Conditions: Carcinoma, Non-Small-Cell Lung
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 2
Healthy volunteers: no

Brief summary:
Investigate the effect of multiple oral doses of nintedanib on the single dose kinetics of a combination of ethinylestradiol and levonorgestrel (Microgynon®)

Detailed description:
Purpose:

Arms:
arm 1: Microgynon alone in Period 1 then with Nintedanib in Period 2

Interventions: intervention 1: Microgynon intervention 2: Nintedanib
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03853814-03
EudraCT No.:
EU Trial No:
2015-005664-41
BI Trial No.:
1199.238
BI Investigational 
Product:
Vargatef®, Nintedanib
Title:
A Phase I trial to investigate the effect of nintedanib on the 
pharmacokinetics of a combination of ethinylestradiol and 
levonorgestrel in patients with non-small cell lung cancer
Lay Title:
Investigation of the effect of nintedanib on the pharmacokinetics 
of a combination of ethinylestradiol and levonorgestrel in patients 
with non-small cell lung cancer
Clinical Phase:
I
Trial Clinical 
Monitor:
Phone:
Fax:
Coordinating 
Investigator:
Telefon:
Fax:
Status:
Final Protocol
(Revised protocol (based on global amendment 2))
Version and Date:
Version: 3.0
Date: 09 Mar 2017
Page 1 of 55
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
Vargatef®
Name of active ingredient:
Nintedanib
Protocol date:
17 February 2016
Trial number:
1199.238
Revision date:
09 Mar 2017
Title of trial:
A Phase I trial to investigate the effect of nintedanib on the 
pharmacokinetics of a combination of ethinylestradiol and 
levonorgestrel in patients with non-small cell lung cancer
Coordinating
Investigator:
Telefon: 
Fax:
Trial sites:
Multi-centre
Clinical phase:
I
Objective:
To investigate the effect of multiple oral doses of nintedanib on the 
single dose kinetics of a combination of ethinylestradiol and 
levonorgestrel (Microgynon®)
Methodology:
Open-label, two-period, fixed sequence
No. of patients: 
Up to approximately 24 patients may be enrolled
total treated:
14 patients who have completed the trial and are evaluable for both 
treatment periods
each treatment:
14
Diagnosis :
Non-small cell lung cancer (NSCLC) with histology of 
adenocarcinoma
Main criteria
for inclusion:
Patients with NSCLC with histology of adenocarcinoma who are 
eligible for therapy with nintedanib in accordance with the 
instructions in the SmPC and who have given informed consent


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Name of company:
Boehringer Ingelheim
Name of finished product:
Vargatef®
Name of active ingredient:
Nintedanib
Protocol date:
17 February 2016
Trial number:
1199.238
Revision date:
09 Mar 2017
Trial product 1:
Microgynon® tablets
dose:
One tablet containing 30 microgram ethinylestradiol (EE) / 150 
microgram levonorgestrel (LE) per tablet in each trial period
mode of 
administration:
Oral with 240 mL of water
Trial product  2:
Nintedanib soft gelatine capsule (containing 100 mg nintedanib) or
Nintedanib soft gelatine capsule (containing 150 mg nintedanib)
dose:
2 x 200 mg per day, dose reduction to 2 x 150 mg if required 
mode of 
administration:
Oral with food and 240 mL of water
Duration of treatment:
Reference (Period 1): 1 tablet Microgynon® will be administered after 
a standardised breakfast, at the latest 7 days before the first 
administration of nintedanib
Test (Period 2): Microgynon® will be administered together with 
nintedanib on the pharmacokinetic (PK) day after continuous intake 
of nintedanib for at least 7 consecutive days
On the PK-profile day, 1 tablet of Microgynon® will be given 
together with the morning dose of nintedanib in the morning after a 
standardised breakfast. 12 hours later the evening dose of nintedanib 
will be administered.
The PK-profile day should be followed by continuous intake of 
nintedanib for at least 2 further days
Treatment with nintedanib may be continued at the discretion of the 
investigator according to the label
Endpoints
Primary endpoints: AUC0-tz and Cmax for ethinylestradiol and 
levonorgestrel
Secondary endpoints: AUC0-for ethinylestradiol and levonorgestrel


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Name of company:
Boehringer Ingelheim
Name of finished product:
Vargatef®
Name of active ingredient:
Nintedanib
Protocol date:
17 February 2016
Trial number:
1199.238
Revision date:
09 Mar 2017
Safety criteria:
Adverse events (AEs) including clinically relevant findings from the 
physical examination, safety laboratory tests, vital signs
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 
provided. The statistical model will be an analysis of variance 
(ANOVA) on the logarithmic scale, including effects for 'subject', 
'period', 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
Overview
#
day of nintedanib intake; 
Microgynon® PK day during Period 1 may take place within day - 27 and day - 7 prior to first intake of nintedanib;
results of screening examinations need to be awaited prior to proceeding with period 1;
if PK sampling in period 1 takes place between day -27 and -20, physical examination, vital signs, laboratory tests and 
12 lead ECG do no not need to be repeated on day -7 unless AE occurred during that timeframe or it is clinically 
indicated; 
laboratory test results need to be checked prior to dispension of Nintedanib;
administration of Microgynon® during Period 2 may take place within day 8 and 16 of continuous nintedanib intake;
day 1 in Period 2 is an optional visit that might be performed in case nintedanib was not handed out in Period 1
##
at the earliest on day 3 after last intake of Microgynon®
*
administration of 240 mL of water
**
It is assumed that Period 2 will happen during the first treatment course of docetaxel/nintedanib. However, if the 
patient would not be able to continuously take nintedanib for at least seven days before intake of Microgynon® during 
the first treatment course, then the second administration of Microgynon® might also be administered during one of 
the next treatment courses
Trial Periods
Screening 
Period
End of Trial
Visit
1
4
Day
-28
 -7#
 -6#
 -5#
 -4#
1
7
8 #
9 # 10 # 11 #
##
Informed consent
x
Demographics
x
Medical history
x
Physical examination
x
x
x
x
Vital signs
x
x
x
x
Laboratory tests
x
x
x
x
x
12 lead-ECG
x
x
x
Review of in-/exclusion criteria
x
x
PK sampling for nintedanib
 -00:35
x
x
x
Dispense nintedanib
x
x
x
x
x
Continuous intake of nintedanib
PK Sampling: predose Microgynon®
x
x
Standardised meal before Microgynon® intake
 -00:30
x
x
Administration  Microgynon® 
x
Administration  Microgynon® and Nintedanib
x
PK Sampling after 
00:30
x
x
Microgynon® 
01:00
x
x
intake (in hours)
01:30
x
x
2:00*
x
x
03:00
x
x
4:00*
x
x
06:00
x
x
08:00
x
x
12:00
x
x
 24:00
x
x
 48:00
x
x
 72:00
x
x
Adverse events
x
x
x
x
x
x
x
x
x
x
x
Compliance check
x
x
x
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
x----------------------------------------------------->
3
Period 2 **
2
Period 1


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Detailed Overview for PK days
Period
Day
Planned Time
Approximate clock 
time of actual day 
[h:min]
Event and comment
PKblood for 
EE and LE
PKblood for 
nintedanib
[h:min]
1
-7
pre-dose
Physical examination
pre-dose
Review inclusion/exclusion criteria
pre-dose
Vital signs
pre-dose
Laboratory tests
pre-dose
12 lead-ECG
pre-dose
Adverse events
pre-dose
Concomitant therapy
pre-dose
Compliance check
 -00:35
X
 -00:30
Breakfast
00:00
Drug administration Microgynon®
 00:30
X
 01:00
X
 01:30
X
 02:00
240 mL tap water
X
 03:00
Adverse events
X
 04:00
240 mL tap water, lunch
X
 06:00
X
 08:00
X
10:00
Snack
 12:00
Adverse events
X
-6
 24:00
Adverse events, Concomitant therapy, Compliance Check
X
-5
 48:00
Adverse events, Concomitant therapy, Compliance Check
X
-4
 72:00
Adverse events, Concomitant therapy, Compliance Check
X
2
8
pre-dose
Physical examination
pre-dose
Vital signs
pre-dose
Laboratory tests
pre-dose
Adverse events
pre-dose
Concomitant therapy
pre-dose
Compliance check
 -00:35
X
X
 -00:30
Breakfast
00:00
Drug administration Microgynon® and Nintedanib intake
 00:30
X
 01:00
X
 01:30
X
 02:00
240 mL tap water
X
 03:00
Adverse events
X
 04:00
240 mL tap water, lunch
X
 06:00
X
 08:00
X
10:00
Snack
 11:55
X
 12:00
Adverse events, Nintedanib intake
9
 23:55
Adverse events, Concomitant therapy, Compliance Check
X
X
 24:00
Nintedanib intake
10
 47:55
Adverse events, Concomitant therapy, Compliance Check, 
Laboratory tests
X
X
 48:00
Nintedanib intake
11
 71:55
Adverse events, Concomitant therapy, Compliance Check
X
 72:00
Nintedanib intake


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................10
1.
INTRODUCTION...............................................................................................12
DRUG PROFILE................................................................................................12
1.2
1.2.1
Nintedanib............................................................................................................12
1.2.2
Ethinylestradiol...................................................................................................15
1.2.3
Levonorgestrel.....................................................................................................16
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................17
2.2
BENEFIT - RISK ASSESSMENT.....................................................................17
2.3
2.3.1
Nintedanib............................................................................................................17
2.3.2
Microgynon®........................................................................................................17
2.3.3
Potential interaction between nintedanib and Microgynon®.........................18
2.3.4
Drug induced liver injury...................................................................................18
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................19
OVERALL TRIAL DESIGN AND PLAN .......................................................19
3.1
3.1.1
Administrative structure of the trial .................................................................19
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................20
SELECTION OF TRIAL POPULATION .......................................................20
3.3
3.3.1
Main diagnosis for trial entry ............................................................................20
3.3.2
Inclusion criteria .................................................................................................21
3.3.3
Exclusion criteria ................................................................................................21
3.3.4
Removal of patients from therapy or assessments...........................................22
Removal of individual patients .............................................................................22
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................23
3.3.4.2
4.
TREATMENTS...................................................................................................24
INVESTIGATIONAL TREATMENTS ...........................................................24
4.1
4.1.1
Identity of the Investigational Medicinal Product (IMP)................................24
4.1.2
Selection of doses in the trial..............................................................................24
4.1.3
Method of assigning patients to treatment groups...........................................25
4.1.4
Drug assignment and administration of doses for each patient......................25
4.1.5
Blinding and procedures for unblinding...........................................................25
Blinding.................................................................................................................25
4.1.5.1
Unblinding and breaking the code ........................................................................25
4.1.5.2


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4.1.6
Packaging, labelling, and re-supply...................................................................26
4.1.7
Storage conditions...............................................................................................26
4.1.8
Drug accountability.............................................................................................26
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS ................................................................................................27
4.2.1
Other treatments and emergency procedures..................................................27
4.2.2
Restrictions ..........................................................................................................27
Restrictions regarding concomitant treatment ......................................................27
4.2.2.1
Restrictions on diet and life style..........................................................................27
4.2.2.2
Restrictions regarding women of childbearing potential......................................28
4.2.2.3
TREATMENT COMPLIANCE........................................................................28
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................29
TRIAL ENDPOINTS..........................................................................................29
5.1
5.1.1
Primary Endpoints..............................................................................................29
5.1.2
Secondary Endpoints..........................................................................................29
.........................................................................................29
ASSESSMENT OF EFFICACY........................................................................29
5.2
ASSESSMENT OF SAFETY.............................................................................29
5.3
5.3.1
Physical examination ..........................................................................................29
5.3.2
Vital Signs............................................................................................................29
5.3.3
Safety laboratory parameters ............................................................................30
5.3.4
Electrocardiogram ..............................................................................................30
5.3.5
Other safety parameters.....................................................................................30
5.3.6
Assessment of adverse events.............................................................................30
Definitions of AEs ................................................................................................30
5.3.6.1
Adverse event collection and reporting ................................................................33
5.3.6.2
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................35
5.4.1
Assessment of Pharmacokinetics.......................................................................35
5.4.2
Methods of sample collection .............................................................................35
5.4.3
Analytical determinations ..................................................................................35
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................36
ASSESSMENT OF BIOMARKER...................................................................36
5.5
5.5.1
Biobanking...........................................................................................................36
OTHER ASSESSMENTS...................................................................................36
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................36
5.7
6.
INVESTIGATIONAL PLAN.............................................................................37
VISIT SCHEDULE.............................................................................................37
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................37
6.2
6.2.1
Screening period..................................................................................................37
6.2.2
Treatment period ................................................................................................37
6.2.3
Trial Completion.................................................................................................38
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................39
STATISTICAL DESIGN - MODEL.................................................................39
7.1


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NULL AND ALTERNATIVE HYPOTHESES ...............................................39
7.2
PLANNED ANALYSES.....................................................................................39
7.3
7.3.1
Primary endpoint analyses.................................................................................40
7.3.2
Secondary endpoint analyses .............................................................................41
................................................................................41
7.3.4
Safety analyses.....................................................................................................41
7.3.5
Pharmacokinetic analyses ..................................................................................42
INTERIM ANALYSES ......................................................................................43
7.4
HANDLING OF MISSING DATA ...................................................................43
7.5
7.5.1
Safety....................................................................................................................43
7.5.2
Plasma concentration - time profiles.................................................................43
7.5.3
Pharmacokinetic parameters.............................................................................43
RANDOMISATION ...........................................................................................44
7.6
DETERMINATION OF SAMPLE SIZE .........................................................44
7.7
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY..................................................................................46
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT ...........................................................................................................46
DATA QUALITY ASSURANCE ......................................................................47
8.2
RECORDS...........................................................................................................47
8.3
8.3.1
Source documents ...............................................................................................47
8.3.2
Direct access to source data and documents.....................................................48
8.3.3
Storage period of records ...................................................................................48
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................48
8.4
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........48
8.5
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................49
TRIAL MILESTONES.......................................................................................49
8.6
9.
REFERENCES....................................................................................................50
PUBLISHED REFERENCES............................................................................50
9.1
UNPUBLISHED REFERENCES......................................................................51
9.2
10.
APPENDICES.....................................................................................................52
DRUGS THAT ARE NOT ALLOWED DURING THE TRIAL...................52
10.1
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................53


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
AMP
Auxiliary Medicinal Product
ANOVA
Analysis Of Variance
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BI
Boehringer Ingelheim
BLQ
Below the Limit of Quantification
CA
Competent Authority
CI
Confidence Interval
gCV
Coefficient of variation
Cmax
Maximum blood concentration
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP3A4
Cytochrome P450 3A4
DEDP
Drug Exposure during Pregnancy
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
EE
EthinylEstradiol
EMA
European Medicines Agency
ES
Entered Set
EDTA
Ethylene Diamine-Tetraacetic Acid
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
γ-GT
Gamma Glutamyl Transferase
GMP
Good Manufacturing Practice
gMean
geometric Mean
ICH
International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
INR
International Normalised Ratio


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IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator Site File
HPLC-MS/MS
High-Performance Liquid Chromatography tandem Mass Spectrometry
LE
Levonorgestrel
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRHD
Maximum Recommended Human Dose
MTD
Maximum Tolerated Dose
NC
Not Calculated
NIMP
Non Investigational Medicinal Product
NOA
Not Analysed
NOS
No Sample
NOR
No valid result
NSCLC
Non-Small Cell Lung Cancer
OPU
Operating Unit
PK
Pharmacokinetic(s)
PKS
PK analysis Set
PMDA
Pharmaceuticals and Medical Devices Agency
PXR
Pregnane X Receptor
RDC
Remote Data Capture
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SOP
Standard Operation Procedures
S(m)PC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UGT1A1
UDP-Glucuronyltransferase 1A1
US
United States of America
WBC
White Blood Cell Count
WHO
World Health Organisation


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1.
INTRODUCTION
Nintedanib was approved on 12 November 2014 by the European Medicines Agency (EMA) 
as follows: Nintedanib is indicated in combination with docetaxel for the treatment of adult 
patients with locally advanced, metastatic or locally recurrent non-small cell lung cancer 
(NSCLC) of adenocarcinoma tumour histology after first-line chemotherapy. The 
recommended dose of nintedanib is 200 mg twice daily, administered approximately 12 hours
apart, on days 2 to 21 of a standard 21 day docetaxel treatment cycle.
In addition to the indication NSCLC, nintedanib is also registered for the treatment of 
Idiopathic Pulmonary Fibrosis (IPF) in adult patients. The recommended dose is 150 mg 
nintedanib twice daily administered approximately 12 hours apart.
In the current Summary of Product Characteristics (SmPC), women of childbearing potential 
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-drug interaction of both drugs as requested by the EMA.
 
 
 
 
 
 
 
 
 
DRUG PROFILE
1.2
1.2.1
Nintedanib
Mechanism of action
Nintedanib is a small molecule kinase inhibitor blocking vascular endothelial growth factor 
receptors 1-3, platelet-derived growth factor receptors α and ß and fibroblast growth factor1


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receptors 1-3 kinase activity. Nintedanib binds competitively to the adenosine triphosphate 
binding pocket of these receptors and blocks the intracellular signalling which is crucial for 
the proliferation and survival of endothelial, as well as perivascular cells (pericytes and 
vascular smooth muscle cells). In addition Fms-like tyrosine-protein kinase -3, lymphocyte-
specific tyrosine-protein kinase and proto-oncogene tyrosine-protein kinase Src are inhibited.
The clinical development programme for nintedanib includes several cancer indications: 
NSCLC, ovarian cancer, colorectal cancer, renal cell carcinoma, and hepatocellular 
carcinoma. Nintedanib has also been studied in the non-cancer indication IPF and has been 
approved for this indication by United States of America Food and Drug Administration (US-
FDA), EMA, Japanese PMDA and in several other countries.
A wide range of nintedanib monotherapy doses was investigated in Phase I and II trials, by 
using doses from 50 to 450 mg once daily and from 150 to 300 mg twice daily. In Phase I 
dose escalation trials, the predominant dose limiting toxicities were gastrointestinal adverse 
events and fully reversible increases of liver enzymes (Alanine Aminotransferase [ALT], 
Aspartate Aminotransferase [AST], gamma glutamyl transferase [γ-GT]) not accompanied by 
relevant bilirubin increases, and the maximum tolerated dose (MTD) was determined as 
2 x 250 mg in Caucasian patients (U10-1846). 
In Phase I trials combining nintedanib with docetaxel, pemetrexed, paclitaxel/carboplatin or 
mFOLFOX6, the recommended dose of nintedanib was established to be 2 x 200 mg in 
Caucasians (c01632700). The pattern of adverse events (AEs) was comparable to the AE 
profile observed in Phase I monotherapy trials, except for the chemotherapy-related AEs. 
Based on the overall safety profile from all Phase I and Phase II trials, a nintedanib dose of 
2 x 200 mg was selected for further Phase III trials.
Of over 3300 cancer patients included in 3 Phase III trials in NSCLC or ovarian cancer, 
approximately 1900 patients have received nintedanib in combination with the cytotoxic 
chemotherapy that is standard for the respective indication, namely, docetaxel, pemetrexed or 
paclitaxel/carboplatin.
After administration as a soft gelatine capsule, nintedanib is absorbed quickly; maximum
plasma concentrations are reached within 2 to 4 h. Nintedanib follows at least bi-phasic 
disposition kinetics. After intravenous administration, it showed a volume of distribution of 
1050 L. Non-clinical data suggest a homogenous distribution of the drug, with the exception 
of the central nervous system, and no marked affinity or retention in any tissue. Nintedanib 
undergoes a high first-pass metabolism and is primarily metabolised by hydrolytic cleavage 
by esterases, resulting in the free acid moiety BIBF 1202. Subsequently, BIBF 1202 is 
glucuronidated by various UGT enzymes, forming BIBF 1202 glucuronide. Metabolism via 
CYP enzymes plays a minor role. After intravenous administration, nintedanib showed a high 
total plasma clearance (gMean: 1390 mL/min). 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. The gMean terminal half-life of 
nintedanib in patients was 10 to 15 h. Dose-proportional behaviour of Cmax and AUC was 
concluded based on several studies in cancer patients investigating doses from 50 to 450 mg 
once daily and from 150 to 300 mg twice daily.
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 


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transporter substrates were considered unlikely. Nintedanib is a P-gp substrate. In the drug-
drug interaction trial 1199.161 (c01762736), exposure to nintedanib in healthy volunteers 
increased by about 1.6- to 1.7-fold for AUC and by about 1.8-fold for Cmax following 
concomitant administration with the potent P-gp inhibitor ketoconazole. Thus, if administered 
concomitantly with nintedanib, potent P-gp inhibitors (e.g. ketoconazole, erythromycin) may 
increase nintedanib exposure. After concomitant administration with the potent P-gp inducer 
rifampicin, exposure to nintedanib decreased to approximately 50% based on AUC and to 
approximately 60% based on Cmax. Thus, potent P-gp inducers (e.g. rifampicin, 
carbamazepine, phenytoin, St. John’s Wort) may decrease the exposure to nintedanib.
Additional data on the pharmacokinetics (PK) of nintedanib in patients with hepatic 
impairment are available from a dedicated 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).
Pharmacodynamic effects
Tumour angiogenesis is an essential feature contributing to tumour growth, progression and 
metastasis formation and is predominantly triggered by the release of pro-angiogenic factors 
secreted by the tumour cell (i.e. vascular endothelial growth factor receptors and fibroblast 
growth factor) to attract host endothelial as well as perivascular cells to facilitate oxygen and 
nutrient supply through the host vascular system. In preclinical disease models nintedanib, as 
a single agent, effectively interfered with the formation and maintenance of the tumour 
vascular system, resulting in tumour growth inhibition and tumour stasis. In particular, 
treatment of tumour xenografts with nintedanib led to a rapid reduction in tumour micro 
vessel density, pericytes vessel coverage and tumour perfusion.
Reproduction toxicity
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).


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Drug-drug interaction
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 
nintedanib´s teratogenic potential it is nevertheless required to perform a clinical study to 
investigate the potential effect of nintedanib on the pharmacokinetics of oral contraceptives.
For a more detailed description of the nintedanib profile please refer to the investigator drug 
brochure (c01632700) and to the product information for nintedanib (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
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).


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For a more detailed description of ethinylestradiol, please refer to the SmPC of Microgynon®
(R12- 0034).
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%).
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).
For a more detailed description of levonorgestrel, please refer to the SmPC of Microgynon®
(R12- 0034 and R16-0717).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
 
 
 
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.
TRIAL OBJECTIVES
2.2
The aim of the trial is to evaluate the effect of chronic nintedanib intake on the 
pharmacokinetics of a contraceptive drug containing ethinylestradiol and levonorgestrel.
BENEFIT - RISK ASSESSMENT
2.3
2.3.1
Nintedanib
The patients will receive nintedanib according to the label in the most current SmPC
(included in the ISF) to treat their underlying NSCLC. The potential side effects of 
nintedanib are as follows (as per SmPC): diarrhoea which may lead to loss of fluid and salts. 
To avoid loss of fluid, patients have to be reminded to drink enough fluid and antidiarrheal
treatment shall be started. Further side effects are: painful, numb and/or tingling feeling in 
fingers and toes (peripheral neuropathy), feeling sick (nausea), throwing up (vomiting), pain 
in the stomach (abdomen), bleeding, rash, mucositis (including stomatitis), decreased 
appetite, electrolyte imbalance, increased liver enzyme values (alanine aminotransferase, 
aspartate aminotransferase, blood alkaline phosphatase) in the blood as seen from blood tests
and neutropenia (including febrile neutropenia and sepsis). Please refer to the SmPC for 
further potential side effects of Nintedanib.
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 medication.
However, their participation in this trial may help guide the safe use of nintedanib together
with ethinylestradiol / levonorgestrel in patients requiring this treatment.
2.3.2
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


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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 (R12-0033).
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® will be administered during this trial. Therefore, no undue risk is 
expected to trial participants.
2.3.3
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®.
2.3.4
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 5.3.6.1.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
The trial will be performed according to an open-label, two-period, fixed sequence design. 
Patients who are considered eligible for therapy with nintedanib to treat their non-small cell 
lung cancer, 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 7 days before 
the first administration of nintedanib. A second dose of Microgynon® will be administered 
after continuous nintedanib intake for at least 7 consecutive days. Depending on the patient 
condition, this time point may vary between Day 8 and Day 16 of nintedanib administration.
Blood for pharmacokinetic evaluation will be collected on the days of Microgynon®
administration, and on the following 3 days. Adverse events and concomitant therapies will 
be recorded throughout the trial period, which ends once the patient has performed the end of 
trial 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.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate Investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities are defined in a contract.
The trial will be performed by investigational sites who are experienced in performing 
clinical trials. The trial sites will be oncological sites, sites experienced in treating cancer 
patients or sites specialised in performance of clinical trials, and/or using a referral network 
of oncologists / physicians.
Boehringer Ingelheim has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating all required activities, in order to 

manage the trial in accordance with applicable regulations and internal Standard 
Operating Procedures (SOPs),

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of local clinical monitors (CMLs), Clinical 
Research Associates (CRAs), and Investigators of participating country(ies).
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 internal SOPs, or by a Contract Research Organisation (CRO) with which the 
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 investigator site file (ISF).


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DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
Patients, who are selected by their physician for therapy with nintedanib to treat their non-
small cell lung cancer according to the market authorisation of nintedanib, may be eligible for 
this trial 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.
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 7 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.
SELECTION OF TRIAL POPULATION
3.3
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 in several centres to achieve the goal that 14 patients completed the trial 
and are evaluable for the pharmacokinetic analysis..
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site, irrespective of whether they have been 
treated with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients, who are selected by their physician for therapy with nintedanib to treat their non-
small cell lung cancer according to the market authorisation of nintedanib, may be eligible for 
this trial if they meet the inclusion and none of the exclusion criteria. Please refer to Section


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8.3.1 (Source Documents) for the documentation requirements pertaining to the in- and 
exclusion criteria.
3.3.2
Inclusion criteria
1. Female patients ≥ 18 years at screening
2. Female patient is postmenopausal or surgically sterilised (a 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 contraception or 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])
3. Patient with locally advanced, metastatic or locally recurrent NSCLC with histology of 
adenocarcinoma
4. Nintedanib (Vargatef®) is planned to be prescribed in accordance with the marketing 
authorisation (SmPC)
5. Signed and dated written informed consent in accordance with Good Clinical Practice
(GCP) and local legislation prior to admission to the trial
3.3.3
Exclusion criteria
1. Any contraindication to nintedanib (Vargatef®), ethinylestradiol or levonorgestrel 
(Microgynon®), as specified in the respective labels
2. Use of hormone containing contraceptives (including vaginal and intrauterine devices and 
including hormone replacement therapy) within 30 days prior to first administration of 
Microgynon®
3. Systemic use of drugs known to induce (e.g. rifampicin, St. John’s Wort, carbamazepine) 
or to inhibit (e.g. azole antimycotics, macrolides) CYP3A4 within 7 days prior to first 
trial drug administration until last PK-sampling in the trial. Exception: allowed is the 
intake of corticosteroids as docetaxel (pre)medication
4. History of major thrombotic or clinically relevant major bleeding event in the past 6 
months
5. Persistence of clinically relevant therapy related toxicities (i.e. > Common Terminology 
Criteria for Adverse Events [CTCAE] grade 2) from previous chemotherapy and/or 
radiotherapy
6. Treatment with other investigational drugs or treatment in another clinical trial within the 
past four weeks before start of therapy or concomitantly with this trial
7. Gastrointestinal disorders or abnormalities that would interfere with absorption of the trial 
drugs
8. Major surgery (major according to the investigator’s assessment) performed within 4 
weeks prior to first treatment within the trial and without complete wound healing 


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9. Patients who must or wish to continue the intake of restricted medications (see Section 
4.2.2.1 and Section 10) or any drug considered likely to interfere with the safe conduct of 
the trial
10. Patients unable to comply with the protocol
11. Previous enrolment in this trial
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An excessive withdrawal rate can have a severe negative impact on the scientific value of the 
trial. Every effort should be made to keep patients in the trial as scheduled. This includes 
careful patient selection and appropriate explanation of the trial requirements and procedures 
prior to enrolment, as well as an explanation of the consequences of premature withdrawal.
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for trial treatment or trial participation, without the need to 
justify the decision

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases)

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 stick to the trial requirements in the future
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 Case 
Report Form (CRF). 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 TCM.

Microgynon® cannot be administered in Period 1 and Period 2

Interruption of nintedanib therapy for a longer period of time so that no continuous intake 
of 7 consecutive days is given within this trial

Dose reduction of nintedanib to less than 2 x 150 mg per day before end of PK sampling

Administration of forbidden drugs (refer to Section 10)

Noncompliance with dietary restrictions

Inability of the patient to comply with the food intake on the days of Microgynon®
administration


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Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract disturbing the 
appropriate conduct of the trial
 


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4.
TREATMENTS
INVESTIGATIONAL TREATMENTS 
4.1
All patients will be treated with Microgynon® and nintedanib. Nintedanib will be considered 
as Investigational Medicinal Product (IMP) in this trial.
4.1.1
Identity of the Investigational Medicinal Product (IMP)
Table 4.1.1: 1
Microgynon®
Substance:
combination of ethinylestradiol and levonorgestrel
Pharmaceutical formulation:
tablet
Source:
local manufacturer
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:
capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
100 mg per capsule, 150 mg per capsule
Posology:
2 x 2 capsules containing 100 mg (2 x 1 capsule 
containing 150 mg in case of dose reduction)*
Route of administration:
oral
*nintedanib shall be taken continuously throughout Period 2. In case of a temporary interruption of nintedanib intake, 
patients can receive Microgynon® in Period 2 only if they have taken nintedanib for 7 consecutive days before intake 
of Microgynon®
4.1.2
Selection of doses in the trial
The recommended dose of nintedanib for treatment of NSCLC is 200 mg twice daily 
administered approximately 12 hours apart.
Dose adjustments of nintedanib shall follow the recommendation in the SmPC (included in 
the ISF). As initial measure for the management of adverse reactions (see SmPC) treatment 
with nintedanib should be temporarily interrupted until the specific adverse reaction has 
resolved to levels that allow continuation of therapy (to grade 1 or baseline). Nintedanib 
treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 


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50 mg reduction per dosing) based on individual safety and tolerability are recommended as 
described in the SmPC.
Microgynon® will be administered only as single administration on the PK profiling days.
One tablet of Microgynon® will be administered.
4.1.3
Method of assigning patients to treatment groups
This is a fixed sequence trial. All patients will undergo the respective treatment periods in an 
identical order.
4.1.4
Drug assignment and administration of doses for each patient
Patients will take one tablet of Microgynon® before the first intake of nintedanib (Period 1) 
and after continuous nintedanib administration for at least 7 consecutive days (Period 2).
On both pharmacokinetic profile days, a standardised meal (breakfast) has to be consumed 
within 30 minutes prior to Microgynon® intake. The meal should preferably be identical in 
both treatment periods. 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 together with Microgynon®.
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 pharmacokinetic 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.
Nintedanib will be taken by the patients at home except for the PK profiling days. The 
patients will be handed out the nintedanib medication (one bottle containing the medication 
for the respective time period) at the time points indicated in the Flow Chart. Nintedanib 
capsules shall be taken orally, preferably with food, swallowed whole with water, and must 
not be chewed or crushed. The patient shall be instructed to not skip any doses. If a dose is 
missed 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.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
This open-label trial will be handled as an unblinded trial by the sponsor.
Unblinding and breaking the code
4.1.5.2
Not applicable.


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4.1.6
Packaging, labelling, and re-supply
 
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
 
 
 
 
The Investigator and/or Pharmacist and/or investigational drug storage manager 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 product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the Investigator / Pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.


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OTHER TREATMENTS, EMERGENCY PROCEDURES, 
4.2
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
All patients are expected to be treated with nintedanib according to the labelling instructions
i.e. in combination with docetaxel on days 2 to 21 of a standard 21 day docetaxel treatment 
cycle. Docetaxel therapy as well as pre-medication therapy for docetaxel shall be documented 
in the CRF.
There are no specific rescue drugs foreseen for the treatment of AEs. For treatment of adverse 
events such as diarrhoea, please refer to the SmPC of nintedanib. No special emergency
procedures are to be followed. Treatment of the underlying cancer disease, concomitant 
diseases and/or adverse events and/or prophylactic antimicrobial therapy is allowed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
In principle, no concomitant therapy shall be administered except for therapy needed to treat 
the underlying cancer disease, baseline conditions, adverse events occurring during the trial,
and/or as prophylaxis if considered necessary by the treating physician.
Concomitant therapy which may influence the motility or absorption of drug substance in the 
gastrointestinal tract (e.g. metoclopramide, erythromycin, loperamide, opioid analgesics) 
should be avoided 72 h prior to PK sampling. If such concomitant therapy is needed less than 
72 h prior to the planned PK day, the PK day should preferably be moved such that 72 h 
without the respective concomitant therapy occurs.
All concomitant or rescue therapies will be recorded (including time of intake on the days of 
PK sampling) on the appropriate pages of the CRF.
Restrictions on diet and life style
4.2.2.2
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 pharmacokinetic 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). 


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A standardised meal will be served 30 min prior to Microgynon® administration.
Restrictions regarding women of childbearing potential 
4.2.2.3
Not applicable.
TREATMENT COMPLIANCE
4.3
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.
Microgynon® will be administered under the supervision of the treating physician or trial 
staff to whom this task was delegated. The intake will be documented in the CRF.
Patients will also be asked to adhere to the dietary restrictions.


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5.
VARIABLES AND THEIR ASSESSMENT
TRIAL ENDPOINTS
5.1
The primary 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.
5.1.1
Primary Endpoints
Cmax and AUC0-tz for ethinylestradiol and levonorgestrel will be analysed after a single dose 
of the combination of ethinylestradiol and levonorgestrel before intake of nintedanib and after
continuous intake of nintedanib for at least 7 consecutive days.
5.1.2
Secondary Endpoints
AUC0-for ethinylestradiol and for levonorgestrel will be assessed after intake of a single 
dose of the combination of ethinylestradiol and levonorgestrel before intake of nintedanib and 
after continuous intake of nintedanib for at least 7 consecutive days.
ASSESSMENT OF EFFICACY
5.2
Not applicable.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A physical examination will be performed at the time point as indicated in the Flow Chart.
Weight and height will be recorded at screening only.
5.3.2
Vital Signs
Vital signs, including blood pressure, temperature and heart rate, will be measured as 
indicated in the Flow Chart. Any new findings observed after the baseline assessment have to 
be reported as adverse events.


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5.3.3
Safety laboratory parameters
Blood samples have to be collected at the time points specified in the Flow Chart. More
frequent blood sampling may be done whenever the investigator deems necessary.
Unscheduled safety laboratory examinations will be reported in the CRF along with the
results. Blood sampling should not be done immediately before ECG recording.
Safety laboratory examinations will include haematology, biochemistry and coagulation
parameters.
Haematology: haemoglobin, white blood cell count (WBC) with differential (manual
differential count and absolute values if possible), platelets.
Biochemistry: glucose, sodium, potassium, calcium, creatinine, AST, ALT, alkaline
phosphatase, lactate dehydrogenase, bilirubin (direct and indirect in case values are above
upper limit of normal), uric acid, total protein, albumin.
Coagulation: activated partial thromboplastin time (aPTT) and international normalised ratio 
(INR).
5.3.4
Electrocardiogram
A 12-lead Electrocardiogram (ECG) has to be recorded at the time points specified in the 
Flow Chart. Any new findings observed after the baseline assessment have to be reported as 
adverse events.
5.3.5
Other safety parameters
Not applicable.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death

is life-threatening, this 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 or

prolongation of existing hospitalisation

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
Planned hospitalisations due to periodic administration of chemotherapy for treatment of the 
underlying cancer disease will not be reported as serious adverse events.
AEs considered “Always Serious”
Every new occurrence of cancer of new histology must be reported as a serious event 
regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. A copy of the latest 
list of “Always Serious AEs” will be provided to the Investigator upon request.  These events 
should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 


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need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs:
Hepatic injury
In this trial protocol, signs of hepatic injury are defined as: 

ALT and/or AST ≥8 fold ULN 

ALT and/or AST ≥3 fold ULN and total bilirubin ≥ 2 fold ULN* 

ALT and/or AST ≥3 fold ULN and unexplained INR > 1,5* 

ALT and/or AST ≥3 fold ULN and unexplained eosinophilia (>5%)* 

ALT and/or AST ≥3 fold ULN and appearance of fatigue, nausea, vomiting, right upper 
abdominal quadrant pain or tenderness, fever and/or rash 
* in the same blood draw sample.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to immediately stop the trial medication or are not allowed to start 
treatment 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.
Gastro-intestinal perforation
Gastro-intestinal perforation shall be reported as AESI.
Intensity of AEs
The intensity of adverse events should be classified and recorded in the CRF according to the 
Common Terminology Criteria for Adverse Events (CTCAE Version 4.03).
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected. 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. 
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug.


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
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 diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.
Adverse event collection and reporting
5.3.6.2
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period (REP), 
until individual patient’s end of trial: 
-all AEs (serious and non-serious) and all AESIs.

However, if an individual patient discontinues trial medication prematurely but stays in 
the trial (i.e. if further visits incl. telephone visits, or vital status assessments are planned)
from then on and until the individual patient’s end of the trial the Investigator must report 
related SAEs and related AESIs. Note: This is not applicable for the present trial.


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
After the individual patient’s end of trial: 
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs and relevant AESIs of which the Investigator may become aware of.
Figure 5.3.6.2: 1
Adverse Event Collection
The REP for Microgynon® is defined as 3 days after the intake of Microgynon®. The REP for 
nintedanib is 30 days. However, collection of adverse events will stop for an individual 
patient once the trial was completed for this respective patient, because nintedanib is 
expected to continue at the end of trial as standard of care. If a relevant SAE or AESI would 
be reported after the end of the trial for an individual patient, then this SAE / AESI would be 
considered as on-treatment for nintedanib if it occurred within 30 days after end of intake of 
nintedanib. All AEs which occurred through the treatment phase and throughout the REP will 
be considered as on-treatment, please see Section 7.3.4.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 h) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form. The Investigator should determine the causal relationship 
to the trial medication and any possible interactions between the investigational drug(s) and a 
Non-Investigational Medicinal Product (NIMP) / Auxiliary Medicinal Product (AMP).
The following should also be recorded as an (S)AE in the CRF and SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions


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
Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
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 
completion of the additional investigations but not later than 5 years upon the final study 
report has been signed.
5.4.2
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, nintedanib and its metabolites BIBF 1202 
and BIBF 1202 glucuronide, venous blood will be collected using a pre-labelled potassium 
ethylene-diamine-tetraacetic acid (EDTA) containing blood drawing tube. For quantification 
of ethinylestradiol, levonorgestrel and nintedanib and its metabolites plasma concentrations, 
approximately 8 mL of blood will be collected per time point. The obtained plasma will be 
transferred into 2-3 aliquots (nintedanib [when applicable], ethinylestradiol, levonorgestrel, 
and one back-up sample).
5.4.3
Analytical determinations
Nintedanib (in form of its free base BIBF 1120 BS), its metabolites BIBF 1202 (in form of 
the free zwitterion BIBF 1202 ZW) and the acylglucuronid thereof (BIBF 1202 glucuronide) 
plasma concentrations will be determined by a validated assay based on liquid
chromatography-tandem mass spectrometry (LC-MS/MS).


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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 (
).
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable.
ASSESSMENT OF BIOMARKER 
5.5
Not applicable.
5.5.1
Biobanking
Not applicable.
OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
All measurements conducted in the trial are using standard methods.
The pharmacokinetic parameters and measurements outlined in Section 5.4 are generally used 
as measurements to assess drug exposure.


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6.
INVESTIGATIONAL PLAN
For details see Flow Chart.
VISIT SCHEDULE
6.1
The patients will come to the hospital or Phase I unit 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 screening and end of trial examination 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 pharmacokinetic 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 or Phase I unit for the purpose of the trial 
(e.g. collection of blood for PK analysis) will not be reported as serious adverse events.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
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. The screening period may have a 
duration of up to 28 days (4 weeks), but may also be shorter.
Baseline Conditions
Any concomitant disease that requires therapy shall be recorded.
Medical History:
The medical history with regard to non-small cell lung cancer shall be documented (i.e. date 
of first diagnosis, as well as details concerning first-line therapy with start and end dates and 
the reason why second-line therapy is indicated i.e. date of most recent progression) and a 
statement is to be provided that the patient is a candidate for therapy with nintedanib 
according to the marketing authorisation.
6.2.2
Treatment period
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 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 h 


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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 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
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. 
It is assumed that Period 2 will happen during the first treatment course of nintedanib. 
However, if the patient would not be able to continuously take nintedanib for at least 7
consecutive days during the first treatment course, then the second administration of 
Microgynon® might also be administered during one of the next treatment courses.
The administration of Microgynon® may vary between Day 8 and Day 16 of nintedanib 
intake. The second PK-profile day may take place only if a continuous intake of nintedanib 
for at least 7 consecutive days was confirmed. 
In the morning of the respective PK day (or the evening before depending on the patient 
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. Microgynon® and Nintedanib will be given concomitantly 
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
At the end of trial examination, the investigations, as documented in the Flow Chart, will be 
performed. The end of trial examination may take place at the earliest 3 days after last intake 
of Microgynon®.
The patient and investigator will assess whether the patient will continue nintedanib therapy 
according to the marketing authorization.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
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 200 mg nintedanib 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).
 
NULL AND ALTERNATIVE HYPOTHESES
7.2
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.
PLANNED ANALYSES
7.3
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 violations will be identified no later than in the Report Planning Meeting and 
provided in the Trial Statistical Analysis Plan (TSAP).
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. This is the full analysis set population in the sense of ICH-E9.

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 
violation 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 
analysis, based on the criteria specified below). Exclusion of a patient’s data will 
be documented in the CTR.


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o
Relevant protocol violations 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.
7.3.1
Primary endpoint analyses
The primary analyses will be based on the PKS (Section 7.3).
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 5.1.1 will be log-transformed (natural 
logarithm). The difference between the expected means for log(T)-log(R) will be estimated 
by the difference in the corresponding Least Squares Means (point estimate).
Furthermore, the two-sided 90% confidence intervals based on the t-distribution will be 
computed. These quantities will then be back-transformed to the original scale to give the 
point estimator (geometric mean) and interval estimates for the ratio between response under 
test treatment and response under reference treatment.
The above mentioned ANOVA model will include effects accounting for the following 
sources of variation: ‘subjects’ and ‘treatment’. The effect ‘subjects’ will be considered as 
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 

k = the kth treatment effect, k = 1, 2,


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
emk = the random error associated with the mth subject who received treatment k.
 
7.3.2
Secondary endpoint analyses
The secondary PK parameters described in Section 5.1.2 will be analysed as described for the 
primary PK endpoints.
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced.
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 5.3.6.2) 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 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 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 trial examination will be assigned to ‘post-
study’ unless they are within 30 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 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 treatment, 
system organ class and preferred term after coding according to the current version of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA).
Laboratory data and vital signs data will only be listed. Laboratory data will be compared to 
their reference ranges. Values outside the reference range will be flagged. 
Relevant ECG findings will be reported as AEs.


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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Sections 5.1.1, 5.1.2 and 5.1.3 will be calculated 
according to the relevant BI internal procedures.
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 pharmacokinetic parameters; however, they will not be 
included in descriptive statistics for plasma concentrations, pharmacokinetic parameters or 
other statistical assessments.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
The 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).


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INTERIM ANALYSES
7.4
An interim analysis may be performed in case recruitment of patients is very slow and 
intermediate data would be needed for submission to regulatory authorities. Due to the 
exploratory nature of the trial, no adjustment of the analyses is necessary.
HANDLING OF MISSING DATA
7.5
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).


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RANDOMISATION
7.6
As this is a single fixed sequence trial, no randomisation is necessary.
DETERMINATION OF SAMPLE SIZE
7.7
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
and the potential intake of co-medication that might interfere with pharmacokinetics of 
Microgynon® (see Section 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 Trial Clinical 
Monitor 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 / 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
Expected two-sided 90% confidence intervals for gCV=20% and 
different ratios T/R (N=8, 10, 12, 14 and 16)
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, 104.38)
90%
(68.98, 117.43)
100%
(76.64, 130.47)
10
1.562
1.250
70%
(56.01, 87.49)
80%
(64.01, 99.99)
90%
(72.01, 112.48)
100%
(80.01, 124.98)
12
1.474
1.214
70%
(57.66, 84.99)
80%
(65.89, 97.13)
90%
(74.13, 109.27)
100%
(82.37, 121.41)
14
1.416
1.190
70%
(58.82, 83.30)
80%
(67.22, 95.20)
90%
(75.63, 107.11)
100%
(84.03, 119.01)


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Table 7.7: 1 (con’t)
Expected two-sided 90% confidence intervals for gCV=20% and 
different ratios T/R (N=8, 10, 12, 14 and 16)
gCV
N
Precision
upper CL/
lower CL
Precision
upper CL/
point estimate
T/R [%]1
90% CI [%]
16
1.372
1.171
70%
(59.77, 81.98)
80%
(68.31, 93.69)
90%
(76.85, 105.40)
100%
(85.38, 117.12)
1 Ratio of the geometric means (test/reference) for a PK endpoint defined by exp(µT)/exp(µR)
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.
For these calculations the MOC3 routine from commercial software nQuery Advisor® 7.0
(Statistical Solutions, Ltd., Cork, Ireland; [R15-1331]) was used.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for GCP, relevant BI Standard Operating Procedures (SOPs), the EU regulation 536/2014 and 
other relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial patients against any immediate hazard, and also 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 contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report
unless otherwise specified in the publication plan.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF.
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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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.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
Case Report Forms (CRF) 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 good documentation practices and be attributable, legible, 
contemporaneous, original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or 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 (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))


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
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 sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by 
assessing all characteristics of the trial, including its nature, objective, methodology and the 
degree of any deviations of the intervention from normal clinical practice.
The Investigator / institution will allow on-site trial-related monitoring, audits, IRB / IEC 
review and regulatory inspections. Direct access must be provided to the CRF 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). The CRA and auditor may review all CRFs 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 ICH GCP.
8.3.3
Storage period of records
Trial sites:
The trial sites must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
8.5
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted below. Patient privacy will 
be ensured by using patient identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 


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processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
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, storage and 
future use of biological samples from clinical trial participants and the corresponding data, in 
particular

A Quality Management System has been implemented to ensure the adherence with the 
Principles of Good Clinical Practice as outlined in 'Note For Guidance On Good Clinical 
Practice' (CPMP/ICH/13 5/95)

The BI-internal facilities storing and analysing biological samples and data from clinical 
trial participants as well as the laboratories' activities for clinical trials sponsored by 
Boehringer Ingelheim are regularly audited. The analytical groups and the banking 
facilityare therefore assessed to be qualified for the storage and use of biological samples 
and data collected in clinical trials.

Samples and data are used only if an appropriate informed consent is available.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial 
(“Last Patient Out”).
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).


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P03-08008
Niemi M, Backman JT, Fromm MF, Neuvonen PJ, Kivisto KT. 
Pharmacokinetic interactions with rifampicin: clinical relevance. Clin 
Pharmacokinet 2003. 42(9):819-850
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_guidel
ine/2012/0 7/WC500129606.pdf (access date: 8 July 2015) ; London: 
European Medicines Agency (EMA) 2012
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992
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
R12-0033
Yasmin 0,03 mg/3 mg Filmtabletten (Bayer Vital), verschreibungspflichtig 
(Fachinformation (Zusammenfassung der Merkmale des Arzneimittels), 
Stand der Information: Mai 2011). 2011
R12-0034
Microgynon 0,03 mg/0,15 mg ueberzogene Tabletten (Bayer Vital), 
verschreibungspflichtig (Fachinformation (Zusammenfassung der 
Merkmale des Arzneimittels, Stand der Informationen: April 2007). 2007
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide. Los Angeles: 
Statistical Solutions (2007)
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
R16-0717
Microgynon ueberzogene Tabletten (Jenapharm), verschreibungspflichtig 
(Fachinformation, Stand der Information: September 2014). 2014


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10.
APPENDICES
DRUGS THAT ARE NOT ALLOWED DURING THE TRIAL
10.1
CYP3A strong inhibitors:

boceprevir,

clarithromycin,

conivaptan,

indinavir, 

itraconazole, 

ketoconazole, 

lopinavir,

mibefradil,

nefazodone, 

nelfinavir,

posaconazole, 

ritonavir, 

saquinavir, 

telaprevir,

telithromycin,

voriconazole.
CYP3A - strong inducers

avasimibe

carbamazepine, 

phenytoin, 

rifampin.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
28 April 2016
EudraCT number
2015-005664-41
BI Trial number
1199.238
BI Investigational Product(s)
Nintedanib, Vargatef®
Title of protocol
A Phase I trial to investigate the effect of 
nintedanib on the pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel 
in patients with non-small cell lung cancer
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
x
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
3.3
Description of change
male patients will not be included in the trial 
Rationale for change
request by German Health Authority
Section to be changed
Synopsis, section 4.1.1, 4.1.2, 4.1.4
Description of change
one tablet of Microgynon® will be administered
Rationale for change
originally two tablets were planned to be 
administered to achieve a higher exposure that 
would be more close to the clinical use. Since 
female patients have a sufficiently high exposure 
after one tablet, it appears justified to administer 
one table as described in the SmPC of Micrgynon®
Section to be changed
5.3.6.2
Description of change
the paragraph describing pregnancy will be 
removed 


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Rationale for change
no female partner of male patients could become 
pregnant as males will not be included in the trial 
and the female patients included are surgically 
sterilised or postmenopausal
Number of global amendment
2
Date of CTP revision
09 Mar 2017
EudraCT number
2015-005664-41
BI Trial number
1199.238
BI Investigational Product(s)
Nintedanib, Vargatef®
Title of protocol
A Phase I trial to investigate the effect of 
nintedanib on the pharmacokinetics of a 
combination of ethinylestradiol and levonorgestrel 
in patients with non-small cell lung cancer
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
x
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Synopsis
Description of change
Change in responsibility:
took 
over TCM ship
Rationale for change
Organisational change
Section to be changed
Flow chart
Description of change
Microgynon® PK day during Period 1 may take 
place within day - 27 and day - 7 prior to first 
intake of nintedanib;
results of screening examinations need to be 
awaited prior to proceeding with period 1;
if PK sampling in period 1 takes place between day 


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-27 and -20, physical examination, vital signs, 
laboratory tests and 12 lead ECG do no not need to 
be repeated on day -7 unless AE occurred during 
that timeframe or it is clinically indicated; 
laboratory test results need to be checked prior to 
dispension of Nintedanib;
Rationale for change
One of the reasons for low recruitment is the fact 
that patients would like to receive their anti-cancer 
therapy as rapidly as possible after the diagnosis of 
relapse. 
In order to meet the patients’ needs, enrolment of 
patients which have fulfilled dietary restrictions 
with regard to intake of green tea, grapefruits, 
Seville oranges (sour or bitter oranges) and their 
juices, dietary supplements and products including 
St. John's wort (Hypericum perforatum) and 
restricted concomitant therapies prior to enrolment 
and 7 days before the first intake of Microgynon®
in Period 1 will be allowed. 
Confirmation and appropriate documentation of 
meeting the dietary restrictions and the restrictions 
regarding concomitant therapies in the time period 
prior to informed consent is regarded acceptable.
Section to be changed
Flow chart
Description of change
Laboratory tests on day -5
Rationale for change
Baseline laboratory tests upfront start of 
Nintedanib therapy are required in order to have 
the possibility to distinguish between Microgynon®
and Nintedanib related effects.
Section to be changed
5.3.6.1
Description of change
These lab findings constitute a hepatic injury alert 
and the patients showing these lab abnormalities 
need to immediately stop the trial medication or are 
not allowed to start treatment and need to be 
followed up according to the “drug-induced liver 
injury (DILI) checklist” provided in the ISF.
Rationale for change
Laboratory test results on day -5 need to be 
checked prior to starting Nintedanib therapy. 
Section to be changed
2.3.1
Description of change
Update of potential side effects of Nintedanib
Rationale for change
Update of Nintedanib SmPC


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03853814
3.0
clinical-trial-protocol-revision-02
A Phase I trial to investigate the effect of nintedanib on the pharmacokinetics of a
combination of ethinylestradiol and levonorgestrel in patients with non-small cell
lung cancer
Approval-Clinical Pharmacokinetics
09 Mar 2017 15:37 CET
Author-Trial Statistician
09 Mar 2017 15:42 CET
Approval-Therapeutic Area
09 Mar 2017 15:43 CET
Approval-Clinical Pharmacokinetics
09 Mar 2017 16:11 CET
Approval-Team Member Medicine
09 Mar 2017 23:22 CET
Approval-Trial Clinical Monitor
10 Mar 2017 08:05 CET
Verification-Paper Signature
Completion
28 Mar 2017 10:11 CEST


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c03853814
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SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c12588444-01
BI Trial No.:
1199.238
Title:
A Phase I trial to investigate the effect of nintedanib on the
pharmacokinetics of a combination of ethinylestradiol and 
levonorgestrel in patients with non-small cell lung cancer
Including revised protocol (based on global amendment 2)
[c03853814-03]
Investigational
Product(s):
Vargatef®, nintedanib
Responsible trial 
statistician(s):
Phone:
Fax: 
Phone: 
Fax:
Date of statistical 
analysis plan:
29 JAN 2018 SIGNED
Version:
“Final”
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINT .................................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoint...............................................................................................9
5.3
FURTHER ENDPOINTS.....................................................................................9
5.3.1
Safety endpoints ....................................................................................................9
5.4
OTHER VARIABLES..........................................................................................9
5.4.1
Demographic and other baseline characteristics ...............................................9
5.4.2
Treatment compliance and treatment exposure ................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENTS...................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
PATIENT SETS ANALYSED...........................................................................13
6.4
SUBGROUPS ......................................................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINTS...................................................................................17
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoint .....................................................................................18
7.5.2
Secondary endpoint.............................................................................................18
7.6
FURTHER ENDPOINTS...................................................................................18
7.6.1
Safety endpoints ..................................................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................18
7.8.1
Adverse events.....................................................................................................18
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG......................................................................................................................20
7.8.5
Others...................................................................................................................20


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8.
REFERENCES....................................................................................................21
9.
ADDITIONAL SECTIONS ...............................................................................22
10.
HISTORY TABLE..............................................................................................23


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LIST OF TABLES
Table 6.1: 1
Treatments ........................................................................................................10
Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory and vital signs..................................................................................11
Table 6.2: 1
Important protocol violations ...........................................................................13
Table 6.3: 1
Patient sets analysed .........................................................................................14
Table 10: 1
History table .....................................................................................................23


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
AESI
Adverse events of special interest
ADS
Analysis data set
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
CARE
Clinical data analysis and reporting environment
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
arithmetic coefficient of variation
DBLM
Database lock meeting
ECG
Electrocardiogram
eCRF
Electronic case report form
EE
Ethinylestradiol
ES
Entered set
EudraCT
European union drug regulating authorities clinical trials
gMean
Geometric mean
gCV
Geometric coefficient of variation
ICH
International Conference on Harmonisation
LE
Levonorgestrel
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics
PKS
Pharmacokinetic analysis set
PV
Protocol violation
R
Reference treatment
RAGe
Report appendix generator system
REP
Residual effect period


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Term
Definition / description
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation
T
Test treatment
TS
Treated set
TSAP
Trial statistical analysis plan


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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 Oracle ClinicalTM 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) and/or SAS® software, version 9.4 (or later) (professional Network version 5.2, 
Pharsight Corporation, Mountain View, CA 94041-1530, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The trial was terminated because of recruitment problems. At the time of trial termination, 
only two patients had been treated and completed the trial. Therefore, no statistical models 
can be applied for the primary and secondary endpoints. Primary and secondary PK endpoints 
will only be summarised with descriptive statistics. 
All other analyses described in this TSAP are in accordance with the statistical methods 
described in the CTP.
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).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
Primary endpoints are defined in Section 5.1.1 of the CTP.
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable, as no key secondary endpoint was specified in the CTP.
5.2.2
Secondary endpoint
The secondary endpoint is defined in Section 5.1.2 of the CTP
5.3
FURTHER ENDPOINTS
5.3.1
Safety endpoints
Safety endpoints are defined in Section 5.3 of the CTP.
5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
At the Screening visit, the medical examination will include documentation of patient 
information, informed consent, demographics including height and body weight, signs and 
symptoms of the trial disease and concomitant therapy.
CTP: The medical history with regard to non-small cell lung cancer shall be documented (i.e. 
date of first diagnosis, as well as details concerning first-line therapy with start and end dates 
and the reason why second-line therapy is indicated i.e. date of most recent progression) […].
Age [years] will be determined as the difference between year of birth and year of informed 
consent.
Body mass index (BMI) will be calculated as weight [kg] / height [m]2.
5.4.2
Treatment compliance and treatment exposure
Treatment compliance will not be analysed as a specific endpoint, cf. Section 4.3 of the CTP.
Treatment exposure is defined as the total dose of nintedanib and the total dose of 
Microgynon® per patient.


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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 were to undergo two treatment periods in a fixed sequence.
Table 6.1: 1
Treatments
Treatment description
Treatment
Period
1 x 1 tablet Microgynon®, single dose
(1 tablet containing 30 microgram ethinylestradiol (EE) / 150 microgram 
levonorgestrel (LE))
Reference
(R)
1
Day 1 - 7:
2 x 2 capsules Vargatef® continuously for at least 7 days (1 capsule containing 100 
mg nintedanib); *
[or in case of dose reduction:
During the 7 days, switch to reduced dosing of 2 x 1 capsule Vargatef® (1 capsule 
containing 150 mg nintedanib) and continued intake up to Day 7;*]
Day 8:
1 x 2 capsules Vargatef® in the morning on Day 8 of continuous Vargatef® intake 
(1 capsule containing 100 mg nintedanib);
[or  in  case of dose reduction:
1 x 1 capsule Vargatef® in the morning on Day 8 of continuous Vargatef® intake 
(1 capsule containing 150 mg nintedanib);]
1 x 1 tablet Microgynon®, single dose in the morning on Day 8 of continuous 
Vargatef® intake (1 tablet containing 30 microgram EE / 150 microgram LE)
1 x 2 capsules Vargatef® in the evening on Day 8 of continuous Vargatef® intake 
(1 capsule containing 100 mg nintedanib);
[or  in  case of dose reduction:
1 x 1 capsule Vargatef® in the evening on Day 8 of continuous Vargatef® intake 
(1 capsule containing 150 mg nintedanib);]
Day 9 - 11:
2 x 2 capsules Vargatef® on Day 9 of continuous Vargatef® intake  until end of trial 
visit (1 capsule containing 100 mg nintedanib);
[or in case of dose reduction:
2 x 1 capsule Vargatef® on Day 9 of continuous Vargatef® intake  until end of trial 
visit (1 capsule containing 150 mg nintedanib);]
Test 
(T)
2
* In case of a temporary interruption of nintedanib intake, patients can receive Microgynon® in Period 2 only if 
they have taken nintedanib for 7 consecutive days before intake of Microgynon®.
For statistical analysis of AEs and for listings of safety laboratory and vital signs, the study 
phases are defined for each patient as described in Table 6.1: 2.


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Table 6.1: 2
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
and vital signs
Study analysis phase
Label
Start
End
Screening
Screening
Date of informed consent or 
date of first laboratory 
assessment, whichever occurs 
earlier *
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 + residual effect phase 
(REP, i.e. 72 h)
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)
Date/time of last administration 
of nintedanib in Treatment 
Period 2 + REP (30 days)
Follow-up
nintedanib
FUP-NIN
Date/time of last administration 
of nintedanib in Treatment 
Period 2 + REP (30 days)
0:00 a.m. on day after trial 
completion date
Post study
Post-study
0:00 a.m. on day after trial 
completion date
Last contact with patient
* E.g., if a patients agrees to use laboratory data which were taken prior to informed consent.
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for the on-treatment phases "MIC", "Loading NIN", "NIN+MIC", and "NIN" only. 
Screening, post-treatment and post-study periods will not be included in this analysis. CTR 
Section 15 AE displays (but not Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 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 16.1.9.2.8.1 displays will present results for all study analysis phases defined 
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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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 VIOLATIONS
Data discrepancies and deviations from the CTP will be identified for all patients in the 
database (i.e., treated patients). Consistency check listings (for identification of violations of 
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 and 
database lock meeting (RPM/DBLM). 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 
violation (PV). For definition of important PVs, and for the process of identification of these, 
refer to the Boehringer Ingelheim (BI) reference document "Protocol Violation Handling 
Definitions" (2).
If any important PVs are identified, they are to be summarised into categories and will be 
captured in the RPM/DBLM minutes via an accompanying Excel spreadsheet (3). The 
following table contains the categories which are considered to be important PVs in this trial. 
If the data show other important PVs, this table will be supplemented accordingly by the time 
of the RPM/DBLM.
PVs will be summarised and listed.


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Table 6.2: 1
Important protocol violations
Category 
/ Code
Description
Example /Comment
A
Entrance criteria not met
A1
Patient less than 18 years old
Violation of inclusion criterion 1
B
Informed consent
B1
Informed consent not available
Violation of inclusion criterion 5
B2
Informed consent too late
Informed consent date was after screening visit date
C
Trial medication and randomisation
C1
Incorrect trial medication taken
This will be captured manually and discussed in 
MQRM (check medication intake details via review 
listings for evidence of extreme non-compliance) or 
RPM
C3
Non-compliance
This will be captured manually and discussed in 
MQRM (check medication compliance details via 
review listings for evidence of extreme non-
compliance) or RPM
C5
Incorrect intake of trial medication
This will be captured manually and discussed in 
MQRM (check medication intake and compliance 
details via review listings for evidence of extreme non-
compliance) or RPM
D
Concomitant medication
D1
Prohibited medication use
This will be captured manually and discussed in 
MQRM (review listings of concomitant medications 
for prohibited medication use) or RPM
E
Missing data
E1
Certain violations of procedures used 
to measure primary or secondary data
This will be captured manually and discussed in 
MQRM (review listings for adherence to blood 
sampling and time points, drug administration times) or 
RPM
F
Incorrect timing
F1
Certain violations of time schedule 
used to measure primary or secondary 
data
This will be captured manually and discussed in 
MQRM (review listings for general quality of PK 
sampling) or RPM
G
Other trial specific important 
violations
G1
Incorrect intake of meal / non-
adherence to dietary restrictions
This will be captured manually and discussed in 
MQRM (review listings of dietary restrictions) or RPM
1 Missing visits, evaluations, and tests will be considered missing data, not PVs
2 Time deviations will only be flagged as important PV, when leading to exclusion of the entire patient from an analysis set
Source: BI reference document 'Protocol Violation Handling Definitions' [001-MCS-50-413_RD-01] (2).
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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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/DBLM.
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
Entered set 
(ES)
Treated set 
(TS)
PK analysis set 
(PKS)
Important PVs
X
Disposition
X
X
Demographic/baseline 
endpoints
X
Safety endpoints 
X
PK endpoints
X
6.4
SUBGROUPS
No subgroup analyses are planned.
6.5
POOLING OF CENTRES
This section is not applicable.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP: 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.
CTP: 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 (4).
Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-36-
472_RD-01) (5). CTP: 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).
CTP: 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.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
None of the planned analyses requires a definition of baseline. 
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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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) (10).
The individual values of both 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.
Descriptive data analysis of primary and secondary PK endpoints will be performed by BI and 
presented in Section 15.6 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 primary and secondary PK endpoints, 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 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.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.


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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.
Medications will be categorised into baseline therapies, on-treatment concomitant therapies, 
and post-study drug discontinuation therapies:

Baseline therapies will be defined as treatments with a start date before first trial drug 
intake and a stop date after (i.e. ongoing after first trial drug intake) or on the day of 
the first trial drug intake.

On-treatment concomitant therapies are defined as treatments with a start date after or 
on the day of first trial drug intake and before or on the day of last trial drug intake.

Post-study drug discontinuation therapies are defined as treatments with a start date 
after last trial drug intake and before trial completion (as defined in Section 6.2.3 of 
the CTP).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint (cf. Section 5.4.2). Any 
deviations from complete intake will be addressed in the RPM/DBLM (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINTS
Primary PK endpoints will be assessed descriptively. The analysis of standard PK parameters 
is performed according to BI standards (see 001-MCS-36-472_RD-01) (5).
Exclusion of PK parameters
The ADS PK6+ contains column variables KPEXC and KPEXCX indicating 
inclusion/exclusion (KPEXC) of a PK parameter and an analysis flag comment (KPEXCX). 
All analyses based on the PKS are based on PK parameters with KPEXC equal to “Included”, 
regardless of the analysis flag comment KPEXCX.
Exclusion of plasma concentrations
The ADS PK4+ (PK concentrations per time-point) contains column variables PKEXC and
PKEXCX indicating inclusion/exclusion (PKEXC) of a plasma concentration and an analysis 
flag comment (PKEXCX). Exclusion of a plasma concentration depends on the analysis flag 
comment PKEXCX. For example, if PKEXCX is set to ‘ALL CALC’, the value will be 
excluded for all types of analyses based on concentrations. If PKEXCX is set to ‘DESC 


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STATS’ the value will be excluded from descriptive evaluations per planned time point. If 
PKEXCX contains the addition ‘TIME VIOLATION’ or ‘TIME DEVIATION’ the value can 
be used for further analyses based on actual times. If PKEXCX is set to ‘HALF LIFE’ the 
value will be excluded from half-life calculation only; the value is included for all other 
analyses.
CTP: However, the excluded concentration itself will be listed in the tables in section 15 of 
the clinical trial report associated with an appropriate flag.
Further details are given in 001-MCS-36-472_RD-01 “Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies” (5) and 001-MCS-36-472_RD-03 
“Description of Analytical Transfer Files and PK/PD Data Files” (6).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoint
The secondary endpoint will be summarised with descriptive statistics.
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.6
FURTHER ENDPOINTS
7.6.1
Safety endpoints
Further safety endpoints 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.


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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 this purpose, AE data will be 
combined in a two-step procedure into AE records.
In a first step, AE occurrences, i.e., AE entries on the electronic case report form (eCRF), will 
be collapsed into a single AE episode provided that all of the following applies:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started in the same hour in which the 
first occurrence ended)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
In a second step, AE episodes will be condensed into a single AE record per patient, treatment 
and dictionary level, provided that the episodes were reported with the same term on the 
respective MedDRA level and that the episodes are assigned to the same treatment.
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' (7) [001-MCG-156 
Version 5] and "Handling of missing and incomplete AE dates" (4) [001-MCG-156_RD-01]. 
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means that 
all AEs will be assigned to the treatment, post-treatment, screening or post-study phases as 
defined in Section 6.1.
Hepatic injury and gastro-intestinal perforation are defined as protocol-specified adverse 
events of special interest (AESIs). For details on the definition of hepatic injury see CTP 
Section 5.3.6.1
Note that these events were called “Protocol specified AE of special interest” in the eCRF. 
The investigator had to classify all observed AEs on the eCRF whether they were of this type 
or not.
According to ICH E3 (9), 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 (9).
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 


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(SAEs), patients with AESIs and patients with other significant AEs (according to ICH E3 
(9)). The frequency of patients with AEs will also be summarised by worst common
terminology criteria grade, primary system organ class and preferred term.
The system organ classes will be sorted according to the standard sort order specified by the 
European Medicines Agency, preferred terms within system organ classes will be sorted by 
descending relative frequency.
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.
7.8.2
Laboratory data
Laboratory data will only be listed. The listing will be based on BI standards (8).
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
Clinically relevant findings in laboratory data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.3
Vital signs
Vital signs data will only be listed.
Clinically relevant findings in vital signs data will be reported as AEs and will be analysed as 
part of AE analysis.
7.8.4
ECG
Clinically relevant findings in electrocardiogram (ECG) data will be reported as AEs and will 
be analysed as part of AE analysis.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent 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.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline 
Topic E9; Note for Guidance on Statistical Principles for Clinical Trials, current 
version
 
 
 
 
 
 
9
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
 


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9.
ADDITIONAL SECTIONS
Not applicable as no additional information is needed.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
29 JAN 2018
None
This is the final TSAP without any 
modification