
AE, CT, Compliance
x
Note:* The exact clock time of intake of Microgynon® and blood sampling must be recorded during the PK
profiling days in this Period; ** Standardized, i.e. the same breakfast in Period 1 and Period 2 for an individual 
patient.


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Detailed overview and order of assessments on PK Visit days in Period 2:
Period 2, Visits 6 - 8
Day
Relative 
time to 
Microgynon 
intake
[h:min]
Approx. 
Clock 
Time*
[h:min]
Assessment/comment
PK blood 
for
EE and LE
PK blood 
for 
nintedanib
Visit 6, 
Day 11
Pre-dose
Physical examination
Pre-dose
Vital signs
Pre-dose
Safety Laboratory tests
Pre-dose
Adverse events
Pre-dose
Concomitant therapy
Pre-dose
Compliance check
-00:35
07:25
x
x
-00:30
07:30
Breakfast (standardized)**
00:00
08:00
Microgynon® intake immediately 
after Nintedanib intake*
(both to be taken within 1 minute)
00:30
08:30
x
01:00
09:00
x
01:30
09:30
x
02:00
10:00
240 mL water
x
03:00
11:00
x
04:00 
12:00
240 mL water + lunch
x
06:00
14:00
x
08:00
16:00
x
10:00
18:00
Snack
11:55
19:55
AE
x
12:00
20:00
Nintedanib intake*
Visit 7, 
Day 12
23:55
07:55
AE, CT, Compliance
x
x
24:00
08:00
Nintedanib intake*
Visit 8, 
Day 13
47:55
07:55
AE, CT, Compliance
x
x
48:00
08:00
Nintedanib intake*
Note:* The exact clock time of intake of trial medication must be recorded in the 3 days prior to and during the 
PK profiling days in Period 2. And also the exact clock time of all blood samples during the PK profiling days 
in Period 2 must be recorded; ** Standardized, i.e. the same breakfast in Period 1 and Period 2 for an individual 
patient.


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................19
1.1
MEDICAL BACKGROUND.............................................................................19
1.2
DRUG PROFILE................................................................................................20
1.2.1
Nintedanib............................................................................................................20
1.2.2
Ethinylestradiol...................................................................................................24
1.2.3
Levonorgestrel.....................................................................................................25
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................26
1.4
BENEFIT - RISK ASSESSMENT.....................................................................26
1.4.1
Nintedanib............................................................................................................26
1.4.2
Microgynon..........................................................................................................28
1.4.3
Potential interaction between nintedanib and Microgynon............................29
1.4.4
Drug induced liver injury...................................................................................29
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................30
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........30
2.1.1
Main objectives....................................................................................................30
2.1.2
Primary endpoints...............................................................................................30
2.1.3
Secondary endpoint.............................................................................................30
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................31
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................32
3.3
SELECTION OF TRIAL POPULATION .......................................................32
3.3.1
Main diagnosis for trial entry ............................................................................33
3.3.2
Inclusion criteria .................................................................................................33
3.3.3
Exclusion criteria ................................................................................................34
3.3.4
Withdrawal of patients from treatment or assessments..................................36
3.3.4.1
Discontinuation of trial treatment .........................................................................37
3.3.4.2
Recommendation to discontinue nintedanib.........................................................37
3.3.4.3
Withdrawal of consent to trial participation .........................................................38
3.3.4.4
Discontinuation of the trial by the sponsor...........................................................39
4.
TREATMENTS...................................................................................................40


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4.1
INVESTIGATIONAL TREATMENTS ...........................................................40
4.1.1
Identity of the Investigational Medicinal Products..........................................40
4.1.2
Selection of doses in the trial and dose modifications......................................40
4.1.3
Method of assigning patients to treatment groups...........................................41
4.1.4
Drug assignment and administration of doses for each patient......................41
4.1.5
Blinding and procedures for unblinding...........................................................42
4.1.5.1
Blinding.................................................................................................................42
4.1.5.2
Unblinding and breaking the code ........................................................................42
4.1.6
Packaging, labelling, and re-supply...................................................................42
4.1.7
Storage conditions...............................................................................................43
4.1.8
Drug accountability.............................................................................................43
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................44
4.2.1
Other treatments and emergency procedures..................................................44
4.2.1.1
Management of diarrhoea .....................................................................................44
4.2.1.2
Management of liver enzyme elevation................................................................46
4.2.2
Restrictions ..........................................................................................................47
4.2.2.1
Restrictions regarding concomitant treatment ......................................................47
4.2.2.2
Cautionary notes ...................................................................................................50
4.2.2.3
Restrictions on diet and life style..........................................................................50
4.2.2.4
Contraception requirements..................................................................................50
4.3
TREATMENT COMPLIANCE........................................................................51
5.
ASSESSMENTS..................................................................................................52
5.1
ASSESSMENT OF EFFICACY........................................................................52
5.2
ASSESSMENT OF SAFETY.............................................................................52
5.2.1
Physical examination ..........................................................................................52
5.2.2
Vital signs.............................................................................................................52
5.2.3
Assessment of Lung Function (Spirometry).....................................................52
5.2.4
Assessment of DLCO ..........................................................................................53
5.2.5
HRCT...................................................................................................................53
5.2.6
Safety laboratory parameters ............................................................................53
5.2.7
Electrocardiogram ..............................................................................................55
5.2.8
Echocardiography...............................................................................................55
5.2.9
Other safety parameters.....................................................................................56
5.2.10
Assessment of adverse events.............................................................................56
5.2.10.1
Definitions of AEs ................................................................................................56
5.2.10.1.1 Adverse event........................................................................................................56
5.2.10.1.2 Serious adverse event............................................................................................56
5.2.10.1.3 AEs considered “Always Serious”........................................................................57
5.2.10.1.4 Adverse events of special interest (AESI) ............................................................57
5.2.10.1.5 Intensity (severity) of AEs....................................................................................58
5.2.10.1.6 Causal relationship of AEs....................................................................................58
5.2.10.2
Adverse event collection and reporting ................................................................59
5.2.10.2.1 AE Collection........................................................................................................59
5.2.10.2.2 AE reporting to the sponsor and timelines............................................................60
5.2.10.2.3 Information required .............................................................................................60


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5.2.10.2.4 Pregnancy..............................................................................................................60
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................60
5.3.1
Assessment of pharmacokinetics .......................................................................60
5.3.2
Methods of sample collection .............................................................................61
5.3.3
Analytical determinations ..................................................................................61
5.3.4
Pharmacokinetic – pharmacodynamic relationship........................................61
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................61
5.5
BIOBANKING ....................................................................................................61
5.6
OTHER ASSESSMENTS...................................................................................61
5.6.1
Assessment of mRSS...........................................................................................61
5.6.2
Assessment of Digital Ulcers ..............................................................................62
5.6.3
Assessment of questionnaires and derived outcomes.......................................62
5.6.3.1
Saint George’s Respiratory Questionnaire (SGRQ) .............................................62
5.6.3.2
Scleroderma Health Assessment Questionnaire (SHAQ).....................................63
5.6.3.3
Scleroderma Gastrointestinal Tract Instrument SCTC GIT 2.0............................63
5.6.3.4
Patient’s and physician’s global impression of health..........................................63
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................64
6.
INVESTIGATIONAL PLAN.............................................................................65
6.1
VISIT SCHEDULE.............................................................................................65
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................65
6.2.1
Screening period..................................................................................................65
6.2.2
Treatment period(s)............................................................................................65
6.2.3
Trial completion ..................................................................................................66
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................68
7.1
STATISTICAL DESIGN - MODEL.................................................................68
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................68
7.3
PLANNED ANALYSES.....................................................................................68
7.3.1
Primary endpoint analyses.................................................................................69
7.3.2
Secondary endpoint analyses .............................................................................70
7.3.4
Safety analyses.....................................................................................................70
7.3.5
Pharmacokinetic and pharmacodynamic analyses..........................................71
7.4
INTERIM ANALYSES ......................................................................................71
7.5
HANDLING OF MISSING DATA ...................................................................72
7.5.1
Safety....................................................................................................................72
7.5.2
Plasma concentration - time profiles.................................................................72
7.5.3
Pharmacokinetic parameters.............................................................................72
7.6
RANDOMISATION ...........................................................................................72
7.7
DETERMINATION OF SAMPLE SIZE .........................................................72
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........75
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................75


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8.2
DATA QUALITY ASSURANCE ......................................................................76
8.3
RECORDS...........................................................................................................76
8.3.1
Source documents ...............................................................................................76
8.3.2
Direct access to source data and documents.....................................................77
8.3.3
Storage period of records ...................................................................................77
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................78
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........78
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................78
8.6
TRIAL MILESTONES.......................................................................................78
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................79
9.
REFERENCES....................................................................................................81
9.1
PUBLISHED REFERENCES............................................................................81
9.2
UNPUBLISHED REFERENCES......................................................................84
10.
APPENDICES.....................................................................................................86
10.1
LUNG FUNCTION CRITERIA........................................................................86
10.2
CREATININE CLEARANCE...........................................................................86
10.3
QUESTIONNAIRES ..........................................................................................87
10.3.1
St. George’s Respiratory Questionnaire (SGRQ)............................................87
10.3.2
Scleroderma Health Assessment Questionnaire (SHAQ)................................93
10.3.3
Scleroderma Gastrointestinal Tract Instrument SCTC GIT 2.0 ...................96
10.3.4
Patients Global Impression of health ..............................................................101
10.3.5
Physician’s Global Impression of patients’s health .......................................102
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .......................................103
11.1
GLOBAL AMENDMENT 1 ............................................................................103
11.2
GLOBAL AMENDMENT 2 ............................................................................108


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ABBREVIATIONS
ACE
Angiotensin-Converting-Enzyme 
ACR
American College of Rheumatology
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original and Accurate
ALK
Alkaline Phosphatase
ALT
Alanine Transaminase (also called Alanine Aminotransferase, ALAT)
ANOVA
Analysis of Variance
AST
Aspartate Transaminase (also called Aspartate Aminotransferase, ASAT)
ATS
American Thoracic Society
AUC0-∞, 
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the time 
interval (from 0 extrapolated to infinity, or 0 to the last quantifiable data point)
b.i.d.
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BLQ
Below Limit of Quantification
BNP
Brain Natriuretic Peptide
CA
Competent Authority
CI
Confidence Interval
CK
Creatine Kinase
CL
Confidence Limit
Cmax
Maximum measured concentration of the analyte in plasma
CML
Clinical Monitor Local (changes to Clinical Trial Manager in 2018)
CNS
Central Nervous System
Cpre,ss
Pre-dose (trough) plasma level concentration (of nintedanib) at steady state
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organization
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTL
Clinical Trial Leader (former TCM)


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CTM
Clinical Trial Manager (former CML)
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP3A4
Cytochrome P450 3A4
DDI
Drug-Drug Interaction
DILI
Drug Induced Liver Injury
dL
Deciliter
DLCO
Carbon Monoxide Diffusion Capacity
DU
Digital Ulcer
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC, EDC
Electronic Data Capture
EDTA
Ethylene-Diamine-Tetraacetic Acid
EE
Ethinylestradiol
e.g.
Example given
EMA
European Medicines Agency
EOS
End of Study
EOT
End of Treatment
ERS
European Respiratory Society
ES
Entered Set
EU
European Union
EudraCT
European Clinical Trials Database
EULAR
European League against Rheumatism
FDA
Food and Drug Administration
FEV1
Forced Expiratory Volume in 1 second
FGFR
Fibroblast Growth Factor Receptor
FSH
Follicle Stimulating Hormone
FU
Follow Up
FVC
Forced Vital Capacity
GAVE
Gastric Antral Vascular Ectasia
GCP
Good Clinical Practice
gCV
intra-individual Coefficient of Variation


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GGT
Gamma-Glutamyl Transferase
GI
Gastro-Intestinal
GLI
Global Lung Initiative
GMP
Good Manufacturing Practice
h
Hour
HA
Health Authority
HAQ-DI
Health Assessment Questionnaire Disability Index
Hb
Haemoglobin
Hct
Haematocrit
HPLC
High Performance Liquid Chromatography
HRCT
High Resolution Computer Tomography
HSCT
Hematopoietic Stem Cell Transplantation
IB
Investigator’s Brochure
IC(F)
Informed Consent (Form)
ICH
International Council (or Conference) on Harmonization
i.e.
Id est (this is)
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product
INR
International Normalized Ratio
IPD
Important Protocol Deviation
IPF
Idiopathic Pulmonary Fibrosis
IQRMP
Integrated Quality and Risk Management Plan
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IU
International Unit
IV
intravenous
kg
Kilogram
kPA
Kilopascal
LC-MS/MS Liquid Chromatography-tandem Mass Spectrometry
LDH
Lactate Dehydrogenase


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LE
Levonorgestrel
LPLT
Last Patient Last Treatment
MedDRA
Medical Dictionary for Drug Regulatory Activities
μg
Microgram
mg
Milligram
min
Minute
mL
Milliliter
mm
Millimeter
mmHg
Millimetres of mercury
mmol
Millimolar
MRHD
Maximum Recommended Human Dose
mRSS
modified Rodnan Skin Score
N
Number (of patients)
ng
Nanogram
NC
Not calculated
NOA
Not analysed
NOR
No valid result
NOS
No sample
nRTK
Non-Receptor Tyrosine Kinase
OPU
Operative Unit
PDGFR
Platelet-Derived Growth Factor Receptor
P-gp
P-glycoprotein
pH
Negative log of hydrogen ion concentration in a water-based solution
(‘potential of Hydrogen’), or acidity scale.
PH
Pulmonary Hypertension
PAH
Pulmonary Arterial Hypertension
PK
Pharmacokinetics
PKS
PK parameter analysis Set
PRO
Patient Reported Outcome
PT
Prothrombin Time
PTT
Partial Thromboplastin Time
PXR
Pregnane X Receptor
R
Reference drug (Microgynon®)


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RA
Regulatory Authority
RBC
Red Blood Cell count
REP
Residual Effect Period
RTK
Receptor Tyrosine Kinase
s.c.
subcutaneous
SAE
Serious Adverse Event
SCTC GIT
Scleroderma Gastrointestinal Tract Instrument
SGRQ
Saint George’s Respiratory Questionnaire
SHAG
Scleroderma Health Assessment Questionnaire
SmPC
Summary of Product Characteristics
SOP
Standard Operating Procedure
Src
Rous sarcoma viral oncogene (Src, Lck and Lyn all belonging to a family of 
proto-oncogene tyrosine-protein kinases).
SSc
Systemic Sclerosis
SUSAR
Suspected Unexpected Serious Adverse Reactions
T
Test drug (nintedanib)
T/R
Test/Reference
t1/2
Half Life Time
TCM
Trial Clinical Monitor (changed to Clinical Trial Leader in 2018)
tmax
Timepoint of Maximum Plasma Concentration
TMF
Trial Master File
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSH
Thyroid Stimulating Hormone
tz
Timepoint of the last quantifiable Plasma Concentration
UGT1A1
uridine glucuronosyltransferase 1A1
ULN
Upper Level of Normal
US
United States
VAS
Visual Analog Scale
VEGFR
Vascular Endothelial Growth Factor Receptor
WHO
World Health Organization
WO(N)CBP Woman of (Non) Childbearing Potential


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1.
INTRODUCTION
Nintedanib has been approved by the European Commission for the treatment of Idiopathic 
Pulmonay Fibrosis (IPF) in adult patients in January 2015. It is currently being investigated 
for the treatment of Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD) and 
patients with other progressive fibrosing ILDs.
In the current Summary of Product Characteristics (SmPC), women of childbearing potential 
(WOCBP) and eligible to treatment with nintedanib must use an effective contraceptive 
method as nintedanib may cause foetal harm in humans due to its mechanism of action. In 
addition, it is stated that the effect of nintedanib on the metabolism and efficacy of 
contraceptives has not been investigated. Thus, barrier methods should be applied as a second 
contraception method, to avoid pregnancy.
Considering the teratogenic potential of nintedanib, the combination of nintedanib and oral 
contraceptives containing ethinylestradiol (EE) and levonorgestrel (LE) may be widely used 
in a real world setting as part of the routine clinical practice. The concomitant administration 
of both nintedanib and an oral contraceptive must be safe and effective. This study will 
investigate the potential drug interaction of nintedanib on the oral contraceptive Microgynon®
(ethinylestradiol + levonorgestrel) as requested by the European Medicines Agency (EMA).
1.1
MEDICAL BACKGROUND
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 European League Against Rheumatism (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)


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(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.
A randomized double-blind phase III trial, SENSCIS® (1199.214), investigating the safety 
and efficacy of nintedanib in Systemic Sclerosis associated Interstitial Lung Disease has been 
completed and has had database lock in December 2018 and the analysis results are planned 
to be reported in the second quarter of 2019.  An independent Data Monitoring Board (DMC)
has reviewed the safety data of this phase III trial on an ongoing basis throughout the trial 
conduct and has recommended that the phase III trial 1199.214 could proceed to its end as 
planned. Furthermore, an open-label extension trial SENSCIS-ON 1199.225, for the patients 
who completed the parent trial SENSCIS® (1199.214),  has been initiated in November 2017. 
The protocol of the open-label extension trial 1199.225 has been amended and will also be 
available for patients who complete the phase I DDI trial 1199-0340 (see also Section 1.4.1).
1.2
DRUG PROFILE
1.2.1
Nintedanib
Mode of action
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, 


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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
Absorption, bioavailability, distribution, metabolism, and excretion
After administration as a soft gelatine capsule, nintedanib is absorbed quickly. 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 predominantly eliminated via metabolism and biliary/faecal excretion (about 
94%). Renal excretion is a minor elimination pathway, both after intravenous and oral 
administration.
Drug interactions
Based on in vitro investigations, relevant interactions of nintedanib with other drugs via the 
CYP enzyme system or via glucuronidation reactions are not expected. Transporter profiling 
was performed for nintedanib and its 2 main metabolites. In general, any interactions with 
transporter substrates were considered unlikely. Nintedanib is a P-gp substrate.
Co-administration of nintedanib with the P-glycoprotein (P-gp) inhibitor ketoconazole 
increased exposure to nintedanib by 60-70% based on area under the curve (AUC) and by 
80% based on a maximum measured concentration of the analyte in plasma (Cmax) in a drug-
drug interaction (DDI) trial (1199.161, (c01762736)). Thus, if administered concomitantly 
with nintedanib, potent P-gp inhibitors (e.g. ketoconazole, erythromycin) may increase 
nintedanib exposure.
In a DDI trial with the P-gp inducer rifampicin (1199.162, U13-1478 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. Thus, potent P-gp inducers (e.g. 
rifampicin, carbamazepine, phenytoin, St. John’s Wort) may decrease the exposure to 
nintedanib.
Based on results from a DDI study (1199.229, c09712613), there was no clinically relevant 
pharmacokinetics (PK) interaction between nintedanib and pirfenidone when co-administered 
in patients with IPF. 
In a DDI study in healthy volunteers (1199.239, c09412738), there was no clinically relevant 
PK effect of steady state treatment with bosentan (an endothelin I antagonist) on nintedanib 
exposure.


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Additional data on the PK of nintedanib in patients with hepatic impairment are available 
from a single dose trial in otherwise healthy patient volunteers with hepatic impairment 
(Child Pugh categories A and B) plus matched healthy controls. Exposure in Study 1199.200 
increased by approximately 2-fold in patients with mild liver impairment defined as Child 
Pugh category A, and by approximately 8-fold in patients with moderate liver impairment 
defined as Child Pugh category B (c03149997). Thus, a lower dose of nintedanib is to be 
used for treatment of patients with mild liver impairment and treatment of patients with 
moderate or severe hepatic impairment is not recommended.
Nintedanib does not induce CYP enzymes in vitro nor in rats in vivo (U09-1731, U04-2195). 
Therefore, the likelihood of nintedanib causing a relevant pharmacokinetic drug-drug 
interaction on oral contraceptives by induction of their metabolism that would lead to a loss 
of the pharmacodynamic action of these drugs is considered to be very low. Due to 
teratogenic potential of nintedanib the EMA DDI guidance from 2012 nevertheless requires
to perform a clinical study to investigate the potential effect of nintedanib on the PK of oral 
contraceptives.
Residual Effect Period
The Residual Effect Period (REP) of nintedanib is 7 days
The Residual Effect Period (REP) of Microgynon® is 3 days.
The REP is the period after the last dose with measurable drug levels and/or 
pharmacodynamic effects still likely to be present.
Data from non-clinical and toxicology studies
In rats, embryo-foetal lethality and teratogenic effects were observed at exposure levels 
below human exposure at the Maximum Recommended Human Dose (MRHD) of 150 mg 
twice daily. Effects on the development of the axial skeleton and on the development of the 
great arteries were also noted at subtherapeutic exposure levels.
In rabbits, embryo-foetal lethality and teratogenic effects were observed at an exposure 
approximately 3 times higher than at the MRHD but equivocal effects on the embryo-foetal 
development of the axial skeleton and the heart were noted already at an exposure below that 
at the MRHD of 150 mg twice daily.
In a pre- and postnatal development study in rats, effects on pre- and post-natal development 
were seen at an exposure below the MRHD.
A study of male fertility and early embryonic development up to implantation in rats did not 
reveal effects on the male reproductive tract and male fertility.
In rats, small amounts of radiolabelled nintedanib and/or its metabolites were excreted into 
the milk (≤ 0.5% of the administered dose).
Data from clinical studies
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 


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in 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 b.i.d. 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 b.i.d. 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 (diarrhoea, nausea, vomiting, abdominal pain, and pancreatitis) and to 
hepatic injury including drug- induced liver injury (DILI) or increases in liver enzymes 
(aspartate transaminase [AST], alanine transaminase [ALT], alkaline phosphatase [ALK], 
gamma-glutamyl transferase [GGT] and bilirubin). 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. Nintedanib must be 
dose-reduced, or interrupted in the event of hepatic toxicity and further treatment withheld 
until recovery of the abnormal laboratory parameters.
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 gastro-intestinal 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 hypertension have also been associated with nintedanib treatment.
Risks of nintedanib treatment also include bleeding, thrombocytopenia, gastrointestinal 
perforation (some of which were fatal) and thromboembolism. The most frequently reported 
bleeding was epistaxis. 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 


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ischemic heart disease, which includes terms such as coronary artery disease, angina pectoris, 
coronary angioplasty, coronary artery stenosis, myocardial ischemia, coronary artery stent 
insertion, electrocardiogram (ECG) ST segment depression. The clinical significance of this 
finding is unknown, and further observation is needed.
Further risks of nintedanib treatment include rash and pruritus.
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 administering nintedanib in patients who may develop QT prolongation.
For patients completing 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 the open-label extension trials has confirmed the safety profile observed in 
the Phase II and III trials (P17-11211 and P18-08712).
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.
Contraindications
Nintedanib is contraindicated in patients with known hypersensitivity to nintedanib, peanut or 
soya, or to any of the excipients in the nintedanib medication. Nintedanib is contraindicated 
during pregnancy.
For a more detailed description of the nintedanib profile in SSc, please refer to the current 
Investigator’s Brochure (IB) ‘Nintedanib in Idiopathic Pulmonary Fibrosis, Systemic 
Sclerosis, Progressive Fibrosing Interstitial Lung Disease’ (c01783972-12) (see Investigator 
Site File [ISF]).
1.2.2
Ethinylestradiol
Ethinylestradiol is a synthetic estrogen with actions similar to those of estradiol. It is 
frequently used as the estrogenic component of combined oral contraceptives; a typical daily 
dose is 20 to 40 μg. Ethinylestradiol is also used as an emergency contraceptive drug 
combined with levonorgestrel or norgestrel. A combined preparation of ethinylestradiol with 
the anti-androgen cyproterone is used for the hormonal treatment of acne and hirsutism, 
particularly when contraception is also required. Ethinylestradiol has also been used for 
hormone replacement therapy; doses of 10 to 20 μg daily are given (with a progestogen in 
women with a uterus), but natural estrogens are usually preferred. Ethinylestradiol is also 
used for the treatment of female hypogonadism and the palliative treatment of prostate cancer 
and malignant breast cancer.
The adverse effects of estradiol and other estrogens are related, in part, to dose and duration 
of therapy, and to the sex and age of the recipient. In addition, adverse effects may be 


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modified by administration of progestogen in combined oral contraceptives or hormone 
replacement therapy. Whether adverse effects of natural and synthetic estrogens differ, and 
whether the route of administration has an effect, is less clear. The use of estrogens in girls 
may cause premature closure of the epiphyses resulting in decreased final adult height. Large 
doses of estrogens used in palliative care have also been associated with nausea, fluid 
retention, venous and arterial thrombosis, and cholestatic jaundice. In men, large doses of 
estrogen cause impotence and feminising effects, such as gynaecomastia. In women, uterine 
bleeding may occur after the cessation of estrogen therapy.
Ethinylestradiol is rapidly and well absorbed from the gastrointestinal tract with maximum 
plasma concentrations occurring after 1 h. The presence of an ethinyl group at the 17-position 
greatly reduces hepatic first-pass metabolism compared with estradiol, enabling the 
compound to be much more active after oral dosing, but there is some initial conjugation by 
the gut wall and systemic bioavailability is only about 45% (20-65%). Ethinylestradiol is 
highly protein bound (98%), but unlike naturally occurring estrogens, which are mainly 
bound to sex-hormone binding globulin, it is principally bound to albumin. The apparent 
volume of distribution is 2.8 to 8.6 L/kg. It is metabolised in the liver by hydroxylation 
(mediated by CYP3A4) followed by glucuronidation (UDP-Glucuronyltransferase 1A1 
[UGT1A1]) and sulfation of metabolites that undergo enterohepatic recycling. Metabolites 
are excreted via urine (40%) and bile (60%). The terminal half-life of ethinylestradiol is 10 
to 20 h (R12-0034). 
For a more detailed description of ethinylestradiol, please refer to the SmPC of Microgynon®,
which will be provided in the ISF.
1.2.3
Levonorgestrel
Norgestrel and its active (-)-isomer, levonorgestrel, are progestogens derived from
nortestosterone. They are more potent inhibitors of ovulation than norethisterone and have
androgenic activity. Levonorgestrel is more commonly used than norgestrel and is twice as
potent. Both are used as hormonal contraceptives. The typical daily levonorgestrel dose is 30 
or 37.5 μg when used as an oral progestogen-only contraceptive, 100 to 250 μg when used for 
the monophasic portion of combined oral contraceptives, and 50 to 125 μg when used in
triphasic preparations. Levonorgestrel is also used as a long-acting progestogen-only
contraceptive by subcutaneous implantation. An intrauterine device containing levonorgestrel
is available for contraception or menorrhagia. For emergency contraception, levonorgestrel
may be given alone or in combination with ethinylestradiol.
Progesterone and the progestogens may cause gastrointestinal disturbances, changes in
appetite or weight, fluid retention, oedema, acne, chloasma (melasma), allergic skin rashes,
urticaria, mental depression, breast changes including discomfort or occasionally
gynaecomastia, changes in libido, hair loss, hirsutism, fatigue, drowsiness or insomnia, fever,
headache, premenstrual syndrome-like symptoms, and altered menstrual cycles or irregular
menstrual bleeding. Anaphylaxis or anaphylactoid reactions may occur rarely (<0.01%).


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Levonorgestrel is rapidly and almost completely absorbed after an oral dose and undergoes
little first-pass hepatic metabolism. Maximum plasma concentrations occur 1 to 2 h after oral 
administration. Levonorgestrel is highly bound to plasma proteins, with 42 to 68% bound to 
sex hormone binding globulin and 30 to 56% bound to albumin. The proportion bound to sex 
hormone binding globulin is higher when levonorgestrel is given with an oestrogen.
Levonorgestrel is metabolised in the liver to sulfate and glucuronide conjugates, which are
excreted in the urine (40 to 68% of dose) and to a lesser extent in the faeces (16 to 48% of
dose). Levonorgestrel distributes into breast milk. The terminal half-life of levonorgestrel is
approximately 25 h (R12-0034).
A commonly used immunosuppressive agent, mycophenolate, may have a drug-drug 
interaction with levonorgestrel. Therefore concomitant use of mycophenolatel is restricted, 
because it may have an affect on the PK
For a more detailed description of levonorgestrel, please refer to the SmPC of Microgynon®, 
which will be provided in the ISF.
1.3
RATIONALE FOR PERFORMING THE TRIAL
Nintedanib is currently being developed for the treatment of systemic sclerosis associated 
ILD, a disease that also concerns women of child bearing potential. Two exploratory 
reproductive toxicity studies in rats revealed a teratogenic effect of nintedanib with a steep 
dose / effect relationship and an early onset of embryofetal deaths at low dosages. It may be 
expected that nintedanib is potentially teratogenic in humans.
According to the EMA guideline on the investigation of drug interactions (P15-06991) “a 
potential human teratogen” needs to be studied in vivo for effects on contraceptive steroids if 
the drug is intended for use in fertile women, regardless of the in vitro induction study 
results”. This trial will be performed to fulfil requirements of the EMA guideline.
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Nintedanib
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.


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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 b.i.d. is considered appropriate.
The risks of treatment with nintedanib have been well delineated in patients with the fibrotic 
lung disease IPF. These risks (potential side effects) of nintedanib are described in Section 
1.2.1, subsection “Data from clinical studies’.
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 the uridine 
glucuronosyltransferase 1A1 gene UGT1A1 and P-gp) should be avoided or 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. Therefore, in accordance with the current 
SmPC for Ofev® (nintedanib), women of childbearing potential who will be treated with 
nintedanib must use adequate contraception during and at least 3 months after the last dose of 
nintedanib and also barrier methods as second form of contraception in order to avoid 
pregnancy. As described in Section 1.3, the effect of nintedanib on the metabolism and 
efficacy of hormonal contraceptives is not know yet and will be investigated in this trial as 
recommended by the EMA. All trial participants will receive the oral contraceptive 
Microgynon® (levonorgestrel and estradiol) as trial medication to investigate the possible 
drug-drug interaction with nintedanib. Therefore, only non-hormonal contraceptives on 
combination with barrier methods are allowed to be used by WOCBP who are enrolled in this 
trial, as described in inclusion criterion 3, Section 3.3.2.
To address the organ-specific manifestations, immunosuppressive agents (e.g. 
mycophenolate, cyclophosphamide, methotrexate, azathioprine, prednisone) are commonly 
used and needs to be considered although appropriate randomised-controlled data for these 
therapies are lacking.
To address current practice, patients without immunosuppressive background therapy as well 
as patients on a stable background therapy of methotrexate will be eligible for the trial. For 


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other immunosuppressive agents, specific washout criteria apply since they are not allowed in 
the trial (see Section 4.2.2). 
Non-immunosuppressant therapies for other SSc manifestations as for digital ulcers (e.g. 
bosentan, sildenafil), GI symptoms (e.g. proton pump inhibitors, prokinetic drugs), renal 
crisis (e.g. angiotensin-converting-enzyme inhibitor (ACE inhibitors), pulmonary 
hypertension PH / pulmonary arterial hypertension PAH (e.g. bosentan, sildenafil, 
epoprostenol) are not restricted. Cautionary notes are included in the protocol (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, to exclude 
pregnancy, to follow-up on 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.
Overall, the extrapolated benefit-risk ratio of chronic treatment of patients with SSc-ILD with 
nintedanib 150 mg b.i.d. to be reduced to nintedanib 100 mg b.i.d., interrupted or 
discontinued during periods of intolerability, is judged positive.
The patients will not receive any additional benefit from participation in this trial, but are 
exposed to the risks of the trial procedures and the known risks of the trial medications.
However, their participation in this trial may help guide the safe use of nintedanib together
with ethinylestradiol / levonorgestrel in patients requiring this treatment. Patients who did not 
discontinue nintedanib treatment and will be rolled-over to Trial 1199.225 may have 
additional benefit from continuous nintedanib treatment.
1.4.2
Microgynon
Microgynon® has been used for over 10 years and is generally well tolerated (R11-0382, 
R11-0385). The intake of combined oral contraceptives is associated with an increased risk of
serious side effects such as cardiovascular diseases (myocardial infarction, cerebrovascular
insult, venous thromboembolism) and breast and liver tumours. The incidence of venous
thromboembolic events is 5-10 per 100,000 women in 1 year, if no hormonal contraceptives
are used. The incidence is increased to about 20/100,000 after intake of 2nd generation
combined oral contraceptives (containing levonorgestrel, e.g. Microgynon®). In contrast, the
intake of 3rd generation combined oral contraceptives (containing gestoden or desogestrel) is
associated with a higher risk (up to 40/100,000) of thromboembolic events (R12-0034).


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The most frequent side effects (>10%) of Microgynon® are headache, spotting and 
intermenstrual bleeding. Furthermore, the following undesirable effects have been observed:
gastric upset, nausea, vomiting, breast tenderness, changes in body weight, changes in libido,
and depression. In predisposed women, use of Microgynon® can sometimes cause chloasma
which is exacerbated by exposure to sunlight. Women with a predisposition to pigment
changes should avoid prolonged exposure to sunlight. Individual cases of poor tolerance of
contact lenses have been reported with use of oral contraceptives; therefore, contact lens
wearers who develop changes in lens tolerance should be assessed by an ophthalmologist.
Menstrual changes associated with the use of oral contraceptives include reduction of
menstrual flow and missed menstruation. Intermenstrual bleeding may occur, but normally
ceases spontaneously.
Two doses of Microgynon® (containing 30 microgram ethinylestradiol (EE) and 150 
microgram levonorgestrel (LE) per tablet) will be administered during this trial. Therefore, no 
undue risk is expected to trial participants.
1.4.3
Potential interaction between nintedanib and Microgynon
The major enzyme involved in biotransformation of ethinylestradiol is CYP3A4. Based on in 
vitro data, nintedanib is neither an inducer nor an inhibitor of CYP enzymes. Therefore, the 
co-administration of nintedanib is not expected to cause an interaction with Microgynon®.
1.4.4
Drug induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.2.10.1.4, adverse events of special interest.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective is to assess the potential influence of continuous intake of nintedanib on 
the systemic exposure of ethinylestradiol and levonorgestrel when administered in 
combination, as assessed by the endpoints described in the following sections.
2.1.2
Primary endpoints
Pharmacokinetic endpoints
The following primary endpoints will be determined for ethinylestradiol and levonorgestrel
based on the sampling times given in the Flow Chart:
∀
AUC0-tz (area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to the last quantifiable data point)
∀
Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
Pharmacokinetic endpoint
The following secondary endpoint will be determined for ethinylestradiol and levonorgestrel
based on the sampling times given in the Flow Chart:
∀
AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial will be performed according to an open-label, two-period, fixed sequence design. 
Female patients, who are considered eligible for therapy with nintedanib to treat their 
systemic sclerosis associated interstitial lung disease (SSc-ILD), have given their informed 
consent, and meet all inclusion criteria and none of the exclusion criteria, will receive the first 
dose of Microgynon® at the latest 3 days before the first administration of nintedanib. A 
second dose of Microgynon® will be administered at Visit 6, after continuous nintedanib 
intake for at least 10 consecutive days. Visit 6 may take place between Day 11 and Day 25 of 
nintedanib administration, depending on the visit scheduling and/or the patient’s condition. 
However, if a temporary interruption or nintedanib dose reduction has to take place (see 
Section 4.2.1), additional bottles of nintedanib may have to be dispensed at Visit 6 (or at an 
Unscheduled Visit) and the Visit 5 - Visit 6 visit window may have to be extended 
accordingly.
Blood for PK evaluation will be collected on the days of Microgynon® administration, and on 
the following 2 days. Adverse events and concomitant therapies will be recorded throughout 
the trial period, which ends once the patient has performed the End of Study (EOS) Visit. An 
overview of all relevant trial activities is provided in the Flow Chart. For visit schedule and 
details of trial procedures at selected visits, refer to Section 6.
Figure 3.1: 1 Visit schedule


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
Female patients with SSc-ILD will be included in this trial, if they are considered eligible for 
this trial, i.e. if they meet the inclusion and none of the exclusion criteria. Patients will be 
asked before starting the nintedanib therapy whether they would agree to participate in this 
Phase I trial. The patients will not have any benefit from intake of Microgynon® on two days 
during the trial period. The patients will be supervised by their treating physicians and 
adverse events occurring during the trial phase will be reported. The patients who complete 
this trial will be given the opportunity to continue nintedanib treatment in the roll-on Trial 
1199-0225. 
For this trial a non-randomised design was selected because the interaction with 
Microgynon® will be investigated in patients with a clearly defined treatment schedule of 
nintedanib. Therefore, kinetics of Microgynon® alone can only be determined before the start 
of nintedanib treatment. Systematic errors resulting from the fixed sequence are expected to 
be low because the trial duration is short enough so that nonspecific time-effects will be less 
important. 
In the fixed sequence design, each patient serves as her own control. The comparison 
between treatments is based on a comparison within patients rather than between patients. 
This trial design, therefore, removes inter-patient variability from the comparison between 
treatments (R94-1529).
As requested per EMA Guideline (P15-06991), this trial will be performed to exclude 
potential inductive effects of nintedanib on the kinetics of Microgynon®. Induction of 
CYP3A4, the major enzyme involved in biotransformation of ethinylestradiol and 
levonorgestrel, is mediated by the nuclear receptor Pregnane X Receptor (PXR). Referring to 
the well characterized PXR inducer rifampicin, a full induction of drug metabolizing 
enzymes is reached in about one week after start of rifampicin treatment (P03-08008). 
Potential inductive effects of nintedanib will be investigated after 10 consecutive dosing days 
with nintedanib.
The open-label treatment is not expected to bias the results, since the study endpoints are 
derived from measurement of plasma concentrations of the analytes.
3.3
SELECTION OF TRIAL POPULATION
A total of 14 patients, who completed the trial and can be analysed for both treatment periods, 
are needed for the purpose of the trial. It is assumed that up to approximately 24 patients may 
have to be enrolled by approximately 12 sites to achieve the goal that 14 patients completed 
the trial and have data evaluable for the PK analysis.


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Sites will be experienced in the management of patient with SSc-ILD and are each expected 
to include approximately 2 patients. Additional sites may be initiated and ‘non-productive’ 
sites may be closed to ensure sponsor’s timelines
Screening of patients for this trial is competitive, i.e. screening for the trial will stop at all 
sites at the same time once a sufficient number of patients has been screened. Investigators 
will be notified about screening completion and will then not be allowed to screen additional 
patients for this trial.
To be able to assess the drug-drug interaction of nintedanib with contraception in female 
patients as accurately as possible, certain restrictions apply: please refer to Section 4.2.2.1. 
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a patient is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.
Re-screening of a previously declared ‘screen failed’ patient is allowed, but only if the 
previous reason(s) for screen failure (e.g. an exclusion criterion) is resolved in the time 
between the previous screening and the re-screening. The re-screened patient must sign a new 
informed consent and will get a new unique patient number.
3.3.1
Main diagnosis for trial entry
Outpatients diagnosed with Systemic Sclerosis associated Interstitial Lung Disease (SSc-
ILD), based upon classification according to the American College for Rheumatologists / 
European League against Rheumatism (ACR / EULAR) 2013 criteria (R14-5055) and a chest 
high resolution computer tomography (HRCT) demonstrating fibrotic/interstitial changes, are 
eligible for inclusion if they fulfil all the 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. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
2. Female patients ≥ 18 years at Screening Visit 1.
3.
A woman of non-child bearing potential, i.e. being postmenopausal1 or permanently 
sterilised (e.g. hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or a 
woman of childbearing potential correctly and consistently using a highly effective 
method of non-hormonal birth control (i.e. IUD or bilateral tubal ligation) together with 
barrier methods2 at least 30 days prior tofirst administration of Microgynon® (Visit 2), 
during the trial and for 3 months after last intake of nintedanib. See also Section 4.2.2.4. 


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A list of contraception methods fulfilling these criteria is provided in the patient 
information.
(Note: 1A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause. A high follicle stimulating hormone (FSH) level in the 
postmenopausal range may be used to confirm a post-menopausal state in women not 
using hormonal replacement therapy; in questionable cases a blood sample with 
simultaneous levels of FSH above 40 U/L and estradiol below 30 ng/L is confirmatory 
[R16-0373]). 2 Possible barrier methods: male or female condom, or diaphragm or 
cervical cap, to be used in combination with spermicide.) For further details, see 
Section 4.2.2.4.
4. Patient with Systemic Sclerosis associated Interstitial Lung Disease (SSc), fulfilling the 
2013 ACR / EULAR classification criteria for SSc.
5. SSc disease onset (defined by first non-Raynaud symptom) must be within 7 years of 
Visit 1. (No longer applicable with global protocol amendment 2)
6. SSc related Interstitial Lung Disease pattern must be confirmed by HRCT performed
within 12 months of Visit 13. The extent of fibrotic disease in the lung must be ≥10% on 
HRCT, assessed by local review.
(Note : 3 If the patient does not have a HRCT within 12 month s of Visit 1, but meets all 
the other inclusion and no exclusion citeria, the HRCT scan can be performed  for the 
purpose of participation in the trial, if accepted by local regulations (except for patients 
in Germany, as was also decided for  the phase III SENSCIS trial 1199.214)
7. FVC ≥40% of predicted normal at Visit 1 (refer to Appendix 10.1). 
8. DLCO (corrected for Hb [Visit 1]): 30 % to 89% of predicted at Visit 1 (refer to 
Appendix 10.1).
3.3.3
Exclusion criteria
1. AST, ALT >1.5 x ULN.*
2. Bilirubin >1.5 x ULN.*
3. Creatinine clearance <30 mL/min* calculated by Cockcroft–Gault formula (10.2).
(Note:* Laboratory parameters from Visit 1 have to satisfy the laboratory threshold 
values as shown above. 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).
4. Clinically relevant anaemia at investigators discretion.
5. Airway obstruction (pre-bronchodilator FEV1/FVC <0.7) at Visit 1, or other clinically 
significant pulmonary abnormalities in the opinion of the investigator.


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6. Significant Pulmonary Hypertension (PH) defined by any of the following:
o
Previous clinical or echocardiographic evidence of significant right heart failure
o
History of right heart catheterisation showing a cardiac index ≤ 2 l/min/m²
o
PH requiring therapy with prostacyclines (parenteral or oral, e.g. epoprostenol, 
treprostinil, selexipag)
7. Cardiovascular diseases, any of the following:
o
Severe hypertension, uncontrolled under treatment (≥160/100 mmHg), within 
6 months of Visit 1
o
Myocardial infarction within 6 months of Visit 1
o
Unstable cardiac angina within 6 months of Visit 1
8. More than 3 digital fingertip ulcers at Visit 1 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, according to the judgement of the 
investigator.
b. Patients who require (also during the trial):
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 
IU 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. Gastric antral vascular ectasia (GAVE)
iv. Major injury or surgery (investigators judgement)
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 major thrombo-embolic event (e.g. stroke/transient ischemic attack, deep vein 
thrombosis, pulmonary embolism) within 12 months of Visit 1.


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11. Previous hematopoietic stem cell transplantation (HSCT), or HSCT planned within the 
next year.
12. Major surgical procedures planned to occur during trial period.
13. 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, clinically 
relevant intestinal pseudoobstruction).
14. Gastrointestinal disorders or abnormalities that would interfere with absorption of the trial 
drugs, including patients with clinical signs of malabsorption or needing parenteral 
nutrition.
15. Patients with underlying chronic liver disease (Child Pugh A, B, C hepatic impairment).
16. Patients with a history of Scleroderma Renal Crisis.
17. Life expectancy of <2.5 years for disease other than SSc in investigator assessment.
18. Patients who must or wish to continue the intake of restricted medications, e.g. P-
glycoprotein (P-gp) , cytochrome P450 3A4 (CYP3A4) inhibitors or inducers
medications, certain immunosuppressive agents, or any other drug considered likely to 
influence the motility or absorbance of the trial medication in the gastrointestinal tract, or 
interfere with the safe conduct of the trial. (see Section 4.2.2.1 for a complete list and 
further details).
19. Known hypersensitivity to the trial medication or its components (i.e. soya lecithin).
20. Any contraindication to nintedanib, ethinylestradiol or levonorgestrel (Microgynon®), as 
specified in the respective labels.
21. Previous treatment with nintedanib or pirfenidone.
22. Previous enrolment in this trial or previous participation in the SENSCIS® trial 
(1199.214) or the roll-over trial 1199.225.
23. Currently enrolled in another investigational device or drug trial, or less than 30 days 
since ending another investigational device or drug trial(s), or receiving other 
investigational treatment(s).
24. Patients not expected to comply with the protocol requirements, not able to understand or 
follow trial procedures, including completion of the self-administered questionnaires, or 
not expected to complete the trial as scheduled.
25. Chronic alcohol or drug abuse or any condition that, in the investigator’s opinion, makes 
the patient an unreliable trial participant or unlikely to complete the trial.
26. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
3.3.4
Withdrawal of patients from treatment or assessments
Patients may discontinue trial treatment or withdraw consent to trial participation as a whole
(“withdrawal of consent”) with very different implications; please see Sections 3.3.4.1 and 
3.3.4.2 below.


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Measures to control the withdrawal rate include careful patient selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the patient files and eCRF. If the reason for discontinuation is
death, this should be reported on the SAE form as well, regardless of causal relationship.
3.3.4.1
Discontinuation of trial treatment
An individual patient will discontinue trial treatment if:
∀
The patient wants to discontinue trial treatment, without the need to justify the decision.
∀
The patient experiences signs of hepatic injury, defined in Section 5.2.10.1.4.
∀
In the opinion of the investigator, the patient experiences unacceptable adverse events 
despite dose adjustments and supportive care.
∀
The patient has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future.
∀
Pregnancy (refer to Section 5.2.10.2.4). 
∀
The patient needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment. See also Section 4.2.2 for restricted or not-
allowed medication. 
∀
The patient can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, or other diseases).
In case of a temporary reason, trial treatment should be restarted if medically justified, please
see Section 4.1.4.
3.3.4.2
Recommendation to discontinue nintedanib
In the following cases discontinuation of nintedanib 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 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 IU s.c. per day), as well as 


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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 during the trial.
∀
Confirmed severe hypertension, uncontrolled under treatment (≥160/100 mmHg) during 
the trial
∀
Unstable cardiac angina during the trial
∀
Increased risk of bleeding e.g. hemorrhagic CNS event, gross / frank haemoptysis or 
haematuria, active gastro-intestinal bleeding or GI-ulcers during the trial.
∀
Scleroderma renal crisis during the trial
∀
Significant pulmonary hypertension during the trial, defined by any of the following:
-
New clinical or echocardiographic evidence of significant right heart failure
-
Right heart catheterisation showing a cardiac index ≤ 2 l/min/m²
-
PH requiring therapy prostacyclines (parentheral or oral, e.g. epoprostenol, 
treprostinil, selexipag)
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart 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 
reported.
If one of the following situations occurs, the patient may be replaced after discussion between 
investigator and the Clinical Trial Leader (CT Leader), former Trial Clinical Monitor 
(TCM)).
∀
Microgynon® cannot be administered in Period 1 and Period 2
∀
Interruption of nintedanib therapy for more than 8 weeks.
∀
No continuous intake of 10 consecutive days possible within this trial
∀
Dose reduction of nintedanib to less than 2 x 100 mg per day before end of PK sampling
∀
Administration of forbidden drugs (refer to Section 4.2.2.1)
∀
Noncompliance with dietary restrictions, or parenteral feeding requirement
∀
Inability of the patient to comply with the food intake on the days of Microgynon®
administration
3.3.4.3
Withdrawal of consent to trial participation
Patients may withdraw their consent to trial participation at any time without the need to 
justify the decision.
If a patient wants to withdraw consent, the investigator should be involved in the discussion
and explanation to the patient.
When the patient prematurely discontinues the trial medication a follow-up Visit will be done 
7 days after last intake of nintedanib, please see Section 3.3.4.1 above and the Flow Chart.


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3.3.4.4
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Violation of GCP, the trial protocol, or the contract impairing the appropriate conduct of 
the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
All patients will be treated with Microgynon® and nintedanib. Both Microgynon® and 
nintedanib will be considered as Investigational Medicinal Product (IMP) in this trial.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1: 1
Microgynon®
Substance:
Combination of ethinylestradiol and levonorgestrel
Pharmaceutical formulation:
Tablet
Source:
Unit strength:
30 microgram ethinylestradiol (EE) /150 microgram 
levonorgestrel (LE) per tablet
Posology:
1 tablet (in each trial period)
Route of administration:
Oral
Table 4.1.1: 2
Nintedanib soft gelatine capsule 
Substance:
Nintedanib
Pharmaceutical formulation:
Soft gelatine capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
150 mg per capsule
(or 100 mg per capsule, in case of dose reduction*)
Posology:
b.i.d.
Route of administration:
Oral
Note: *Nintedanib shall be taken continuously throughout Period 2. In case of a temporary 
interruption of nintedanib intake or a dose reduction, patients can receive Microgynon® in Period 2 
only if they have taken a stable dose of nintedanib for at least10 consecutive days before intake of 
Microgynon®
4.1.2
Selection of doses in the trial and dose modifications
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 
b.i.d. was selected. With 150 mg b.i.d., 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. 


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However, to manage adverse events, the dose may be reduced to 100 mg b.i.d. (refer to
Section 4.2.1 and Section 6.2.2).
Microgynon® will be administered as a single administration on the PK profiling days only. 
One tablet of Microgynon® will be administered on the first PK day in in Period 1 and one 
tablet of Microgynon® on the first PK day in Period 2.
4.1.3
Method of assigning patients to treatment groups
This is a fixed sequence trial. After assessment of all in- and exclusion criteria, each eligible 
patient will undergo the respective treatment periods in an identical order.
An Interactive Response Technology (IRT) will be used for this trial, which will manage the 
IMP shipments to and returns from the sites. Allocation of the trial medication to the patient 
will be done by the investigator or delegated person at the site. Further details will be 
provided in the ISF.
The site will receive a sufficient supply of uniquely numbered Microgynon® and nintedanib 
treatment packages and initially one Microgynon® blister package (containing 21 tablets) and 
two (150 mg) nintedanib boxes will be assigned per patient. Additional nintedanib bottles 
(containing 150 mg or 100 mg nintedanib capsules) will be assigned to a patient when 
needed, e.g. if a patient has an adverse event (AE) resulting in temporary nintedanib 
interruption or dose reduction leading to prolongation of the total treatment period. (See 
further details in Section 4.1.4).
The assigned Microgynon® and nintedanib medication numbers will be recorded in the eCRF
for that patient.
4.1.4
Drug assignment and administration of doses for each patient
Patients will take one tablet of Microgynon® at least 3 days before the first intake of 
nintedanib (at Visit 2 in Period 1) and one tablet of Microgynon® after continuous nintedanib 
administration for at least 10 consecutive days (at Visit 6 in Period 2). The remaining 19 
tablets in the Microgynon® blister will not be used.
Nintedanib will be taken by the patients at home except for the PK profiling days. The 
patients will be handed out the nintedanib medication (two bottles with 30 capsules each, 
containing 150 mg nintedanib per capsule, for the respective time period) at the time point 
indicated in the Flow Chart. 
Nintedanib will be administered orally on a twice daily basis (b.i.d.). The nintedanib capsule 
should be taken with food, swallowed whole with water (~250 mL) and must not be chewed 
or crushed. Nintedanib needs to be taken with a dose interval of approximately 12 hours, i.e. 
at approximately the same time every day: one capsule between 06:00 and 11:00 in the 
morning, and one capsule between 18:00 and 23:00 in the evening.
Nintedanib treatment (150 mg twice daily) will start at Visit 5 (Day 1) and will continue at 
stable dose for at least 14 days, in order to ensure that at least 10 days of continuous 
nintedanib treatment is taken before the PK profiling in Period 2 will start at Visit 6. The 
patient will have the last intake of nintedanib trial medication the evening prior to, or at the 


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End of Treatment (EOT) Visit, which has to take place at least 3 days after Microgynon®
intake at Visit 6.
On both PK profile days (the first PK days in Period 1 and Period 2), a standardised meal 
(breakfast) has to be consumed within 30 minutes prior to Microgynon® intake. 
A standardized meal means that, for the individual patient, the meal should preferably be 
identical in Period 1 and Period 2. 30 Minutes after start of the standardised meal, 
Microgynon® will be administered. On the day of Microgynon® administration in Period 2, 
the morning dose of nintedanib will be taken first, immediately followed by the Microgynon®
tablet and both have to be taken within one minute.
The trial drugs will be administered in the standing position under supervision of the 
investigating physician or an authorized designee.
During the first 4 h after Microgynon® administration on the PK profile days, patients are not 
allowed to lie down (i.e. no declination of the upper body of more than 45 degrees from 
upright posture) unless supine positioning is required for trial related measurements.
The patient shall be instructed to not skip any doses. A forgotten or missed dose must be 
skipped if the time window to the next dose is less than 8 hours. The next dose should be 
taken as scheduled. Under no circumstances should two doses be taken at the same time. In 
case of vomiting, the patient should not take a replacement dose.
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
List”. The authorized person(s) must instruct the patients on how and when to take the 
medication, how to store it and when to return the used and unused medication (bottles), in 
addition to the instructions on the label.
In case of adverse events requiring dose reduction between planned visits (see Section 4.2.1
for details) an additional site visit is required. The dose can be reduced without prior 
interruption, i.e., immediately stepping down from 150 mg b.i.d. to 100 mg b.i.d. The color of 
capsules (100 mg capsule) will be slightly different.
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
4.1.5.1
Blinding
Not applicable, since this is an open-label trial with only one fixed treatment sequence.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
Nintedanib will be provided by Boehringer Ingelheim (BI) or a designated Contract Research 
Organisation (CRO) and will be packaged and labelled in accordance with the principles of 
Good Manufacturing Practice (GMP).


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Depending on local laws and regulations in the countries of the participating sites, 
Microgynon® will be provided by BI or a designated CRO and packaged and labelled in 
accordance with the principles of Good Manufacturing Practice (GMP). For details of 
packaging and the description of the label, refer to the ISF.
An IRT system will be used to manage the shipment of open-label trial medication supplies 
to the site, and returns and destruction.
A re-supply of trial medication is not planned, but can be managed by the IRT system, if 
necessary, e.g. if the trial treatment expires due to unexpected prolongation of the study. In 
that case 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.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:
∀
Approval of the clinical trial protocol by the Institutional Review Board (IRB) / 
Independent Ethics Committee (IEC),
∀
Availability of a signed and dated clinical trial contract between the sponsor and 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,
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. Patients should be instructed to return 
unused investigational drug.
The investigator or designee 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 warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
patients. The investigator or designee will maintain records that document adequately that the 
patients were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 


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sponsor and/or appointed CRO, the investigator or designee 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.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
Rescue medications to reverse the action of nintedanib are not available.
Dose reduction (from 150 mg b.i.d. to 100 mg b.i.d.) or treatment interruption should be 
considered to manage adverse events. No further dose reduction is possible for patients on the 
100 mg b.i.d. regimen. In case of persistent adverse events observed at this dose, or severe 
effects at 150 mg b.i.d., requiring a second treatment interruption or interruption longer than 
8 weeks, the nintedanib treatment must be permanently discontinued.
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency
procedures are to be followed.
Table 4.2.1: 1 Allowed treatment reduction / interruption periods:
AEs considered drug related
AEs not considered drug related
Number of interruptions
One
One
Maximum interruption
4 weeks
8 weeks
Recommended restart
with reduced dose (100 mg 
b.i.d.).
with the same dose (150 mg b.i.d),
or reduced dose (100 mg b.i.d.)
4.2.1.1
Management of diarrhoea
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.
If a patient is having diarrhoea prior to, or during the PK profiling in Period 1 or Period 2 
then the PK profiling should be postponed, since this may affect the efficacy of both 
medicines Microgynon® and nintedanib and therefore also the PK. 


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Table 4.2.1.1: 1 Management of diarrhoea (considered related to nintedanib)
Description
Symptomatic Treatment1
Action with nintedanib
Diarrhoea with 
increase of <4 stools 
per day over baseline2.
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 nintedanib dose.
Diarrhoea with 
increase of 4 to 6 
stools per day over 
baseline2.
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 intravenous 
(IV) fluids and electrolyte 
replacement as clinically 
indicated.
If diarrhoea persists for ≥48 to 72 
hours despite optimal symptomatic 
care:
1.
Interrupt nintedanib until 
recovery3.
2.
Reduce dose to 100 mg b.i.d.
after recovery. 
Diarrhoea with 
increase of ≥7 stools 
per day over baseline2; 
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 nintedanib until 
recovery3.
2.
Reduce dose to 100 mg b.i.d.
after recovery.
In case of reoccurrence of diarrhoea 
of this severity despite optimal 
symptomatic treatment and dose 
reduction, treatment with 
nintedanib should be permanently 
discontinued.
Footnotes:
1
Other causes for diarrhoea should always be considered and treated accordingly (e.g. viral 
infections, SSc related diarrhoea, bacterial overgrowth, antibiotic treatment). The use of 
loperamide should be avoided 72 hours prior to and during PK sampling days (see Table 
4.2.2.1: 1), so in case his happens it is advised to postpone or interrupt the PK assessments and to 
repeat the PK assessments again after 10 days of nintedanib use, if possible and agreed by patient 
and investigator.
2
Baseline defined as usual stools/day prior to start of nintedanib at Day 1 (Visit 5) of Period 2.
3
See Section 4.2.1: Maximum interruption of 4 weeks allowed, if diarrhoea is related to nintedanib. 
If diarrhoea is not recovered within 4 weeks, the patient must be discontinued from treatment and 
the trial.


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4.2.1.2
Management of liver enzyme elevation
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
Hepatic injury1
(See also Section 
5.2.10.1.4)
>1.5x to <3x
ULN
≥3x to <5x
ULN and no 
signs of hepatic 
injury1
≥5x to <8x
ULN , and no 
signs of hepatic 
injury1
Period 1
(before 
nintedanib 
treatment)
Discontinue from 
study or justify 
continuation2
Discontinue from 
study
Discontinue from 
study 
Discontinue from 
study
Period 2
(on 
nintedanib 
treatment)
Continue as 
planned2, 3
Reduce dose or 
interrupt 
nintedanib4, 5
Interrupt 
nintedanib5
Withdraw trial 
medication and 
discontinue study
CLINICAL 
EVALUATION OF 
HEPATIC INJURY
(Section 5.2.10.1.4) 
Close 
observation6
After 2 weeks or 
any time later
Close 
observation6
After 2 weeks or 
any time later
<3x ULN
≥3x ULN
<3x ULN
≥3x ULN
Reduced: Monitor 
bi-weekly for at 
least 8 weeks
Interrupted: restart 
at reduced dose.
Monitor bi-weekly 
for at least 8 weeks
Permanently 
discontinue trial 
Close 
observation6
Restart at reduced 
dose
Monitor weekly 
for 4 weeks, then 
bi-weekly for at 
least 8 weeks
Permanently 
discontinue trial 
medication.
Close observation6
Footnotes:
1
A hepatic injury is defined by the following alterations of hepatic laboratory parameters (see Section 
5.2.10.1.4:
a)
ALT and/or AST ≥8 fold ULN
b)
ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN*
c)
ALT and/or AST ≥3 fold ULN and unexplained INR > 1,5*
d)
ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*
e)
ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right upper abdominal 
quadrant pain or tenderness, fever and/or rash
(Note * within the same blood sample)
2 
Investigator to confirm in writing that continuation is justified (e.g. intermittent fluctuation of 
transaminases).
3 
According to visit schedule. Consider additional control visits as adequate.
4 
To reduce or interrupt nintedanib is to be decided by Investigator and is based on individual risk assessment.


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5 
When the safety lab reports of Visit 6 show that the liver enzymes are ≥ 3x ULN and < 8x ULN then the 
following must be done: to stop the PK profiling assessments, since nintedaninb has to be interrupted or dose 
has to be decreased which will affect the PK. However, the patient may continue the trial when liver 
enzymes are again < 3x ULN and start or continue with reduced dose. This means that the PK profiling has 
to be repeated again after 10 days of continued nintedanib at lower dose (100 mg b.i.d). And the monitoring 
of (elevated) liver enzymes should continue for 8 weeks, so also when the patient is rolling over in Trial 
1199-0225. If - after 2 weeks observation- the liver enzymes are still ≥3xULN (with interrupted or reduced 
dose) then the patient must be permanently discontinued from nintedanib treatment and the trial.
6
Close observation: Re-test ALT and AST, alkalinephosphatase, total bilirubin, and eosinophils within 48 to 
72 hours, then after approximately 7 days, then after approximately 2 weeks by using intermediate visit lab 
kit.
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
4.2.2.1
Restrictions regarding concomitant treatment
Medication as individually indicated per discretion of the investigator is allowed unless 
covered by medication restrictions in Table 4.2.2.1:1.
Please also refer to cautionary notes (Section 4.2.2.2).
All concomitant or rescue therapies will be recorded (including time of intake on the days of 
PK sampling) on the appropriate pages of the eCRF.
Table 4.2.2.1:1. Medication restrictions and requirements
Screening and Period 1
Period 2
After EOT*
Metoclopramide, 
loperamide, opioid 
analgetics1
AVOID use 72 hours prior 
to and during PK sampling 
days
AVOID use 72 hours prior 
to and during PK sampling 
days
Permitted
P-glycoprotein (P-gp) and Cytochrome P450 3A4 (CYP3A4) inhibitors
Ketoconazol, 
cyclosporine A (or 
ciclosporin), boceprevir, 
clarithromycin, 
conivaptan, 
erythromycin, indinavir, 
itraconazole, lopinavir, 
mibefradil, nefazodone, 
nelfinavir, posaconazole,
ritonavir, saquinavir, 
telaprevir, telithromycin, 
voriconazole.
NOT permitted:
stop at least 7 days prior to 
1st Microgynon® intake
NOT permitted
until last PK sampling day
Permitted


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Table 4.2.2.1:1. Medication restrictions and requirements (con’t)
P-gp and CYP3A4 strong inducers
Avasimibe, 
carbamazepine, 
phenytoin, rifampin
NOT permitted:
stop at least 7 days prior to 
1st Microgynon® intake
NOT permitted
until last PK sampling day
Permitted
Products including St. 
John’s wort
NOT permitted:
stop at least 7 days prior to 
1st Microgynon® intake 
NOT permitted
until last PK sampling day
Permitted
Anticoagulant and antiplatelet therapies
Full dose therapeutic 
anticoagulation3
NOT permitted
(see Section 3.3.3
exclusion criterion 9b and 
Section 3.3.4.1)
NOT permitted
discontinuation of 
nintedanib is highly 
recommended
(see Section 3.3.4.1)
Permitted
High-dose antiplatelet 
therapy4
NOT permitted
(see Section 3.3.3
exclusion criterion 9b and 
Section 3.3.4.1)
NOT permitted
discontinuation of 
nintedanib is highly 
recommended
(see Section 3.3.4.1)
Permitted
Low dose antiplatelet 
therapy5
Permitted
Permitted
Permitted
Prophylactic low dose 
heparin or heparin flush6
permitted
Permitted
Permitted
Immunosuppressive agents
Mycophenolate7
Not permitted
2 weeks prior Visit 2
Not permitted
Permitted
Methotrexate
Permitted if stable dose for 
at least 6 months prior 
Visit 1 (otherwise washout 
for 8 weeks prior Visit 1)
Stable pre-trial dose to be 
continued7
Permitted
Azathioprine
NOT permitted
8 weeks prior Visit 1
NOT permitted8
Permitted
Cyclophosphamide
NOT permitted
6 month prior Visit 1
NOT permitted8
Permitted
Ciclosporine A9
Not permitted at least 7 
days prior to 1st
Microgynon® intake
NOT permitted until last 
PK sampling day
Permitted


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Table 4.2.2.1:1. Medication restrictions and requirements (con’t)
Corticosteroids
Prednisone ≤10 mg/day
or equivalent 
Permitted
Permitted
Permitted
Prednisone >10 mg/day
or equivalent
NOT permitted
2 weeks prior Visit 1
NOT permitted
Permitted
Hormone containing contraceptives
Hormone containing 
contraceptives (including 
vaginal and intrauterine 
devices and including 
hormone replacement 
therapy), e.g. used for
post-menopausal 
symptoms 
NOT permitted within 30 
days prior to first 
administration of 
Microgynon®
NOT permitted
Permitted
Other restricted medications
Pirfenidone
NOT permitted
NOT permitted
Permitted
Nintedanib
(outside of the trial)
NOT permitted
NOT permitted
Permitted
Other investigational 
drugs
Washout 1 month or 6 half-
lives (whichever is greater) 
prior Visit 1
NOT permitted
Permitted
Footnotes:
*
After EOT: Permitted co-medications to be evaluated based upon whether the patient will 
participate in 1199-0225 with same, or other restrictions.
1
These drugs may influence the motility or the absorption of drug substances in the 
gastrointestinal tract.
3
Fibrinolysis, full-dose therapeutic anticoagulation (e.g. vitamin K antagonists, direct thrombin 
inhibitors, heparin, hirudin)
4
E.g. acetyl salicylic acid >325 mg/day, or clopidogrel >75 mg/day, or equivalent doses of other 
antiplatelet therapy.
5
E.g. acetyl salicylic acid ≤325 mg/day, or clopidogrel ≤75 mg/day, or equivalent doses of 
other antiplatelet therapy.
6
As needed for maintenance of an indwelling intravenous device (e.g. enoxaparin 4000 IU s.c. 
per day).
7
Mycophenolate is not allowed because of possible drug-drug interactions with levonorgestrel. 
(see Section 1.2.3)
8
In case of clinically significant deterioration of SSc-ILD (e.g. increase in symptoms, decline in 
FVC > 10% and change in mRSS relative to Visit 1, if determined during the study) which 
warrants the initiation or dose change of an immunosuppressive agent, it is recommended to 
prematurely discontinue the intake of nintedanib, and proceed to the End of Treatment Visit.
9
Ciclosporine (cyclosporine) restriction only applies for the oral formulation. Topical 
applications like eye drops or skin cream are allowed.


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4.2.2.2
Cautionary notes
As the most common side effects known for nintedanib are gastrointestinal effects, the 
concomitant use of medication with an overlapping safety profile should be carefully 
considered.
Nintedanib is also associated with increases in liver enzymes and bilirubin. If additional
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 8 weeks.
The concomitant use of other medication(s) to treat SSc-ILD or related symptoms, e.g 
hydroxychloroquine, colchicine, D-penicillamine, sulfasalazine, rituximab, tocilizumab, 
abatacept, leflunomide, tacrolimus, newer anti-arthritic treatments like tofacitinib, potassium 
para-aminobenzoate, is not restricted, but the patient’s safety should be carefully monitored.
4.2.2.3
Restrictions on diet and life style
While admitted to the trial site the patients are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed for 4 h after Microgynon® intake.
Green tea, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first intake of Microgynon® in Period 1 and until the last 
PK sample has been collected in the trial in Period 2.
Alcoholic beverages are not allowed on the days when PK sampling takes place.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during in-house confinement at the trial site.
On the PK profile days, between breakfast and lunch, fluid intake is restricted to the water 
administered with the study drugs, and an additional 240 mL of water at 2 h and 4 h after 
intake of trial medication (mandatory for all patients).
On the PK profile days, a standardised meal will be served 30 min prior to Microgynon®
and/or nintedanib administration.
4.2.2.4
Contraception requirements
As described in Section 3.3.2, inclusion criterion 3, women of childbearing potential
(WOCBP) must use two medically approved highly effective non-hormonal 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, if their sexual partner is a man able to father a child. A list of 
contraception methods meeting these criteria is provided in the patient information.


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At least 30 days prior to start of the first administration of Microgynon®at Visit 2, during the 
trial and at least 3 months after the last intake of nintedanib, the patient must use a highly 
effective non-hormonal method, such as Intra-Uterine Device (IUD) (e.g. Copper containing), 
or bilateral tubal occlusion/tubal ligation and in addition also use barrier methods, like male 
or female condom, diaphragm or cervical cap, which must be used in combination with a 
spermicide.
Only non-hormonal contraceptives are allowed, since patients participating in this trial (all 
females) will take one tablet Microgynon® in Period 1 and 1 tablet Microgynon® in Period 2, 
as specified in the Flow Chart, in order to asses the drug-drug interaction with nintedanib.
4.3
TREATMENT COMPLIANCE
Patients will be asked to take their nintedanib medication as instructed by their treating 
physician. They shall be asked to report any instances when they could not take nintedanib as 
prescribed. The trial site will document the intake of nintedanib medication and provide an 
explanation in case the number of capsules expected to be taken differs from the actual 
number.
At clinic visits, Microgynon® (in Period 1) and Microgynon® together with nintedanib (in 
Period 2) will be administered under the supervision of the treating physician or trial staff to 
whom this task was delegated. The intake of both Microgynon® and nintedanib will be 
documented in the eCRF. During the phone contact 5A, after 9 days of nintedanib intake and 
one day prior to Visit 6 and also at Visit 6, the patient’s treatment compliance will be checked 
using the PK Diary information filled in by the patient and also an overall drug accountability 
check will be done to verify if the patient took the required number of capsules consistent 
with a twice daily intake during the last 10 days prior to Visit 6.
In the following situations the PK Visit 6 must be postponed, because the nintedanib 
treatment intake will not be considered continuous or compliant and might affect the PK 
analysis for this trial:
∀
The patient did not continuously take at least 10 days of a stable dose of nintedanib 
(b.i.d.) prior to the PK visit assessments in Period 2, due to interruption or dose 
reduction of nintedanib, because of an AE or other reason. 
∀
The patient missed two (or more) nintedanib capsules in the first 7 days.
∀
The patient missed one (or more) nintedanib capsules in the 3 days prior to (which 
can be checked on the PK Diary) and during the PK days in Period 2.
Patients will also be asked to adhere to the dietary restrictions.
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points as indicated in the 
Flow Chart. Weight and height will be recorded at screening Visit and weight will again be 
recorded at the End of Treatment (EOT) Visit and Follow-Up (FU) Visit, if applicable.
The results must be included in the source documents available at the site.
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.
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the Flow Chart, prior to blood 
sampling.
This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a seated position after 5 minutes of rest. 
The results must be included in the source documents available at the site.
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.
5.2.3
Assessment of Lung Function (Spirometry)
FVC, but also FEV1 (Forced Expiratory Flow in 1 second), will be assessed using the site’s 
own spirometer at the screening visit and EOT. See Appendix 10.1 for the calculation of FVC 
in % predicted.
Spirometry measurements must be performed according to American Thoracic Society/ 
European Respiratory Society (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 must be selected according to the guidelines and 
noted on the printed spirometry report. 
The best of three efforts will be defined as the highest FVC and the highest FEV1 obtained on 
any of the three blows (the highest FVC and FEV1 do not have to come from the same blow), 
which meet the ATS/ERS criteria with preferably a maximum of five maneuvers.


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Patients must refrain from strenuous activity at least 12 hours prior to pulmonary function 
testing. Smoking should be discouraged throughout the visit day (clinic visit) and will not be 
permitted in the 30-minute period prior to spirometry. Patients should also avoid cold 
temperatures, environmental smoke, dust, or areas with strong odours (e.g. perfumes). If 
treated with bronchodilators, washout of 24 hours for long acting and 8 hours for short acting 
bronchodilators should be observed before spirometry.
Further instructions regarding spirometry measurements will be provided in the site’s ISF.
5.2.4
Assessment of DLCO
The site will use its own carbon monoxide diffusion capacity (DLCO) equipment and use the 
same DLCO equipment for all enrolled patients at the site (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 the Screening Visit 1 only. The DLCO assessment should be 
performed after the FVC assessment at Visit 1, after the patient has rested. 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 (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.
Further instructions regarding DLCO measurements will be provided in the ISF.
5.2.5
HRCT
A High Resolution Computer Tomography (HRCT) of the lung, performed within 12 months 
of Visit 1 should be available for entry criteria assessment of extent of fibrosis. If the patient 
does not have a HRCT within 12 month s of Visit 1, but meet all the other inclusion and no 
exclusion citeria , the HRCT scan can be performed for the purpose of participation in the 
trial, if allowed by local regulations (except for patients in Germany).
5.2.6
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.6: 1. For the sampling time 
points please see the Flow Chart. More frequent (unscheduled) blood sampling may be done 
whenever the investigator deems it necessary, which will then also be assessed and reported 
by the central laboratory. Blood sampling should not be done immediately before ECG 
recording.
All safety analyses will be performed by a central laboratory. 


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Patients do not have to be fasted for the blood sampling for the safety laboratory, except at 
Visit 2 and Visit 6. The patient should be instructed not to have breakfast at home, as a 
standardized breakfast will be provided in the clinic. 
Instructions regarding sample collection, sample handling/ processing and sample shipping
are provided in the Laboratory Manual in the ISF. 
Table 5.2.6:1 
Safety laboratory tests 
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 V1 and EOT)
Creatinine
Glucose (non fasting, except at V2 and V6)
Uric acid
Thyroid stimulating hormone (TSH, only at V1 and EOT)
ß-HCG* (at Visit 1, in women of childbearing potential 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.
Note: * Pregnancy testing (ß-HCG in serum or urine dipstick) can either be done by central or local laboratory.
It is the responsibility of the investigator to evaluate the laboratory reports. Clinically relevant 
abnormal findings as judged by the investigator will be reported as adverse events (please 
refer to Section 5.2.10).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see Section 5.2.10.1.4 and the DILI Checklist provided in the ISF). The 


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amount of blood taken from the patient concerned will be increased due to this additional 
sampling.
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 in case of Hepatic Injury (see Section 5.2.10.1.4 for DILI 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 the amount of blood, 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. The approximate blood sample volume collected 
from each patient will also be included in the patient information/informed consent form 
provided to the patient.
5.2.7
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.
The ECGs must be administered by a qualified technologist and results will be recorded as 
scheduled in the Flow Chart. The investigator or a designee will evaluate whether the ECG is 
normal or abnormal and assess clinical relevance
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in patient’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.
5.2.8
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).
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.


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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.
5.2.9
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.
5.2.10
Assessment of adverse events
5.2.10.1
Definitions of AEs 
5.2.10.1.1 Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a medicinal product and which does not necessarily have to have a 
causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the eCRF and BI SAE form (if 
applicable):
f) Worsening of the underlying disease or of other pre-existing conditions
g) Changes in vital signs, ECG, physical examination, laboratory test results, and
spirometry results, if they are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
5.2.10.1.2 Serious adverse event
A serious adverse event (SAE) is defined as any AE, which fulfils at least one of the 
following criteria:
-
results in death,
-
is life-threatening, which 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,
-
requires inpatient hospitalisation,
-
requires prolongation of existing hospitalisation,
-
results in persistent or significant disability or incapacity,
-
is a congenital anomaly / birth defect,
-
is deemed serious for any other reason if it is an important medical event when based 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 


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above definitions. Examples of such events are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalisation or development of dependency or abuse. 
5.2.10.1.3 AEs considered “Always Serious”
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.10.2, subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. These events should 
always be reported as SAEs as described above.
5.2.10.1.4 Adverse events of special interest (AESI)
The term AESI relates to any specific AE that has been identified at the project level as being
of particular concern for prospective safety monitoring and safety assessment within this 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, please see above.
The following adverse events will be considered AESIs:
∀
Gastrointestinal perforation 
∀
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:
h) ALT and/or AST ≥8 fold ULN
i)
ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN*
j)
ALT and/or AST ≥3 fold ULN and unexplained INR > 1.5*
k) ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)*
l)
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 “drug-induced liver injury (DILI) checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy,
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results
(ALT, AST 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.


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See also Table 4.2.1.2: 1 for recommendations on liver enzyme elevation during the trial and 
how to manage the trial medication and continuation of the trial.
5.2.10.1.5 Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated.
Moderate:
Sufficient 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 5.2.10.1.5: 1).
Table 5.2.10.1.5: 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
5.2.10.1.6 Causal relationship of AEs
Medical judgement should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:
∀
The event is consistent with the known pharmacology of the drug.
∀
The event is known to be caused by or attributed to the drug class.
∀
A plausible time to onset of the event relative to the time of drug exposure.
∀
Evidence that the event is reproducible when the drug is re-introduced.
∀
No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).
∀
The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).
∀
An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:
∀
No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks 
of drug administration; allergic reaction weeks after discontinuation of the drug 
concerned).
∀
Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.
∀
Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).
∀
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged.
5.2.10.2
Adverse event collection and reporting
5.2.10.2.1 AE Collection
The investigator shall maintain and keep detailed records of all AEs in the patient files.
The following must be collected and documented on the appropriate eCRF(s) by the 
investigator:
∀
From signing the informed consent onwards until the individual patient’s End of Study 
(EOS):
•
All AEs (serious and non-serious) and all AESIs.
∀
After the individual patient’s End of Study: 
•
The investigator does not need to actively monitor the patient for new AEs but should 
only report any occurrence of cancer and related SAEs and related AESIs of which 
the investigator may become aware by any means of communication, e.g. phone call.
Those AEs should however not be reported in the eCRF but via SAE form.
•
For an individual patient that completes the study and will participate in the roll-on 
Trial 1199-0225 and continues nintedanib treatment in that trial, the collection of 
adverse events for this trial will stop once the trial was completed for this respective 
patient. Any ongoing AE or new AE that occurs after End of Study (EOS) Visit must 
be reported in the roll-on trial 1199-0225.
•
For an individual patient that discontinues the trial early in Period 1, after intake of 
Microgynon®, the collection of AE will stop after the end of the REP of Microgynon®
(i.e. 3 days).
•
For an individual patient that discontinues the trial early in Period 2 or for any patient 
that decides not to participate in the roll-on Trial 1199-0225, nintedanib treatment will
stop and the collection of AE will stop after the end of the REP for nintedanib (i.e. 7
days) at the Follow-Up (FU) Visit.


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5.2.10.2.2 AE reporting to the sponsor and timelines
The investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions,
the investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.10.2.3 Information required
All (S)AEs, including those persisting after individual patient’s End of Study (EOS) must be 
followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.10.2.4 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 any drug exposure during 
pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the 
Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Parts A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
Cmax, AUC0-tz, and AUC0-# for ethinylestradiol and levonorgestrel will be evaluated to assess 
whether or not nintedanib has an influence on ethinylestradiol and/or levonorgestrel exposure. 
Pharmacokinetic plasma sampling will occur according to the Flow Chart. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) including anti-drug antibodies (if applicable) will be 
generated by these additional investigations. The study samples will be discarded after 


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completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.3.2
Methods of sample collection
A detailed description of sample collection and handling is provided in the ISF. For plasma 
sampling time points, please refer to the Flow Chart. For quantification of drug plasma 
concentrations of ethinylestradiol, levonorgestrel and nintedanib, venous blood will be 
collected using a pre-labelled potassium ethylene-diamine-tetraacetic acid (EDTA) 
containing blood drawing tube. For more details, please refer to the ISF.
5.3.3
Analytical determinations
Nintedanib (in form of its free base BIBF 1120 BS) plasma concentrations will be determined 
by a validated assay based on liquid chromatography-tandem mass spectrometry 
(LC-MS/MS).
Plasma concentrations of ethinylestradiol and levonorgestrel will be determined by a 
validated HPLC-MS/MS assay (high performance LC-MS/MS).
The procedures and specifications of the analytical method are available at the bioanalytical 
site (
).
5.3.4
Pharmacokinetic – pharmacodynamic relationship
Not applicable
5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
The following assessments will be done at Screening Visit 1, or at least prior to first 
nintedanib intake and the results will be considered baseline values if the patient decides to 
participate in the roll-over Trial 1199-0225.
5.6.1
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: fingers, dorsum of hands, forearms, upper arms, 
face, anterior chest, abdomen, thighs, lower legs, dorsum of feet (right and left separately). 
These individual values are added and the sum is defined as the total skin score (R15-1205).


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The result will be considered as baseline mRSS values, prior to intake of nintedanib, if the 
patient decides to participate in the roll-over Trial 1199-0225.
Further instructions regarding mRSS assessment will be provided in the ISF.
5.6.2
Assessment of Digital Ulcers
A Digital Ulcer (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.
The results will be considered baseline DU values, prior to nintedanib intake, if the patient 
decides to participate in the roll-over Trial 1199-0225.
Further instructions regarding Digital Ulcers assessment will be provided in the ISF.
5.6.3
Assessment of questionnaires and derived outcomes
The patient should complete patient reported outcome (PROs) questionnaires on her own in 
the pre-specified order defined in the Flow Chart 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 outcomes will be used as baseline values if the patient 
decides to participate in the roll-over Trial 1199-0225.
The PRO questionnaires should be presented and filled out in the following order:
1. Saint George’s Respiratory Questionnaire (SGRQ)
2. Scleroderma Health Assessment Questionnaire (SHAQ)
3. Scleroderma Gastrointestinal Tract Instrument (SCTC GIT 2.0)
4. Patient’s global impression of health visual analog scale (VAS).
5. Physician’s global impression of health visual analog scale (VAS).
5.6.3.1
Saint George’s Respiratory Questionnaire (SGRQ)
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 the time point 
indicated in the Flow Chart.


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5.6.3.2
Scleroderma Health Assessment Questionnaire (SHAQ)
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 10.3.2) will be self-administered by the patient at the time point
indicated in the Flow Chart. Detailed further instructions regarding the SHAQ administration 
to the patient and scoring is provided in the ISF.
5.6.3.3
Scleroderma Gastrointestinal Tract Instrument SCTC GIT 2.0
The Scleroderma Gastrointestinal Tract Instrument SCTC GIT 2.0 measures and 
differentiates reflux symptoms from the symptoms of distention and bloating. It comprises 8 
scales, which cover the domains: reflux, distention/bloating, diarrhea, fecal soilage (to assess 
rectal incontinence), constipation, pain, emotional well-being and social functioning. 
The SCTC GIT (Appendix 10.3.3) will be self-administered by the patient at the time point
indicated in the Flow Chart at selected sites (if the locally required language is available).
5.6.3.4
Patient’s and physician’s global impression of health
The patient’s global impression of health visual analog scale (VAS; Appendix 10.3.4) will be 
self-administered by the patient at the time point indicated in the Flow Chart and Section 6.
The physician’s global impression of health VAS (Appendix 10.3.5) will be filled out by the 
patient’s physician at the time point outlined in the Flow Chart 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. 


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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).
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements conducted in the trial are using standard methods.
The PK parameters and measurements outlined in Section 5.4 are generally used as 
measurements to assess drug exposure.


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6.
INVESTIGATIONAL PLAN
For details see Flow Chart.
6.1
VISIT SCHEDULE
The patients will come to the hospital(s) or Phase I unit(s) at the time points specified. If a 
patient misses an appointment, it will be rescheduled if possible.
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for the Screening Visit 1 until End of Study Visit are given in the 
Flow Chart.
For planned individual plasma concentration sampling times, refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times 
will be recorded and used for determination of PK parameters
The relevance of measurements outside the permitted time windows will be assessed no later 
than at the Report Planning Meeting.
Days spent (including overnight stays) in hospital(s) or Phase I unit(s) for the purpose of the 
trial (e.g. collection of blood for PK analysis) will not be reported as serious adverse events.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Screening Period
The screening period starts with signature of the informed consent by the patient and ends 
before the administration of Microgynon® in Period 1. 
Baseline Conditions
Any concomitant disease that requires therapy shall be recorded.
Medical History:
The medical history with regard to SSc-ILD shall be documented (i.e. date of first diagnosis, 
as well as details concerning concomitant therapy with start and end dates and the reason why 
therapy is indicated).
6.2.2
Treatment period(s)
Period 1: Microgynon®
Administration of Microgynon® alone will be performed in the time interval given in the 
Flow Chart. In the morning of the respective PK day (or the evening before depending on the 
patient’s situation and the agreement between investigator and patient) the patients will be 
admitted to the hospital or Phase I unit and kept under medical surveillance for at least 12 
hours following drug administration. The patients will then be allowed to leave the trial site 
after formal assessment and confirmation of their fitness. In case the patient and the 


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investigator would decide that the patient will stay overnight for administrative reasons, this 
planned overnight stay will not be reported as SAE. All other blood samplings of this trial 
period will be performed in an ambulatory fashion.
Period 2: Microgynon® during continuous intake of nintedanib
At Day 1 of Period 2 the patients will be instructed to take nintedanib every morning and 
every evening with food during Period 2. The intake of nintedanib on the non-PK days may 
be performed in an ambulatory fashion. 
If the patient would not be able to continuously take nintedanib for at least 10 consecutive 
days (e.g. because of an interruption or dose reduction of nintedanib due to AE), then the 
second administration of Microgynon® has to be postponed until the patient has had 
continuous intake of a stable dose of nintedanib for at least 10 consecutive days.
The administration of Microgynon® may occur on one on the days between Day 11 and Day 
25 of nintedanib intake (see Section 3.1 for further Visit scheduling options). The PK-
profiling in Period 2 may take place only if a continuous intake of nintedanib for at least 10 
consecutive days was confirmed. 
In the morning of the respective PK-day (or the evening before depending on the patient’s
situation and the agreement between investigator and patient) the patients will be admitted to 
the hospital or Phase I unit and kept under medical surveillance for at least 12 hours 
following drug administration. In the morning of the first PK day, nintedanib will be 
swallowed first, followed by Microgynon® (both to be taken within 1 minute with a glass of 
water) and 30 minutes after the breakfast started. After the 12 h blood sample has been 
obtained, the evening dose of nintedanib will be administered. Thereafter the patients will be 
allowed to leave the trial site after formal assessment and confirmation of their fitness. In 
case the patient and the investigator would decide that the patient will stay overnight for 
administrative reasons, this planned overnight stay will not be reported as SAE.
All other blood samplings of this trial period may be performed in an ambulatory fashion.
Nintedanib should be administered at least for the following 2 days (i.e. the morning 
administration is to be done after blood sampling at the trial site, while the evening intake is 
ambulatory).
6.2.3
Trial completion
Before trial completion the patient and investigator will assess whether the patient will 
a) Stop nintedanib treatment in this trial and continue nintedanib therapy in the roll-on 
Trial 1199-0225, or 
b) Permanently stop the nintedanib treatment and perform a Follow-Up Visit 7 days after 
permanent discontinuation of nintedanib.


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For patients who complete this trial (a) and continue in the roll-on Trial 1199-0225, the 
investigations, as documented in the Flow Chart EOT Visit and EOS Visit, will be performed
simultaneously at the earliest 3 days after last intake of Microgynon®. These last assessments
performed at the EOT/EOS Visit will be considered the baseline data for the roll-on trial 
1199-0225, in which the patients will enroll the same day or shortly after.
For patients who permanently discontinue the nintedanib treatment (prematurely or not) (b) 
and/or who will not continue in the roll-on Trial 1199-0225, the investigations as documented 
in the Flow Chart EOT Visit will be done immediately after stop of nintedanib, or at least 3 
days after Microgynon® intake (if applicable) and the FU Visit and EOS Visit will be 
performed simultanously 7 days after last intake of nintedanib.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The primary objective of the current study is to investigate the relative systemic exposure of 
EE and LE when given alone compared to administration in combination with steady-state 
nintedanib.
This open-label study consists of two periods. There will be a fixed sequence design: a single 
oral dose of Microgynon® will be administered alone (reference treatment, R), and in 
combination with 2 x 150 mg nintedanib (or 2 x 100 mg nintedanib, when dose has been 
reduced) at steady-state (test treatment, T).
For each comparison between test and reference treatment, the statistical model used will be 
an ANOVA (analysis of variance) model on the logarithmic scale (see Section 7.3.1).
7.2
NULL AND ALTERNATIVE HYPOTHESES
There is no hypothesis to be tested in a confirmatory sense. Instead, all parameters will be 
described in their entirety and evaluated by descriptive methods. Relative exposure of 
ethinylestradiol and levonorgestrel will be estimated based on the ratios (test to reference 
treatment) of the geometric means (gMeans) of the primary and secondary endpoints. 
Additionally, their 2-sided 90% confidence intervals (CIs) will be provided. 
7.3
PLANNED ANALYSES
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 
protocol deviations (IPD) will be identified no later than in the Report Planning Meeting. The 
IPD criteria and definitions will be described in the Integrated Quality and Risk Management 
Plan (IQRMP), which will be archived in the Trial Master File (TMF).
The following analysis sets will be defined for this trial:
∀
Entered set (ES):
This patient set includes all patients who entered the trial, i.e., who have been assigned a 
patient number, whether treated or not.
∀
Treated set (TS):
This patient set includes all patients in the ES who were documented to have received one 
dose of study drug. 
∀
PK parameter analysis set (PKS):
o
Plasma concentration data and parameters of a patient will be included in the 
statistical PK analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the 
Report Planning Meeting) or due to PK non-evaluability (as revealed during data 


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analysis, based on the criteria specified below). Exclusion of a patient’s data will 
be documented in the Clinical Trial Report (CTR).
o
Relevant protocol deviations may be
•
incorrect trial medication taken, i.e. the patient received at least one 
dose of trial medication the patient was not assigned to
•
incorrect dose of trial medication taken
•
use of restricted medications.
o
Plasma concentrations and/or parameters will be considered as non-evaluable if,
for example
•
the patient experienced emesis that occurred at or before two times 
median tmax of the respective treatment (Median tmax is to be 
determined excluding the patients experiencing emesis),
•
a pre-dose concentration is >5% of the Cmax value of that patient,
•
missing samples/concentration data at important phases of PK 
disposition curve.
o
The PK parameter analysis set includes all patients in the TS who provide at least 
one primary or secondary PK parameter that was not excluded according to the 
description above. Thus, a patient will be included in the PKS, even if she 
contributes only one PK parameter value for one period to the statistical 
assessment.
More details about the statistical analysis will be provided in the Trial Statistical Analysis 
Plan (TSAP), which will be archived in the TMF.
7.3.1
Primary endpoint analyses
The primary analyses will be based on the PKS (Section 7.3).
All PK endpoints listed in Section 2.1 will be calculated according to the BI Standard 
Operating Procedure (SOP) ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
For each comparison between test and reference treatment, the statistical model used will be 
an ANOVA (analysis of variance) model on the logarithmic scale. Thus, prior to fitting the 
ANOVA model, the PK parameters described in Section 2.1.2 will be log-transformed 
(natural logarithm). The difference between the expected means for log(T)-log(R) will be 
estimated by the difference in the corresponding Least Squares Means (point estimate).
Furthermore, the two-sided 90% confidence intervals based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to give the 
point estimator (geometric mean) and interval estimates for the ratio between response under 
test treatment and response under reference treatment.
The above mentioned ANOVA model will include effects accounting for the following 
sources of variation: ‘subjects’ and ‘treatment’. The effect ‘subjects’ will be considered as 


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random, whereas the ‘treatment’ effect will be considered as fixed. The model is described by 
the following equation:
∀
ykm = μ + sm + %k + ekm, where
∀
ykm = logarithm of response (AUC0-tz / Cmax) measured on subject m receiving treatment k
∀
μ = the overall mean,
∀
sm = the effect associated with the mth subject, m = 1, 2, … , n
∀
%k = the kth treatment effect, k = 1, 2,
∀
emk = the random error associated with the mth subject who received treatment k.
As a sensitivity analysis, the model above will be fitted with all effects as fixed (in particular, 
also the ‘subject’ effect).
7.3.2
Secondary endpoint analyses
The secondary PK parameters described in Section 2.1.3 will be analysed as described for the 
primary PK endpoints.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. 
The safety analysis will be based on the TS. In general, safety analyses will be descriptive in 
nature and will be based on BI standards. No hypothesis testing is planned.
The analyses will be done by ‘treatment at onset’.
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 REP (see Section 1.2 and Section 5.2.10.2.1) will be considered ‘treatment-emergent’. 
Therefore, AEs recorded prior to first intake of trial medication will be assigned to 
'screening', those between first Microgynon® intake until end of the REP of Microgynon® in 
Period 1 will be assigned to the Microgynon® treatment period. AEs from intake of 
Microgynon® until the end of REP of Microgynon® during Period 2 will be considered as on-
treatment for Microgynon® plus nintedanib. All other AEs during nintedanib treatment up to 
the end of the trial will be assigned to on-treatment on nintedanib. Events after the end of the 
REP of Microgynon® during Period 1 but prior to the start of nintedanib treatment in Period 2
will be considered as ‘post-treatment’ for Microgynon®. AEs after the End of Study (EOS)
examination will be assigned to ‘post-study’ unless they are within 7 days after last 
nintedanib intake. In this event they would be counted as on-treatment for nintedanib. 
Adverse events that start before first drug intake and deteriorate under treatment will also be 


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considered as ‘treatment-emergent’. These assignments including the corresponding time 
intervals will be defined in detail in the TSAP.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the End of Treatment/End of Study or Follow 
Up/End of Study evaluation will be assessed with regard to possible changes compared to 
findings before start of treatment.
7.3.5
Pharmacokinetic and pharmacodynamic analyses
The PK parameters listed in Sections 2.1.2, 2.1.3 and 2.2.2 will be calculated according to the 
relevant BI internal procedures.
Descriptive evaluations of PK parameters will be based on the PKS (refer to Section 7.3).
Patients who are not included in the PKS will be reported with their individual plasma 
concentrations and individual PK parameters; however, they will not be included in 
descriptive statistics for plasma concentrations, PK parameters or other statistical 
assessments.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format provided in the bioanalytical report, (that is, to the same number of 
decimal places provided in the bioanalytical report).
The following descriptive statistics will be calculated for plasma concentrations and PK 
parameters: number (N), arithmetic mean, standard deviation, minimum, median, maximum, 
arithmetic coefficient of variation, geometric mean, and geometric coefficient of variation. 
The exception to this is tmax, where only median, minimum and maximum will be calculated. 
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. Thereafter, the individual values, as well as the 
descriptive statistics, will be reported with three significant digits in the clinical trial report.
For handling of missing data, please refer to Section 7.5.3.
Analyses will be carried out using Phoenix® WinNonlin® 6.3 (or later) and/or SAS® software, 
version 9.4 (or later).
7.4
INTERIM ANALYSES
No interim analysis is planned.


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7.5
HANDLING OF MISSING DATA
7.5.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.5.2
Plasma concentration - time profiles
Handling of missing PK data will be performed according to the relevant Corporate 
Procedure of the Sponsor (001-MCS-36-472).
Concentration data identified with NOS (no sample), NOR (no valid result), NOA (not 
analysed), or BLQ (below the limit of quantification) will be ignored and not replaced by 
zero at any time point (applies also to the lag phase). Descriptive statistics of concentrations 
at specific time points will be calculated only when at least 2/3 of the individuals have 
concentrations within the validated concentration range. The overall sample size to decide 
whether the “2/3 rule” is fulfilled will be based on the total number of samples intended to be 
drawn for that time point (i.e. BLQ, NOR, NOS, NOA are included)
7.5.3
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ values in the lag phase will be set to zero. The lag phase is 
defined as the period between time zero and the first time point with a concentration above 
the quantification limit. All other BLQ values of the profile will be ignored. 
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case-by-case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis.
∀
If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.
∀
If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However, the excluded concentration itself will be listed in the tables in 
Section 15 of the clinical trial report associated with an appropriate flag. 
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time is not 
recorded or is missing for a certain time point, the planned time will generally be used for this 
time point instead. Pharmacokinetic parameters which cannot be determined will be 
identified by "not calculated" (NC).
7.6
RANDOMISATION
As this is a single fixed sequence trial, no randomisation is necessary.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to obtain 14 patients who can be analysed with regard to the pharmacokinetic 
parameters in both periods. This sample size is considered sufficient to achieve the aims of 
this exploratory trial. Considering possible drop outs due to safety or administrative reasons 


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and the potential intake of co-medication that might interfere with pharmacokinetics of 
Microgynon® (see 4.2.2.1) a total of approximately 24 patients may be enrolled (see Section 
3.3.4.1). If there are less than 14 patients evaluable in both periods, the CT Leader together 
with the Trial Pharmacokineticist and the Trial Statistician are to decide if and how many 
patients will have to be enrolled in addition.
The observed intra-individual coefficient of variation (gCV) for EE and LE in previous trials 
in healthy volunteers (U12-1031; U09-1393; U07-1867; U03-3408; U09-1853) was roughly 
up to 20% for Cmax and 15% for AUC0-tz or AUCτ,ss, respectively. Assuming a gCV of 20% 
and given the chosen sample size of 14 patients, the precision of the two-sided 90% 
confidence interval of the ratio test/reference (AUC and Cmax) will be approximately 1.19 
(upper confidence limit (CL) / point estimate); if only 12 patients will be evaluable in both 
periods, the precision would still be approximately 1.21. Table 7.7: 1 provides an overview of 
the 90% confidence intervals that are expected with 95% probability, for possible scenarios 
of the gCV and intra-patient ratios (test/reference) (T/R), and assuming available data for 
both periods.
Table 7.7: 1
Precision that can be expected with 95% tolerance probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric means 
(T/R) for different gCVs in a fixed sequence trial 
gCV
N
Precision
upper CL/
lower CL
Precision
upper CL/
point estimate
T/R [%]1
90% CI [%]
20%
8
1.702
1.305
70%
(53.65, 91.33)
80%
(61.32, 104.37)
90%
(68.98, 117.42)
100%
(76.65, 130.47)
10
1.561
1.249
70%
(56.03, 87.45)
80%
(64.03, 99.95)
90%
(72.04, 112.44)
100%
(80.04, 124.93)
12
1.475
1.214
70%
(57.65, 85.00)
80%
(65.88, 97.15)
90%
(74.12, 109.29)
100%
(82.35, 121.43)
14
1.416
1.190
70%
(58.83, 83.29)
80%
(67.23, 95.19)
90%
(75.64, 107.09)
100%
(84.04, 118.99)
16
1.373
1.172
70%
(59.74, 82.02)
80%
(68.28, 93.74)
90%
(76.81, 105.45)
100%
(85.35, 117.17)
1 Ratio of the geometric means (test/reference) for a PK endpoint defined by exp(μT)/exp(μR)


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The expected 90% confidence limits in the table were derived by
CI limitupper,lower = exp(ln() ± )
with  being the ratio T/R on original scale and  the distance from the estimate  to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.3.2.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
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 Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014 and other relevant regulations. Investigators and site staff must adhere to 
these principles. Deviation from the protocol, the principles of ICH GCP or applicable 
regulations, will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains 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 patients against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor
with regard to publication of the results of this trial are described in the investigator’s
contract. As a rule, no trial results should be published prior to finalization 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.
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 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 the patient’s participation in the trial, written informed consent must be obtained 
from each patient (or the patient’s legally accepted representative) according to ICH-GCP 
and to the regulatory and legal requirements of the participating country. Each signature must 
be personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be given sufficient time to consider participation in the trial. The 
investigator or delegate 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 or 
 delegate 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.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
The patients will receive reimbursement for participation in the trial which will cover the 
time they spent in the trial unit on the days of PK sampling, and the adherence to the dietary 
and other restrictions.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan (iQRMP) documents the rationale and strategies for risk management
during trial conduct including monitoring approaches, vendor management and other 
processes focusing on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
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.
8.3
RECORDS
Electronic CRFs for individual patients will be provided by the sponsor. For drug 
accountability, refer to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained.
The current medical history of the patient may not be sufficient to confirm eligibility for the 
trial and the investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case, the investigator must make three documented attempts to 
retrieve previous medical records. If this fails, a verbal history from the patient, documented 
in their medical records, would be acceptable.
In the unexpected event that copies of source documents need to be provided to the sponsor 
(e.g. ECG, lab or examination report as an addendum to a SAE report), the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 


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security number) have properly been removed or redacted from any copy of the patients’
source documents, before sending or uploading those copies.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient’s file.
For the eCRF, data must be derived from source documents, for example:
∀
Patient identification: gender, year of birth (in accordance with local laws and 
regulations)
∀
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)
∀
Dates of patient’s visits, including dispensing of trial medication
∀
Medical history (including trial indication and concomitant diseases, if applicable)
∀
Medication history
∀
Adverse events and outcome events (onset date (mandatory), and end date (if available))
∀
Serious adverse events (onset date (mandatory), and end date (if available))
∀
Concomitant therapy (start date, changes)
∀
Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)
∀
Completion of patient’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
∀
Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the patient or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all eCRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in Section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).


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Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the World Health 
Organisation (WHO)GCP handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised 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 at the site
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.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data 
Measures are in place to comply with the applicable rules for the collection of biological 
samples and clinical data, in particular
∀
The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.
∀
An appropriate sample and data management system, including audit trail for clinical 
data and samples to identify and destroy such samples according to ICF is in place.
∀
A fit for the purpose documentation (PK assessment proposal, analysis plan and 
report) ensures compliant usage.
∀
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the PK data.
∀
Samples and/or data may be transferred to third parties and other countries as 
specified in the ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first patient in the whole trial signs 
informed consent.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Completed”).
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment (as scheduled per 
protocol or prematurely). Individual investigators will be notified of Suspected Unexpected 


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Serious Adverse Reactions (SUSAR) occurring with the trial medication until 30 days after 
LPLT at their site. Early termination of the trial is defined as the premature termination of 
the trial due to any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at the different sites 
participating in this trial and to provide input on the CTP, CTR and amendments, if 
applicable. Tasks and responsibilities are defined in a contract. 
Relevant documentation on the participating (Principal) Investigators (e.g. their curricula 
vitae) will be filed in the ISF. The investigators will have access to the BI clinical trial portal 
(Clinergize) to facilitate document exchange and maintain electronic ISF. 
Central laboratory facilities will handle the laboratory analyses of the trial. Samples for 
intermediate measurements (e.g. liver enzymes, creatinine) may be collected by using trial 
specific lab kits that will be sent to central laboratory for analyses. If additional testing is 
required (e.g. pregnancy tests) analysis may also be done by a local laboratory, provided that 
the test results are documented.
Interactive Response technology (IRT) vendor will be used in this trial.
Details will be provided in IRT Manual, the Central Laboratory Manual, available in the ISF. 
BI has appointed a CT Leader responsible for coordinating all required activities, in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of Clinical Trial Managers (CT 
Managers) (former Local Clinical Monitors (CML)), Clinical Research Associates 
(CRAs), and investigators of participating countries.
The organisation of the trial in the participating countries will be performed by the respective 
local or regional BI-organisation (Operating Unit, OPU) in accordance with applicable 
regulations and BI SOPs, or by a Contract Research Organisation (CRO) with which the 


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responsibilities and tasks will have been agreed and a written contract filed before initiation 
of the clinical trial.
Data Management, Pharmacokinetics and Statistical Evaluation will be done by BI according 
to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, 
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Pellegrino R, Viegi G, Wanger J. Standardisation of spirometry. Eur 
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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.
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.
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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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P15-06991
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions (21 
June 2012, CPMP/EWP/560/95/rev. 1 corr. 2). 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_gui
deline/2012/0 7/WC500129606.pdf (access date: 8 July 2015); London: 
European Medicines Agency (EMA) 2012.
P17-11211
Richeldi L, Kreuter M, Selman M,  Crestani B,4 Kirsten AM, Wuyts 
WA, Xu Z, Bernois K, Stowasser S, Quaresma M, Costabel U. Long-
term treatment of patients with idiopathic pulmonary fibrosis with 
nintedanib: results from the TOMORROW trial and its openlabel 
extension. Thorax 73 (6), 581-583 (2018).
P18-08712
Crestani B, Huggins JT, Kaye M, Costabel U , Glaspole I, Ogura T, 
Song JW, Stansen W, Quaresma M, Stowasser S, Kreuter M. Long-term 
safety and tolerability of nintedanib in patients with idiopathic 
pulmonary fibrosis: results from the open-label extension study, 
INPULSIS-ON. Lancet Respir Med 7(1), 60-68 (2019).
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Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992
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Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum 
creatinine. Nephron 1976. 16(1):31-41.
R98-0966
Jones PW, Quirk FH, Baveystock CM. The St.George's respiratory 
questionnaire. Respir Med 1991. 85(Suppl B):25-31.
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.
R11-0382
Ragueneau-Majlessi I, Levy RH, Janik F. Levetiracetam does not alter 
the pharmacokinetics of an oral contraceptive in healthy women. 
Epilepsia 2002. 43(7):697-702
R11-0385
Kelly S, Davies E, Fearns S, McKinnon C, Carter R, Gerlinger C, 
Smithers A. Effects of oral contraceptives containing ethinylestradiol 
with either drospirenone or levonorgestrel on various parameters 
associated with well-being in healthy women: a randomized, single-
blind, parallel-group, multicentre study. Clin Drug Invest 2010. 
30(5):325-336


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Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor &
Francis Group 2010.
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Microgynon 0,03 mg/15 mg ueberzogene Tabletten (Bayer Vital), 
verschreibungspflichtig (Fachinformation (Zusammenfassung der 
Merkmale des Arzneimittels), Stand der Information: April 2007.
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.
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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.
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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.
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Bruce B, Fries JF. The Health Assessment Questionnaire (HAQ). Clin 
Exp Rheumatol 2005. 23(Suppl 39):S14-S18.
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Tashkin DP, et al. Cyclophosphamide versus placebo in scleroderma 
lung disease. N Engl J Med 2006. 354(25):2655-2666.
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.
R15-2010
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.
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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.


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R16-0373
Recommendations related to contraception and pregnancy testing in 
clinical trials (final version - 2014-09-15). 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/ 
CTFG/2014_09_HMA_CTFG_Contraception.pdf (access date: 2 
February 2016); Clinical Trial Facilitation Group (CTFG), Head of 
Medicine Agencies (HMA) 2014
9.2
UNPUBLISHED REFERENCES
c01783972-12
Investigator’s Brochure (IB) ‘Nintedanib in Idiopathic Pulmonary 
Fibrosis, Systemic Sclerosis, Progressive Fibrosing Interstitial Lung 
Disease’.
c09412738
Influence of bosentan on the pharmacokinetics of nintedanib in healthy 
male subjects, Study 1199.239, 10 November 2016
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)
c01762736
 Relative bioavailability of nintedanib given 
alone and in combination with ketoconazole at steady state in healthy 
male volunteers (an open-label, randomised, two-way cross-over clinical 
Phase I study) 1199.161 15 Nov 2012
c03149997
: Pharmacokinetics, 
safety and tolerability of nintedanib single oral dose in male and female 
patients with different degrees of hepatic impairment (Child-Pugh 
classification A and B) as compared with nintedanib administration to 
male and female healthy subjects (a non-blinded, parallel group study of 
Phase I). 20 May 2015
U03-3408
Appendix 16.1.9.2 Statistical analysis. 1188.22. 30 Apr 2003
U04-2195
: The effect of BIBF 1120 ES and known model CYP inducers 
on hepatic levels of cytochrome P450 and related parameters in male 
Wistar rats after administration for 4 days. 24 Nov 2004
U07-1867
. An 
open, randomised, two-way cross-over trial to evaluate the effect of 
multiple doses of flibanserin on the single dose pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel. 511.93. 23 Apr 2008
U09-1393
. 16.1.9 Documentation of statistical - bioanalytical 
and pharmacokinetic analysis. 1218.44. 
U09-1731
 BIBF 1120 ES: In vitro cytochrome P450 enzyme induction 
in primary human hepatocytes. 03 Sep 2009
U09-1853
. 
Assessment of the effect of 480 mg and 1200 mg of BI 201335 as single 
dose on the QT interval in healthy female and male subjects; a 


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randomised, placebo-controlled, double-blind, four-way crossover Phase 
I study with moxifloxacin as positive control. 1220.16. 23 Sep 2009
U12-1031
. 16.1.9 Documentation of statistical -
bioanalytical and pharmacokinetic analysis. 1245.41
U13-1478
. 
Relative bioavailability of a single oral dose of nintedanib given alone 
and in combination with multiple oral doses of rifampicin in healthy 
male volunteers (an open-label, two-period, fixed-sequence Phase I 
trial), Study report 1199.162.
001-MCS-36-472
SOP “Standards and processes for analyses performed within Clinical
Pharmacokinetics/Pharmacodynamics


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10.
APPENDICES
10.1
LUNG FUNCTION CRITERIA 
At Visit 1, 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 site’s own spirometer. FVC percent
predicted is a key inclusion criterion.
At End of Treatment, FVC is required as final safety assessment and when a patient will be 
rolling over into trial 1199.225.
At Visit 1, 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/(9.38+Hb)) for 
females.
For decision on inclusion / exclusion, DLCO results from Visit 1 will be corrected for
haemoglobin (value obtained at Visit 1) by the site. 
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.
10.2
CREATININE CLEARANCE
Creatinine clearance calculation is done according to Cockroft and Gault (R96-0690).
∀
Creatinine clearance = (140 - age) x (Weight in kg) x (0.85 if female) / (72 x serum 
creatinine in mg/dL)


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10.3
QUESTIONNAIRES
10.3.1
St. George’s Respiratory Questionnaire (SGRQ)


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10.3.2
Scleroderma Health Assessment Questionnaire (SHAQ)
HAQ-DI part:


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SHAQ-VAS part:


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10.3.3
Scleroderma Gastrointestinal Tract Instrument SCTC GIT 2.0


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10.3.4
Patients Global Impression of health


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10.3.5
Physician’s Global Impression of patients’s health


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Number of global amendment
01
EudraCT number
2018-001177-24
BI Trial number
1199-0340
BI Investigational Product(s)
Nintedanib
Title of protocol
A Phase I trial to investigate the effect of 
nintedanib on the pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel 
in female patients with Systemic Sclerosis 
associated Interstitial Lung Disease (SSc-ILD)
Global amendment due to urgent safety reasons
☐
Global amendment
☒
Section to be changed
1.
Cover Page 1 
2.
Synopsis; Section 3.3.2. (inclusion crit. 3);
Section 4.2.2.4; Section 5.2.10.2.4
3.
Flow Chart and footnote 11; Section 3.3.4.1; 
Table 5.2.6: 1.
4.
Flow Chart (AE)
5.
Flow Chart footnote 3; Section 3.3.2 (incl 6); 
Section 5.2.5
6.
Flow Chart footnote 5
7.
Abbreviations.
8.
Section 1.1
9.
Section 1.2.1; Section 9.1
10. Section 1.4.1; Section 3.3.4.1; Section 
5.2.10.2.4
11. Section 3.1; Section 5.2.1; Sections 5.2.10.2.1, 
5.2.10.2.3, Section 6.1; Section 7.3.4
12. Section 3.2
13. Section 3.3.3 exclusion criterion 26.
14. Flow Chart (time window FU, EOS); Section 
3.3.3 Section 3.3.4.2; Sections 4.1.1, 4.1.2, 
4.1.3, 4.2.1.1; Section 4.3; Section 5.2.6; 
Section 5.2.10.1.4; Section 5.6.3; Section 
7.3.4; Section 8.7; Section 10.1.
15. Section 4.1.3
16. Sections 4.1.3 and 4.1.4
17. Section 4.2.2.1
18. Section 4.2.2.1
19. Section 4.3
20. Section 5.2.3


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21. Section 5.2.6; Section 8.7
22. Section 5.2.10.2.1; Section 7.3.4
23. Section 7.3; Section 8
24. Section 8.5
25. Section 8.6
Description of change
1. EudraCT no. had been incorrectly copied and 
has been corrected; 
2. Not only permanently sterilized or post-
menopausal women but also women of 
childbearing potential (WOCBP) will be 
allowed to participate, including additional 
information on the types of birth control 
methods to be used by WOCBP during the 
trial. 
3. Pregnancy testing at Visits 1, Visit 5 EOT and 
FU Visit for WOCBP.
4. Mark added in Flow Chart specifying that AE, 
SAE, AESI will be checked at Visit 1 as well.
5. To allow HRCT to be performed at Visit 1, if 
no scan is available < 12 months old. HRCT 
scan at Visit 1 was not allowed in Germany in 
the SENSCIS trial 1199.214, so it will also not 
be done in Germany for this trial.
6. Echocardiography was incorrectly abbreviated 
and therefore ‘(ECG)’ was removed
7. Some abbreviations added/corrected.
8. A paragraph was added with information on 
the completed phase III trial in SSc-ILD, 
SENSCIS (1199.214), the DMC and open 
label extension SENSCIS-ON trial 1199.225.
9. Correction: open-label extension trials 
TOMORROW and INPULSIS are not 
ongoing anymore, but have been completed 
and references to their publications have been 
added.
10. Added risk information on the possible effect 
of nintedanib on (hormonal) contraceptive and 
birth control methods to be used, including 
safety monitoring to exclude pregnancy.
11. End of trial changed to End of Study (EOS), 
conform wording in Flow chart and eCRF and 
to avoid confusion/mixup with abbreviation 
EOT for End of Treatment.
12. As stated elsewhere in the protocol, potential 
inductive effect of nintedanib will be 
investigated after 10 days of continuous 
dosing, not after 7 days, so the number of days 


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has been corrected to 10.
13. Addition of exclusion criterion 26, stating that 
women who are pregnant, nursing or plan to 
become pregnant are excluded from the trial.
14. Various minor textual corrections, spelling or 
inconsistency errors in the protocol version.
15. Registration of trial participants and allocation 
of the trial medication in/by the IRT system 
has been removed.
16. Added information that the Microgynon®
blister package contains 21 tablets. And 
correction of the remaining number of tablets
in the blister from 26 to 19.
17. Change the mycophenolate restriction from 8 
weeks prior to Visit 1 to 2 weeks prior to Visit 
2.
18. Ciclosporine (mentioned twice in Table 
4.2.2.1: 1) restriction was aligned and footnote 
9 was added to indicate that topical 
applications of Ciclosporine A are allowed.
19. Added information: for treatment compliance 
check also the drug accountabilty forms must 
be used.
20. Reference to Appenix 10.1 added on how to 
calculate FVC in % of predicted.
21. Addition of an explanation that pregnancy 
testing (ß-HCG in serum or urine dipstick) can 
either be done by central or local laboratory
(in a footnote underneath Table 5.2.6: 1,  and 
in Section 8.7)
22. ‘Collection of AE will stop after the REP 
of …’ has been changed to ‘Collection of AE 
will stop after the end of REP of…’
23. IPDs are described in the IQRMP. And the 
addition that any deviations from the protocol, 
the principles of ICH GCP or applicable 
regulations will be treated as ‘protocol 
deviation’.
24. Reference to principle 6 and 12 was corrected 
to principle 7 and 12 in WHO (GCP) 
handbook and sentence on confidentiality of 
individual patient data should not refer to 
Section 8.7, but to the last two sentences in 
this paragraph. 
25. Bullet point with explanation underneath the 
‘end of trial’ definition was removed.
Rationale for change
1.
Administrative correction.


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2.
By including WOCPB the potential pool of 
eligible patients is expanded to ensure the trial 
meets recruitment targets, whilst maintaining 
the safety for the participants by putting in 
place adequate contraception measures. 
3.
Added safety (pregnancy) check for WOCBP.
4.
Added AE/SAE/AESI check at Visit 1, e.g. to 
check if a patient who has (temporarily) 
stopped restricted medication for the trial, 
after giving informed consent, has
experienced adverse events because of 
changed concomitant therapy.
5.
After discussion and request by investigator(s)
because potentially eligible patients were 
identified without HRCT scan, for which they 
need do perform an HRCT in order to confirm 
ILD diagnosis and extend of fibrosis in the 
lung.
6.
Administrative correction.
7.
Administrative correction.
8.
Updated information on the phase III trial 
SENSCIS 1199.214, DMC monitoring the 
phase III safety data and extension trial 
SENSCIS-ON 1199.225 in SSc-ILD, since 
part of this was missing in the introduction.
9.
Updated information with references to the 
publications of the open-label extension trials 
with nintedanib in IPF (TOMORROW and 
INPULSIS) was added.
10. Because WOCPB can be included now as 
well.
11. Administrative correction.
12. Error correction.
13. Pregnancy must be excluded because of 
potential teratogenic effect of nintendanib and 
nursing should also be discontinued during 
treatment with nintedanib, because there may 
be a risk for harm to the breast-feeding child
(see SmPC for Ofev®).
14. To clarify and avoid misunderstanding and 
increase readability.
15. Patient registration and medication allocation 
of the IRT system will not be used for this 
trial, since these funcitonalities were not 
considered necessary for a non-randomized 
open-label trial. The IRT system will only be 
used for managing the ordering, shipment and 


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return of IMP to and from the sites.
16. The text erroneously implied that the 
dispensed Microgynon® blister would contain 
28 tablets, but there are only 21 tablets in the 
blister. One blister per patient will be 
dispensed and only 2 tablets will be used per 
patient in this trial, therefore 19 tablets will 
remain unused in the blister.
17. After discussion and request by several 
investigators, because potentially eligible 
patients were identified using mycophenolate. 
The trial pharmacokineticist confirmed that,
based upon the half-life of mycophenolate
(about 18± 6.5 hours), a washout of 2 weeks 
prior to start of Microgynon (at Visit 2) would 
be sufficient to rule out possible interaction
between mycophenolate and levonorgestrel. 
18. Ciclosporine (mentioned twice in Table 
4.2.2.1: 1) restriction was inconsistent. Project 
phamacokineticist confirmed that restriction 
only applies to the oral formulation.
19. Clarification.
20. Missing relevant information.
21. It is planned that all safety laboratory analyses 
will be performed at the central laboratory. 
However, serum or urine pregnancy 
laboratory kits and analysis may also be 
provided and assessed locally, if needed.
22. Clarification.
23. Explanation and renaming protocol violations 
to protocol deviations. The IPD definitions are 
not described in the TSAP anymore, but are 
described in the IQRMP, in accordance with 
the revised sponsor’s SOP.
24. Error corrections
25. The definition for ‘end of trial’ is already 
given. The bullet point with explanation ‘EOS 
Visit for all individual patients’ is redundant 
and might lead to confusion and was therefore 
removed.


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BI Trial No.: 1199-0340
c21847264-03
Clinical Trial Protocol
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001-MCS-40-106-RD-03 (15.0) / Saved on: 30. Nov 2017
11.2
GLOBAL AMENDMENT 2
Number of global amendment
02
EudraCT number
2018-001177-24
BI Trial number
1199-0340
BI Investigational Product(s)
Nintedanib
Title of protocol
A Phase I trial to investigate the effect of 
nintedanib on the pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel 
in female patients with Systemic Sclerosis 
associated Interstitial Lung Disease (SSc-ILD)
Global amendment due to urgent safety reasons
☐
Global amendment
☒
Section to be changed
Synopsis and Section 3.3.2
Description of change
Inclusion criterion 5:  1st onset non-Raynaud 
symptom within 7 year of Visit 1, is no longer 
applicable in global protocol amendment 2
Rationale for change
Ensure trial conduct feasibility and completion.
This inclusion criterion 5 was taken over from the 
phase III SENSCIS trial 1199.214, where this entry 
criterion was considered relevant in relation to the 
efficacy assessment. In DDI trial 1199-0340 
efficacy is not one of the endpoints (and in the 
extension trial 1199.225 efficacy is also not the 
main objective), therefore it has been decided that 
this inclusion criterion 5 should be removed, since 
this might facilitate enrolment of patients, who had 
their 1st non-Raynaud symptom more than 7 years 
from Visit1, and completion of the study.
For technical reasons (EDC/ eCRF database) we 
have decided to strike through the text concerning 
inclusion criterion 5 and not to completely delete 
it. A deletion of the inclusion criterion 5 text would 
have resulted in a shift in numbering of the 
inclusion criteria thereafter, which might lead to 
technical programming complications.


 
 
 
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Technical Version Number:
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Title: 
                                                                                                                   
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SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c25923826-02
BI Trial No.:
1199-0340
Title:
A Phase I trial to investigate the effect of nintedanib on the 
pharmacokinetics of a combination of ethinylestradiol and 
levonorgestrel in female patients with Systemic Sclerosis 
associated Interstitial Lung Disease (SSc-ILD)
Including Protocol Amendment 1 [c21847264-02]
Including Protocol Amendment 2 [c21847264-03]
Investigational
Products:
Nintedanib
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
08 NOV 2019 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINTS.............................................................................10
5.2.1
Key secondary endpoints....................................................................................10
5.2.2
Secondary endpoints...........................................................................................10
5.3.1
Safety parameters ...............................................................................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................13
6.1
TREATMENTS...................................................................................................13
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................16
6.3
PATIENT SETS ANALYSED...........................................................................18
6.5
POOLING OF CENTRES .................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................19
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................20
7.
PLANNED ANALYSIS......................................................................................21
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........22
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................22
7.4
PRIMARY ENDPOINTS...................................................................................22
7.5
SECONDARY ENDPOINTS.............................................................................23
7.5.1
Key secondary endpoints....................................................................................23
7.5.2
Secondary endpoints...........................................................................................23
7.6.1
Safety parameters of interest .............................................................................24
7.7
EXTENT OF EXPOSURE.................................................................................24
7.8
SAFETY ANALYSIS..........................................................................................24
7.8.1
Adverse events.....................................................................................................24


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7.8.2
Laboratory data ..................................................................................................26
7.8.3
Vital signs.............................................................................................................26
7.8.4
ECG......................................................................................................................26
7.8.5
Others...................................................................................................................26
7.8.5.1
Spirometry.............................................................................................................26
7.8.5.2
Body weight ..........................................................................................................27
7.8.5.3
Physical examination ............................................................................................27
7.8.5.4
Doppler echocardiography....................................................................................27
7.8.5.5
Pregnancy test .......................................................................................................27
8.
REFERENCES....................................................................................................28
10.
HISTORY TABLE..............................................................................................30


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs and vital signs ..14
Table 6.1: 2
Flow chart of analysis phases for statistical analyses of safety laboratory......16
Table 6.2: 1
Handling of important PDs ..............................................................................18
Table 6.3: 1
Patient sets analysed.........................................................................................19
Table 10: 1
History table .....................................................................................................30


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ACR
American College of Rheumatology
AE
Adverse event
AESI
Adverse events of special interest
ADS
Analysis data set
ANOVA
Analysis of variance
ALT
Alanine transaminase (also called alanine aminotransferase, ALAT)
AST
Aspartate transaminase (also called aspartate aminotransferase, ASAT)
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
CARE
Clinical data analysis and reporting environment
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DLCO
Carbon monoxide diffusion capacity of the lungs
ECG
Electrocardiogram
eCRF
Electronic case report form
ES
Entered set
EudraCT
European union drug regulating authorities clinical trials
EULAR
European League against Rheumatism
FEV1
Forced expiratory volume in 1 second
FVC
Forced vital capacity
gMean
Geometric mean
gCV
Geometric coefficient of variation
Hb
Haemoglobin
HRCT
High resolution computer tomography
ICH
International Conference on Harmonisation
ILD
Interstitial lung disease
iPD
Important protocol deviation
IQRMP
Integrated quality and risk management plan


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Term
Definition / description
MedDRA
Medical Dictionary for Regulatory Activities
mRSS
modified Rodnan Skin Score
NOA
Not analysed
NOR
No valid result
NOS
No sample available
PD
Protocol deviation
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter analysis set
R
Reference treatment
RAGe
Report appendix generator system
REP
Residual effect period
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
SDL
Subject data listing
SI
Système international d'unités
SSc
Systemic sclerosis
T
Test treatment
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper level of normal
VAS
Visual analog scale


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9 (1), the purpose of this 
document is to provide a more technical and detailed elaboration of the principal features of 
the analysis described in the Clinical Trial Protocol (CTP), and to include detailed procedures 
for executing the statistical analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the CTP. 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.
Study data will be stored in a trial database within the Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE 
(Clinical data Analysis and Reporting Environment), including SASTM (current Version 9.4, 
by SAS Institute Inc., Cary, NC, USA), and providing SASTM-based tools (e.g., macros for 
the analyses of adverse event (AE) data or laboratory data; Report Appendix Generator 
system (RAGe) for compilation/formatting of the clinical trial report (CTR) appendices). 
Pharmacokinetic (PK) parameters will be calculated using Phoenix® WinNonlin® 6.3 (or 
later, Pharsight Corporation, Mountain View, CA 94041-1530, USA) and/or SAS® software, 
version 9.4 (or later).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
As compared to the CTP, the following changed in the planned analysis of this study:
For the display of adverse event data, the time intervals after residual effect periods of 
treatments have been renamed from ‘post-treatment’ to ‘follow-up’ (in contrast to Section 
7.3.4 of the CTP).
CTP states in Section 7.3.4: Treatment groups will be compared descriptively with regard to 
distribution parameters [of laboratory data] as well as with regard to frequency and 
percentage of patients with abnormal values or clinically relevant abnormal values.
This analysis was not adopted by the initial TSAP. Considering the rather sparse time points 
of safety laboratory sampling, and the absence of samples within the residual effect period of 
Microgynon® in both treatment periods (as per CTP), the value of a descriptive analysis was 
considered to be questionable.
CTP states in Section 2.2.1: Pre-dose (trough) plasma concentration monitoring of steady-
state nintedanib will be performed in order to assess whether ethinylestradiol and/or 
levonorgestrel have an influence on the exposure of nintedanib. CTP Section 2.2.2 clarifies: 
Pre-dose (trough) plasma levels concentration (Cpre,ss) of nintedanib at steady state will be 
assessed to prove [nintedanib] exposure. This TSAP adopts the statement from Section 2.2.2.
As compared to the initial TSAP of this trial, the following changed in the planned analysis 
of this study:
As specified in CTP Section 5.2.10.2.1, AEs that started after the individual patient's End of 
Study will not be reported in the eCRF. (For an individual patient who completes the study 
and will participate in the roll-on Trial 1199-0225, any ongoing AE or new AE that occurs 
after End of Study must be reported in the roll-on trial 1199-0225.) Therefore, assignment of 
AEs after the End of Study examination to the "post-study" phase is not applicable. There 
will be no such AEs in the database and no "post-study" phase in AE analyses. The "post-
study" phase defined in Table 6.1: 1 of the initial TSAP was not adopted by this final TSAP.
As specified in CTP Section 7.3.4: All other AEs [except for AEs from intake of 
Microgynon® until the end of REP of Microgynon® during Period 2] during nintedanib 
treatment up to the end of the trial will be assigned to on-treatment on nintedanib.
In Table 6.1: 1 of the initial TSAP, a nintedanib follow-up phase was defined, which is not in 
accordance with the definition quoted above. Therefore, the nintedanib follow-up phase was 
not adopted by this final TSAP and the definition of the on-treatment nintedanib phase was 
adapted to match the definition quoted above.


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Further changes compared to the initial TSAP:
∀
Definition of further safety parameters of interest was added to Section 5.3.1.
∀
Baseline parameters were added to list of baseline characteristics in Section 5.4.1, 
respective analyses were added to Section 7.1.
∀
Definition of nintedanib treatment compliance was added to Section 5.4.2 and its 
presentation was specified in Section 7.3.
∀
Definition of nintedanib treatment exposure was revised in Section 5.4.2.
∀
Definition of AE analysis phases in Table 6.1: 1 and definition of AE collapsing in 
Section 7.8.1 were adapted to the decision that clock time will not be collected in the 
eCRF.
∀
Definition of analysis phases in Section 6.1 was restricted to AE, vital signs and 
laboratory data, will not be needed for spirometry.
∀
Table 6.2: 1 was added to specify which important PDs could potentially lead to 
exclusion from which analysis set.
∀
Definition of an enrolled set was added to Section 6.3.
∀
Analyses of AEs by safety topic were added to Section 7.8.1.
∀
Descriptive analysis of vital signs were added to Section 7.8.3.
∀
Presentation of pregnancy test results was added in Section 7.8.5.5.
∀
A few additional clarifications were added, text was adapted to the new BI standard 
process (e.g., use of a decision log to capture RPM decisions).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are defined in Section 2.1.2 of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable, as no key secondary endpoint was specified in the CTP.
5.2.2
Secondary endpoints
The secondary endpoint is defined in Section 2.1.3 of the CTP.
5.3.1
Safety parameters
Safety will be assessed based on the following further parameters of interest:
∀
AEs (including clinically relevant findings from the physical examination)
∀
Safety laboratory tests
∀
Vital signs (blood pressure, pulse rate)
∀
Spirometry
∀
Clinically relevant findings from physical examination, 12-lead ECG. and 
echocardiography (as part of AE analysis)
Marked changes in vital signs will be defined as follows.
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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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on the treatments to be administered and selection of dose, cf. 
Section 4 of the CTP. All patients will undergo two treatment periods in a fixed sequence.
Each patient is planned to be treated in two subsequent treatment periods. In the first 
treatment period, patients will receive a single dose of Microgynon® (30 mcg ethinylestradiol 
and 150 mcg levonorgestrel; reference treatment, R). In the second treatment period, patients 
will receive a single dose of Microgynon® after continuous intake of a stable dose of 
nintedanib (150 mg b.i.d. or 100 mg b.i.d.) for at least 10 consecutive days (test treatment, T).
Nintedanib treatment will be continued for at least 14 days to approximately 28 days in this 
trial. The sequence of these treatment periods is fixed and the same for all patients.
Microgynon® intake in the first treatment period will be at least 3 days before first nintedanib 
intake in the second treatment period.
For statistical analysis of AEs and vital signs, and for listings of safety laboratory, study 
phases are defined for each patient as described in Table 6.1: 1 and Table 6.1: 2. Note that 
only the date of AE onset is reported in the eCRF, but not the clock time.


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Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs and vital signs
Study analysis phase
Label
Start (included in phase)
End (excluded from phase)
Screening
Screening
Date of informed consent
Date of first administration of 
study drug
On-treatment
microgynon
MIC
Date of administration of 
microgynon in Treatment 
Period 1
I.e., the day of administration of 
microgynon is included in this 
phase.
Day of end of REP (3 days) of 
microgynon:
Date of administration of 
microgynon in Treatment 
Period 1 + 3 days
I.e., the day of end of REP is 
excluded from this phase.
OR
Date of first administration of 
nintedanib in Treatment 
Period 2
(whichever occurs first).
Follow-up
microgynon
FUP-MIC
Date of administration of 
microgynon in Treatment 
Period 1 + 3 days
Date of first administration of 
nintedanib in Treatment 
Period 2
This phase does not exist, if 
start ≥ end.
On-treatment
nintedanib loading 
phase
Loading NIN
Date of first administration of 
nintedanib in Treatment 
Period 2
Date of administration of 
microgynon in Treatment 
Period 2
On-treatment
nintedanib plus 
microgynon
NIN+MIC
Date of administration of 
microgynon in Treatment 
Period 2
I.e., the day of administration of 
microgynon is included in this 
phase.
Day of end of REP (3 days) of 
microgynon:
Date of administration of 
microgynon in Treatment 
Period 2 + 3 days
I.e., the day of end of REP of 
microgynon is excluded from 
this phase.


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Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs and vital signs
(continued)
Study analysis phase
Label
Start (included in phase)
End (excluded from phase)
On-treatment
nintedanib
NIN
Date of administration of 
microgynon in Treatment 
Period 2 + 3 days
Day after last contact date
OR
If patient is reported to 
continue into the 1199-0225 
rollover study: Day after day 
of End of Treatment visit 
(which will be done 
simultaneously to End of 
Study visit)
This phase does not exist, if 
start ≥ end.
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phases "MIC", "Loading NIN", "NIN+MIC", and "NIN"
only. Screening and FUP-MIC will not be included in this analysis. CTR Section 15 AE 
displays (but not Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays) will 
additionally present the following totals:
∀
"Total NIN", defined as the total over on-treatment phases involving nintedanib, i.e. 
"Loading NIN" + "NIN+MIC" + "NIN".
∀
"Total on-trt", defined as the total over all on-treatment phases, i.e., "MIC" + 
"Loading NIN" + "NIN+MIC" + "NIN".
CTR Appendix 16.1.13.1.8.1 displays will present results for all study analysis phases 
defined in Table 6.1: 1 above, and will additionally present the following totals:
∀
"Total NIN", defined as the total over on-treatment phases involving nintedanib, i.e. 
"Loading NIN" + "NIN+MIC" + "NIN".
∀
"Total", defined as the total over all study analysis phases.


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Table 6.1: 2
Flow chart of analysis phases for statistical analyses of safety laboratory
Study analysis phase
Label
Start (included in phase)
End (excluded from phase)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
microgynon
MIC
Date/time of administration of 
microgynon in Treatment 
Period 1
Date/time of administration of 
microgynon in Treatment 
Period 1 + REP (72 h)
OR
Date/time of first 
administration of nintedanib in 
Treatment Period 2
(whichever occurs first).
Follow-up
microgynon
FUP-MIC
Date/time of administration of 
microgynon in Treatment 
Period 1 + REP (72 h)
Date/time of first 
administration of nintedanib in 
Treatment Period 2
On-treatment
nintedanib loading 
phase
Loading NIN
Date/time of first administration 
of nintedanib in Treatment 
Period 2
Date/time of administration of 
microgynon in Treatment 
Period 2
On-treatment
nintedanib plus 
microgynon
NIN+MIC
Date/time of administration of 
microgynon in Treatment 
Period 2
Date/time of administration of 
microgynon in Treatment 
Period 2 + REP (72 h)
On-treatment
nintedanib
NIN
Date/time of administration of 
microgynon in Treatment 
Period 2 + REP (72 h)
12:00 a.m. on day after last 
contact date
More details on the technical implementation of these analyses are provided in the Analysis 
Data Set (ADS) Plan of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
entered set, as defined in Section 7.3 of the CTP.
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the report planning meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol deviation (PD). For definition of important PDs, and for 
the process of identification of these, refer to the Boehringer Ingelheim (BI) reference 
document "Integrated Quality and Risk Management Process" (2).
If any important PDs are identified, they are to be summarised into categories and will be 
captured in the decision log and DV domain specification sheet (11). Categories which are 
considered to be important PDs in this trial are defined in the integrated quality and risk 


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management plan (IQRMP). If the data show other important PDs, the definition in the 
IQRMP will be supplemented accordingly by the time of the RPM.
Important PDs will be summarized and listed. Table 6.2: 1 below specifies which kind of 
important PDs could potentially lead to exclusion from which analysis set. The decision on 
exclusion of subjects from analysis sets will be made at the latest at the Report Planning
Meeting, after discussion of exceptional cases and implications for analyses. If the data show 
other important PDs, this table will be supplemented accordingly by the time of the Report 
Planning Meeting.


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Table 6.2: 1
Handling of important PDs
PD code
PD Category & Brief Description
Excluded from which analysis set
A1.01 –
A1.08
Inclusion Criteria Not Met
PKS
A2.01 –
A2.26
Exclusion Criteria Violated
PKS
B1
Informed consent not available/not 
done
TS, PKS
B2
Informed consent too late
None
C1
Incorrect trial medication taken (i.e., 
deviation from the correct intended 
medication)
PKS
C2
Incorrect dose of trial medication taken
PKS
C3
Patient did not continuously take at 
least 10 consecutive days of a stable 
dose of nintedanib (b.i.d.) prior to the 
PK visit assessments in Period 2 (Visit 
6)
PKS
C4
The patient missed one (or more) 
nintedanib capsules in the 3 days prior 
to or during PK profiling at Visits 6, 7, 
8
PKS
D1
Prohibited medication use (cf. CTP 
Table 4.2.2.1:1)
PKS
D2
Improper washout of concomitant 
medication (cf. CTP Table 4.2.2.1:1)
PKS
G1
Incomplete intake of meal. Or non-
adherence to dietary restrictions (cf. 
CTP Section 4.2.2.3)
PKS
G2
Treatment compliance not in 
accordance with protocol definition (cf. 
CTP section 4.3)
None
6.3
PATIENT SETS ANALYSED
All patients who received study medication will be included in the safety analysis and in the 
PK analysis depending on the availability of measurement values, and on their adherence to 
the CTP.


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The enrolled set (ENR) includes all patients who signed informed consent.
Other analysis sets are defined in Section 7.3 of the CTP. The discussion of all exceptional 
cases and problems and the decisions on the allocation of patients to analysis sets will be 
made at latest at the RPM.
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
Enrolled 
set (ENR)
Entered set 
(ES)
Treated set 
(TS)
PK parameter 
analysis set (PKS)
Important PDs
X
Disposition
X
X
X
Demographic/baseline 
characteristics
X
Safety parameters of interest
X
PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable because centre is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
The reason for withdrawal (e.g. adverse events) as recorded in the electronic Case Report 
Form (eCRF). will be reported.
With respect to safety evaluations, it is not planned to impute missing values.
The only exception where imputation might be necessary for safety evaluation is AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see 001-MCG-
156_RD-01 (3).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (4). Concentration data identified with NOS (no sample), NOR (no valid 
result), NOA (not analysed), or BLQ (below the limit of quantification) will be ignored and 
not replaced by zero at any time point (applies also to the lag phase).
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ values in the lag phase will be set to zero. The lag phase is 


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defined as the period between time zero and the first time point with a concentration above 
the quantification limit. All other BLQ values of the profile will be ignored.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as the last value prior to first administration of study drug.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (001-MCG-159) (9).
The individual values of all patients will be listed by patient number and visit (if visit is 
applicable in the respective listing). Listings will also show treatment sequence, although all 
patients received treatments in the same sequence. AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in 
Appendix 16.2 of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters, the following descriptive 
statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
Moreover, the 10th, 25th, 75th and 90th percentiles will be also presented in Section 15.6.2 for 
the descriptive statistics of the PK parameters.
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. 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 CTR.
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 
total number of patients. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all patients in the respective patient set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
For Saint George’s Respiratory Questionnaire (SGRQ), Scleroderma Health Assessment 
Questionnaire (SHAQ) and Scleroderma Gastrointestinal Tract Instrument (SCTC GIT 2.0), 
all answers will be listed.
For all other demographic and baseline characteristics, descriptive statistics are planned.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded
according to the most recent version of the World Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR. All reported diseases and 
medications will be summarized and listed.
A medication will be considered concomitant to study drug treatment, if it
∀
is ongoing at the time of first administration of study drug (Microgynon® or 
nintedanib) or
∀
starts after the time of first administration of study drug (Microgynon® or nintedanib)
(see also Section 6.1).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
7.3
TREATMENT COMPLIANCE
Nintedanib treatment compliance [%] and the assessment of whether the patient was
compliant according to the protocol (yes/no, additional specification if no), will be listed as 
reported by the investigator in the eCRF. A footnote will explain that, in case of a treatment 
interruption, the compliance could be low (e.g. less than 80%) although the patient was 
compliant with the protocol.
Any deviations from complete intake will be addressed in the RPM (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
Analysis of relative exposure on the basis of primary endpoints will be performed as defined 
in Section 7.3.1 of the CTP, based on the PKS.
The statistical model defined in the CTP is an analysis of variance (ANOVA) model on the 
logarithmic scale including "treatment" as fixed effect and "patient" as random effect. 
In addition, a sensitivity analysis will be performed, using both effects as fixed effects. For 


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this sensitivity analysis, a statistical SASTM raw output will be presented only (in 
Appendix 16.1.13.3 of the CTR).
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameters with APEXC equal to “Included”, 
regardless of the analysis flag comment APEXCO.
Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point) contains column variables ACEXC and
ACEXCO indicating inclusion/exclusion (ACEXC) of a plasma concentration and an analysis 
flag comment (ACEXCO). Exclusion of a plasma concentration depends on the analysis flag 
comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value will be 
excluded for all types of analyses based on concentrations. If ACEXCO is set to ‘DESC 
STATS’ the value will be excluded from descriptive evaluations per planned time point. If 
ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’ the value can 
be used for further analyses based on actual times. If ACEXCO is set to ‘HALF LIFE’ the 
value will be excluded from half-life calculation only; the value is included for all other 
analyses.
The excluded concentration itself will be listed in the tables in Section 15 of the CTR
associated with an appropriate flag.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (4) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (5).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
Analysis of relative exposure on the basis of the secondary endpoint will be performed in the 
same way as for the primary endpoints.
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.


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7.6.1
Safety parameters of interest
Further safety parameters of interest will be analysed as described in Section 7.8 of this 
TSAP.
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on TS.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs and not on the number of AEs. 
For analysis, multiple AE occurrence data on the electronic case report form (eCRF) will be 
collapsed into one event provided that all of the following applies:
∀
All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest (AESI))
∀
The occurrences were overlapping or adjacent (adjacency of two occurrences is given if 
the second occurrence started on the same day or on the day after the first occurrence 
ended)
For further details on summarisation of AE data, please refer to 'Handling and summarisation 
of adverse event data for clinical trial reports and integrated summaries' (6) [001-MCG-156 
Version 5] and "Handling of missing and incomplete AE dates" (3) [001-MCG-156_RD-01]. 


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The analysis of AEs will be based on the concept of treatment-emergent AEs. That means 
that all AEs will be assigned to the screening, treatment or follow-up phases as defined in 
Section 6.1.
Hepatic injury and gastro-intestinal perforation are defined as protocol-specified AESIs. For 
details on the definition of hepatic injury see CTP Section 5.2.10.1.4.
According to ICH E3 (8), AEs classified as ‘other significant’ need to be reported and will 
include those non-serious and non-significant AEs with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) marked haematological and other lab abnormalities or leading to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting. 
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8).
The frequency of patients with AEs will be summarised by primary system organ class and 
preferred term. AEs which were considered by the investigator to be drug-related will be 
summarised separately. Separate tables will also be provided for patients with serious AEs 
(SAEs), patients with AESIs and patients with other significant AEs (according to ICH E3
(8)). The frequency of patients with AEs will also be summarised by worst common
terminology criteria, primary system organ class and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending relative frequency.
In addition, the frequency of patients with AEs, SAEs and drug related AEs will be 
summarised by safety topic, subcategory and preferred term for the organ systems 
'Hepatobiliary' and 'Liver laboratories'. Safety topics and subcategories are defined on project 
level and stored in PDMAP in the TMF (10). The most recent version of this file will be used 
for the analysis.
For disclosure of AE data on ClinicalTrials.gov, the frequency of patients with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by primary system organ class and preferred term. The frequency of patients with SAEs will 
also be summarised.
For disclosure of AE data in the European union drug regulating authorities clinical trials
(EudraCT) register, the frequency of AEs, the frequency of non-serious AEs with an 
incidence of greater than 5 % (in preferred terms) and the frequency of SAEs will be 
summarised.
For support of lay summaries, the frequency of patients with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
Details collected in the eCRF regarding bleeding AEs and AEs of diarrhoea will be listed.


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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 (7).
Possibly clinically significant abnormalities will be identified based on BI standard rules 
which are based on normalized converted lab values, i.e. on values transformed to SI units 
and to a standard reference range. These rules will be listed in the SDL appendix of the CTR. 
Frequency tables will summarize the number of patients with possibly clinically significant 
abnormalities.
All individual laboratory data will be listed. Values outside the reference range will be 
flagged. In addition, possibly clinically significant values will be flagged in the listing.
Clinically relevant findings in laboratory data, as judged by the investigator, were to be 
reported as baseline conditions (if condition already existed before intake of first study drug) 
or as AEs (during the trial), and will be analysed as such.
7.8.3
Vital signs
Summary statistics will be presented for observed values and change from baseline. 
The frequency of patients with marked changes in vital signs will be summarised according 
to the definitions in Section 5.3.1 of this document.
Clinically relevant abnormal findings in vital signs data, as judged by the investigator, were 
to be reported as baseline conditions (if condition already existed before intake of first study 
drug) or as AEs (during the trial) and will be analysed as such.
7.8.4
ECG
Clinically relevant abnormal findings in electrocardiogram (ECG) data, as judged by the 
investigator, were to be reported as baseline conditions (if condition already existed before 
intake of first study drug) or as AEs (during the trial) and will be analysed as such.
7.8.5
Others
7.8.5.1
Spirometry
With regard to spirometry, the highest FVC and highest FEV1 each obtained on any of three 
efforts which meet the criteria of the American Thoracic Society and European Respiratory 
Society – with preferably a maximum of five manoeuvres – were to be recorded in the eCRF.
Spirometry data (except for baseline data) will only be listed.
Clinically relevant abnormal changes in spirometry data, indicative of worsening of lung 
function since baseline, as judged by the investigator, were to be reported as AEs and will be 
analysed as part of AE analysis.


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7.8.5.2
Body weight
Body weight (at screening and end of study visit) will be listed.
7.8.5.3
Physical examination
Physical examination abnormal findings were to be reported as relevant medical 
history/baseline condition (if condition already existed before intake of first study drug) or as 
AE and will be summarised as such. No separate listing or analysis of physical examination 
findings will be prepared.
7.8.5.4
Doppler echocardiography
Clinically relevant abnormal findings in Doppler echocardiography were to be reported as 
relevant medical history/baseline condition (if condition already existed before intake of first 
study drug) or as AEs and will be analysed as part of AE analysis.
7.8.5.5
Pregnancy test
Pregnancy test results (as reported in the eCRF) will be listed.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
001-MCS-40-135: “Integrated Quality and Risk Management Process”, current 
version; IDEA for CON
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", IDEA for CON
6
001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", Version 5; IDEA for CON
7
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON
8
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
9
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON.
10 "8-07-other-safety-topic-definition_v4.0" in PDMAP in BIRDS:
http://birdslinkp.eu.boehringer.com/fdrd/drl/objectId/09000cb186bdcbc5
11 "Template Domain DV", current version; Section "Resources and Key User 
Emails" on ICBI homepage


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-
YY)
Author
Sections changed
Brief description of change
Initial
11-OCT-2018
None
This is the initial TSAP with 
necessary information for 
trial conduct
Final
08-NOV-2019
See Section 4 for a 
summary of 
changes
This is the final TSAP