Conditions: Healthy
Keywords: Non-small cell lung cancer (NSCLC) P-glycoprotein Tepotinib Dabigatran Etexilate
Allocation: NA | Intervention model: CROSSOVER
Enrollment: 20
Healthy volunteers: yes

Brief summary:
This study investigated the effect of Tepotinib on the pharmacokinetics (PK) of the p-glycoprotein (P-gp) probe substrate Dabigatran etexilate.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Dabigatran Etexilate intervention 2: Tepotinib
Intervention descriptions: intervention 1: Participants received single oral dose of Dabigatran etexilate on Day 1 of Treatment period 1 and co-administration of Dabigatran with Tepotinib on Day 8 of Treatment period 2. intervention 2: Participants received single oral dose of Tepotinib for 8 days in Treatment period 2.

Protocol document:
Prot_000.pdf: 
Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of T e p oti ni b on t he P K of t he P -g p S u bstr ate 
M S 2 0 0 0 9 5- 0 0 3 2
D a bi g atr a n E te xil ate
C O N F I D E N T I A L
I N F O R M A T I O N
1/ 8 4
Cli nic al Tri al Pr ot oc ol
Cli nic al Tri al Pr ot oc ol N u m ber
M S 2 0 0 0 9 5 - 0 0 3 2
Title
P hase I, O pe n -la bel, Si n gle Se q ue nce, T w o -Peri o d 
St u d y  to E val uate 
t he Effect 
of Te p oti ni b 
o n 
P- Gl y c o pr otei n
b y  
In vesti gati n g 
t he 
P har mac o ki netics 
of 
t he P- Gl y c o pr otei n Pr o be 
S u bstrate Da bi gatra n Ete xilate i n Healt h y  S u bjects
P h ase
I
I N D N u m ber
N ot a p plica ble
E u dr a C T N u m ber
2 0 1 7- 0 0 4 0 7 4- 3 4
Pri nci p al I n vesti g at or
, 
 
, Ger ma n y
S p o ns or
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
Me dical Res p o nsi ble:
, 
 
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 
6 4 2 9 3 Dar msta dt, Ger ma n y
P h o ne:
M o bile: 
Cli nic al Tri al Pr ot oc ol Versi o n
2 3 A pril 2 0 1 8 / Versi o n 3. 0
i ncl u di n g A me n d me nt 1. 0 t o Versi o n 1. 0 a n d 
A me n d me nt 2 t o Versi o n 2. 0
Re pl aces Versi o n
6 Marc h 2 0 1 8 / Versi o n 2 . 0
- C o nfi de ntial –
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its s u bsi diaries. 
It is i nte n de d f or restricte d use o nl y a n d m a y  not – i n f ull or part – be passe d o n, re pr o d uce d, 
p u blis he d or use d wit h o ut e x press per missi o n of Merc k 
K Ga A, Dar msta dt, Ger ma n y,  or its 
s u bsi diar y. C o p yri g ht © 2 0 1 8 b y Merc k K Ga A, Dar msta dt, Ger ma n y, or its s u bsi diar y. All ri g hts 
reser ve d.
D o c u me nt N o. 
O bject N o. 
0 9 0 0 ba be 8 0f 5 2 d 6 d v 2. 0
0 9 0 0 ba be 8 0f 6 5 3c 0
PI
PI
PI
PI
PI
PI
PI


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
2/84
Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................6
Table of In-Text Figures ......................................................................................................6
List of Abbreviations ...........................................................................................................7
1
Synopsis..............................................................................................10
2
Sponsor, Investigators and Trial Administrative Structure ................17
3
Background Information.....................................................................17
3.1
Trial Rationale ....................................................................................20
4
Trial Objectives ..................................................................................21
4.1
Primary Objective...............................................................................21
4.2
Secondary Objectives .........................................................................21
4.3
Exploratory Objectives .......................................................................21
5
Investigational Plan ............................................................................21
5.1
Overall Trial Design and Plan ............................................................21
5.2
Discussion of Trial Design .................................................................23
5.2.1
Inclusion of Special Populations ........................................................24
5.2.2
Scientific Rationale for Trial Design..................................................24
5.2.3
Justification for Dose..........................................................................25
5.2.4
Rationale for Endpoints......................................................................25
5.3
Selection of Trial Population..............................................................26
5.3.1
Inclusion Criteria ................................................................................26
5.3.2
Exclusion Criteria...............................................................................27
5.4
Criteria for Initiation of Trial Treatment ............................................28
5.5
Criteria for Subject Withdrawal..........................................................28
5.5.1
Withdrawal from Trial Treatment ......................................................28
5.5.2
Withdrawal from the Trial..................................................................29
5.6
Premature Termination of the Trial ....................................................30
5.7
Definition of End of Trial...................................................................30
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................30
6.1
Description of the Investigational Medicinal Product........................31
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
3/84
6.2
Dosage and Administration ................................................................31
6.3
Assignment to Treatment Groups.......................................................32
6.4
Noninvestigational Medicinal Products to be Used............................32
6.5
Concomitant Medications and Procedures .........................................32
6.5.1
Permitted Medicines...........................................................................32
6.5.2
Prohibited Medicines..........................................................................33
6.5.3
Permitted/Prohibited Procedures ........................................................33
6.5.4
Other Interventions.............................................................................34
6.5.5
Special Precautions.............................................................................34
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................34
6.6
Packaging and Labeling of the Investigational Medicinal Product....34
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................34
6.8
Investigational Medicinal Product Accountability.............................35
6.9
Assessment of Investigational Medicinal Product Compliance .........36
6.10
Blinding ..............................................................................................36
6.11
Emergency Unblinding.......................................................................36
6.12
Treatment of Overdose .......................................................................36
6.13
Medical Care of Subjects after End of Trial.......................................36
7
Trial Procedures and Assessments......................................................37
7.1
Schedule of Assessments....................................................................37
7.1.1
Screening Examination.......................................................................37
7.1.2
Treatment Periods...............................................................................38
7.1.3
End of Trial Visit................................................................................41
7.2
Demographic and Other Baseline Characteristics ..............................41
7.3
Efficacy Assessments .........................................................................42
7.4
Assessment of Safety..........................................................................42
7.4.1
Adverse Events ...................................................................................42
7.4.2
Pregnancy and In Utero Drug Exposure.............................................46
7.4.3
Clinical Laboratory Assessments .......................................................47
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............49
7.5
Pharmacokinetics................................................................................50
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
4/84
7.5.1
Blood Sampling ..................................................................................50
7.5.2
Calculation of Pharmacokinetic Variables .........................................51
7.6
Biomarkers..........................................................................................52
7.7
Pharmacogenomics.............................................................................52
7.8
Other Assessments..............................................................................52
8
Statistics..............................................................................................52
8.1
Sample Size ........................................................................................52
8.2
Randomization....................................................................................53
8.3
Endpoints............................................................................................53
8.3.1
Primary Endpoints ..............................................................................53
8.3.2
Secondary Endpoints ..........................................................................53
8.3.3
Exploratory Endpoints........................................................................53
8.4
Analysis Sets.......................................................................................54
8.5
Description of Statistical Analyses.....................................................54
8.5.1
General Considerations.......................................................................54
8.5.2
Analysis of Primary Endpoint ............................................................55
8.5.3
Analysis of Secondary Endpoints.......................................................55
8.5.4
Analysis of Safety and Other Endpoints.............................................55
8.6
Interim and Additional Planned Analyses ..........................................56
9
Ethical and Regulatory Aspects..........................................................56
9.1
Responsibilities of the Investigator ....................................................56
9.2
Subject Information and Informed Consent .......................................56
9.3
Subject Identification and Privacy......................................................57
9.4
Emergency Medical Support and Subject Card..................................57
9.5
Clinical Trial Insurance and Compensation to Subjects.....................58
9.6
Independent Ethics Committee or Institutional Review Board..........58
9.7
Health Authorities...............................................................................58
10
Trial Management...............................................................................58
10.1
Case Report Form Handling...............................................................58
10.2
Source Data and Subject Files............................................................59
10.3
Investigator Site File and Archiving...................................................60
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................60
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
5/84
10.5
Changes to the Clinical Trial Protocol................................................60
10.6
Clinical Trial Report and Publication Policy......................................61
10.6.1
Clinical Trial Report...........................................................................61
10.6.2
Publication..........................................................................................61
11
References Cited in the Text...............................................................62
12
Appendices .........................................................................................63
Appendix I
Signature Pages and Responsible Persons for the Trial......................64
Signature Page – Protocol Lead.........................................................................................65
Signature Page – Principal Investigator.............................................................................66
Sponsor Responsible Persons Not Named on the Cover Page ..........................................67
Appendix II
Planned Numbers of Blood Samples for Clinical Laboratory, PK, 
and PGx and Total Blood Sampling Volume .....................................68
Appendix III
Contraception Guidance .....................................................................69
Appendix IV
Protocol Amendments and List of Changes .......................................71
Amendment 1
............................................................................................................72
Amendment 2
............................................................................................................78
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
6/84
Table of In-Text Tables
Table 1
Schedule of Assessments - Period 1 (Administration of 
Dabigatran Etexilate alone) ................................................................13
Table 2
Schedule of Assessments - Period 2 (Administration of Tepotinib 
and Dabigatran Etexilate) ...................................................................15
Table 3
Safety Laboratory Evaluations ...........................................................48
Table 4
Time Windows....................................................................................50
Table 5
Definition of PK Parameters for Dabigatran after Single Dose 
Administration....................................................................................51
Table 6
Definition of PK Parameters for Tepotinib and Metabolites 
MSC2571109A and MSC2571107A after Multiple Dose 
Administration....................................................................................52
Table of In-Text Figures
Figure 1
Study Design.......................................................................................22
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
7/84
List of Abbreviations
Abbreviation
Definition of Terms
AE
Adverse event
anti-HCV
Hepatitis C virus antibody
ALT
Alanine aminotransferase
aPTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-t
Area under the plasma concentration-time curve from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above 
the lower limit of quantification
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0-∞. AUCextra% = (extrapolated area/AUC0-∞) x 100
AUC
The area under the plasma concentration-time curve (AUC) over the dosing 
interval from T1 = 0 h to T2 = h
beta-HCG
Beta-human chorionic gonadotrophin 
bpm
Beats per minute 
CI
Confidence Interval
CK MB
Creatinine phosphokinase myocardium/brain type
CL/f
Apparent total body clearance considering the fraction of dose (f) absorbed
CLSS/f
Apparent total body clearance of drug at steady state following oral 
administration, considering the fraction of dose (f) absorbed.
Cmax
Maximum plasma concentration observed
Cmax,SS
Maximum plasma concentration observed in steady state
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
8/84
Abbreviation
Definition of Terms
Cmin,SS
Minimum plasma concentration observed in steady state
c-Met
Mesenchymal-epithelial transition factor
CRO
Contract research organization
CV
Coefficient of variation
DDI
Drug-drug interaction
ECG
Electrocardiograms 
eGFR
Estimated glomerular filtration rate
eCRF
Electronic case report form
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone 
GeoCV
Coefficient of variation of the geometric mean
GeoMean
geometric mean
h
hours
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
HIV1/HIV2
Human immunodeficiency virus 1 and 2 
IC50
Half maximal inhibitory concentration
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
λz
Apparent terminal rate constant
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
9/84
Abbreviation
Definition of Terms
LLOQ
Lower limit of quantification
min
minutes
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for AEs
NSCLC
Non-small cell lung cancer
P-gp
P-glycoprotein 
PGx
Pharmacogenetics
PK
Pharmacokinetics
QTcF
Corrected QT interval per Fridericia’s formula
RP2D
Recommended Phase II dose
SAE
Serious adverse event
SD
Standard deviation 
SS
Steady state
t1/2
Terminal half-life
TEAE
Treatment emergent adverse event
TF2
Tablet formulation 2
tlast
The last sampling time at which the concentration is at or above the lower 
limit of quantification
tmax
Time to reach the maximum plasma concentration
tmax,SS
Time to reach the maximum plasma concentration in steady state
T/R ratio
Test/Reference ratio
TSH
Thyroid stimulating hormone
TT
Thrombin time
ULN
Upper limit of normal range
VZ/f
Apparent volume of distribution during the terminal phase
Document No. 
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Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of T e p oti ni b on t he P K of t he P -g p S u bstr ate 
M S 2 0 0 0 9 5- 0 0 3 2
D a bi g atr a n E te xil ate
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 /8 4
1
S y n o psis
Cli nic al Tri al Pr ot oc ol N u m ber
M S 2 0 0 0 9 5 - 0 0 3 2
Title
P hase I, O pe n -la bel, Si n gle Se q ue nce, T w o-
Peri o d St u d y  t o E val uate t he Effect of Te p oti ni b 
o n P- Gl y c o pr otei n b y In vesti gati n g t he 
P har mac o ki netics of t he P -Gl y c o pr otei n Pr o be 
S u bstrate Da bi gatra n Ete xilate i n Healt h y  
S u bjects
Tri al P h ase
I
I N D N u m ber
N ot a p plica ble
F D A c o vere d tri al
N o
E u dr a C T N u m ber
2 0 1 7- 0 0 4 0 7 4- 3 4
Pri nci p al I n vesti g at or
 
, Ger ma n y
S p o ns or 
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 
Dar msta dt, Ger ma n y
Tri al ce nter
 
, Ger ma n y
Pl a n ne d tri al peri o d
(first s u bject i n-l ast s u bject o ut)
Q 1 -Q 2 2 0 1 8
Tri al Re gistr y
E U Cli nical Trials Re gister, Cli nical Trials. g o v
Pri m ar y O bjecti ve:

T o i n vesti gate t he effect of te p oti ni b o n t he pri mar y  p har mac o ki netic ( P K) e n d p oi nts of 
da bi gatra n f oll o wi n g oral a d mi nistrati o n of t he P- g p pr o be s u bstrate da bi gatra n 
ete xilate after m ulti ple d ose a d mi nistrati o n of te p oti ni b i n healt h y  s u bjects.
Sec o n d ar y O bjecti ves:

T o i n vesti gate t he P K effect of te p oti ni b o n t he sec o n dar y PK e n d p oi nts of da bi gatra n 
f oll o wi n g oral a d mi nistrati o n of da bi gatra n ete xilate

T o assess t he safet y an d t olera bilit y of te p oti ni b al o ne a n d u p o n c o-a d mi nistrati o n of 
da bi gatra n ete xilate.
E x pl or at or y O bjecti ves:

T o i n vesti gate t he m ulti ple d ose P K of te p oti ni b a n d its m eta b olites ( M S C 2 5 7 1 1 0 9 A 
a n d M S C 2 5 7 1 1 0 7 A)
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0f 5 2 d 6 d v 2. 0
0 9 0 0 ba be 8 0f 6 5 3c 0
PI
PI
PI


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
11/84

To explore the effect of pharmacogenetics (PGx) and variations of associated genes on 
the PK profile of dabigatran and/or tepotinib (if applicable; participation is optional).
Methodology: Open-label, single-sequence, 2-period drug-interaction trial.
The study will be divided into 2 periods: Period 1 will evaluate the PK of dabigatran after 
single dose administration of 75 mg dabigatran etexilate (Pradaxa®, given as mesilate). In 
Period 2, tepotinib will be administered for 7 days. On Day 8, dabigatran etexilate and 
tepotinib will be co-administered and PK of total dabigatran (unconjugated plus conjugated) 
will be evaluated over 72 hours (h) post-dose. 
The subjects will be admitted to the study site on Day -1. They will be resident at the study site 
under medical supervision from Days -1 of Period 1 until Day 11 of Period 2. After the first 6 
subjects completed administration in Period 2, safety and PK data will be reviewed by the 
responsible functional representatives.
Planned number of subjects: Overall, 20 healthy subjects are planned to be included.
Primary endpoint:

PK profile of dabigatran in terms of area under the concentration-time curve (AUC) 
from time zero to the last sampling time (AUC0-t), AUC from time zero extrapolated to 
infinity (AUC0-∞), maximum plasma concentration (Cmax) of total dabigatran 
(unconjugated plus conjugated) at Day 1 of Period 1 and Day 8 of Period 2 from time 
zero to 72 h post-dose. 
Secondary endpoints: 

PK profile of total dabigatran (unconjugated plus conjugated) in terms of time of the 
maximum drug concentration (tmax), terminal half-life (t1/2), percentage of AUC0-∞ 
obtained by extrapolation (AUCextra%), apparent total body clearance (CL/f), apparent 
volume of distribution during terminal phase (VZ/f) at Day 1 of Period 1 and Day 8 of 
Period 2 from time zero to 72 h post-dose.

Occurrence of treatment emergent adverse events (TEAEs, incidence, frequency, 
intensity and causality), occurrence of changes in safety laboratory assessments, 
12-lead electrocardiograms (ECGs) and vital signs in subjects receiving tepotinib alone 
and together with dabigatran etexilate assessed from Day -1 of Period 1 until the End of 
Trial Visit.
Exploratory endpoints: 

PK profile of tepotinib and its metabolites MSC2571109A and MSC2571107A in 
terms of AUC over the dosing interval (AUCτ), Cmax at steady state (Cmax,SS), minimum 
concentration at steady state (Cmin,SS), tmax at steady state (tmax,SS), CL/f at steady state 
(CLSS/f) (parent drug only), and t1/2 if appropriate 

Genetic variants and mutations in genes that potentially influence the PK of tepotinib 
and/or dabigatran. 
Document No. 
 
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
12/84
Pharmacokinetics: 
Blood samples for determination of plasma concentrations of total dabigatran will be taken at 
pre-dose until 72 h after dosing on Day 1 of Period 1 and Day 8 of Period 2. 
Blood samples for determination of plasma concentrations of tepotinib and its metabolites 
MSC2571109A and MSC2571107A will be taken pre-dose on Day 6 and at pre-dose until 24 h 
after dosing on Day 7 of Period 2. 
Other assessments: Not applicable.
Diagnosis and key inclusion and exclusion criteria: Healthy males and females (of non-
childbearing potential) between 18 and 44 years of age (inclusive) with total body weight 
between 50 to 100 kg (inclusive) and body mass index (BMI) between 18.5 and 29.9 kg/m2
(inclusive) at the time of the Screening examination. 
Investigational Medicinal Product: dose/mode of administration/ dosing schedule: 
Tepotinib film-coated tablet (Tablet Formulation 2, TF2) containing 500 mg of drug substance, 
oral administration.
Dabigatran etexilate 75 mg hard capsules, provided as mesilate salt.
Period 1: A single oral dose of 75 mg dabigatran etexilate will be administered together with 
240 mL of water in the morning of Day 1 of Period 1, 30 minutes (min) after start of a 
standardized breakfast (which must be consumed completely within 25 min). 
Period 2: Single doses of 500 mg tepotinib will be administered together with 240 mL of water 
in the morning of Days 1 to 7 of Period 2, 30 min after start of a standard breakfast (which 
must be consumed completely within 25 min).
On Day 8 of Period 2, 500 mg tepotinib and 75 mg dabigatran etexilate will be administered 
together with 240 mL of water 30 min after start of the breakfast (which must be consumed 
completely within 25 min).
Reference therapy: dose/mode of administration/dosing schedule: Not applicable
Planned trial and treatment duration per subject: About 7 weeks from Screening to End of 
Trial Visit, treatment on Day 1 of Period 1 and Days 1 to 8 of Period 2. 
Statistical methods: A general linear model with TREATMENT and SUBJECT as fixed 
effects will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞of 
dabigatran (measured as total dabigatran) based on the PK analysis set. Treatment differences 
on the log scale of dabigatran with tepotinib vs dabigatran alone will be estimated for Cmax, 
AUC0-t, and AUC0-∞together with their 90% confidence intervals (CIs). Point estimates and 
CIs will be back-transformed to the original scale. 
Individual estimates of relative bioavailability of dabigatran will be calculated for each subject.
Summary statistics will be provided for all parameters.
Document No. 
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
13/84
Table 1
Schedule of Assessments - Period 1 (Administration of Dabigatran Etexilate alone)
Assessment/ Activity
Screening
Study Period 1
Day -28 to Day -2
Day -1
Day 1
Day 2
Day 3
Day 4 f
Written informed consent a
X
Hospitalization
X
X
X
X
X
In-/exclusion criteria
X
X
Demographic data (incl. height, weight, BMI)
X
Medical history
X
Physical examination
X
X
Vital signs (blood pressure, pulse rate, body
temperature)
X
X
X b
X i
12-lead ECG
X
X
X b
X i
Clinical laboratory (hematology, 
biochemistry, urinalysis)
X
X
X i
Coagulation
X
X g
X g
Test for occult blood in feces
X
Serology (HIV/hepatitis)
X
Alcohol breath test
X
X
Pregnancy test c
X
X
Drugs of abuse 
X
X
Administration of dabigatran etexilate 
X d
PK blood sampling total dabigatran 
(unconjugated and conjugated)
X e
X e
X e
X e
PGx blood sampling (optional)
X h
Adverse event (AE) monitoring
X -------------------------------------------------------------------------------------------------------------------------X
Prior and concomitant medication
X -------------------------------------------------------------------------------------------------------------------------X
ECG = electrocardiogram, HIV = human immunodeficiency virus, PK = pharmacokinetics, PGx = pharmacogenetics
Adverse events and concomitant medication will be assessed from screening throughout the whole study until End of Trial Visit.
a
Written informed consent must be obtained prior to any screening activities.
b Vital signs (blood pressure and pulse rate) and ECG will be measured after at least 5 min rest at pre-dose (within 60 min prior to dosing).
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
14/84
c
Women of nonchildbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day -1. 
Females are considered postmenopausal if they have age-related amenorrhea ≥12 consecutive months and increased FSH > 40 mIU/mL), or if they 
have undergone hysterectomy, or bilateral oophorectomy or bilateral salpingecectomy.
d A standardized breakfast will be administered 30 min prior to dabigatran etexilate administration and must be consumed completely within 25 min. 30 min after 
start of the breakfast, 75 mg dabigatran etexilate will be taken together with 240 mL of water.
e
PK blood samples for determination of total dabigatran will be collected at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 
12, 24, 36, 48 and 72 h post-dose.
f
Day 4 measurements (72 h measurements) may be performed (within 60 min, PK sampling within 30 min) prior to tepotinib dosing on Day 1 of Period 2.
g
Coagulation parameters will be determined pre-dose and 4 h post-dose on Day 1 and 24 h post-dose on Day 2.
h
PGx blood samples of 2 x 2 mL (optional) to be drawn at pre-dose Day 1.
i 
Only to be performed in case of a prolonged interval of more than 7 days between Period 1 (Day 4) and Period 2 (Day 1)
.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
15/84
Table 2
Schedule of Assessments - Period 2 (Administration of Tepotinib and Dabigatran Etexilate)
Assessment/ Activity
Study Period 2
End of Trial 
Visit a
Day 1
Day 2 - 6
Day 7
Day 8
Day 9
Day 10
Day 11
Day 15 (±1)
Hospitalization
X
X
X
X
X
X
X j
Ambulatory Visits
X
Physical examination
X
Vital signs (blood pressure, pulse rate, 
body temperature)
X b
X b
X b
X c
X c
X c
X c
X
12-lead ECG
X d
X d
X d
X d
X d
X d
X d
X
Clinical laboratory (hematology, 
biochemistry, urinalysis)
X e
X e
X e
X e
X e
X
Coagulation
X i
X i
X i
X
Serum pregnancy test
X
Administration of tepotinib
X f
X f
X f
X f
Administration of dabigatran etexilate 
X f
PK blood sampling (tepotinib and its 
metabolites) 
X g
X g
X g
PK blood sampling total dabigatran 
(unconjugated and conjugated)
X h
X h
X h
X h
Adverse events
-------------------------------------------------------------------------------------------------------------------
X
Concomitant medication
-------------------------------------------------------------------------------------------------------------------
X
ECG = electrocardiogram, PK = pharmacokinetics 
Adverse events and concomitant medication will be assessed from screening throughout the whole study until End of trial Visit.
a
7 ± 1 days after last drug administration in Period 2 (Day 15).
b 
Vital signs (blood pressure and pulse rate) will be measured after at least 5 min rest before each (within 60 min prior to dosing) and 6 h after each tepotinib 
administration.
c
Vital signs will be measured after at least 5 min rest before (within 60 min prior to dosing) as well as 4, 8, 24, 48 and 72 h after the combined dabigatran 
etexilate and tepotinib administration.
d 
After at least 5 min rest before each time point 12-lead ECGs will be recorded and printed out. Days 1 to 7 within 60 min prior to dosing and 6 h after each 
tepotinib administration. Day 8 within 60 min prior to dosing, as well as 4, 8, 24, 48 and 72 h after the combined dabigatran etexilate and tepotinib 
administration.
e
Laboratory assessments will be performed on Day 1, 2, 7 and 8 pre-dose, and on Day 11.
Document No. 
Object No. 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
16/84
f
On Days 1 to 7, 500 mg tepotinib will be administered together with 240 mL of water 30 min after start of a standardized breakfast (completely consumed 
within 25 min).
On Day 8, a standardized breakfast will be administered 30 min prior to tepotinib and dabigatran etexilate administration and must be consumed completely 
within 25 min. 30 min after start of the breakfast, 500 mg tepotinib and 75 mg dabigatran etexilate will be taken together with 240 mL of water.
g
PK blood samples for determination of tepotinib and its metabolites will be collected on Day 6 at pre-dose (within 60 min prior to administration), on Day 7 at 
pre-dose (within 60 min prior to administration) and 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12 and 24 h post-dose prior to dosing on Day 8 (within 60 min 
prior to administration).
h
PK blood samples for determination of total dabigatran will be collected at pre-dose (within 60 min prior to administration) and 15, 30, 45, 60, 90 min, and 2, 
3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose.
i
Coagulation parameters: Pre-dose on Day 1, pre-dose and 4 h post-dose on Day 8, and 24 h after the last dose on Day 9.
j
Discharge after completion of all 72 h post-dose activities.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of T e p oti ni b on t he P K of t he P -g p S u bstr ate 
M S 2 0 0 0 9 5- 0 0 3 2
D a bi g atr a n E te xil ate
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 /8 4
2
S p o ns or, I n vesti g at ors a n d Tri al A d mi nistr ati ve Str uct ure
T his cli nical trial will be s p o ns ore d b y:  
Merc k K Ga A, Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y.
T he trial will be c o n d ucte d at o ne site i n Ger ma n y.
T he Pri nci pal I n vesti gat or (
, 
) will pr o vi de e x pert me dical 
i n p ut a n d a d vice relati n g t o trial desi g n a n d e xec uti o n a n d is res p o nsi ble f or t he re vie w a n d 
si g n off of t he cli nical trial re p ort.
Si g nat ure pa ges f or t he Pr ot oc ol Lea ds a n d t he Pri nci pal I n vesti gat or as well as a list of S p o ns or 
res p o nsi ble pers o ns f or t he trial are i n A p pe n di x I .
T he trial will a p pear i n t he f oll o wi n g cli nical trial re gistries: E U Cli nical Trials Re gister, 
Cli nical Trials. g o v.
N u visa n 
G m b H, 
We ge nerstrasse 
1 3, 
8 9 2 3 1 
Ne u -Ul m, 
Ger ma n y,  a co ntract 
researc h 
or ga ni zati o n, will c o n d uct t he cli nical part of t he trial i ncl u di n g trial set-u p, c o or di nati o n, safety 
a n d a nal yt ical la b, m o nit ori n g, data ca pt ure, data ma na ge me nt, statistical a nal ys is, a n d cli nical 
trial re p orti n g. N u visa n G m b H will als o s u b mit t he necessar y  a p plicati o ns t o t he a p plica ble 
I n de pe n de nt Et hics C o m mittee (I E C) a n d re g ulat or y bo dies o n be half of a n d i n cl ose ali g n me nt 
wit h t he S p o ns or. 
La b orat or y  sa m ple pr ocessi n g, ha n dli n g, a n d st ora ge i nstr ucti o ns will be prese nte d i n a se parate 
La b Ma n ual 
w hic h
will be pre pare d b y  Nu visa n G m b H i n c o o perati o n wit h t he S p o ns or. 
M o nit ori n g a n d data ma na ge me nt pr oce d ures will be defi ne d i n a se parate M o nit ori n g a n d Data 
Ma na ge me nt Pla ns w hic h will be pre pare d b y N u visa n G m b H.
T he S p o ns or will pr o vi de t he I n vesti gati o nal Me dici nal Pr o d ucts (I M Ps) te p oti ni b a n d da bi gatra n 
ete xilate. Pac ka gi n g, la beli n g a n d distri b uti o n of all I MPs t o t he trial site will be c o n d ucte d b y  a 
desi g nate d c o ntract ma n ufact uri n g or ga nizati o n ( N u visa n G m b H, We ge nerstrasse 
1 3, 8 9 2 3 1 
Ne u -Ul m, Ger ma n y). T he S p o ns or will s u per vise all o uts o urce d acti vities. 
3
B ac k gr o u n d I nf or m ati o n
T he mese nc h y mal -e pit helial tra nsiti o n fact or (c-Met), 
al o n g wit h its li ga n d, t he he pat oc y t e 
gr o wt h fact or ( H G F) ha ve bee n i m plicate d i n carci n o ge nesis a n d metastatic t u m or pr o gressi o n, 
beca use of t heir a bilit y t o e n ha nce a n gi o ge nesis, ca ncer cell pr oliferati o n, mi grati o n 
a n d 
i n vasi o n, as well as c o nferri n g resista nce t o a p o pt osis. P har mac ol o gical i nterfere nce wit h t he 
H G F/c -Met a xis is c o nsi dere d as a pr o misi n g strate g y to i n hi bit pri mar y  tu m or gr o wt h a n d 
metastasis.
I n pri mar y  phar mac o d y n a mic ( P D) st u dies, te p oti ni b ( M S C 2 1 5 6 1 1 9J) p ote ntl y i n hi bite d c-Met 
ki nase acti vit y in a d ose -de pe n de nt ma n ner. T his i n hi bit or y effect was c o nfir me d b ot h i n t u m or 
cells e x pressi n g f ull -le n gt h c-Met u p o n sti m ulati o n wit h H G F, a n d i n t u m or cells i n w hic h c -Met 
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0f 5 2 d 6 d v 2. 0
0 9 0 0 ba be 8 0f 6 5 3c 0
PI
PI


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
18/84
was activated in a ligand independent manner, ie in cells harboring c-Met gene amplification or 
expressing the oncogenic fusion protein translocated promoter region (TPR) Met.
Until 30 September 2017, 452 subjects have been exposed to tepotinib. Five studies have been 
completed; 3 of these were conducted as single dose studies in healthy subjects (EMR200095-
002, EMR200095-007, and MS200095-0012; n = 79 subjects), and 2 as multiple dose studies in 
subjects with different solid tumors (EMR200095-001 and EMR200095-003; n = 161). In 
addition, 4 studies in subjects with hepatocellular carcinoma (HCC; EMR200095-004, 
EMR200095-005) or epidermal growth factor receptor (EGFR) mutated or c-Met mutated non-
small cell lung cancer (NSCLC; EMR200095-006, and MS200095-0022) are ongoing. In the 
ongoing studies, subjects with HCC received tepotinib as multidose monotherapy, and subjects 
with NSCLC received either multidose tepotinib monotherapy or a multidose combination with 
gefitinib in Phase I or Phase Ib/II studies. Doses of tepotinib of up to 1400 mg daily in subjects 
with solid tumors (EMR200095-001) and up to 1000 mg daily in subjects with HCC 
(EMR200095-004) have been explored.
Based on the currently available nonclinical as well as clinical safety data, short term multi-day 
dosing of tepotinib in healthy subjects is reasonable considering the preclinical safety 
pharmacology and toxicity data, and the absence of genotoxicity, in conjunction with the 
predicted exposures at steady state after multiple dosing of 500 mg/day in healthy subjects, and 
the clinical experience in oncology patient populations, and implementing close medical 
monitoring of safety and tolerability. It is recognized that healthy subjects will not get benefit by 
participating in this study. Considering the current clinical exposure after the recommended 
Phase II dose (RP2D) of 500 mg tepotinib once daily, and the non-clinical observation that 
tepotinib was identified as a substrate of the efflux transporter P-glycoprotein (P-gp), as well as 
an inhibitor of P-gp (half maximal inhibitory concentration, IC50 ~ 0.4 µM), the need to 
investigate tepotinib clinically for any potential to cause P-gp-mediated drug-drug interaction 
(DDI) was triggered. This study will generate human data about the potential of DDI of tepotinib 
as perpetrator on the pharmacokinetics (PK) of the P-gp probe substrate dabigatran etexilate. 
Drug interaction with P-gp is of importance in the context of concomitant medication in tumor 
patients treated with tepotinib. This is basic information to safeguard the further clinical 
development of tepotinib in patients suffering from malignancies such as HCC and NSCLC. 
Healthy subjects (n = 9) well tolerated a single dose or 3 single doses of tepotinib (different dose 
levels up to 500 mg single dose). All treatment emergent adverse events (TEAEs) were mild to 
moderate, except one Grade 3 asymptomatic transient lipase elevation in 1 subject. TEAEs did 
not show a pattern across all 3 trials. No serious adverse events (SAEs) were reported and no 
subject died. No clinically significant findings regarding laboratory parameters, vital signs and 
electrocardiogram (ECG) including Corrected QT interval per Fridericia’s formula (QTcF) 
values were noted.
Elevations in serum lipase and amylase are considered as identified risks for subjects 
administered tepotinib. These elevations were observed in 5 of 79 healthy subjects exposed to 
tepotinib and were mild to moderate in severity (exception: one Grade 3 lipase elevation) and 
without apparent dose dependency. All increases of serum amylase/lipase were asymptomatic 
and not associated with a pancreatitis.
Document No. 
Object No. 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
19/84
Subjects enrolled in this study might be exposed to a risk, including pancreatic enzyme elevation. 
However, inclusion of healthy subjects is justified when the administration of tepotinib is limited 
to a single dose or short term multiple administrations that will be given under close monitoring 
conditions to reduce the risk for untoward effects.
Knowing that the inhibition of c-Met shows teratogenic effects in knockout mice, stringent 
criteria are applied to ensure exclusion of women of childbearing potential in this study. Only 
healthy women that are known to be postmenopausal or surgically sterile (ie due to 
hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy) will be enrolled in this 
study (for details see Section 5, Investigational Plan). Male subjects will be required to take 
precautions regarding female partners.
In this drug-drug interaction (DDI) study tepotinib will be administered the first time in multiple 
doses of the RP2D of 500 mg to healthy subjects. To achieve steady-state levels and robustly 
evaluate its potential as perpetrator on the P-gp probe substrate dabigatran etexilate, further risk 
mitigation measures are incorporated. A close safety monitoring will be implemented in this 
healthy subject study. Subjects will be admitted to the study site and remain resident there for at 
least 72 h after dabigatran etexilate administration in Period 1 and until at least 72 h after last 
administration in Period 2, to allow continuous safety monitoring of the clinical laboratory 
parameters, ECG, and vital signs. After the first 6 subjects completed administration in Period 2, 
safety and PK data will be reviewed by the responsible functional representatives. In addition, 
frequent monitoring of subjects is ensured by subsequent Ambulant Visits and by choosing a 
contract research organization (CRO) experienced in the conduct of clinical pharmacology trials.
The 500 mg tepotinib single oral dose has been studied in previous studies with 36 healthy 
subjects in total (EMR200095-007: 12 subjects received 1 single dose of 500 mg; MS200095-
0012: 24 subjects received 2 single doses of 500mg tepotinib in crossover) and was well 
tolerated. A dose of 500 mg once daily is the RP2D. Refer to the Investigator’s Brochure for 
further information about the nonclinical and clinical programs and the implemented Guidance 
for the Investigator.
Dabigatran
Dabigatran, the active principle of the prodrug dabigatran etexilate, which is formulated as 
mesilate salt in Pradaxa® (DE; Pradaxa®, Boehringer Ingelheim Pharma GmbH & Co KG, 
Biberach, Germany), is an oral, direct thrombin inhibitor with potent antithrombotic effects. 
After oral administration, the prodrug dabigatran etexilate, which is pharmacologically inactive, 
is rapidly absorbed and nearly completely converted to the pharmacologically active dabigatran 
by esterase-catalyzed hydrolysis in plasma and in the liver. The pro-drug dabigatran etexilate but 
not dabigatran is a substrate of the efflux transporter P-gp. Dabigatran is a potent, competitive, 
reversible direct thrombin inhibitor and is the main active principle in plasma. Since thrombin 
(serine protease) enables the conversion of fibrinogen into fibrin during the coagulation cascade, 
its inhibition prevents the development of thrombus. Dabigatran inhibits free thrombin, as well 
as fibrin-bound thrombin, and thrombin-induced platelet aggregation. 
After oral administration of dabigatran etexilate in healthy subjects, the PK profile of dabigatran 
will be determined as total dabigatran (unconjugated plus conjugated) in plasma. It is 
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
20/84
characterized by a rapid increase in plasma concentration with Cmax attained within 0.5 and 2.0 h 
post administration. The absolute bioavailability of dabigatran following oral administration of 
Pradaxa®
was approximately 6.5%. Dabigatran is subject to conjugation forming 
pharmacologically active acylglucuronides, but is eliminated primarily in the unchanged form in 
the urine (85%). Food does not affect the bioavailability of dabigatran etexilate but delays the 
time to peak plasma concentrations of dabigatran by 2 h. Cmax and AUC were dose proportional. 
Plasma concentrations of dabigatran showed a bi-exponential decline with a terminal half-life of 
8.4 h (coefficient of variation for the geometric mean, GeoCV = 12.0%) in healthy subjects [1]. 
Since dabigatran etexilate has been previously studied in healthy subjects in single dose as well 
as in multiple dose settings with up to 400 mg 3 times daily [2], and since the thrombin 
inhibitory effects in the current study will be closely monitored, the 2 single dose administrations 
of 75 mg dabigatran etexilate in healthy subjects is reasonable and considered safe. 
Dabigatran etexilate (Pradaxa®, provided as mesilate) is currently approved in the USA, 
European Union, Canada and Japan for the prevention of stroke and systemic emboli in patients 
with non-valvular atrial fibrillation. Furthermore, Pradaxa® is also approved for the primary 
prevention of thromboembolism in adults after elective total hip or knee replacement surgery in 
more than 75 countries, including Europe and Canada [1]. 
For reference see Summary of Product Characteristics Pradaxa® 75 mg hard capsules [2].
3.1
Trial Rationale
Tepotinib was identified as a substrate of the efflux transporter P-glycoprotein (P-gp), as well as 
an inhibitor of P-gp. Nonclinical data indicate that tepotinib inhibits P-gp with IC50 values of 
about 0.4 μM, which is several folds lower than the plasma concentrations, and magnitudes 
lower than the expected intestinal concentrations. This represents potential to cause P-gp-
mediated DDI considering the current clinical exposure after the RP2D of 500 mg tepotinib once 
daily.
This study will investigate the effect of tepotinib on P-gp by measurement of the PK of the P-gp 
probe substrate dabigatran etexilate. The study design is based on the regulatory guidance of the 
Food and Drug Administration (FDA) [4] and of the European Medicines Agency (EMA) [5]. 
Per guidance from both authorities, dabigatran etexilate is presently recommended as probe for 
P-gp inhibition.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP and 
any additional applicable regulatory requirements.
Based on the available nonclinical and clinical data to date, the conduct of the trial specified in 
this protocol is considered justifiable. 
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
21/84
4
Trial Objectives
4.1
Primary Objective

To investigate the effect of tepotinib on the primary pharmacokinetic (PK) endpoints of 
dabigatran following oral administration of the P-gp probe substrate dabigatran etexilate 
after multiple dose administration of tepotinib in healthy subjects.
4.2
Secondary Objectives

To investigate the PK effect of tepotinib on the secondary PK endpoints of dabigatran 
following oral administration of dabigatran etexilate

To assess the safety and tolerability of tepotinib alone and upon co-administration of 
dabigatran etexilate.
4.3
Exploratory Objectives

To investigate the multiple dose PK of tepotinib and its metabolites (MSC2571109A and 
MSC2571107A).

To explore the effect of pharmacogenetics (PGx) and variations of associated genes on 
the PK profile of dabigatran and/or tepotinib (if applicable; participation is optional).
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase I, open-label, single-sequence, 2-period, crossover study to investigate the effect 
of tepotinib on the PK of the P-gp probe substrate dabigatran etexilate determined from 
concentrations of total dabigatran (unconjugated plus conjugated) in 20 healthy subjects. A 
flowchart summarizing the overall study design is shown in Figure 1.
The study will be divided into 2 periods: Period 1 will evaluate the PK of total dabigatran after 
single dose administration of 75 mg dabigatran etexilate (Pradaxa®, given as mesilate) over a 
sampling period 72 h post-dose, which covers > 5 times the geometric mean t1/2 of 8.4 h [1]. In 
Period 2, tepotinib will be administered for 7 days and the PK of tepotinib and its metabolites 
will be evaluated on Day 7. On Day 8, dabigatran etexilate and tepotinib will be co-administered 
and the PK of total dabigatran will be evaluated again over 72 h post dose. Dosing will be 
performed 30 min after start of a standardized breakfast (completely consumed within 25 min). 
Considering that in Period 2 dabigatran etexilate will be administered on Day 8 (= 168 h), the 
resulting interval between the 2 administrations of dabigatran etexilate will be 240 h (= 72 h 
[Day 1 to Day 4 of Period 1] + 168 h [Day 1 to Day 8 of Period 2]) or 10 days (see Figure 1).
A Screening period will occur from Day -28 to Day -2. 
The subjects will be admitted to the study site on Day -1. They will be resident at the study site 
under medical supervision from Day -1 of Period 1 until Day 11 of Period 2.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
22/84
Blood and urine samples will be collected for laboratory assessments (hematology, coagulation, 
biochemistry, urinalysis), which will be performed at Screening, throughout the inpatient period 
of each treatment period as explained in detail in Table 1 and Table 2 (also see Figure 1) and for 
the End of Trial Visit. 
Serial blood samples for PK assessments will be collected for 72 h after administration of 75 mg 
dabigatran etexilate (Pradaxa®, given as mesilate) in Periods 1 and 2. Tepotinib PK will be 
assessed in Period 2. 
The End of Trial Visit is planned 7 days (± 1 day) after the last drug administration in Period 2 
(Day 15 ± 1). An Early Termination Visit will be conducted for subjects who withdraw 
prematurely. The same assessments as for the End of Trial Visit will be conducted at the Early 
Termination Visit.
Figure 1
Study Design 
Period 1
Period 2
End of 
Trial 
Visit 
Study Day
Study Day
Day
-1
1
2 – 4 a
1 - 6
7
8
9 - 11
15 (±1)
Dabigatran etexilate 
administration
Tepotinib 
administration
PK blood sampling 
total dabigatran
PK blood sampling 
tepotinib and its 
metabolites
X b
Safety assessments
X c
Hospitalization
a 
Day 4 of Period 1 = Day 1 of Period 2.
b 
PK sample prior to dosing on Day 6. 
c
End of Trial Visit safety assessments 
A detailed schedule of study procedures and assessments is provided in Table 1 and Table 2.
Since to date tepotinib 500 mg was administered to healthy subjects only as single doses (study 
EMR200095-007, single dose; study MS200095-0012, 2 single doses), the safety and tolerability 
as well as the PK of multiple dose tepotinib (up to Day 8 inclusive in Period 2) will first be 
assessed in a subgroup of 6 subjects, followed by group(s) of the remaining subjects. Dosing of 
the subsequent group(s) will only be started if the safety and tolerability of multiple dosing of 
tepotinib was assessed as reasonable and no stopping rules applied. The decision will be 
documented and will be filed in the trial documentation files.
Document No. 
Object No. 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
23/84
Stopping rules of the study:

Further dosing will be temporarily stopped after occurrence of an SAE. Dosing will only 
be restarted if further investigation of the SAE clearly demonstrates another plausible 
scientific reason for the SAE other than the study drug.

The trial will be permanently stopped if 4 or more subjects were withdrawn from the 
study because they fulfill the individual stopping criteria as defined in Section 5.5.2.

Dosing will be permanently stopped if clinically relevant TEAEs of moderate or severe 
intensity of similar nature occur in at least 50% of subjects which are considered related 
to the study drug by the Investigator.
Primary endpoint:

PK profile of dabigatran in terms of AUC from time zero to the last sampling time 
(AUC0-t), AUC from time zero extrapolated to infinity (AUC0-∞), maximum plasma 
concentration (Cmax) of total dabigatran (unconjugated plus conjugated) at Day 1 of 
Period 1 and Day 8 of Period 2 from time zero to 72 h post-dose. 
Secondary endpoints: 

PK profile of total dabigatran (unconjugated plus conjugated) in terms of time of the 
maximum drug concentration (tmax), terminal half-life (t1/2), percentage of AUC0-∞ 
obtained by extrapolation (AUCextra%), apparent total body clearance (CL/f), apparent 
volume of distribution during terminal phase (VZ/f) at Day 1 of Period 1 and Day 8 of 
Period 2 from time zero to 72 h post-dose.

Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of 
changes in safety laboratory assessments, 12-lead ECGs and vital signs in subjects 
receiving tepotinib alone and together with dabigatran etexilate assessed from Day -1 of 
Period 1 until the End of Trial Visit.
Exploratory endpoints: 

PK profile of tepotinib and its metabolites MSC2571109A and MSC2571107A in terms 
of AUC over the dosing interval (AUCτ), Cmax at steady state (Cmax,SS), minimum 
concentration at steady state (Cmin,SS), tmax at steady state (tmax,SS), CL/f at steady state 
(CLSS/f) (parent drug only), and t1/2, if appropriate.

Genetic variants and mutations in genes that potentially influence the PK of tepotinib 
and/or dabigatran.
Note: Pharmacogenetic sample collection is optional. The results of the pharmacogenetic 
analysis, as applicable, will be described in a separate report.
5.2
Discussion of Trial Design
The trial design is based on the regulatory guidelines of the FDA and the EMA (see Section 3.1).
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
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5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Scientific Rationale for Trial Design
The study design and endpoints are typical for a drug interaction study of this type. The effect of 
tepotinib on P-gp by measurement of the PK of the P-gp substrate dabigatran etexilate will be 
investigated. Thus, dabigatran etexilate will be administered as a single dose once alone and once 
at steady state of tepotinib.
The study will utilize a single sequence crossover design with both treatments applied to the 
same subject. No carryover of dabigatran is expected between the first and second dose due to 
sufficient wash-out time. Moreover, the total dabigatran concentration should be below the 
quantification limit when starting the multiple dosing of tepotinib (period of 72 h, considering a 
mean elimination t1/2 [GeoMean] of about 8.4 h for dabigatran in healthy adult subjects [1]). It is 
anticipated that a possible period effect is very small and negligible compared to relevant 
treatment effects. The potential drug-drug interaction investigated in this study is expected to 
occur mainly in the intestine, where the P-gp mediated efflux of dabigatran etexilate could be 
inhibited by tepotinib. However, the effect on dabigatran will only be measured indirectly by the 
concentration-time profile of total dabigatran (unconjugated plus conjugated) in plasma. 
Healthy subjects will be included in the study to minimize variability, which is expected to be 
higher in a patient population. Non-clinical safety investigations did not reveal a genotoxicity 
potential or other findings with relevance for human use. Therefore, it is reasonable that tepotinib 
can be administered to healthy subjects such as in this study in which careful safety monitoring is 
conducted. Knowing that tepotinib shows teratogenic effects, only healthy women that are 
postmenopausal or surgically sterile (ie, due to hysterectomy, or bilateral oophorectomy, or 
bilateral salpingectomy) will be enrolled in this study and male subjects must take precautions 
with female partners.
The study will be performed as an open-label study. This is not considered to introduce bias, 
because the main assessment criteria are based on PK parameters. For risk mitigation, an initial
group of 6 subjects will be dosed first. Only if tepotinib multiple dosing was considered 
reasonable safe and tolerated by these subjects, the remaining group(s) will be dosed. A close 
monitoring of the safety laboratory parameters, ECG, and vital signs will be performed in all 
subjects. Subjects will be admitted to the study site and remain resident there until at least 72 h 
after the last administration, to allow continuous safety monitoring. A hospitalization period of 
72 h after the last dose of tepotinib is regarded as sufficient to ensure close safety monitoring of 
the subjects during the initial elimination of about 70 - 80%. The end of trial visit is set at 7 (1) 
days after last dose of tepotinib, hence covering full elimination of tepotinib. The Investigator 
can extend the inpatient period as appropriate. In addition, monitoring of subjects is ensured by 
choosing a CRO experienced in the conduct of clinical pharmacology studies.
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Effect of Tepotinib on the PK of the P-gp Substrate 
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5.2.3
Justification for Dose
Up to 2 single doses of 500 mg (MS200095-0012) have been studied in previous studies in 
healthy subjects and were found to be well tolerated. Multiple dosing of 500 mg tepotinib was 
well tolerated in patients (refer to Section 3). Also, multiple doses of tepotinib up to 1400 mg
daily have been explored in few patients and were well tolerated. The tepotinib dose of 500 mg is 
the RP2D for the treatment of human malignant tumors. Tepotinib will be administered for 
8 days. Considering an apparent elimination t1/2 of about 30 h, tepotinib should be at steady state 
on Day 7. This is the first time that multiple doses of tepotinib are administered to healthy 
subjects. 
Dabigatran will be administered as a single dose of a 75 mg dabigatran etexilate (Pradaxa®, 
given as mesilate) film-coated tablet on Day 1 of Period 1 and Day 8 of Period 2. 
The recommended daily therapeutic dose of dabigatran etexilate is 220 mg once daily for the 
prevention of venous thromboembolic events in adult patients who have undergone elective total 
hip replacement surgery or total knee replacement surgery, and 300 mg taken as one 150 mg 
capsule twice daily for treatment of deep vein thrombosis and pulmonary embolism and 
prevention of recurrent deep vein thrombosis and pulmonary embolism in adults. A dose of 
150 mg dabigatran etexilate was used in several DDI studies investigating the effect on P-gp and 
proved to be sensitive enough to detect such an effect [6] [7]. The fact that only the pro-drug 
dabigatran etexilate is a substrate of the efflux transporter P-gp, but not the pharmacologically 
active dabigatran or its acylglucuronides, renders dabigatran etexilate very specific and sensitive 
to intestinal inhibition of P-gp efflux transport. 
Factors which may increase the hemorrhagic risk (refer to the Summary of product 
characteristics [2]) will be excluded in this study. Recommended doses of dabigatran etexilate 
are up to 300 mg daily. In this study, a single dose of 75 mg dabigatran etexilate will be 
administered, which will minimize the hemorrhagic risk but is high enough to result in 
measurable plasma concentration time profiles. Therefore, safety concern due to higher exposure 
of dabigatran, should pronounced DDI occur, and is not expected after a single dose of 75 mg 
dabigatran etexilate.
As dabigatran reduces the thrombin activity and therefore could prolong the thrombin time (TT) 
and activated partial thromboplastin time (aPTT), these coagulation parameters and the 
Hemoclot Thrombin Inhibitor (Anti-Factor II) will be measured. In case of dabigatran-induced 
bleeding, subjects will be referred to a collaborating clinic for treatment with the dabigatran 
antidote idarucizumab, as appropriate. 
5.2.4
Rationale for Endpoints
The peak exposure (Cmax) and extent (AUC) of exposure of total dabigatran (unconjugated plus 
conjugated) after single dose administration are considered adequate endpoints to evaluate the 
effect of tepotinib on the PK on the P-gp probe substrate dabigatran etexilate. These endpoints 
are in line with the regulatory guidance of the FDA and the EMA (see Section 3.1).
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Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
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5.3
Selection of Trial Population
Only persons meeting all inclusion criteria and no exclusion criteria may be enrolled into the trial 
as subjects. Prior to performing any trial assessments, the Investigator will ensure that the subject 
or the subject’s legal representative has provided written informed consent following the 
procedure described in Section 9.2.
5.3.1
Inclusion Criteria
To be eligible, the subject must fulfill all the following criteria:
1. Male or female, aged 18 to 44 years inclusive (at Screening)
2. Body mass index (BMI) ≥18.5 and ≤29.9 kg/m2 and body weight between 50 to 100 kg,
inclusive (at Screening)
3. A female participant is eligible to participate if she is of non-childbearing potential,
confirmed at Screening, by fulfilling at least one of the following criteria:

Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and
increased follicle-stimulating hormone [FSH] > 40 mIU/mL)

Documentation of irreversible surgical sterilization by hysterectomy, or bilateral
oophorectomy, or bilateral salpingectomy
4. A male participant must agree to use and to have his female partner of childbearing potential
to use highly effective method of contraception (ie methods with a failure rate of less than
1% per year) as detailed in the Clinical Trial Facilitation Group (CTFG) recommendations
[8] during the period of participation in the study and for at least 3 months after the last
investigational medicinal product (IMP) administration (see Appendix III). Males must also
refrain from donating sperm during this period and should always use a barrier method such
as condom concomitantly. The male participants will be asked to report pregnancies in their
female partners up to 3 months after the last IMP intake
5. Subject must be healthy, as assessed by the Investigator, with no clinically significant
abnormality identified on physical examination and no active clinically significant disorder,
condition, infection or disease that would pose a risk to subject safety or interfere with the
study evaluation, procedures, or completion (at Screening and Day -1)
6. Subject must have given written informed consent before any study-related activities are
carried out and must be able to understand the full nature and purpose of the study, including
possible risks and adverse effects
7. All values for hematology, coagulation, and biochemistry tests of blood and urinalysis within
the normal range (at Screening). Minor (solitary) non-clinically relevant deviation(s) are
allowed as judged by the Investigator; however, amylase, lipase and alanine-amino-
transferase [ALT] or aspartate-amino-transferase [AST] values should not exceed the upper
limit of normal (ULN).
Document No. 
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
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5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1.
Participation in the treatment phase of a clinical study within 60 days or 5 half-lives after 
last dosing of the previous study drug, whatever is longer, before administration of study 
drug within this study
2.
Whole blood donation or loss of > 450 mL within 60 days before administration of study 
drug
3.
Any surgical or medical condition, including findings in the medical history or in the 
prestudy assessments, or any other significant disease, that in the opinion of the Investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or that 
could interfere with the study objectives, conduct, or evaluation
4.
Supine systolic blood pressure (SBP) > 140 mmHg or < 90 mmHg, diastolic blood pressure 
(DBP) > 90 or < 50 mmHg, and pulse rate > 90 or < 50 bpm at Screening and at admission 
on Day -1. (Any abnormal vital signs results may be repeated once and if the repeat result is 
within the normal range, it is not considered to have met the exclusion criterion)
5.
12-Lead ECG showing a QTcF > 450 ms, PR > 215 ms, or QRS > 120 ms (at Screening)
6.
Creatinine clearance estimated glomerular filtration rate (eGFR) < 90 mL/min) as assessed 
by using the estimated measure with the Cockcroft-Gault equation (at Screening)
7.
Subjects with gall bladder removal or other relevant surgery of gastrointestinal tract
8.
History of any malignancy except for adequately treated superficial basal cell carcinoma 
9.
History of epilepsy
10. Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or 
excipients; history of anaphylaxis to drugs or serious allergic reactions leading to 
hospitalization or any other allergy reaction in general, which the Investigator considers may 
affect the safety of the subject and/or outcome of the study
11. Subjects who in the Investigator's judgment were perceived as having an increased risk of 
bleeding, for example because of: 
Hemorrhagic disorders or bleeding diathesis
Occult blood in feces 
Trauma or surgery within the last month or if an excessive risk of bleeding persisted after 
these events
History of arteriovenous malformation or aneurysm
History of gastroduodenal ulcer disease, gastrointestinal hemorrhage, and hemorrhoids
History of intracranial, intraocular, spinal, retroperitoneal, or atraumatic intraarticular 
bleeding
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Effect of Tepotinib on the PK of the P-gp Substrate 
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Use of drugs that may have interfered with hemostasis during trial conduct (eg acetylic
salicylic acid or other non-steroidal anti-inflammatory drugs) within 14 days or 5 half-
lives after last dosing, whatever is longer, prior to start of dosing or during the trial
12. Positive screen for alcohol or drugs of abuse (at Screening and Day -1)
13. Positive screen for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-
HCV), and human immunodeficiency virus 1 and 2 antibodies (HIV1/HIV2 antibodies) (at
Screening)
14. Excessive consumption of xanthine-containing food or beverages (> 5 cups of coffee or
equivalent a day) or inability to stop consuming caffeine, from 48 h before study drug
administration until collection of last PK sample in each period (at Screening and Day -1)
15. Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives,
whatever is longer, before study drug administration (apart from paracetamol up to 1500 mg
per day, as judged appropriate by the Investigator)
16. Smoker (cigarettes, pipes, cigars, or others) or former smoker who stopped smoking less
than 6 months before the time of the Screening Visit
17. Intake of grapefruit, Seville orange, cranberry or juices of these 3 fruits, or St. John’s Wort,
from 14 days prior to Day -1
18. Inability to communicate or cooperate with the Investigator (eg, language problem,
illiteracy, poor mental status) or to comply with the requirements of the entire study,
including dietary restrictions
19. Other factors, which in the opinion of the Investigator may interfere with study conduct (at
Screening and Day -1 of first Period only)
20. Legal incapacity or limited legal capacity
21. Subjects kept in detention.
5.4
Criteria for Initiation of Trial Treatment
Inclusion and exclusion criteria will be checked within the screening period and again on Day -1. 
Subjects meeting all the inclusion and none of the exclusion criteria will be enrolled into the 
study.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from Trial Treatment
A subject must be withdrawn from IMPs administration if any of the following occur: 

The subject requires treatment with any medication suspected or known to interfere with
the IMPs.

The subject is suspected or known not to comply with the protocol directives (use of
prohibited medication, noncompliance with the sampling schedule, nonadherence to
dietary rules, and nonattendance at study assessments).
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
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Withdrawal of a subject from study drug due to any of the above reasons means that this subject 
prematurely discontinues the study, ie before completion of the full profiling and all safety 
investigations. Subjects who dropped out, must be encouraged to attend the End of Trial 
examination for safety reasons (see Table 2).
If the number of evaluable subjects decreased below 16 a discussion should occur between the 
Investigator and the Sponsor regarding whether a replacement may be considered. 
5.5.2
Withdrawal from the Trial
Subjects must be withdrawn from the study by the Investigator at any time for any of the 
following reasons:
Subject withdrew consent
Subject lost to Follow-up
Participation in another clinical study
Relevant adverse events (AEs) occur that do not justify the subject’s continuation in the
study
Pregnancy
Protocol noncompliance judged as significant by the Investigator and/or Sponsor
Use of a non-permitted concomitant drug as defined in Section 6.5. However, any
medications that are considered necessary for the subject’s wellbeing (eg paracetamol up to
1500 mg per day) may be given at the discretion of the Investigator.
Subject is no longer able to participate for other medical reasons (eg surgery, intercurrent
illness).
Any other condition which to the opinion of the Investigator no longer justifies or permits
a safe participation of the subject.
Any of the following individual stopping criteria is met unless deemed unrelated to study
drug by the Investigator with alternate etiology identified:
-
Abnormal clinically relevant vital signs confirmed on 2 or more measurements (min.
5 minute intervals), including abnormal blood pressure 
o
hypotension defined as systolic < 80 mmHg and/or diastolic < 40 mmHg, or
o
hypertension defined as systolic > 160 mmHg and/or diastolic > 100 mmHg
-
Abnormal clinically relevant ECG findings, including a corrected QT-interval (ad
modus Fridericia; QTcF) > 500 ms or an increase in QTcF > 60 ms compared to 
baseline, confirmed on ≥2 repeat measurements.
-
Marked increases in liver or renal parameters (ALT/AST ≥3 x upper limit of normal
range (ULN), total bilirubin ≥2 x ULN, creatinine ˃ 1.5 x ULN) confirmed by ≥2 
repeat measurements.
Document No. 
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
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-
Any clinically relevant symptom or sign which in the opinion of the Investigator 
and/or Sponsor warrants subject withdrawal
-
Coagulation tests that may be associated with an increased risk of bleeding except for 
thrombin inhibitory effects expected due to dabigatran but not exceeding 3-fold 
prolongation in the aPTT upper limit of normal at peak.
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
In case a subject should be withdrawn from the trial, the medical monitor and clinical trial leader 
at the Sponsor will be informed immediately.
If there is a medical reason for the withdrawal, appropriate medical care will be provided.
In case of premature withdrawal from the trial, the assessments scheduled for the last End of 
Trial Visit should be performed, as Early Termination Visit, if possible with focus on the most 
relevant assessments (see Table 2). In any case, the appropriate eCRF section must be 
completed.
Subjects who withdraw from the trial prior to the first administration of IMPs, or for any reason 
do not have a full PK dataset may be replaced. A discussion should occur between the 
Investigator and the Sponsor regarding whether a replacement may be considered.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health 
Authorities or if new safety or efficacy information leads to an unfavorable risk benefit judgment 
for any IMPs. The Sponsor may discontinue the trial if it becomes unjustifiable for medical or 
ethical reasons, for poor enrollment, or because of discontinuation of clinical development of an 
IMP or withdrawal of an IMP or comparator from the market for safety reasons.
Health Authorities and IEC will be informed about the discontinuation of the trial in accordance 
with applicable regulations.
5.7
Definition of End of Trial
The end of the trial is defined by the last contact (related to this trial) with the last subject who 
participates in this trial (last subject’s End of Trial Visit or telephone call, independent of 
whether the subject is in End of Trial Visit or discontinued from the study).
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term “Investigational Medicinal Product” refers to any active substance or a placebo being 
tested or used as a reference therapy in a clinical trial, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
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Effect of Tepotinib on the PK of the P-gp Substrate 
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used for an unauthorized indication, or used to gain further information about the authorized 
form.
6.1
Description of the Investigational Medicinal Product
Investigational Medicinal Product: 

Tepotinib (MSC2156119J), 3-(1-(3-(5-(1-methylpiperidin-4-ylmethoxy)-pyrimidin-2-yl)-
benzyl)-1,6-dihydro-6-oxo-pyridazin-3-yl)-benzonitrile 
hydrochloride 
hydrate, 
is 
supplied as 500 mg (oblong, light yellow) film-coated tablets (Tablet Formulation 2, 
TF2) for oral administration. 
The percentage of active ingredient is approximately 50%. Tepotinib 500 mg film-coated 
tablets contain the excipients D-mannitol, silica colloidal anhydrous, crospovidone, 
magnesium stearate, and Opadry® II yellow.
All excipients used in the tablet formulation are of compendial grade. Supplier’s 
certificates show that there is no transmissible spongiform encephalopathy risk. Tepotinib 
is provided in aluminum blisters and should be stored at or below 25°C.

Dabigatran etexilate: Commercially available dabigatran etexilate ie Pradaxa® (provided 
as mesilate salt) will be used. Each Pradaxa® hard capsule contains 86.48 mg dabigatran 
etexilate mesilate equivalent to 75 mg of the prodrug dabigatran etexilate.
Reference product: Not applicable
Specific rules for treatment modifications: Not applicable.
6.2
Dosage and Administration
Subjects will receive the following 2 treatments:
Treatment A (Period 1): Dabigatran Etexilate alone
In the morning of Day 1 of Period 1, a single oral dose of 75 mg dabigatran etexilate capsule will 
be administered in a fed state. 
A standardized breakfast (see below) will be administered 30 min prior to dabigatran etexilate 
administration and must be consumed completely within 25 min. 30 min after start of the 
breakfast, the 75 mg dabigatran etexilate capsule will be taken together with 240 mL of water.
The standardized breakfast is a continental breakfast consisting of: 2 rolls, 20 g butter, 25 g jam, 
1 slice of cheese, 1 slice of cold cut, fruit tea or decaffeinated coffee without milk and sugar.
Subjects will stay in a semi-recumbent position for 4 h post-dose, except for use of toilet, when 
the subjects are allowed to leave the bed without undue physical stress/activity.
Standardized meals will be served 4 h (lunch), 8 h (snack) and 10 h (dinner) after administration 
of dabigatran etexilate; thereafter, meals will be served at customary times during the inpatient 
period.
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Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
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Treatment B (Period 2): Tepotinib and Dabigatran Etexilate
On Days 1 to 7 of Period 2, 500 mg tepotinib will be administered together with 240 mL of water 
after a standard breakfast (about 30 min after start of breakfast). A standardized breakfast must 
be consumed completely within 25 min.
On Day 8 of Period 2, a single dose of 75 mg dabigatran etexilate and 500 mg tepotinib will be 
administered concomitantly in a fed state with 240 mL water. A standardized breakfast will be 
administered 30 min prior to tepotinib and dabigatran etexilate dosing and must be consumed 
completely within 25 min. 30 min after start of the breakfast, 500 mg tepotinib and 75 mg 
dabigatran etexilate will be administered together with 240 mL of water. 
The minimum washout period after administration of dabigatran etexilate as mesilate in Period 1 
is at least 72 h (Day 4) from dosing on Day 1 of Period 1 to prevent PK carryover effects 
between periods. Considering that in Period 2 dabigatran etexilate will be administered on Day 8 
(= 168 h) of Period 2, the resulting interval between the 2 administrations of dabigatran etexilate 
will be 240 h (= 72 h [Day 1 to Day 4 of Period 1] + 168 h [Day 1 to Day 8 of Period 2]) or 10 
days.
On Days 7 and 8 of Period 2, subjects will stay in a semi-recumbent position for 4 h post-dose, 
except for use of the toilet, when the subjects will be allowed to leave the bed without undue 
physical stress/activity.
Standardized meals will be served 4 h (lunch), 8 h (snack) and 10 h (dinner) after dosing on Days 
7 and 8; other meals will be served at customary times during the inpatient period.
6.3
Assignment to Treatment Groups
Not applicable.
6.4
Noninvestigational Medicinal Products to be Used
Not applicable.
6.5
Concomitant Medications and Procedures
All concomitant medications taken by the subject during the trial, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, 
dose, route, duration, regimen, status and indication of each drug. Nondrug interventions and any 
changes to a concomitant medication or other intervention should also be recorded in the eCRF.
6.5.1
Permitted Medicines
Paracetamol is the only permitted medication. Paracetamol will be permitted up to a maximum 
daily dosage of 1500 mg.
Any medications that are considered necessary to protect subject’s welfare and will not interfere 
with the IMPs may be given at the Investigator’s discretion. The potential DDIs with tepotinib 
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Effect of Tepotinib on the PK of the P-gp Substrate 
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are still under evaluation. Therefore, medically required concomitant medication might have to 
be adjusted based on tolerability and the clinical response.
The Investigator will record, in the appropriate section of the eCRF, all previous/concomitant 
medications taken by the subject during the trial, from the date of signature of informed consent.
6.5.2
Prohibited Medicines
The following treatments and therapies are not permitted during this trial:
The subjects are prohibited from using prescription or over-the-counter medications (apart from 
paracetamol up to 1500 mg per day, as judged appropriate by the Investigator) within 2 weeks or 
5 half-lives, whichever is longer, prior to the first IMPs administration during the trial, and until 
after the End of Trial Visit. 
6.5.3
Permitted/Prohibited Procedures
Subjects should drink about 2 L fluids per day during the hospitalization phase and will be 
reminded regularly.
Throughout the PK profiling day of Periods 1 and 2, the following restrictions must be met:

Drug administration of dabigatran etexilate as well as tepotinib will be performed after
intake of a standardized breakfast. Subjects will be fasting the 10 hours before intake of
the breakfast

Drinking is not allowed 1 h after administration of dabigatran etexilate or tepotinib

Chewing gum is not allowed during the PK profile days.
Throughout the study, the following restrictions must be met:

No smoking or use of tobacco products

No alcohol intake

No intake of food or beverages other than that provided to the subjects by the CRO
during the inpatient period

No intake of caffeine- and xanthine-containing food and beverages (eg coffee, black or
green tea, chocolate or chocolate-containing food or beverages) 48 h before first
administration of study drug until collection of last PK sample in each period.

No intake of herbs/fruits that can have an influence on PK (eg St. John’s Wort, Seville
oranges, grapefruits, cranberry or the juice of these fruits), from 14 days prior to Day -1
until final examination.

No intake of concomitant medication within 14 days before first administration of study
drug until final examination (except for paracetamol up to 1500 mg per day, may be
given at the discretion of the Investigator).
Document No. 
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
No intake of recreational drugs within 14 days before first administration of study drug 
until final examination. 

No exhausting physical activities (body building, sports) from at least 72 h before the first 
administration of study drug until the final examination. 

No sun baths, solarium or sauna at least 12 h before first administration of study drug 
until final examination. 
6.5.4
Other Interventions
Not applicable.
6.5.5
Special Precautions
Not applicable.
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures are proposed at this stage. Standard medical care will be provided at the 
trial site for all AEs occurring during the trial.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
The investigational product tepotinib will be provided by the Sponsor packed in alu/alu blister. 
Dabigatran etexilate will be purchased from commercially available supplies.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
The pharmacy or designee will receive the IMPs labeled and packaged according to the local 
regulatory requirements and the storage requirements. Tepotinib and the interaction drug will be 
supplied in ready to use oral formulations. The responsible pharmacist will dispense the 
necessary amount of the IMP. Detailed guidance will be provided in an IMP handling manual.
The IMPs supplies will be recorded in an IMPs inventory.
Tepotinib must be carefully stored at the trial site in a closed room or cabinet with restricted 
access, safely and separately from other drugs and protected from environmental extremes until 
used in the trial. Tepotinib should be stored at or below 25°C. Any deviations from the 
recommended storage conditions should be immediately reported to the Sponsor, and the IMPs 
Document No. 
 
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should not be used until authorization has been received from the Sponsor. The preparation, 
handling and storage of the IMPs will be documented.
Detailed recommendations for the use and storage of dabigatran etexilate are described in the 
Summary of Product Characteristics. 
The IMPs must not be used for any purpose other than the trial in question.
It must be ensured at the trial site that the IMPs are not used after the use-by date. This is to be 
closely monitored by the responsible monitor.
6.8
Investigational Medicinal Product Accountability
The Clinical Trial Supply Department of Nuvisan GmbH is responsible for ensuring IMPs 
accountability, including reconciliation of drugs and maintenance of records. Drug accountability 
will also be confirmed by the study monitor.

Upon receipt of IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation 
and returning it to the location specified. A copy will be archived for the Investigator Site 
File

IMP dispensing will be recorded on the appropriate drug accountability forms so that 
accurate records will be available for verification at each monitoring visit

Trial site IMP accountability records will include the following:

Confirmation of IMP receipt, in good condition and in the defined temperature range

The inventory of IMPs provided for the clinical trial and prepared at the site

The use of each dose by each subject

The disposition (including return, if applicable) of any unused IMP

Dates, quantities, batch numbers, kit numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject trial numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. 
A Trial Monitor will periodically collect the IMP accountability forms.
At the conclusion or termination of this trial, all used and unused IMP kits will be destroyed at 
the trial site according to local regulations and institutional guidelines. All used and unused 
medications will be carefully recorded and documented before destruction.
Document No. 
 
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6.9
Assessment of Investigational Medicinal Product Compliance
During the treatment periods, drug administrations will be performed by a Nuvisan GmbH staff 
member in accordance with the specifications of the Investigator. This includes checking the oral 
and buccal cavity with the aid of a flashlight and tongue depressor. The proper administration of 
the trial medication will be documented on the individual eCRF.
6.10
Blinding
Blinding is not applicable as this is a single arm open-label trial.
6.11
Emergency Unblinding
Not applicable.
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest daily dose included in a clinical trial 
protocol or planned for an individual subject enrolled in the trial. Even if it does not meet other 
criteria for an SAE, any overdose must be recorded in the trial medication section of the eCRF 
and reported to Patient Safety in an expedited manner using the SAE Report Form, and following 
the procedure in Section 7.4. 
The effects of an overdose of tepotinib are unknown, and therefore no standard treatment is 
currently established. In the event of an overdose, the Investigator or treating physician should 
use appropriate clinical judgment for the management of any clinical symptoms or evaluation 
results.
Antidote in case of unexpected bleeding risk for the reversal of anticoagulant effects of 
dabigatran etexilate: 

Idarucizumab (Praxbind®) 2.5 g/50 mL solution for injection/infusion.
Praxbind® is a specific reversal agent for dabigatran and is indicated in adult patients treated with 
Pradaxa® (dabigatran etexilate) when rapid reversal of its anticoagulant effects is required. The 
recommended dose of Praxbind® is 5 g (2 x 2.5 g/50 mL). The administration is restricted to
hospital use only. An administration of a second 5 g dose of Praxbind® may be considered. 
Relevant coagulation parameters are aPTT, diluted TT or Hemoclot Thrombin Inhibitor.
6.13
Medical Care of Subjects after End of Trial
Not applicable in a trial with healthy subjects.
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7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Detailed schedule of trial procedures/assessments is provided in Table 1 (Period 1) and Table 2
(Period 2).
Prior to performing any trial assessments, the Investigator will obtain written informed consent 
as described in Section 9.2.
7.1.1
Screening Examination
All subjects will undergo an entry examination to evaluate their health status and their eligibility 
for inclusion in the study. This Screening examination will be conducted not more than 28 days 
prior to the planned first drug administration, ie between Day -28 to Day -2 before commencing 
to study Period 1. Only subjects who meet the inclusion criteria and none of the exclusion 
criteria will be admitted to the trial. 
During the Screening examination, the subjects are identified by a screening number. 
There is a notification on the subject’s card as well as in the electronic subject’s data base on the 
last participation in a trial. In addition, all subjects are reported to a central checking organization 
(VIP Check) before inclusion into the trial.
Prior to any Screening examinations the subjects must sign the informed consent form. This 
Screening examination will consist of the following:

Demographic information including body height and body weight and BMI

Medical history

Physical examination

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments 

Blood sampling for coagulation parameters

Test for occult blood in feces

Serological tests for hepatitis B, C, and HIV1/HIV2 

Serum pregnancy test for women 

Urine drug screen (including test for cotinine) and an alcohol breath test

Prior medication and concomitant medication

AEs

Preliminary evaluation of inclusion and exclusion criteria.
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7.1.2
Treatment Periods
The subjects willing to participate in the trial will only be included when all Screening 
examination procedures have demonstrated that all inclusion criteria and none of the exclusion 
criteria apply. They will be assigned a subject number within the trial prior to the first 
administration. 
For time points and assessments please refer to Table 1 and Table 2.
Period 1: Dabigatran Etexilate alone
Day -1 (admission)
Subjects will be hospitalized from the morning of Day -1 until completion of the 72 h 
assessments in the morning of Day 11 of Period 2. 
On admission on Day -1 the following will be done:

Physical examination 

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments (including drugs of abuse and 
a urine pregnancy test in females) 

Alcohol breath test

Prior medication and concomitant medication

AEs

Evaluation of inclusion and exclusion criteria.
Days 1 to 4 (inpatient)
Prior to dosing on Day 1 the following will be done:

Vital signs 

12-lead ECG 

Blood sample for PGx (optional) 

Pre-dose PK blood sample for determination of total dabigatran and coagulation 
parameters. 
After completion of the pre-dose assessments breakfast will be served and dabigatran etexilate 
will be administered 30 min after start of breakfast. At 4 h after administration the subjects will 
consume a standardized lunch.
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After dosing blood samples for determination of total dabigatran, coagulation parameters will be 
taken (please refer to Table 1). 
Subjects will be asked regularly about their well-being and any concomitant medication taken. 
Day 4 measurements (72 h measurements) may be performed immediately (within 60 min, PK 
sampling within 30 min) prior to tepotinib dosing on Day 1 of Period 2.
In case of a prolonged interval between Day 4 of Period 1 and Day 1 of Period 2 of more than 7 
days, safety laboratory parameters will be determined, a physical examination will be performed 
as well as vital signs measured and an ECG recorded.
Period 2: Tepotinib and Dabigatran Etexilate
Days 1 to 6 (inpatient)
The subjects will be dosed with tepotinib in the morning of Days 1 to 6 of Period 2, 30 min after 
a standardized breakfast. Before and after dosing safety assessments (vital signs, 12-lead ECGs) 
will be performed regularly on each dosing day. Blood and urine samples for safety laboratory 
assessments (including coagulation) will be performed on Days 1 and 2 at pre-dose (coagulation 
on Day 1 only); in the morning of Day 6 a blood sample will be taken pre-dose for determination 
of tepotinib and metabolites (please refer to Table 2). Subjects will be asked regularly about their 
well-being and any medication taken.
Day 7 (inpatient)
Prior to dosing of tepotinib on Day 7 the following will be done:

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments

Pre-dose PK blood sample for determination of tepotinib and metabolites parameters
After completion of the pre-dose assessments a standardized breakfast will be served and 
tepotinib will be administered 30 min after start of breakfast. At 4 h after administration the 
subjects will consume a standardized lunch. Six hours after drug administration, vital signs will 
be measured and an ECG recorded.
After dosing blood samples for determination of tepotinib and its metabolites will be taken 
(please refer to Table 2). Subjects will be asked regularly about their well-being and any 
medication taken.
Day 8 to 11 (inpatient)
Prior to dosing on Day 8 the following will be done:

Vital signs 
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
12-lead ECG 

Blood and urine samples for safety laboratory assessments

Pre-dose PK blood sample will be taken for determination of total dabigatran, tepotinib 
and its metabolites and coagulation parameters
After completion of the pre-dose assessments a standardized breakfast will be served and 
dabigatran etexilate and tepotinib will be administered 30 min after start of breakfast. At 4 h after 
administration of study drugs the subjects will consume a standardized lunch.
After dosing safety assessments (vital signs, 12-lead ECGs) will be performed regularly and 
blood samples for determination of total dabigatran and coagulation parameters will be taken 
(please refer to Table 2). Prior to discharge on Day 11 blood and urine samples will be taken in 
addition for safety laboratory assessments. Subjects will be asked regularly about their well-
being and any medication taken.
Details about the measurements are provided in Sections 7.4 and 7.5.1.
Dietary Regimen:
The subjects will be fasting at least 10 h before a standardized breakfast will be provided. 
Thereafter administration of dabigatran etexilate and/or tepotinib will occur (see Section 6.2). 
Four (4) hours after administration of dabigatran etexilate, a standardized lunch will be served. 
An afternoon snack will be provided 8 h and dinner 10 h post-dose. 
On Day 1 of Period 1 and on Day 1 to 8 of Period 2, tepotinib and/or dabigatran etexilate will be 
administered 30 min after a defined standardized breakfast. All other meals during the inpatient 
period will be served as customary at the trial center.
During hospitalization subjects are not allowed to eat other than the provided meals. 
Subjects should drink about 2 L fluids per day during the hospitalization phase (as provided by 
the site) and will be reminded regularly (for restrictions of fluids see below).
Restrictions:
Foods, sweets and beverages:
Intake of herbs/fruits that can have an influence on PK (eg St. John’s Wort, Seville oranges, 
grapefruits, cranberry or the juice of these fruits) are not allowed from 14 days before Day -1 of 
Period 1 until final examination. Methylxanthines (eg coffee, tea, cola, and cocoa) and alcohol 
containing food or beverages are not allowed from 48 h prior to the intended start of trial drug 
administration until the last PK blood sample. Poppy seeds (eg poppy seed rolls, poppy seed 
cake, yoghurt containing poppy seed etc.) will not be allowed from 72 h prior to dosing until 
completion of final examinations.
Drinking of fluids:
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Drinking of fluids is not allowed 1 h after administration of dabigatran etexilate or tepotinib.
Smoking:
Only non-smokers or smokers who stopped smoking at least 6 months before the time of the 
Screening Visit will be included in the trial. Moreover, smoking is not allowed from Screening 
Visit until completion of End of Trial Visit. 
Exercise Regimen:
Subjects will be advised to avoid heavy physical exertion 72 h prior to first drug administration 
until completion of all post trial examinations.
7.1.3
End of Trial Visit
The End of Trial examination should verify that all values tested in the Screening have remained 
within a clinically acceptable range. The assessments will be performed on 7 ± 1 day after last 
drug administration in Period 2 or upon premature termination. Unacceptable values and AEs 
will be followed up until they return to the reference ranges/resolved or there is an adequate 
explanation which is not related to the trial. 
The End of Trial examination will consist of the following:

Physical examination

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments and coagulation parameters 
(including a serum pregnancy test)

Concomitant medication

Assessment of AEs
No medical treatment is planned after the end of the trial.
The end of the trial is defined as the last contact (related to this trial) of the last subject 
undergoing the trial.
7.2
Demographic and Other Baseline Characteristics
At Screening, the following demographic data will be collected: age (year of birth), height, 
weight, BMI, gender, race and ethnicity. 
Furthermore, the following will be documented:

Clinically relevant findings in the medical history are recorded

Prior medication within 14 days (any prescribed medicine or over-the-counter drug or 
dietary supplement including herbal remedies, vitamins, and minerals)
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
Smoking status, alcohol intake

Female status (contraception, postmenopausal, sterilization).
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the IMPs will be assessed through the recording, reporting and analysis of 
baseline medical conditions, AEs, physical examination findings including vital signs, ECGs and 
laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be 
performed from the time of giving informed consent and throughout the trial. The Investigator 
will report any AEs, whether observed by the Investigator or reported by the subject (see Section 
7.4.1.2). The reporting period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable 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. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE. Investigators will 
reference the National Cancer Institute - Common Terminology Criteria for AEs (NCI-CTCAE), 
Version 5.0 (publication date: 27 Nov 2017), a descriptive terminology that can be used for AE 
reporting. A general grading (severity/intensity; hereafter referred to as severity) scale is 
provided at the beginning of the above referenced document, and specific event grades are also 
provided. If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is 
to use the general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best 
medical judgment.
The 5 general grades are:
Grade 1 or Mild
Grade 2 or Moderate
Grade 3 or Severe 
Grade 4 or Life-threatening 
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Grade 5 or Death
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as hemoglobin decreased or neutrophils count 
decreased, is considered serious only if the condition meets one of the serious criteria specified 
below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (eg, sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to IMPs (including 
any other non-IMPs, radiation therapy, etc.) using the following definitions. Decisive factors for 
the assessment of causal relationship of an AE to the IMPs include, but may not be limited to, 
temporal relationship between the AE and the IMPs known side effects of IMPs, medical history, 
concomitant medication, course of the underlying disease, trial procedures.
Unrelated:
Not 
reasonably 
related 
to 
the 
IMPs. 
AE 
could 
not 
medically 
(pharmacologically/clinically) be attributed to the IMP/trial treatment under trial in 
this clinical trial protocol. A reasonable alternative explanation must be available
Related:
Reasonably related to the IMPs. AE could medically (pharmacologically/clinically) 
be attributed to the IMPs under trial in this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (for example, on an 
ECG trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfills these criteria, the identified medical 
condition (for example, anemia, increased ALT) must be reported as the AE rather than the 
abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused 
death if it was more severe.)
Requires inpatient hospitalization or prolongs an existing hospitalization
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect
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Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.)
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is 
also considered an SAE, as described in Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (for 
example, an overnight stay to facilitate chemotherapy and related intravenous fluid 
administration) are not considered SAEs. However, all events leading to unplanned 
hospitalizations or unplanned prolongation of an elective hospitalization (for example, 
undesirable effects of any administered treatment) must be documented and reported as SAEs.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. All SAEs must be additionally documented and reported using the appropriate Report 
Form as described in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates (and times) when it is important to assess the time of AE onset relative to the 
recorded treatment administration time), its severity, its causal relationship with the trial 
treatment, any other potential causal factors, any treatment given or other action taken, including 
dose modification or discontinuation of the IMP, and its outcome. In addition, serious cases 
should be identified and the appropriate seriousness criteria documented.
Specific guidance can be found in the eCRF Completion and Monitoring Conventions.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in 
the trial (date of first signature of informed consent) and continues until the End of Trial Visit. 
Any SAE assessed as related to the IMPs must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of IMPs. 
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7.4.1.4
Procedure for Reporting Serious Adverse Events, Adverse 
Events of Special Interest and Dose Limiting Toxicities
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE 
Report Form, which must be completed by the Investigator following specific completion 
instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-specific 
SAE Report Form. 
Relevant pages from the eCRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report, and autopsy report). In all cases, the information 
provided on the SAE Report Form must be consistent with the data about the event recorded in 
the eCRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
Adverse Events of Special Interest
Healthy subjects might experience asymptomatic elevations in serum lipase and amylase. Any 
elevation in serum lipase and amylase of Grade ≥3 will lead to the recording of an adverse event 
of special interest (AESI). The severity of these AEs should be defined based on clinical 
judgment of the Investigator and defined according to NCI-CTCAE Severity Scale.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
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The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC that approved the trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the IEC’s 
approval/favorable opinion to continue the trial.” In line with respective regulations, the 
Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected and 
are considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or SUSARs). The Investigator should place copies of Safety Reports in the 
Investigator Site File. National regulations regarding Safety Report notifications to Investigators 
will be considered.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC and will maintain records of these 
notifications. When direct reporting is not clearly defined by national or site-specific regulations, 
the Investigator will be responsible for promptly notifying the concerned IEC of any Safety 
Reports provided by the Sponsor/designee and of filing copies of all related correspondence in 
the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
AEs are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) and are 
assessed for final outcome at the End of Trial Visit. All SAEs ongoing at the End of Trial Visit 
must be monitored and followed up by the Investigator until stabilization or until the outcome is 
known, unless the subject is documented as “lost to follow-up”. Reasonable attempts to obtain 
this information must be made and documented. It is also the responsibility of the Investigator to 
ensure that any necessary additional therapeutic measures and follow-up procedures are 
performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (for example, 
resulting from a drug interaction with a contraceptive medication) are considered to be AEs. 
However, all pregnancies with an estimated conception date during the period defined in Section 
7.4.1.3 must be recorded by convention in the AE page/section of the eCRF. The same rule 
applies to pregnancies in female subjects and to pregnancies in female partners of male subjects. 
The Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy 
using the Pregnancy Report Form, which must be transmitted according to the same process as 
described for SAE reporting in Section 7.4.1.4. 
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
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The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from trial medication immediately. The Sponsor/designee must be notified 
without delay and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Fasted blood samples and urine samples will be collected for the clinical laboratory tests
(hematology, biochemistry, coagulation, virology, drugs of abuse, hormones, and urinalysis, 
Table 3) following the timing noted in the Schedule of Assessments (Table 1 and Table 2). 
Additional laboratory safety examinations during the trial are at the discretion of the Investigator. 
All blood and urine samples will be worked up and analyzed in Nuvisan's clinical laboratory. 
Any abnormalities in any of the laboratory parameters will be judged by a physician individually 
in relation to the reference ranges from the laboratory. In addition, feces samples will be 
collected.
For all findings with major deviation and/or possible pathological relevance, follow-up 
examinations will be carried out until the deviation returns to normal or the absence of 
pathological relevance can be confirmed. If a deviation considered clinically relevant has not 
returned to a normal or not clinically relevant value when it is checked during the screening 
laboratory tests, the subject will not be included in the trial.
Laboratory abnormalities considered clinically relevant by the Investigator will be reported as
AE. The following parameters will be determined: 
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Table 3
Safety Laboratory Evaluations
Biochemistry
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Lactate dehydrogenase
Creatine phosphokinase b
Amylase
Lipase
Bilirubin (total) a
Cholesterol
Triglycerides
Uric acid
Sodium
Potassium
Creatinine
Urea
Glucose
Coagulation
Thrombin Time
Activated partial thromboplastin time
Hemoclot Thrombin Inhibitor (Anti-Factor II)
Hematology
Hematocrit
Hemoglobin
Red blood cell count 
Mean corpuscular volume
Mean corpuscular hemoglobin 
Mean corpuscular hemoglobin 
concentration
Platelet count
White blood cell count
White blood cell differentials 
and absolute counts c:
Basophiles 
Eosinophiles 
Lymphocytes 
Monocytes 
Neutrophiles
Urinalysis
pH
Nitrite
Protein
Glucose
Ketone bodies
Urobilinogen
Bilirubin
Urine pregnancy test
White blood cell count
Red blood cell count
Microscopic examination d
Urine drug screen
Cocaine
Amphetamines
Methamphetamines
Opiates
Barbiturates
Benzodiazepines
Methadone
Cannabinoids
Tricyclic antidepressants
Cotinine
Ecstasy
Other tests:
Hepatitis B surface antigen
Hepatitis B core antibody 
Hepatitis C antibody
HIV1/HIV2 antibodies 
Follicle stimulating hormone (if applicable)
Thyroid stimulating hormone
Serum pregnancy test (beta-HCG)
eGFR e
Breath Alcohol test (at Screening and Admission)
Feces
Occult blood in feces (Haemoccult)
HIV = human immunodeficiency virus, HCG = human chorionic gonadotropin
a
In case of an increased Bilirubin (total) the direct Bilirubin will be determined.
b
In case of an increased creatine phosphokinase (CK), myocardium/brain type (CK-MB) will be determined; if the 
ratio of CK/CK-MB is above 6, troponin will be determined as well.
c
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
d
Only if blood, protein, nitrite, or leucocytes are positive on the dipstick. 
e
Estimated glomerular filtration rate (eGFR) calculated using the Cockcroft-Gault equation.
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMPs. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor, 
including laboratory certificates.
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For the amount of blood taken in this study, see Appendix II.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Blood pressure (systolic blood pressure [mmHg] and diastolic blood pressure [mmHg]) will be 
measured according to the oscillometric method using an automated device, which also indicates 
the corresponding pulse rate (bpm). Blood pressure and pulse rate will be measured after at least 
5 min in a supine position, according to the schedule of assessments (Table 1 and Table 2).
Body temperature will be measured auricular.
Further vital sign measurements during the course of the study are at the discretion of the 
Investigator.
7.4.4.2
ECG
Twelve-lead ECGs will be recorded as scheduled in the trial schedule of assessments (Table 1
and Table 2) using the ECG system (CardioPerfect®, Welch Allyn). The ECGs will be recorded 
in supine position after at least 5 min rest.
ECGs will be plotted with a paper speed of 50 mm/s and 10 mm/mV amplitude, with 10 seconds 
recording duration for all leads and at least 3 complexes, but preferably 5 complexes in each 
lead. 
Per time-point, the ECG will be stored electronically, printed and reviewed in a timely manner 
by the Investigator. The original printout will be stored with the subject’s source data. Electronic 
data may be transferred to a central ECG laboratory for central reading and further analysis; 
these results would be reported separately.
ECG printouts must be signed and dated by the person evaluating the ECG. The ECG will be 
interpreted by the Investigator (normal/abnormal). For abnormal ECGs, the clinical significance 
(yes/no) must be judged by the Investigator and the abnormality is to be specified.
Additional ECGs during the course of the study are at the discretion of the Investigator.
7.4.4.3
Physical Examination
The physical examination comprises general appearance, skin, head, neck (including thyroid), 
eyes, ears, nose, throat, abdomen, as well as neurological, peripheral vascular, musculoskeletal, 
cardiovascular and pulmonary system.
Physical examination will be scheduled according to the study flow chart (see Table 1 and Table 
2). Further physical examinations during the course of the study are at the discretion of the 
Investigator. Any relevant findings are to be recorded on the Medical History form in the eCRF 
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(for findings from the past that occurred prior to ICF signature) or on the AE form in the eCRF 
(for findings presently occurring; events existing but unresolved prior to drug administration). 
7.5
Pharmacokinetics
7.5.1
Blood Sampling
On the PK profiling day, an indwelling venous catheter will be positioned in a suitable forearm 
vein for blood sampling and should be kept, if possible, until at least 24 h after dosing. After 
removing the indwelling venous cannula, samples will be taken by venipuncture. 
Blood samples will be taken and plasma levels of total dabigatran will be determined as closely 
as possible to the following time points: 

Day 1 of Period 1 at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, 
and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose, and 

Day 8 of Period 2 at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, 
and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose. 
Blood samples will be taken and plasma levels of tepotinib and its metabolites MSC2571109A 
and MSC2571107A will be determined as closely as possible to the following time points: 

Day 6 of Period 2 at pre-dose (within 60 min prior to dosing), and 

Day 7 of Period 2 at pre-dose (within 60 min prior to dosing) and 15, 30, 45, 60, 90 min, 
and 2, 3, 4, 6, 8, 12 and 24 h post-dose (prior to dosing on Day 8, within 60 min prior to 
administration). 
The exact date and time of sample collection must be recorded in the eCRF and will be used in 
the calculation of PK parameters. Blood samples should be taken as close as possible to the 
scheduled time points. Samples taken outside of the time periods shown in Table 4 need an 
explanation and will be considered a protocol violation.
Table 4
Time Windows 
Planned Blood Sampling 
Time Windows (min)
Pre-dose
- 60
15, 30, 45 and 60 min post-dose
± 2
90 min, and 2, 3, 4, 6, 8 and 12 h post-dose
± 5
24, 36 and 48 h post-dose
± 15
72 h post-dose
± 30
At visits where assessment time points coincide with each other, the vital signs and ECG 
assessments should be performed slightly before the specific time point and the PK blood 
sampling should be performed on time.
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Details of blood sample collection, labeling, processing, storage and shipment requirements will 
be described in a separate laboratory manual. For the amount of blood taken in this study see 
Appendix II.
All sample handling procedures, including the time of each sample collection, the time of 
placement into frozen storage (at the end of the sample preparation), and the date of transfer or 
shipment of the samples to the responsible analyst will be documented in detail. 
Concentrations of total dabigatran and tepotinib and its metabolites MSC2571109A and 
MSC2571107A will be measured using validated liquid chromatography and tandem mass 
spectrometry (LC-MS/MS) methods at Nuvisan. The assays will be carried out in accordance 
with GLP regulations and the EMA reflection paper (GCP). A separate bioanalytical protocol 
will be provided before the start of the analytical part of the study. Full details of the 
bioanalytical method used will be described in a separate bioanalytical report.
7.5.2
Calculation of Pharmacokinetic Variables
The following non-compartmental PK parameters (see Table 5 and Table 6) will be calculated 
from the individual plasma total dabigatran (unconjugated plus conjugated) and tepotinib 
concentration-time data using commercial software such as Phoenix®/WinNonlin® (Version 6.2 
or higher) at Nuvisan GmbH.
Table 5
Definition of PK Parameters for Dabigatran after Single Dose 
Administration
Symbol
Definition
AUC0-t
Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to the last 
sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), 
calculated per the mixed log linear trapezoidal rule (ie linear up/log down)
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing time) extrapolated to 
infinity, calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-∞
calculated by Clastpred/λz, where Clastpred is the predicted plasma concentration at the last sampling 
time point, calculated from the log-linear regression line for λz determination at which the measured 
plasma concentration is at or above LLOQ
Cmax
Maximum plasma concentration observed
tlast
The last sampling time at which the plasma concentration is at or above the lower limit of 
quantification
tmax
Time to reach the maximum plasma concentration
t1/2
Terminal half-life, calculated as ln(2)/λz
λz
Terminal rate constant determined from the terminal slope of the log-transformed plasma 
concentration curve using linear regression on terminal data points of the curve
CL/f 
Apparent total body clearance of drug from plasma following extravascular administration, 
calculated as dose/AUC0-∞
Vz/f 
Apparent volume of distribution during the terminal phase following extravascular administration
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of AUC0-∞. AUCextra% = 
(extrapolated area/AUC0-∞) x100.
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Table 6
Definition of PK Parameters for Tepotinib and Metabolites 
MSC2571109A and MSC2571107A after Multiple Dose Administration
Symbol
Definition
AUC
The area under the plasma concentration-time curve (AUC) at steady state over the dosing interval 
from
T1 = 0 h to T2 = h. Calculated using the mixed log linear trapezoidal rule (linear up, log down), = 
24 h
CLSS/f
Apparent total body clearance of drug at steady state following extravascular administration, 
considering the fraction of dose absorbed. CLSS/f = Dose po / AUC(parent drug only)
Cmax,SS
Maximum observed plasma concentration during a complete dosing interval at steady state
Cmin,SS
Minimum observed plasma concentration during a complete dosing interval at steady state
tmax,SS
The time to reach the maximum observed plasma concentration collected during a dosing interval 
(unless otherwise defined, take the 1st occurrence in case of multiple/identical Cmax values)
Individual PK parameters will be calculated using actual sampling times. The predose sample 
will be considered as if it had been taken simultaneously with the administration of study drug. 
PK variables will be evaluated and listed for all subjects who provide sufficient concentration-
time data.
Plasma concentrations below LLOQ before the last quantifiable data point will be taken as zero 
for calculating the AUC (ie embedded BLQ values set to zero). Plasma concentrations below 
LLOQ after the last quantifiable data point will not be considered for the determination of λz.
7.6
Biomarkers
Not applicable.
7.7
Pharmacogenomics 
Pharmacogenetic sample collection is optional. An additional separate Informed Consent Form 
(ICF) will be used. One blood sample should be collected in duplicate on Day 1 pre-dose 
administration. The pharmacogenetic samples will be analyzed conditionally in case of 
unexpected PK profiles. The results of the pharmacogenetic analysis, as applicable, will be 
described in a separate report.
7.8
Other Assessments
Not applicable.
8
Statistics
8.1
Sample Size
A total of 20 subjects will be dosed in this study to obtain at least 16 evaluable subjects for the 
primary endpoint analysis. Four subjects will be added for drop-out compensation.
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For the statistical analysis of AUC, data a-priori ordered hypotheses will be tested. The 
procedure is intended to classify tepotinib as a P-gp inhibitor. 
Test 1
H01: T/R ratio ≥2.0
versus
HA1: T/R ratio < 2.0 
Test 2
H02: T/R ratio ≥1.5
versus
HA1: T/R ratio < 1.5
In published studies of dabigatran, coefficient of variations (CVs) up to 30% were observed for 
the AUC following a single dose of dabigatran etexilate; after fed administration CV may be 
slightly lower [2] [9]. With 16 evaluable subjects and CV = 30%, Test 1 would have at least 80% 
power to reject H01, if the true T/R ratio is 1.5 or smaller, and Test 2 would have at least 80% 
power to reject H02, if the true T/R ratio is 1.14 or smaller. The one-sided significance level was 
set to alpha = 0.05.
8.2
Randomization
Not applicable.
8.3
Endpoints
8.3.1
Primary Endpoints

PK profile of dabigatran in terms of AUC0-t, AUC0-∞, Cmax of total dabigatran 
(unconjugated plus conjugated) at Day 1 of Period 1 and Day 8 of Period 2 from time 
zero to 72 h post-dose.
8.3.2
Secondary Endpoints

PK profile of total dabigatran (unconjugated plus conjugated) in terms of tmax, t1/2, CL/f, 
Vz/f, AUCextra% at Day 1 of Period 1 and Day 8 of Period 2 from time zero to 72 h post-
dose

Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of 
changes in safety laboratory assessments, 12-lead ECGs and vital signs in subjects 
receiving tepotinib alone and together with dabigatran etexilate assessed from Day -1 of 
Period 1 until the End of Trial Visit.
8.3.3
Exploratory Endpoints

PK profile of tepotinib and its metabolites MSC2571109A and MSC2571107A in terms 
of AUCτ, Cmax,ss, Cmin,ss, tmax,ss, CLss/f (parent drug only), and t1/2, if appropriate.

Genetic variants and mutations in genes that potentially influence the PK of tepotinib 
and/or dabigatran. 
Note: Pharmacogenetic sample collection is optional. The results of the pharmacogenetic 
analysis, as applicable, will be described in a separate report. 
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8.4
Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Screening
The screening analysis set will include all subjects who provided signed 
informed consent, regardless of treatment status in the trial. This set will 
be used for subject disposition. 
Safety
The Safety Analysis Set will include all subjects who have received at 
least 1 dose of planned IMP. Subjects will be analyzed according to the 
actual treatment they receive. 
Pharmacokinetic
The PK Analysis Set will include all subjects who have completed at least 
1 period without any relevant protocol violations with respect to factors 
likely to affect the comparability of PK results, with adequate study 
medication compliance, and with evaluable dabigatran PK data.
Assessment of data sufficiency will be done by the responsible 
pharmacokineticist before database lock, ie PK data will be available and 
included in the database before data base lock.
Subjects may be excluded after vomiting or following diarrhea in a 
particular period as this could render the plasma concentration-time 
profile unreliable. The use of a concomitant medication that might 
interfere with the PK of any investigational drug could be a reason for 
excluding a subject.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA).
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as 
appropriate.
For demographic, baseline and safety assessments, continuous measurements will be 
summarized by means of descriptive statistics (ie number and percentage of observations, 
number and percentage of missing observations, mean, standard deviation [SD], median, 25th 
and 75th percentiles [Q1 and Q3], minimum, and maximum) and categorical data will be 
summarized by means of frequency tables (ie count and percentages), if not stated otherwise.
Concentrations of total dabigatran, tepotinib and its metabolites in plasma will be presented in 
tables and descriptively summarized by treatment and nominal time point using n, arithmetic 
mean, SD, standard error of the mean (SEM), median, minimum, maximum, and CV%. Values 
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below the LLOQ will be taken as zero for descriptive statistics of PK concentrations. Descriptive 
statistics of PK parameters will additionally show the geometric mean (GeoMean), the geometric 
coefficient of variation (GeoCV), and the 95% confidence interval (CI) for the GeoMean.
Since the statistical analyses will be predominantly descriptive presentations in tables and 
individual data listings, no action will be taken to handle missing data. A subject who withdraws 
prior to the last planned observation in a trial period will be included in the analyses up to the 
time of discontinuation.
Changes in the conduct of the trial or planned analyses, if any, will be reported in the appropriate 
section of the statistical analysis plan and in the clinical trial report.
8.5.2
Analysis of Primary Endpoint
A general linear model with TREATMENT and SUBJECT as fixed effects will be applied to 
log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞of dabigatran (measured as total 
dabigatran) based on the PK analysis set. Treatment differences on the log scale of dabigatran 
with tepotinib vs dabigatran alone will be estimated for Cmax, AUC0-t, and AUC0-∞together with 
their 90% CIs. Point estimates and CIs will be back-transformed to the original scale. 
Individual estimates of relative bioavailability of dabigatran will be calculated for each subject.
The primary endpoint will be descriptively summarized. Scatterplots will be produced by 
treatment also showing the median, Q1 and Q3.
8.5.3
Analysis of Secondary Endpoints
Summary statistics will be provided for all secondary PK parameters as well as for the 
concentrations of dabigatran in plasma by time point. 
For tmax of dabigatran the Hodges-Lehmann shift estimator will be calculated together with the 
90% confidence interval according to Tukey.
PK variables will be evaluated and listed for all subjects of the PK population.
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the statistical analysis plan.
8.5.4
Analysis of Safety and Other Endpoints
Safety data analysis will be conducted on the Safety Analysis Set. The number and percentage of 
subjects experiencing at least 1 AE will be summarized by treatment as well as the number of 
events. Tables by relationship to trial drug and by severity will be generated. AEs will be coded 
using Medical Dictionary for Regulatory Activities terminology. 
All laboratory data will be reported with SI units. Laboratory parameters will be summarized 
using descriptive statistics for absolute values and change from baseline over time, by post-dose 
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shifts relative to baseline, and data listings of abnormalities as per the NCI-CTCAE severity 
scale.
Vital signs and ECG data will be summarized by changes-from-baseline values by treatment 
using descriptive statistics. Clinical noteworthy ECG findings for individual subjects will be 
listed and summarized as appropriate.
PK concentrations will be descriptively summarized. Individual and mean concentration-time 
plots will be produced in linear and log-linear scale. 
Analysis of exploratory endpoints
Summary statistics will be provided for all exploratory PK parameters as well as for the 
concentrations of the tepotinib and metabolites in plasma by time point. PK variables of tepotinib 
and the metabolites will be evaluated and listed for all subjects who provide sufficient 
concentration-time data. Graphical displays will be given, where appropriate. Further details of 
the statistical analysis will be described in the statistical analysis plan.
8.6
Interim and Additional Planned Analyses
Not applicable.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure that the trial 
is performed in accordance with this protocol, the ethical principles outlined in the Declaration 
of Helsinki, ICH GCP, and any other applicable regulations. The Investigator must ensure that 
only subjects who have given informed consent are included in the trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written 
informed consent, which must be given before any trial-related activities are carried out. 
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained. 
A subject information sheet must be prepared in the local language in accordance with ICH GCP 
and will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or a designate will 
inform the subject verbally of all pertinent aspects of the trial, using language chosen so that the 
information can be fully and readily understood by laypersons. The subject will be given 
sufficient time to read the information and the opportunity to ask questions and to request 
additional information and clarification.
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After the information is provided by the Investigator, the Informed Consent Form must be signed 
and dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing 
and inspection purposes. A copy of the signed and dated information and Informed Consent 
Form should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed 
consent, the Investigator will revise the subject information sheet and any other written 
information to be provided to the subjects and submit them to the IEC for review and opinion. 
Using the approved revised subject information sheet and other written information, the 
Investigator will explain the changes to the previous version to each trial subject and obtain new 
written consent for continued participation in the trial. The subject will be given sufficient time 
to read the information and the opportunity to ask questions and to request additional information 
and clarification about the changes.
A separate subject information and Informed Consent Form will be prepared and signed by the 
subjects for pharmacogenomic examination. 
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject, immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical 
trial database. All subject data collected in the trial will be stored under the appropriate subject 
number. Only the Investigator will be able to link trial data to an individual subject via an 
identification list kept at the site. For each subject, original medical data will be accessible for 
the purposes of source data verification by the Monitor, audits and regulatory inspections, but 
subject confidentiality will be strictly maintained.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, 
and storing subject data. Subjects will be informed accordingly, and will be requested to give 
their consent on data handling procedures in accordance with national regulations.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by Nuvisan GmbH 
for use during trial participation in order to provide clinical trial subjects with a way of 
identifying themselves as participating in a clinical trial and to give health care providers access 
to any information about this participation that may be needed to determine the course of 
medical treatment for the subject. 
The first point of contact for all emergencies will be the clinical trial Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, he will answer 
any questions. Any subsequent action will follow the standard process established for 
Investigators.
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In cases where the Investigator is not available, the Phase I facility will provide the appropriate 
means to contact a physician. This includes the provision of a 24 h contact number at the facility, 
whereby the health care providers will be given access to an appropriate physician to assist with 
the medical emergency.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for the trial. Insurance conditions will meet good local 
standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review 
Board
Prior to commencement of the trial, this clinical trial protocol will be submitted together with its 
associated documents (for example, Informed Consent Form, insurance certificate) to the 
responsible IEC for its favorable opinion or approval, which will be filed in the Investigator Site 
File. A copy will be filed in the Sponsor Trial Master File.
The IEC will document the date at which the favorable opinion or approval was given. A 
members list of the IEC will be provided. Written evidence of favorable opinion or approval that 
clearly identifies the clinical trial protocol version and the Subject Information and Informed 
Consent Form version reviewed will be provided. Where possible, copies of the meeting minutes 
should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC, before 
implementation of substantial changes (see Section 10.5). Relevant safety information will be 
submitted to the IEC during the course of the trial in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (for example, Investigational 
Medicinal Product Dossier, Subject Information and Informed Consent Form) will be submitted 
or notified to the Health Authorities in accordance with all local and national regulations for each 
site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Operations for eCRF handling guidelines 
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a 
complete, accurate, legible and timely manner. The data in the eCRF should be consistent with 
the relevant source documents.
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The Investigator or designee is responsible for ensuring that the data collected in the course of 
this trial is accurate and documented. They will then be processed, evaluated, and stored in 
anonymous form in accordance with applicable data protection regulations. The Investigator 
must ensure that the eCRFs and any other associated documents forwarded to data management 
contain no mention of any subject names.
The data will be entered into a validated database. Nuvisan GmbH will be responsible for data 
processing, in accordance with the Sponsor’s data management procedures. Database lock will 
occur once quality control and quality assurance procedures have been completed. PDF files of 
the eCRFs will be provided to the Investigators at the completion of the trial.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or 
electronically for every subject in the trial. It must be possible to identify each subject by using 
this subject file. This file will contain the demographic and medical information for the subject 
listed below and should be as complete as possible. 

Subject’s full name, date of birth, sex, height, weight

Medical history and concomitant diseases

Prior and concomitant therapies (including changes during the trial)

Trial identification, that is, the Sponsor trial number for this clinical trial, and subject 
number

Dates for entry into the trial (informed consent) and visits to the site

Any medical examinations and clinical findings predefined in this clinical trial protocol

All AEs

Date that the subject left the trial including any reason for early withdrawal from the trial 
or IMP (if applicable).
All documents containing source data must be filed, including, but not limited to ECG 
recordings, and laboratory results. Such documents must bear the subject number and the date of 
the procedure. If possible, this information should be printed by the instrument used to perform 
the assessment or measurement. As necessary, medical evaluation of such records should be 
performed; all evaluations should be documented, signed, and dated by the Investigator.
Electronic subject files will be printed whenever the Monitor performs source data verification. 
Printouts must be signed and dated by the Investigator, countersigned by the Monitor and kept in 
a safe place at the site.
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10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and 
updated as necessary. The file must be available for review by the Monitor, during Sponsor 
audits and for inspection by Health Authorities during and after the trial, and must be safely 
archived for at least 15 years after the end of the trial. 
The documents to be archived include the Subject Identification List and the signed subject 
Informed Consent Forms. If archiving of the Investigator Site File is no longer possible at the 
site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by the applicable regulations, and/or as per 
ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP and any other applicable 
regulations. The site Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance 
activities. Audits may be conducted at any time during or after the trial to ensure the validity and 
integrity of the trial data. Representatives of the Quality Assurance unit from the Sponsor or a 
designated organization, as well as Health Authorities, must be permitted to access all trial 
documents and other materials at the site, including the Investigator Site File, the completed 
eCRFs, all IMPs and IMP accountability records, and the original medical records or files for 
each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the clinical trial protocol will be documented in writing. Substantive amendments 
will usually require submission to the Health Authorities and to the relevant IEC for approval or 
favorable opinion. In such cases, the amendment will be implemented only after approval or 
favorable opinion has been obtained.
Minor (no-substantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC or to Health Authorities 
only where requested by pertinent regulations. Any amendment that could affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
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10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by Nuvisan GmbH following 
the guidance in ICH Topic E3 [10].
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints. The results 
of this study may be published or presented at scientific meetings. If this is foreseen, the 
Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. This 
allows Merck to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. 
Posting of data on ClinicalTrials.gov and EudraCT is planned and will occur 12 months after the 
last clinic visit of the final trial subject or another appropriate date to meet applicable 
requirements.
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11
References Cited in the Text
1. Härtter S, Sennewald R, Nehmiz G, et al. Oral bioavailability of dabigatran etexilate 
(Pradaxa®) after co-medication with verapamil in healthy subjects. BJCP 2013;75(4), 
1053-1062.
2. Stangier J. Clinical Pharmacokinetics and Pharmacodynamics of the Oral Direct 
Thrombin Inhibitor Dabigatran Etexilate. Clin Pharmacokinet 2008;47(5): 285-295.
3. Summary of product characteristics Pradaxa 75 mg hard capsules. Updated 02 November 
2017 Boehringer Ingelheim Limited. Downloaded from ‘www.medicines.org.uk’ on 07 
November 2017.
4. Guidance for Industry; Drug Interaction Studies - Study Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations, Food and Drug Administration 
2012.
5. Guideline on the investigation of drug interactions, CPMP/EWP/560/95/Rev. 1 Corr. 2**, 
European Medicines Agency 2012.
6. Drug Interaction Study With Dabigatran Etexilate and Dronedarone in Healthy Subjects. 
NCT01306162 (ClinTrials.gov). Homepage visited on 07 November 2017.
7. Drug 
Interaction 
Study 
Between 
Bosutinib 
And 
Dabigatran. 
NCT02102633 
(ClinTrials.gov). Homepage visited on 07 November 2017. 
8. Recommendations related to contraception and pregnancy testing clinical trials. Clinical 
Trial Facilitation Group (CTFG), Heads of Medicines Agencies. 15 September 2014. 
Downloaded from ‘www.hma.eu’ on 07 November 2017.
9. Stangier J, Stähle H, Rathgen K, et al. Pharmacokinetics and pharmacodynamics of the 
direct oral thrombin inhibitor dabigatran in healthy elderly subjects. Clin Pharmacokinet. 
2008;47:47-59.
10. ICH Topic E 3 Note for Guidance on Structure and Content of Clinical Study Reports 
(CPMP/ICH/137/95); July 1996.
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12
Appendices
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Appendix I
Signature Pages and Responsible Persons for the Trial
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T e p oti ni b ( M S C 2 J 5 6 1 1 9 J) 
M S 2 0 0 0 9 5- 0 0 3 2 
Efi e ct of T e p oti ni b o n t he P K of t he P- g p S u bst r at e 
D a bi g at r a n Ete xil ate 
Si g n at u r e P a g e - P r ot o c ol L e a d 
T ri al Title: 
E u d r a C T N u m b e r: 
P h as e 1, O p e n-l a b el, 
Si n gl e S e q u e n c e , T w o- P eri o d 
St u d y t o E v al u at e t h e Eff e ct of T e p oti ni b 
o n P-
G l y c o pr ot ei n b y I n v esti g ati n g t h e P h ar m a c o ki n eti cs of 
t h e 
P- G l yc o pr ot ei n 
Pr o b e 
S u bstr at e 
D a bi g atr a n 
Et e xil at e i n H e alt h y S u bj e cts 
2 0 1 7- 0 0 4 0 7 4- 3 4 
Cli ni c al 
T ri al 
P r ot o c ol 
D at e 
I 2 3 A pril 2 0 1 8 I V ersi o n 3. 0 
Versi o n: 
P r ot o c ol Le a d: 
1 a p pr o v e t h e d esi g n of t h e cli ni c al trial: 
Si g n at ur e 
D at e of Si g n at ur e 
N a m e, 
d e gr e e: 
a c a d e mi c 
, 
 
F u n cti o n I Title: 
M e di c al R es p o nsi bl e I 
 
I nstit uti o n: 
M er c k K G a A 
A d dr ess: 
Fr a n kf urt er Str ass e 2 5 0, 6 4 2 9 3 D ar mst a dt, G er m a n y 
T el e p h o n e n u m b er: 
 
E- m ail a d dr ess: 
 
D o c u m e nt N o. 0 9 0 0 b a b e 8 0f 5 2 d 6 d v 2. 0 
O bj e ct N o. 0 9 0 0 b a b e 8 0f 6 5 3 c 0 
C O N F I D E N T
I A L 
I N F O R M A T I O N 
6 5 /8 4 
PI
PI
PI
PI
PI
PI
PI


T e p oti ni b ( MS C 2 1 5 6 1 1 9 J) 
M S 2 0 0 0 9 5- 0 0 3 2 
Eff e ct of T e p oti ni b o n t h e P K of t h e P- g p S u bst r at e 
D a bi g at r a n E te xila te 
Si g n at u r e P a g e - P ri n ci p al I n v est ig at o r 
T ri al T itl e 
P h as e I,  O p en-l a b el , Si n g le S e q u e n c e, T w o - Pe rio d 
St u d y t o E v a l uat e t h e Eff e c t of T e p o ti ni b o n P-
Gl y c o p r ot ei n  b y I n v esti g ati ng t h e P h ar m a c o ki n e tics of 
t he 
P- G ly c o p r ot ei n 
P r obe 
S u b str ate  
D a bi g at ran 
Et e xi late i n He alt hy S u bj e c ts 
E u d r a C T N u m b e r 
2 0 1 7- 0 0 4 0 7 4 -3 4 
C li nical Tri a l Pr ot o c o l D at e I V ers io n 
2 3 A pr il 2 0 1 8 I V ersi o n 3. 0 
C e nt e r N u m b e r 
 
P ri n ci p al In ve sti gat o r 
 
I, t he u n d ersi g n e d, a m res p o ns i ble f or t h e c o n d u ct of t h e tri al at t his  s it e a n d a ffir m t hat I 
u n d e rsta n d a n d wi ll c o n d u ct t he trial  a c c o r di ng  t o t he c li ni cal tri al p r ot o c ol, a n y a p p r o v ed 
p r oto c o l a m en d m e nt s, I nt er n atio n a l C o u n cil of H a r mo ni z a tio n G o o d C li ni c a l P r acti c e ( T opi c E 6) 
a n d a ll a p p,lica bl e He alt h7
rit y req uire m e nts a n d n at ional la ws. 
 
Si g n at ur e 
D a t e of Si g n at ur e 
N a m e, a c a d e mi c de gr e e : 
, 
 
F u n ct i on I T itle : 
Pri n c i pal I nv es tig a t or 
I nstituti o n: 
 
A d dr ess: 
, G er m a n y 
T el e p h o n e n u m b er: 
 
Fa x n u m b er: 
 
E - m ail a d dr ess: 
 
D o c u m e nt N o. 0 9 0 0 b a bc 8 0f5 2 d 6 d v 2. 0 
O bj e c t N o. 0 9 0 0 b a b e 8 0f 6 5 3 c 0 
C  O  N F I  D E  N T I  A L 
I N F O R M
A T I  O  N 
6 6 /8 4 
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J)
Effect of T e p oti ni b on t he P K of t he P -g p S u bstr ate 
M S 2 0 0 0 9 5- 0 0 3 2
D a bi g atr a n E te xil ate
C O N F I D E N T I A L
I N F O R M A T I O N
6 7 /8 4
S p o ns or Res p o nsi ble Pers o ns N ot N a me d o n t he C o ver P a ge
Na me:
F u ncti o n / Title:
I nstit uti o n:
Merc k K Ga A 
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
E- mail a d dress:
Na me:
F u ncti o n / Title:
I nstit uti o n:
Merc k K Ga A 
A d dress:
Fra n kf urter Strasse 2 5 0, 6 4 2 9 3 Dar msta dt, Ger ma n y
Tele p h o ne n u m ber:
E- mail a d dress:
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0f 5 2 d 6 d v 2. 0
0 9 0 0 ba be 8 0f 6 5 3c 0
PI
PI
PI
PI
PI
PI
PI
PI


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Appendix II
Planned Numbers of Blood Samples for Clinical Laboratory, 
PK, and PGx and Total Blood Sampling Volume
Amount 
per 
sample 
(mL)
Number of Samples
Total 
amount 
(mL)
Blood sample
Screening
Period 1
Period 2
End of 
Trial 
Visit
Total
Clinical laboratory tests 
Biochemistry (incl. viral 
serology, TSH and FSH 
levels, if applicable)
4.7
1
1a
5b
1
8
37.6
Hematology
2.7
1
1a
5b
1
8
21.6
Coagulation
3.0
1
3c
4d
1
9
27.0
PK total dabigatran 
(unconjugated and 
conjugated
2.0
16e
16f
32
64.0
PK tepotinib and its 
metabolites
2.0
14g
14
28.0
PGx
2.0
2h
2
4.0
Total
3
23
44
3
73
182.2
Note: the number of blood samples may increase above the scheduled number. Blood samples for 
clinical laboratory follow-up determinations may become necessary. Technical failure of PK/PGx blood 
drawing may lead the Investigator to decide immediately to repeat a single blood drawing to have a 
sample.
Maximal blood volume drawn: Estimate per subject in this study that will not be exceeded in this 
planned trial as by experience of the Investigating institution
250
Clinical laboratory (biochemistry and hematology) blood samples
a
Period 1: Day -1 = 1 sample
b
Period 2: pre-dose on Days 1, 2, 7 and 8 and on Day 11 = 5 samples
Coagulation
c
Period 1: pre-dose and 4 h post-dose on Day 1 and 24 h post-dose on Day 2 = 3 samples
d
Period 2: pre-dose on Day 1, pre-dose and 4 h post-dose on Day 8 and 24 h after the last dose on Day 9 = 4 
samples
Dabigatran (unconjugated plus conjugated) PK blood samples: 
e
Period 1, Day 1: at pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose = 
16 samples
f
Period 2, Day 8: at pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose = 
16 samples
Tepotinib and its metabolites PK blood sampling:
g
Period 2: Day 6 pre-dose and Day 7 pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24 h post-dose = 
14 samples
PGx blood samples:
h
PGx blood samples of 2 x 2 mL (optional) to be drawn in Period 1 Day 1 at pre-dose = 2 samples.
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Appendix III
Contraception Guidance
Definitions
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered women of childbearing potential
1.
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview.
2.
Premenarchal
3.
Postmenopausal female
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy. If 
necessary to confirm postmenopausal status, FSH will be re-tested at Screening.
Females on hormone replacement therapy (HRT) and whose menopausal status is in 
doubt will be required to use one of the non-hormonal highly effective contraception 
methods if they wish to continue their HRT during the study. However, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
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Contraceptive Guidance for Women of Childbearing Potential:
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly a. 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation b

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulation b

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation b

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

Vasectomized partner 
(Bilateral vasectomy of the partner is a highly effective contraceptive method provided that the partner is the sole 
male sexual partner of the woman of childbearing potential and the absence of sperm has been confirmed. If not, 
an additional highly effective method of contraception should be used.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy 
of the contraceptive method. In this case another highly effective (not hormone based) method of contraception 
must be utilized during the treatment period and for at least 3 months after the last dose of study treatment 
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Appendix IV
Protocol Amendments and List of Changes
Previous Protocol Amendments 
None
Table of Amendments
Amendment 
Number
Substantial
(Y/N)
Date
Region or Country
Included in the 
current document
(Y/N)
1
Y
06 March 2018
Global
Y
2
Y
23 April 2018
Global
Y
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Amendment 1
Rationale
This amendment is written to include an additional exclusion criterion as requested by the Ethics 
Committee.
Major Scientific Changes
The following exclusion criterion is added:
22.
Abnormal liver function tests (alanine-amino-transferase [ALT] or aspartate-amino-
transferase [AST] values above 1.1 x upper limit of normal [ULN]) at Screening. In case 
of marginal deviation, a re-testing is allowed for confirmation.
The following laboratory assessment has been changed:
Ecarin Clotting Time was replaced by the more advanced Hemoclot Thrombin Inhibitor 
determination.
Administrative and Editorial Changes
Misleading footnotes in Table 3 “Safety Laboratory Evaluations” were corrected.
Packaging, labelling and distribution will now be handled by Nuvisan instead of Catalent.
In inclusion criterion #4 the reference to CTFG was corrected.
The wording of "Restrictions” were aligned with Exclusion Criterion.
A sentence was added to the clinical laboratory assessments, which allows Investigators to 
request analysis of additional blood samples.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
73/84
Comparison with Clinical Trial Protocol Version 1.0, dated 07 December 2017 (Amendment No. 1, dated 06 February 2018)
Change
Section
Page (in 
CTP v1)
Previous Wording
New Wording
Major Scientific Changes
Justification of 
Dose
5.2.3
26
As dabigatran prolongs the thrombin time (TT), the 
Ecarin Clotting Time (ECT) and the activated partial 
thromboplastin time (aPTT), appropriate coagulation-
related parameters will be measured regularly.
As dabigatran prolongs reduces the thrombin activity 
and therefore could prolong the thrombin time (TT), 
ecarin clotting time (ECT), and activated partial 
thromboplastin time (aPTT), appropriate these
coagulation-related parameters and the Hemoclot 
Thrombin Inhibitor (Anti-Factor II) will be measured 
regularly.
Additional 
exclusion 
criterion
5.3.2
29
-
22. Abnormal liver function tests (alanine-amino-
transferase [ALT] or aspartate-amino-transferase 
[AST] values above 1.1 x upper limit of normal [ULN]) 
at Screening. In case of marginal deviation, a re-
testing is allowed for confirmation.
Clinical 
Laboratory 
Assessments
7.4.3 –
Table 3
48
Coagulation: Ecarin Clotting Time
Coagulation: Ecarin Clotting Time Hemoclot Thrombin
Inhibitor (Anti-Factor II)
Administrative and Editorial Changes
List of 
Abbreviations
8
ECT      Ecarin clotting time
ECT      Ecarin clotting time
Sponsor, 
Investigator and 
Trial 
Administrative 
Structure
2
18
Packaging, labeling and distribution of all IMPs to the 
trial site will be conducted by a designated contract 
manufacturing organization (Catalent Pharma 
Solutions, Inchwood, Bathgate, West Lothian, EH48 
2FY, United Kingdom). 
Packaging, labeling and distribution of all IMPs to the trial 
site will be conducted by a designated contract 
manufacturing organization (Catalent Pharma Solutions, 
Inchwood, Bathgate, West Lothian, EH48 2FY, United 
Kingdom Nuvisan GmbH, Wegenerstrasse 13, 89231 
Neu-Ulm, Germany).
Inclusion 
Criteria
5.3.1
27
4. A male participant must agree to use and to have his 
female partner of childbearing potential to use highly 
effective method of contraception (ie methods with a 
failure rate of less than 1% per year) as detailed in the 
EMA CTFG
guidelines [8] during the period of 
participation in the study and for at least 3 months after 
the 
last 
investigational 
medicinal 
product 
(IMP) 
administration. 
4. A male participant must agree to use and to have his 
female partner of childbearing potential to use highly 
effective method of contraception (ie methods with a 
failure rate of less than 1% per year) as detailed in the 
EMA Clinical Trial Facilitation Group (CTFG) guideline 
recommendations [8] during the period of participation 
in the study and for at least 3 months after the last 
investigational medicinal product (IMP) administration. 
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
74/84
Change
Section
Page (in 
CTP v1)
Previous Wording
New Wording
Treatment of 
Overdose
6.12
37
Relevant coagulation parameters are aPTT, diluted TT 
or ECT.
Relevant coagulation parameters are aPTT, diluted TT or 
ECT Hemoclot Thrombin Inhibitor.
Treatment 
Periods
Restrictions
7.1.2
41
Foods, sweets and beverages:
Intake of herbs/fruits that can have an influence on PK 
(eg St. John’s Wort, Seville oranges, grapefruits, 
cranberry or the juice of these fruits) are not allowed 
from 14 days before first administration of study 
medication until final examination. Methylxanthines (eg 
coffee, tea, cola, cocoa) and alcohol containing food or 
beverages are not allowed from 48 h prior to the 
intended start of trial drug administration until the final 
examination.
Foods, sweets and beverages:
Intake of herbs/fruits that can have an influence on PK 
(eg St. John’s Wort, Seville oranges, grapefruits,
cranberry or the juice of these fruits) are not allowed from 
14 days before first administration of study medication
Day -1 
of 
Period 1
until 
final 
examination. 
Methylxanthines (eg coffee, tea, cola, cocoa) and alcohol 
containing food or beverages are not allowed from 48 h 
prior to the intended start of trial drug administration until 
the final examination last PK blood sample. 
Clinical 
Laboratory 
Assessments
7.4.3
47
Fasted blood samples and urine samples will be 
collected for the clinical laboratory tests (hematology, 
biochemistry, coagulation, virology, drugs of abuse, 
hormones, and urinalysis, Table 3) following the timing 
noted in the Schedule of Assessments (Table 1 and 
Table 2). All blood and urine samples will be worked up 
and analyzed in Nuvisan's clinical laboratory.
Fasted blood samples and urine samples will be collected 
for the clinical laboratory tests (hematology, biochemistry, 
coagulation, virology, drugs of abuse, hormones, and 
urinalysis, Table 3) following the timing noted in the 
Schedule of Assessments (Table 1 and Table 2). 
Additional laboratory safety examinations during the 
trial are at the discretion of the Investigator. All blood 
and urine samples will be worked up and analyzed in 
Nuvisan's clinical laboratory.
Clinical 
Laboratory 
Assessments
7.4.3 –
Table 3
48
Biochemistry: Creatine phosphokinase
Hematology: White blood cell differentials and absolute 
counts:
Urinalysis: Microscopic examination b
Other tests: eGFR c
Biochemistry: Creatine phosphokinase b
Hematology: White blood cell differentials and absolute
counts c:
Urinalysis: Microscopic examination b d
Other tests: eGFR c e
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
75/84
Change
Section
Page (in 
CTP v1)
Previous Wording
New Wording
Clinical 
Laboratory 
Assessments
7.4.3 -
Table 3
48
Footnotes to Table 3
a.
In case of abnormal findings, manual differential 
blood count, direct/indirect bilirubin and CK MB 
(CK myocardium/brain type) can be requested by 
the Investigator.
b. 
Only if blood, protein, nitrite, or white blood cell 
count are positive on the dipstick.
c.
Estimated glomerular filtration rate (eGFR) 
calculated using the Cockcroft-Gault equation. 
Footnotes to Table 3
a.
In case of abnormal findings, manual differential 
blood count, direct/indirect bilirubin and CK MB (CK 
myocardium/brain type) can be requested by the 
Investigator.
a
In case of an increased Bilirubin (total) the direct 
Bilirubin will be determined. 
b
In case of an increased creatine phosphokinase 
(CK), myocardium/brain type (CK-MB) will be 
determined; if the ratio of CK/CK-MB is above 6, 
troponin will be determined as well.
c
In case of abnormal findings, manual differential 
blood count can be requested by the 
Investigator.
b d Only if blood, protein, nitrite, or white blood cell count
leucocytes are positive on the dipstick.
c e Estimated glomerular filtration rate (eGFR) 
calculated using the Cockcroft-Gault equation.
Physical 
Examination
7.4.4.3
49
Further medical examinations during the course of the 
study are at the discretion of the Investigator.
Further medical physical examinations during the course 
of the study are at the discretion of the Investigator.
Planned 
Numbers of 
Blood Samples 
for Clinical 
Laboratory, PK, 
and PGx and 
Total Blood 
Sampling 
Volume
Appendix II
67
Previous Wording of Appendix II see below
New Wording of Appendix II see below
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
76/84
Previous Wording
Appendix II Planned Numbers of Blood Samples for Clinical Laboratory, PK, and PGx 
and Total Blood Sampling Volume
Amount 
per 
sample
(mL)
Number of Samples
Total 
amount 
(mL)
Blood sample
Screening
Period 1
Period 2
End of 
Trial 
Visit
Total
Viral serology
4.7
1
1
4,7
Clinical laboratory tests 
Biochemistry (incl. TSH 
and FSH levels, if 
applicable)
4.7
1
1a
5b
1
8
37.6
Hematology
2.7
1
1a
5b
1
8
21.6
Coagulation
3.0
1
3c
4d
1
9
27.0
PK total dabigatran 
(unconjugated and 
conjugated
2.0
16e
16f
32
64.0
PK tepotinib and its 
metabolites
2.0
14g
14
28.0
PGx
2.0
2h
2
4.0
Total
4
23
44
3
74
186.9
Note: the number of blood samples may increase above the scheduled number. Blood samples for 
clinical laboratory follow-up determinations may become necessary. Technical failure of PK/PGx blood 
drawing may lead the Investigator to decide immediately to repeat a single blood drawing to have a 
sample.
Maximal blood volume drawn: Estimate per subject in this study that will not be exceeded in this 
planned trial as by experience of the Investigating institution
250
Clinical laboratory (biochemistry and hematology) blood samples
a
Period 1: Day -1 = 1 sample
b
Period 2: pre-dose on Days 1, 2, 7 and 8 and on Day 11 = 5 samples
Coagulation
c
Period 1: pre-dose and 4 h post-dose on Day 1 and 24 h post-dose on Day 2 = 3 samples
d
Period 2: pre-dose on Day 1, pre-dose and 4 h post-dose on Day 8 and 24 h after the last dose on Day 9 = 4 
samples
Dabigatran (unconjugated plus conjugated) PK blood samples: 
e
Period 1, Day 1: at pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose = 
16 samples
f
Period 2, Day 8: at pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose = 
16 samples
Tepotinib and its metabolites PK blood sampling: 
g
Period 2: Day 6 pre-dose and Day 7 pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24 h post-dose = 
14 samples
PGx blood samples:
h
PGx blood samples of 2 x 2 mL (optional) to be drawn in Period 1 Day 1 at pre-dose = 2 samples.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
77/84
New Wording
Appendix II Planned Numbers of Blood Samples for Clinical Laboratory, PK, and PGx 
and Total Blood Sampling Volume
Amount 
per 
sample 
(mL)
Number of Samples
Total 
amount 
(mL)
Blood sample
Screening
Period 1
Period 2
End of 
Trial 
Visit
Total
Viral serology
4.7
1
1
4,7
Clinical laboratory tests 
Biochemistry (incl. viral 
serology, TSH and FSH 
levels, if applicable)
4.7
1
1a
5b
1
8
37.6
Hematology
2.7
1
1a
5b
1
8
21.6
Coagulation
3.0
1
3c
4d
1
9
27.0
PK total dabigatran 
(unconjugated and 
conjugated
2.0
16e
16f
32
64.0
PK tepotinib and its 
metabolites
2.0
14g
14
28.0
PGx
2.0
2h
2
4.0
Total
4 3
23
44
3
74 73
186,9
182.2
Note: the number of blood samples may increase above the scheduled number. Blood samples for 
clinical laboratory follow-up determinations may become necessary. Technical failure of PK/PGx blood 
drawing may lead the Investigator to decide immediately to repeat a single blood drawing to have a 
sample.
Maximal blood volume drawn: Estimate per subject in this study that will not be exceeded in this 
planned trial as by experience of the Investigating institution
250
Clinical laboratory (biochemistry and hematology) blood samples
a
Period 1: Day -1 = 1 sample
b
Period 2: pre-dose on Days 1, 2, 7 and 8 and on Day 11 = 5 samples
Coagulation
c
Period 1: pre-dose and 4 h post-dose on Day 1 and 24 h post-dose on Day 2 = 3 samples
d
Period 2: pre-dose on Day 1, pre-dose and 4 h post-dose on Day 8 and 24 h after the last dose on Day 9 = 4 
samples
Dabigatran (unconjugated plus conjugated) PK blood samples: 
e
Period 1, Day 1: at pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose = 
16 samples
f
Period 2, Day 8: at pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36, 48 and 72 h post-dose = 
16 samples
Tepotinib and its metabolites PK blood sampling: 
g
Period 2: Day 6 pre-dose and Day 7 pre-dose, 15, 30, 45, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24 h post-dose = 
14 samples
PGx blood samples:
h
PGx blood samples of 2 x 2 mL (optional) to be drawn in Period 1 Day 1 at pre-dose = 2 samples.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
78/84
Amendment 2
Rationale
This amendment is written including updates as requested by the German Competent Authority.
Major Scientific Changes
The 1st sentence in the 4th paragraph in Section 3 “Background Information” has been revised by 
deleting the term “showing a broad safety margin”. The updated sentence is given in the table 
below.
As the SMC is not considered necessary for this study, all text related to the originally planned 
SMC has been deleted in the synopsis and in protocol sections 3 “Background Information” and 
5.1 “Overall Trial Design and Plan”.
The following inclusion and exclusion criteria have been revised as listed below:
Inclusion criterion #1: The upper limit of age has been reduced from 55 years to 44 years.
Inclusion criterion #4: The inclusion criteria has been revised by adding the following 
sentence: “The male participants will be asked to report pregnancies in their female partners 
up to 3 months after the last IMP intake.”.
In addition, a Contraception Guidance was added (as Appendix III) to provide guidance to the 
Investigator.
Inclusion criterion #7 / Exclusion criterion #22: The limits for ALT and AST as well as 
amylase and lipase has been reduced to the upper limit of normal (ULN). The Inclusion
criterion #7 has been revised as well as the Exclusion criterion #22 has been deleted. 
Exclusion criterion #4: The pulse rate has been updated from > 100 or ≤40 bpm to > 90 or 
< 50 bpm at Screening and at admission on Day -1. 
Exclusion criterion #11.7: The wording “…5 half-lives after last dosing, whatever is longer, 
…” has been added to the sub-topic.
The updated wording in the Inclusion and Exclusion criteria is shown in the table below.
Administrative and Editorial Changes
Clarification on vital signs assessments including also body temperature measurement if not 
explicitly excluded.
Update of the NCI-CTCAE used for AE grading.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
79/84
Comparison with Clinical Trial Protocol Version 2.0, dated 6 March 2018 (Amendment No. 2, dated 23 April 2018)
Change
Section
Page (in 
CTP v2)
Previous Wording
New Wording
Major Scientific Changes
Synopsis
-
12
Methodology:
The subjects will be admitted to the study site on Day -1. 
They will be resident at the study site under medical 
supervision from Days -1 of Period 1 until Day 11 of 
Period 2.
A safety monitoring committee (SMC) will take the 
decision about stopping or continuing the trial, as in this 
trial multiple doses of tepotinib will be given for the first 
time to healthy subjects. Details of the SMC composition 
and roles and responsibilities will be described in an SMC 
charter.
Methodology:
The subjects will be admitted to the study site on Day -1. 
They will be resident at the study site under medical 
supervision from Days -1 of Period 1 until Day 11 of 
Period 2. After the first 6 subjects completed 
administration in Period 2, safety and PK data will be 
reviewed by the responsible functional 
representatives.
A safety monitoring committee (SMC) will take the 
decision about stopping or continuing the trial, as in this 
trial multiple doses of tepotinib will be given for the first 
time to healthy subjects. Details of the SMC composition 
and roles and responsibilities will be described in an SMC 
charter.
Synopsis
-
13
Diagnosis and key inclusion and exclusion criteria:
Healthy males and females (of non-childbearing potential) 
between 18 and 55 years of age (inclusive) with total body 
weight between 50 to 100 kg (inclusive) and body mass 
index (BMI) between 18.5 and 29.9 kg/m2 (inclusive) at 
the time of the Screening examination.
Diagnosis and key inclusion and exclusion criteria:
Healthy males and females (of non-childbearing potential) 
between 18 and 55 44 years of age (inclusive) with total 
body weight between 50 to 100 kg (inclusive) and body 
mass index (BMI) between 18.5 and 29.9 kg/m2 (inclusive) 
at the time of the Screening examination.
Background 
Information
3
19
Based on the currently available nonclinical as well as 
clinical safety data, short term multi-day dosing of 
tepotinib in healthy subjects is reasonable considering the 
preclinical safety pharmacology and toxicity data showing 
a broad safety margin, and the absence of genotoxicity, in 
conjunction with the predicted exposures at steady state 
after multiple dosing of 500 mg/day in healthy subjects, 
and the clinical experience in oncology patient 
populations, and implementing close medical monitoring 
of safety and tolerability.     
Based on the currently available nonclinical as well as 
clinical safety data, short term multi-day dosing of 
tepotinib in healthy subjects is reasonable considering the 
preclinical safety pharmacology and toxicity data showing 
a broad safety margin, and the absence of genotoxicity, in 
conjunction with the predicted exposures at steady state 
after multiple dosing of 500 mg/day in healthy subjects, 
and the clinical experience in oncology patient 
populations, and implementing close medical monitoring 
of safety and tolerability.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
80/84
Change
Section
Page (in 
CTP v2)
Previous Wording
New Wording
Background 
Information
3
20
After the first 6 subjects completed administration in 
Period 2, a safety monitoring committee (SMC) meeting is 
scheduled before continuing with the next cohort.
After the first 6 subjects completed administration in 
Period 2, a safety monitoring committee (SMC) meeting is 
scheduled before continuing with the next cohort. safety 
and PK data will be reviewed by the responsible 
functional representatives.
Overall Trial 
Design and Plan
5.1
23
Since to date tepotinib 500 mg was administered to 
healthy subjects only as single doses (study EMR200095-
007, single dose; study MS200095-0012, 2 single doses), 
the safety and tolerability of multiple dose tepotinib 
(Period 2) will first be assessed in a subgroup of 6 
subjects, followed by group(s) of the remaining subjects. 
Dosing of the subsequent group(s) will only be started if 
the safety and tolerability of multiple dosing of tepotinib 
was assessed as reasonable and no stopping rules 
applied.
Since to date tepotinib 500 mg was administered to 
healthy subjects only as single doses (study EMR200095-
007, single dose; study MS200095-0012, 2 single doses), 
the safety and tolerability as well as the PK of multiple 
dose tepotinib (up to Day 8 inclusive in Period 2) will first 
be assessed in a subgroup of 6 subjects, followed by 
group(s) of the remaining subjects. Dosing of the 
subsequent group(s) will only be started if the safety and 
tolerability of multiple dosing of tepotinib was assessed as 
reasonable and no stopping rules applied. The decision 
will be documented and will be filed in the trial 
documentation files.
Overall Trial 
Design and Plan
5.1
24
A SMC will take the decision about stopping or continuing 
the trial, as in this trial multiple doses of tepotinib will be 
given for the first time to healthy subjects. Details of the 
SMC composition and roles and responsibilities will be 
described in an SMC charter.
The committee will be composed of at least:

The global patient safety project lead (chair of the 
SMC)

The medical responsible of the Sponsor

The clinical pharmacokineticist of the Sponsor

The Principal Investigator.
Clinical safety and safety laboratory data (from the 
electronic case report form [eCRF]) up to
Day 8 
(including) will be provided to the SMC members for 
review. Based on the safety data the SMC decides 
whether the dosing of the remaining group can start. The 
decisions of these meetings/telephone conferences will be 
documented and will be filed in the trial documentation
files.
A SMC will take the decision about stopping or continuing 
the trial, as in this trial multiple doses of tepotinib will be 
given for the first time to healthy subjects. Details of the 
SMC composition and roles and responsibilities will be 
described in an SMC charter.

The committee will be composed of at least: The global 
patient safety project lead (chair of the SMC)

The medical responsible of the Sponsor

The clinical pharmacokineticist of the Sponsor

The Principal Investigator.
Clinical safety and safety laboratory data (from the 
electronic case report form [eCRF]) up to Day 8 
(including) will be provided to the SMC members for 
review. Based on the safety data the SMC decides 
whether the dosing of the remaining group can start. The 
decisions of these meetings/telephone conferences will be 
documented and will be filed in the trial documentation
files.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
81/84
Change
Section
Page (in 
CTP v2)
Previous Wording
New Wording
Inclusion Criteria
5.3.1
27
1.
Male or female, aged 18 to 55 years inclusive (at 
Screening)
1.
Male or female, aged 18 to 55 44 years inclusive 
(at Screening)
Inclusion Criteria
5.3.1
27
4.
A male participant must agree to use and to have 
his female partner of childbearing potential to use highly 
effective method of contraception (ie methods with a 
failure rate of less than 1% per year) as detailed in the 
Clinical Trial Facilitation Group (CTFG) recommendations 
[8] during the period of participation in the study and for at 
least 3 months after the last investigational medicinal 
product (IMP) administration. Males must also refrain from 
donating sperm during this period and should always use 
a barrier method such as condom concomitantly. 
4.
A male participant must agree to use and to have 
his female partner of childbearing potential to use highly 
effective method of contraception (ie methods with a 
failure rate of less than 1% per year) as detailed in the 
Clinical Trial Facilitation Group (CTFG) recommendations 
[8] during the period of participation in the study and for at 
least 3 months after the last investigational medicinal 
product (IMP) administration (see Appendix III). Males 
must also refrain from donating sperm during this period 
and should always use a barrier method such as condom 
concomitantly. The male participants will be asked to 
report pregnancies in their female partners up to 3 
months after the last IMP intake.
Inclusion Criteria
5.3.1
28
7.
All values for hematology, coagulation, and 
biochemistry tests of blood and urinalysis within the 
normal range (at Screening). Minor (solitary) non-clinically 
relevant deviation(s) are allowed as judged by the 
Investigator; however, amylase and lipase should not 
exceed the upper limit of normal.
7.
All values for hematology, coagulation, and 
biochemistry tests of blood and urinalysis within the 
normal range (at Screening). Minor (solitary) non-clinically 
relevant deviation(s) are allowed as judged by the 
Investigator; however, amylase, lipase and alanine-
amino-transferase [ALT] or aspartate-amino-
transferase [AST] values should not exceed the upper 
limit of normal (ULN).  
Exclusion Criteria
5.3.2
28
4.
Supine systolic blood pressure (SBP) > 140 mmHg 
or < 90 mmHg, diastolic blood pressure (DBP) > 90 
mmHg or < 50, and pulse rate > 100 or ≤40 bpm at 
Screening and at admission on Day -1. (Any abnormal 
vital signs results may be repeated once and if the repeat 
result is within the normal range, it is not considered to 
have met the exclusion criterion)
4.
Supine systolic blood pressure (SBP) > 140 mmHg 
or < 90 mmHg, diastolic blood pressure (DBP) > 90 
mmHg or < 50 mmHg, and pulse rate > 100 90 or ≤ 40
< 50 bpm at Screening and at admission on Day -1. (Any 
abnormal vital signs results may be repeated once and if 
the repeat result is within the normal range, it is not 
considered to have met the exclusion criterion)
Exclusion Criteria
5.3.2
29
11.
• Use of drugs that may have interfered with hemostasis 
during trial conduct (eg acetylic salicylic acid or other non-
steroidal anti-inflammatory drugs) within 14 days prior to 
start of dosing or during the trial
11.
• Use of drugs that may have interfered with hemostasis 
during trial conduct (eg acetylic salicylic acid or other non-
steroidal anti-inflammatory drugs) within 14 days or 5 
half-lives after last dosing, whatever is longer, prior to 
start of dosing or during the trial
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
82/84
Change
Section
Page (in 
CTP v2)
Previous Wording
New Wording
Exclusion Criteria
5.3.2
29
22.
Abnormal liver function tests (alanine-amino-
transferase [ALT] or aspartate-amino-transferase [AST] 
values above 1.1 x upper limit of normal [ULN]) at 
Screening. In case of marginal deviation, a re-testing is 
allowed for confirmation.
22.
Abnormal liver function tests (alanine-amino-
transferase [ALT] or aspartate-amino-transferase [AST] 
values above 1.1 x upper limit of normal [ULN]) at 
Screening. In case of marginal deviation, a re-testing is 
allowed for confirmation.
Contraception 
Guidance
Appendix 
III
-
-
New Wording
added as Appendix III, see below
Administrative and Editorial Changes
Abbreviation
-
9
SMC       Safety monitoring committee
SMC       Safety monitoring committee
Schedule of 
Assessments –
Period 1
Table 1
14
Vital signs (blood pressure, pulse rate)
Vital signs (blood pressure, pulse rate, body 
temperature)
Schedule of 
Assessments –
Period 2
Table 2
16
Vital signs (blood pressure, pulse rate)
Vital signs (blood pressure, pulse rate, body 
temperature)
Screening 
Examination
7.1.1
38
• Vital signs (supine blood pressure and pulse rate)
• Vital signs (supine blood pressure and pulse rate)
End of Trial Visit
7.1.3
42
• Vital signs (supine blood pressure and pulse rate)
• Vital signs (supine blood pressure and pulse rate)
Adverse Event
7.4.1.1
44
Investigators will reference the National Cancer Institute -
Common Terminology Criteria for AEs (NCI-CTCAE), 
Version 4.03 (publication date: 14 June 2010), a 
descriptive terminology that can be used for AE reporting.
Investigators will reference the National Cancer Institute -
Common Terminology Criteria for AEs (NCI-CTCAE), 
Version 4.03 5.0 (publication date: 14 June 2010 27 Nov 
2017), a descriptive terminology that can be used for AE 
reporting.
Procedure for 
Reporting Serious 
Adverse Events
7.4.1.4
46
Additional documents may be provided by the 
Investigator, if available (for example, laboratory results, 
hospital report, autopsy report).
Additional documents may be provided by the 
Investigator, if available (for example, laboratory results, 
hospital report, and autopsy report).
Protocol 
Amendments and 
List of Changes
Appendix 
III
70
Appendix III - Protocol Amendments and List of Changes
Appendix III IV - Protocol Amendments and List of 
Changes
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
83/84
New Wording
Appendix III
Contraception Guidance
Definitions
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming post-menopausal unless permanently sterile. Permanent 
sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered women of childbearing potential
4.
Premenopausal female with 1 of the following:
Documented hysterectomy
Documented bilateral salpingectomy
Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical records, medical examination, or 
medical history interview.
5.
Premenarchal
6.
Postmenopausal female
Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and increased follicle-stimulating 
hormone [FSH] > 40 mIU/mL), or who have undergone documented hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy. If necessary to confirm postmenopausal status, FSH will be re-tested at Screening.
Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the 
non-hormonal highly effective contraception methods if they wish to continue their HRT during the study. However, they 
must discontinue HRT to allow confirmation of postmenopausal status before study enrollment.
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0


Tepotinib (MSC2156119J)
Effect of Tepotinib on the PK of the P-gp Substrate 
MS200095-0032
Dabigatran Etexilate
C O N F I D E N T I A L
I N F O R M A T I O N
84/84
Contraceptive Guidance for Women of Childbearing Potential:
Highly Effective Contraceptive Methods That Are User Dependent
Failure rate of <1% per year when used consistently and correctly a. 

Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation b

oral 

intravaginal 

transdermal 

Progestogen-only hormonal contraception associated with inhibition of ovulation b

oral 

injectable 
Highly Effective Methods That Are User Independent

Implantable progestogen-only hormonal contraception associated with inhibition of ovulation b

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

Vasectomized partner 
(Bilateral vasectomy of the partner is a highly effective contraceptive method provided that the partner is the sole male sexual partner of the woman of 
childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent with local regulations regarding the use of 
contraceptive methods for participants participating in clinical studies. 
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. In this case 
another highly effective (not hormone based) method of contraception must be utilized during the treatment period and for at least 3 months after the last dose 
of study treatment
Document No. 
 
Object No. 
 
0900babe80f52d6dv2.0
0900babe80f653c0

SAP_001.pdf: 
Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Effect of Te p oti ni b  o n t he P K of t he P -g p S u bstr ate  
M S 2 0 0 0 9 5- 0 0 3 2 versi o n 1. 0 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1/ 2 5  
 
 
 
I nte gr ate d A n al ysis Pl a n 
Cli nic al Tri al Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 0 9 5- 0 0 3 2  
Title  
P hase  I,  O pe n -l a bel,  Si n gle  Se q ue nce,  T w o-Peri o d  St u d y  t o 
E val uate  t he  Effect  of  Te p oti ni b  o n  P -Gl yc o pr otei n  b y 
I n v esti gati n g  t he  P har mac o ki netics  of  t he  P- Gl yc o pr otei n 
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Tri al P h ase  
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Te p oti ni b ( M S C 2 1 5 6 1 1 9J)  
Cli nic al Tri al Pr ot oc ol 
Versi o n  
2 3 A pril 2 0 1 8 / Versi o n 3. 0 
I nte gr ate d A n al ysis Pl a n 
A ut h or  
 
C o or di n ati n g A ut h or  
 
, M er c k 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
, N u vi s a n  
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n  
2 8 A u g ust 2 0 1 8 / Versi o n 1. 0  
I nte gr ate d A n al ysis Pl a n 
Re vie w ers  
F u n cti o n  
N a m e  
 
M e di c al R e s p o n si bl e, M er c k  
  
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T his d o c u me nt is t h e pr o p ert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o n e of its affiliate d c o m p a nies.  
It is i nte n d e d f or restricte d use o nl y a n d ma y n ot - i n f ull or p art - be p asse d o n, re pr o d u ce d, p u blis h e d or use d wit h o ut 
e x press p er missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate.  
C o p y ri g ht © 2 0 1 8  b y M erc k K G a A, D ar mst a dt, Ge r m a n y or its aff ili ate. All ri g hts reser ve d. 
Pa ge 2 of 2 7 0
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T e p oti ni b ( M S C 2 1 5 6 1 1 9J) 
Eff e ct of T e p oti ni b o n t h e P K of t h e P- g p S u bstr at e 
M S 2 0 0 0 9 5- 0 0 3 2 v ersi o n 1. 0 
Si g n at ur e P a g e 
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P h as e I, O p e n-l a b el , Si n g le S e q u e n c e, T w o- P eri o d St u d y t o E v a l uat e t h e Eff e ct of T e p oti ni b o n 
P- Gly c o pr ot ei n b y I nv esti g at i ng t h e P h ar m a c o ki n eti cs of t h e P- Gi y c o pr ot ei n Pr o b e S u b str at e 
D a bi g atr a n Et e xil at e i n H e alt h y S u bj e cts 
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N U V l SA N G m b H , 
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D at e 
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I N F O R M A TI O N 
Si g n at ur e 
2/ 2 5 
Pa ge 3 of 2 7 0
PI
PI
PI
PI
PI
PI
PI
PI
PI


Tepotinib (MSC2156119J) 
Effect of Tepotinib on the PK of the P-gp Substrate  
MS200095-0032 version 1.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
3/25 
 
 
1 
Table of Contents 
Integrated Analysis Plan ......................................................................................................1 
Signature Page 
2 
1 
Table of Contents ..................................................................................3 
2 
List of Abbreviations and Definition of Terms ....................................5 
3 
Modification History ............................................................................6 
4 
Purpose of the Integrated Analysis Plan ...............................................6 
5 
Objectives and Endpoints .....................................................................7 
6 
Overview of Planned Analyses .............................................................7 
7 
Changes to the Planned Analyses in the Clinical Trial Protocol ..........8 
8 
Protocol Deviations and Analysis Sets .................................................8 
8.1 
Definition of Protocol Deviations and Analysis Sets ...........................8 
8.2 
Definition of Analysis Sets and Subgroups ..........................................9 
9 
General Specifications for Data Analyses ............................................9 
10 
Trial Subjects ......................................................................................11 
10.1 
Disposition of Subjects and Discontinuations ....................................11 
10.2 
Protocol Deviations ............................................................................12 
10.2.1 
Important Protocol Deviations ............................................................12 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................12 
11 
Demographics and Other Baseline Characteristics .............................12 
11.1 
Demographics .....................................................................................12 
11.2 
Medical History ..................................................................................13 
11.3 
Other Baseline Characteristics ............................................................13 
12 
Previous or Concomitant Medications/Procedures .............................13 
13 
Treatment Compliance and Exposure .................................................14 
14 
Efficacy Analyses ...............................................................................14 
15 
Safety Analyses ..................................................................................14 
15.1 
Adverse Events ...................................................................................14 
15.1.1 
All Adverse Events .............................................................................14 
15.1.2 
Adverse Events Leading to Treatment Discontinuation .....................16 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................16 
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Tepotinib (MSC2156119J) 
Effect of Tepotinib on the PK of the P-gp Substrate  
MS200095-0032 version 1.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
4/25 
 
 
15.2.1 
Deaths .................................................................................................16 
15.2.2 
Serious Adverse Events ......................................................................16 
15.2.3 
Other Significant Adverse Event ........................................................17 
15.2.3.1 
Adverse Events of Special Interest .....................................................17 
15.3 
Clinical Laboratory Evaluation ...........................................................17 
15.4 
Vital Signs ..........................................................................................18 
15.5 
ECG Evaluation ..................................................................................18 
16 
Analyses of Other Endpoints ..............................................................19 
16.1 
Pharmacokinetics ................................................................................19 
General Specifications for Plasma Concentration Data .....................................................19 
General Specifications for PK Parameter Data ..................................................................19 
16.1.1 
Primary Endpoints ..............................................................................20 
16.1.2 
Secondary Endpoints ..........................................................................20 
16.1.3 
Exploratory Endpoints ........................................................................21 
16.1.4 
Plasma Concentration Data for Dabigatran, Tepotinib and 
Metabolites .........................................................................................21 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters .......................21 
16.2 
Pharmacogenetics ...............................................................................25 
17 
References ...........................................................................................25 
18 
Appendices .........................................................................................25 
 
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Effect of Tepotinib on the PK of the P-gp Substrate  
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I N F O R M A T I O N 
5/25 
 
 
2 
List of Abbreviations and Definition of Terms 
AE 
Adverse Event 
AUC 
Area under the plasma concentration-time curve 
AUC0-t 
Area under the plasma concentration-time curve from time zero (= 
dosing time) to the last sampling time (tlast) at which the concentration is 
at or above the lower limit of quantification 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero (= 
dosing time) extrapolated to infinity 
AUCextra 
The AUC from time tlast extrapolated to infinity 
AUCextra% 
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0-∞. AUCextra% = (extrapolated area/AUC0-∞) x 100 
AUCτ 
The area under the plasma concentration-time curve (AUC) over the 
dosing interval from T1 = 0 h to T2 = τ h 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CL/f 
Apparent total body clearance considering the fraction of dose (f) 
absorbed 
CLSS/f 
Apparent total body clearance of drug at steady state following oral 
administration, considering the fraction of dose (f) absorbed. 
Cmax 
Maximum plasma concentration observed 
Cmax,SS 
Maximum plasma concentration observed in steady state 
Cmin,SS 
Minimum plasma concentration observed in steady state 
CV% 
Coefficient of Variation 
CSR 
Clinical Study Report 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
GeoCV% 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
IAP 
Integrated Analysis Plan 
ICH 
International Conference on Harmonization 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
Page 6 of 270


Te p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
Effect of Te p oti ni b  o n t he P K of t he P -g p S u bstr ate  
M S 2 0 0 0 9 5- 0 0 3 2 versi o n 1. 0 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6/ 2 5  
 
 
N CI -C T C A E  
Nati o nal  Ca ncer  I nstit ute – C o m m o n  Ter mi n ol o g y  Criteria  f or  A d v erse 
E ve nts  
P T  
Preferre d Ter m  
P K  
P har mac o ki netics  
S A E  
Seri o us A d verse E v e nt  
Q 1  
2 5t h Perce ntile  
Q 3  
7 5t h Perce ntile  
Q Tc F  
C orrecte d Q T i nter val per Fri dericia’s f or m ula  
S E M  
Sta n dar d Err or of t he Mea n  
S O C  
S yste m Or ga n Class  
S D  
Sta n dar d De viati o n  
S E M  
Sta n dar d Err or of t he Mea n  
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
U L O Q  
U p per Li mit of Q ua ntificati o n  
 
3  
M o dific ati o n Hist or y  
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n  
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
1. 0  
2 8 -A U G -2 0 1 8  
 
Ori gi n al d o c u m e nt  
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n 
T he p ur p ose of t his I A P is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns f or t he fi nal a nal ysis 
of data c ollect e d f or pr ot oc ol M S 2 0 0 0 9 5- 0 0 3 2 . Res ults of t he a nal ys es des cri be d i n t his I A P will 
b e i ncl u de d i n t he Cli nical St u d y Re p ort ( C S R). A d diti o nall y, t he pla n ne d a nal yses  i de ntifie d i n 
t his I A P will  be  i ncl u de d  i n  re g ulat or y  s u b missi o ns  or  f ut ure  ma n uscri pts.  A n y  p ost -h o c,  or 
u n pla n ne d a n al yses p erf or me d t o pr o vi d e r es ults f or i n cl usi o n i n t he C S R b ut n ot i de ntifie d i n 
t his pr os pecti ve I A P will be clearl y i d e ntifie d i n t he  C S R.  
T he I A P is bas e d u p o n s ecti o n 8 ( Statistics) of t h e trial pr ot oc ol a n d pr ot o c ol a me n d me nts a n d is 
pre pare d i n c o m plia nce wit h I C H E 9.  
 
 
Pa ge 7 of 2 7 0
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Tepotinib (MSC2156119J) 
Effect of Tepotinib on the PK of the P-gp Substrate  
MS200095-0032 version 1.0 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
7/25 
 
 
5 
Objectives and Endpoints 
 
Objective 
Endpoint 
IAP 
section 
Primary 
Objective 
To investigate the effect of tepotinib 
on the primary pharmacokinetic (PK) 
endpoints of dabigatran following oral 
administration of the P-gp probe 
substrate dabigatran etexilate after 
multiple dose administration of 
tepotinib in healthy subjects. 
PK profile of dabigatran in terms of area under 
the concentration-time curve (AUC) from time 
zero to the last sampling time (AUC0-t), AUC from 
time zero extrapolated to infinity (AUC0-∞), 
maximum plasma concentration (Cmax) of total 
dabigatran (unconjugated plus conjugated) at Day 
1 of Period 1 and Day 8 of Period 2 from time 
zero to 72 h post-dose. 
16.1.1 
 
 
 
Secondary 
Objective 
To investigate the PK effect of 
tepotinib on the secondary PK 
endpoints of dabigatran following oral 
administration of dabigatran etexilate 
 
PK profile of total dabigatran (unconjugated plus 
conjugated) in terms of time of the maximum drug 
concentration (tmax), terminal half-life (t1/2), 
percentage of AUC0-∞ obtained by extrapolation 
(AUCextra%), apparent total body clearance (CL/f), 
apparent volume of distribution during terminal 
phase (VZ/f) at Day 1 of Period 1 and Day 8 of 
Period 2 from time zero to 72 h post-dose. 
 
16.1.2 
To assess the safety and tolerability 
of tepotinib alone and upon co-
administration of dabigatran etexilate. 
 
Occurrence of treatment emergent adverse 
events (TEAEs, incidence, frequency, intensity 
and causality), occurrence of changes in safety 
laboratory assessments, 12-lead 
electrocardiograms (ECGs) and vital signs in 
subjects receiving tepotinib alone and together 
with dabigatran etexilate assessed from Day -1 of 
Period 1 until the End of Trial Visit. 
15 
Exploratory 
Objective 
To investigate the multiple dose PK 
of tepotinib and its metabolites 
(MSC2571109A and MSC2571107A) 
PK profile of tepotinib and its metabolites 
MSC2571109A and MSC2571107A in terms of 
AUC over the dosing interval (AUCτ), Cmax at 
steady state (Cmax,SS), minimum concentration at 
steady state (Cmin,SS), tmax at steady state (tmax,SS), 
CL/f at steady state (CLSS/f) (parent drug only), 
and t1/2 if appropriate  
 
16.1.3 
To explore the effect of 
pharmacogenetics (PGx) and 
variations of associated genes on the 
PK profile of dabigatran and/or 
tepotinib (if applicable; participation is 
optional). 
Genetic variants and mutations in genes that 
potentially influence the PK of tepotinib and/or 
dabigatran.  
16.2 
6 
Overview of Planned Analyses 
All final, planned analyses identified in the Clinical Trial Protocol and in this IAP will be 
performed only after the last subject has completed the last visit, i.e. end of trial visit/early 
termination visit with all trial data in-house, all data queries resolved, and the database locked.  
An interim evaluation of the safety and tolerability as well as the PK data will be performed after 
the first 6 subjects have completed Period 2. The description of these analyses will not be part of 
this IAP.  
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Effect of Tepotinib on the PK of the P-gp Substrate  
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I N F O R M A T I O N 
8/25 
 
 
The data presented will include: 
• Treatment emergent adverse events 
• Plasma concentrations of tepotinib 
• PK parameters of tepotinib 
• Vital signs 
• ECG parameters 
• Safety laboratory values 
A data review meeting will be held prior to database lock. In addition, no database can be locked 
until this IAP has been approved. 
7 
Changes to the Planned Analyses in the Clinical Trial 
Protocol 
The statistical methods as described in the protocol were adopted.  
Scatter plots for the primary endpoint will show geometric means (GeoMean) instead of median, 
25th Percentile and 75th Percentile (Q1 and Q3). 
 
8 
Protocol Deviations and Analysis Sets 
8.1 
Definition of Protocol Deviations and Analysis Sets 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being.  
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest.  
Important protocol deviations include 
• Deviations from the inclusion and exclusion criteria 
• Concomitant medication violations (see Section 6.5.1 of the protocol) 
• Use of prohibited medicines (see Section 6.5.2. of the protocol) 
• Subjects that receive incorrect treatment or dose 
• Sample processing errors that may lead to inaccurate bioanalytical results 
• Vomiting or diarrhea following oral dosing (these instances will be discussed on a case-
by-case basis) 
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Effect of Tepotinib on the PK of the P-gp Substrate  
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I N F O R M A T I O N 
9/25 
 
 
• Deviation from Good Clinical Practice 
• Non-compliance to study procedures or deviations from study procedures likely to affect 
the primary endpoints (e.g. subject develops withdrawal criteria whilst on the study but is 
not withdrawn) 
• Deviation from study medication compliance in terms of medical conditions and/or AEs 
that may have interfered with drug disposition or with respect to factors likely to affect 
the primary endpoints 
All important protocol deviations will be documented in CDISC datasets whether identified 
through sites monitoring or medical review.  
8.2 
Definition of Analysis Sets and Subgroups 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Screening 
The screening analysis set will include all subjects who provided signed 
informed consent, regardless of treatment status in the trial. This set will 
be used for subject disposition.  
Safety 
The Safety Analysis Set will include all subjects who have received at 
least 1 dose of planned IMP. Subjects will be analyzed according to the 
actual treatment they receive.  
Pharmacokinetic 
The PK Analysis Set will include all subjects who have completed at least 
1 period without any relevant protocol violations with respect to factors 
likely to affect the comparability of PK results, with adequate study 
medication compliance, and with evaluable dabigatran PK data. 
  
Assessment of data sufficiency will be done by the responsible 
pharmacokineticist before database lock, ie PK data will be available and 
included in the database before data base lock. 
 
Subjects may be excluded after vomiting or following diarrhea in a 
particular period as this could render the plasma concentration-time 
profile unreliable. The use of a concomitant medication that might 
interfere with the PK of any investigational drug could be a reason for 
excluding a subject. 
 
9 
General Specifications for Data Analyses 
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA). 
Page 10 of 270


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C O N F I D E N T I A L 
I N F O R M A T I O N 
10/25 
 
 
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as 
appropriate. 
For demographic, baseline and safety assessments, continuous measurements will be 
summarized by means of descriptive statistics (ie, number and percentage of observations, 
number and percentage of missing observations, mean, standard deviation [SD], median, 25th 
and 75th percentiles [Q1 and Q3], minimum, and maximum) and categorical data will be 
summarized by means of frequency tables (ie, count and percentages), if not stated otherwise. 
Mean, Median, Q1, Q3, Min, Max will have the same precision as the SDTM data (decimal 
places). SD will be presented with one decimal place more than the mean. Unless otherwise 
stated the calculation of proportions will be based on t he number of subjects at risk or with 
available measurements in the analysis set of interest for safety outputs. For subject disposition 
and demographic tables the denominator will be the number of subjects in the analysis set. 
Counts of missing observations will be included as a separate category. 
If not otherwise specified, ‘baseline’ refers to the last scheduled measurement before 
administration of the first drug in each period. However, if a subject is missing the baseline 
collection, the previous non-missing evaluation could become the baseline value (e.g. from 
screening/admission). If no baseline or previous to baseline evaluations exist then the baseline 
value will be treated as missing. 
The following calculations and derivations, as applicable, will be used:  
• Change from baseline: post-baseline visit value - baseline value  
• Duration of AE (in days hh:mm) = end date and time - start date and time of the AE, if 
missing time for either the beginning or end then = end date – start date + 1 
• Days hh:mm from dosing = start date and time of the event - date and time dose 
administration; (for treatment- emergent AEs), if missing time for either the beginning or end 
then = end date – start date + 1 
• Rel. Day in study of AE = start date of the event – date of First Admin + 1 (for AEs on or 
after the day of dosing)  
• Rel. Day in study of AE = start date of the event – date of First Admin (for AEs before the 
day of dosing)  
Repeated laboratory assessments will be flagged as repeats in the subject data listings and not 
included in summary tables statistics (unless the scheduled measurement was considered 
unreliable, e.g. due to technical reasons, and needed to be replaced by an unscheduled repeat 
measurement). 
In this phase 1 P K study missing observations will be assumed to be missing completely at 
random (MCAR). No action will be taken to handle missing data. A subject who withdraws prior 
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to the last planned observation in a trial period will be included in the analyses up to the time of 
discontinuation. 
The following treatmentlabels will be used in listing and tables: 
• dabigatran 
• dabigatran + tepotinib 
 
10 
Trial Subjects 
10.1 
Disposition of Subjects and Discontinuations 
This following will be presented in a summary table:  
• Total number of subjects screened (ie, subjects who gave informed consent) 
• Number of screened subjects who discontinued from the trial prior to treatment overall and 
grouped by the main reason for discontinuation: 
o Subject did not meet all eligibility criteria 
o Withdrew consent 
o Other  
• Number of treated subjects 
• Number and percentage of treated subjects who completed study 
• Number and percentage of treated subjects who discontinued the study, with the primary 
reason of discontinuation: 
o Adverse event 
o Lost to follow-up 
o Protocol non-compliance 
o Death 
o Withdrew consent 
o Other 
• Number and percentage of subjects who completed period (for periods 1 and 2) 
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• Number and percentage of subjects who discontinued study in period and reason for 
discontinuation (for periods 1 and 2) 
 
A listing of discontinued subjects will be provided. 
 
10.2 
Protocol Deviations 
10.2.1 
Important Protocol Deviations 
Listings of important protocol deviations will be provided including the date and relative day in 
relation to dosing in the relevant period. 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set 
All criteria/reasons leading to the exclusion of a subject from an analysis set will be listed based 
on the safety set.  
Reasons for excluding individual PK concentrations will also be listed separately and flagged in 
the main listing based on the safety analysis set. 
11 
Demographics and Other Baseline Characteristics 
11.1 
Demographics 
Summaries will be given for both the safety and the pharmacokinetic set, if different. 
Demographic characteristics will be listed by subject and summarized using the following 
information from the Screening/Baseline Visit eCRF pages.  
Demographic characteristics: 
• Sex: male, female  
• Race: Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or Pacific Islander, White, Other 
• Ethnic origin: Hispanic or Latino, Not Hispanic or Latino, Japanese, Not Japanese 
• Age (years): summary statistics 
• Height (cm) at Baseline: summary statistics 
• Weight (kg) at Baseline: summary statistics 
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• BMI (kg/m²) at Baseline: summary statistics 
Age will be taken from the eCRF and cannot be derived from the data because only the year of 
birth is collected in the eCRF. 
BMI will be re-derived (ie, not taken directly from the database) according to the following 
formula: 
• BMI (kg/m²) = weight (kg) / (height (m) * height (m)) 
11.2 
Medical History 
The medical history will be listed by subject including the preferred term and MedDRA system 
organ class (SOC) body using MedDRA, current version. 
11.3 
Other Baseline Characteristics 
Other baseline characteristics will be listed by subject and summarized using the following 
information from the Screening/Baseline Visit eCRF pages.  
Other baseline characteristics: 
• Smoking status 
• Alcohol consumption 
12 
Previous or Concomitant Medications/Procedures 
Previous medications are medications, other than trial medications and pre-medications for trial 
drug, which started and stopped before first administration of trial drug.  
Concomitant treatments are medications, other than trial medications, which are taken by 
subjects any time on-trial (on or after the first day of trial drug treatment for each subject).  
In case the date values will not allow to unequivocally allocating a medication to previous or 
concomitant medication the medication will be considered as concomitant medication 
Any previous and concomitant medication will be encoded with WHO-DD, latest version. Prior 
and concomitant medications will be listed by subject (all subjects). 
The following information will be displayed in a listing: generic or trade name (as reported in 
eCRF), WHO drug name (including ATC-2nd level and preferred term), dose/unit, route, 
frequency, reason for use, start/end date and time. 
Concomitant procedures will be presented in a data listing. 
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13 
Treatment Compliance and Exposure 
A listing of date and time of each drug administration and each blood sampling including time 
deviations will be provided sorted by subject. 
  
14 
Efficacy Analyses 
Not applicable. 
15 
Safety Analyses 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs. 
Safety data analysis will be conducted on the Safety Analysis Set.  
 
15.1 
Adverse Events 
The number and percentage of subjects experiencing at least one TEAE will be summarized by 
treatment as well as the number of events. A TEAE is an AE with onset after start of treatment. 
Tables by relationship to trial drug and by severity will be generated. AEs will be coded using 
Medical Dictionary for Regulatory Activities terminology, latest version.  
Incomplete TEAE-related dates will be handled as follows: 
• In case the onset date is missing completely or missing partially but the onset month and year, 
or the onset year are equal to the start of trial treatment then the onset date will be replaced by 
the minimum of start of trial treatment and TEAE resolution date.  
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of subject's death. In the latter case, the date of death 
will be used to impute the incomplete stop date.  
• In all other cases the incomplete stop date will not be imputed.  
 
15.1.1 
All Adverse Events 
All AEs recorded during the course of the trial (ie, assessed from signature of informed consent 
until the end of the Follow-up/End of Trial visit) will be coded according to MedDRA latest 
version and assigned to a SOC and PT. 
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TEAEs will be summarized by worst severity, using MedDRA latest version preferred term as 
event category and MedDRA primary system organ class (SOC) body term as Body System 
category. The severity of AEs will be graded using the “National Cancer Institute - Common 
Terminology Criteria for Adverse Events” (NCI-CTCAE) guideline, as detailed in the study 
protocol. 
TEAEs related to trial treatment are those events with relationship missing, unknown or related. 
The following will be summarized in an overview table with the number and percentage of 
subjects (and the number of events) by treatment and overall: 
• Any TEAE  
• Any trial treatment related TEAE 
• Any TEAE related to dabigatran 
• Any TEAE related to tepotinib  
• Any serious TEAE 
• Any trial treatment related serious TEAE 
• Any dabigatran related serious TEAE 
• Any tepotinib related serious TEAE 
• Any severe TEAE (grade >=3) 
• Any trial treatment related severe TEAE (grade >=3)  
• Any dabigatran related severe TEAE (grade >=3)  
• Any tepotinib related severe TEAE (grade >=3)  
• Any TEAE leading to death 
• Any trial treatment related TEAE leading to death 
• Any dabigatran related severe TEAE leading to death 
• Any tepotinib related severe TEAE leading to death 
 
TEAEs will be summarized by treatment and overall in tables with: 
• The number and percentage of subjects by treatment with at least one TEAE and the number 
of events overall and by SOC and PT.  
• The number and percentage of subjects by treatment with at least one non-serious TEAE and 
the number of non-serious TEAE applying frequency threshold of 5%.  
Group/SOC terms will be sorted alphabetically and PTs within each group/SOC term will be 
sorted by descending frequency (based on all treatment groups combined).  
 
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In addition the following tables will be provided:  
• A table by severity of TEAEs with the number and percentage of subjects by treatment with at 
least one TEAE and the number of events by SOC and PT.  
• A table by relationship to trial treatment with the number and percentage of subjects by 
treatment with at least one TEAE and the number of events by SOC and PT.  
Group/SOC terms will be sorted alphabetically and PTs within each group/SOC term will be 
sorted by descending frequency (based on all treatment groups combined) 
Pre-treatment AEs (AEs with onset after informed consent but before start of treatment) and 
TEAEs will be listed separately. 
 
15.1.2 
Adverse Events Leading to Treatment Discontinuation 
TEAEs leading to permanent discontinuation of trial treatment will be summarized by treatment 
and overall including number of subjects, percentage and number of events. 
A listing of TEAEs leading to permanent discontinuation of a trial treatment will additionally be 
provided. 
 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
15.2.1 
Deaths 
All deaths as well as reason for death will be based on information from the “Report of Subject 
Death” eCRFs.  
Listing of deaths, if any, will be provided displaying date and cause of death (including TEAE 
leading to death and relatedness to trial treatment, when applicable), and date and time of 
treatment administration. 
 
15.2.2 
Serious Adverse Events 
A summary table of SAEs, if any, by treatment and overall will be provided displaying the 
number and percentage of subjects by treatment with at least one SAE and the number of SAE 
overall and by system organ class and preferred term. Group/SOC terms and PTs within each 
group/SOC term will be sorted alphabetically. 
Listing of SAEs, if any, will be provided in addition. 
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15.2.3 
Other Significant Adverse Event 
15.2.3.1 
Adverse Events of Special Interest 
Healthy subjects might experience asymptomatic elevations in serum lipase and amylase. Any 
elevation in serum lipase and amylase of Grade ≥ 3 will lead to the recording of an adverse event 
of special interest (AESI). The severity of these AEs should be defined based on clinical 
judgment of the Investigator and defined according to NCI-CTCAE Severity Scale. 
Adverse events of special interest will be presented in a separate data listing. 
 
15.3 
Clinical Laboratory Evaluation 
All laboratory data will be reported with SI units. Laboratory parameters will be listed by subject 
and time-point and summarized indicating the treatment at the respective time-point using 
descriptive statistics for absolute values and change from baseline over time. Data listings of 
abnormalities as per the NCI-CTCAE guideline will be provided. Shift tables for laboratory tests 
will be presented by treatment. Shift tables will be based on NCI-CTCAE grades, where 
possible, and on normal ranges otherwise. They will be produced for 
- 
End of Trial versus Screening 
- 
Discharge versus Pre-dose (Tepotinib admistration) within periods. 
 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges and NCI-CTCAE grade and will additionally be listed 
separately.  
 
See section 7.4.3 of the clinical study protocol for a table of the safety laboratory evaluations. 
Safety laboratory values are separated into: 
• Hematology (including coagulation) 
• Biochemistry 
• Urinalysis 
• Other tests 
Tables will be produced for the groups hematology (including coagulation), and biochemistry.  
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15.4 
Vital Signs 
Vital signs will be listed by subject and time-point and summarized for absolute values and 
changes-from-baseline by visit and treatment using descriptive statistics. Descriptive statistics 
tables will start at baseline. 
 
15.5 
ECG Evaluation 
ECG data will be listed by subject and time-point and  summarized for absolute values and 
changes-from-baseline by treatment group using descriptive statistics. Descriptive statistics 
tables will start at baseline. Clinically significant ECG findings for individual subjects will be 
listed and summarized. 
 
The time intervals (PR, QRS, RR, QT and corrected QT intervals [based on Fridericia’s formula, 
QTcF]) will be summarized descriptively by treatment. 
 
The Fridericia’s Correction (QTcF) is derived as follows:  
 
Fridericia’s Correction (QTcF)  
3 RR
QT
QTc f =
 
 
where: RR = RR-interval measured in seconds. 
Observed QTcF values will be categorized according to their absolute values into the categories 
• ≤ 430 ms, 
• > 430 and ≤ 450 ms, 
• > 450 and ≤  480 ms, 
• > 480 and ≤  500 ms, and 
• > 500 ms, 
and categorized according to their absolute change from baseline into the categories 
• ≤ 30 ms, 
• > 30 and ≤  60 ms, and 
• > 60 ms. 
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The number and percentage of subjects by these categories at any post-dose assessment will be 
tabulated by treatment group.  
All ECG measurements will be listed, with abnormalities indicated. 
 
Investigator reported interpretation results will also be listed and tabulated treatment using the 
number and percentage of subjects for each interpretation category (Normal, Abnormal Not 
Clinically Significant [NCS], Abnormal Clinically Significant [CS]. 
16 
Analyses of Other Endpoints 
16.1 
Pharmacokinetics 
General Specifications for Plasma Concentration Data 
PK concentration data of total dabigatran and tepotinib and its metabolites in plasma will be 
presented in tables and descriptively summarized by treatment and nominal time point using n, 
arithmetic mean, SD, SEM, median, minimum, maximum, and CV%. Values below the LLOQ 
will be taken as zero for descriptive statistics of PK concentrations.Descriptive statistics of PK 
concentration data will be calculated using values with the same precision as the source data, and 
rounded for reporting purposes only. The following conventions will be applied when reporting 
descriptive statistics of PK concentration data: 
Mean, Min, Median, Max:  
 
 
 
3 significant digits 
SD, SEM: 
 
 
 
 
 
4 significant digits 
CV%:  
 
 
 
 
 
1 decimal place  
For final evaluations values greater than the upper limit of quantification (ULOQ) are not 
accepted and should be replaced by valid numeric values from dilution measurement. Missing 
concentrations (e.g. no sample, insufficient sample volume for analysis, no result or result not 
valid) will be reported and used generally as “N.R.”. Pre-dose samples that occur before the first 
drug administration will be assigned a time of 0 hour s, as if the sample had been taken 
simultaneously with the study drug administration. 
General Specifications for PK Parameter Data 
PK parameter data of total dabigatran, tepotinib and its metabolites in plasma will be presented 
in tables and descriptively summarized by treatment using n, arithmetic mean, SD, standard error 
of the mean (SEM), median, minimum, maximum, CV%, GeoMean, the geometric coefficient of 
variation (GeoCV%), and the 95% CI for the GeoMean. 
PK parameter Cmax will be reported with the same precision as the source data. All other PK 
parameters will be reported to 3 significant figures. In export datasets, as well as in the SDTM 
PP domain, PK parameters will be provided with full precision, and will not be rounded. 
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Descriptive statistics of PK parameter data will be calculated using full precision values, and 
rounded for reporting purposes only.  
The following conventions will be applied when reporting descriptive statistics of PK parameter 
data: 
Mean, Min, Median, Max, GeoMean, 95% CI:  
3 significant digits 
SD, SEM: 
 
 
 
 
 
4 significant digits 
CV%, GeoCV%: 
 
 
 
 
1 decimal place  
Ratio of GeoMean and 95% CI 
 
 
4 decimal places 
To ensure a reliable estimate of the extent of exposure, AUCextra should be less than or equal to 
20%. If AUCextra is greater than 20%, all parameters derived using λz  (ie, λz, t1/2, AUC0-∞ 
AUCextra, Vz/f, CL/f) will be listed, but set to missing for the calculation of descriptive statistics.  
All statistical analyses and descriptive summaries of pharmacokinetic data will be performed on 
the PK Analysis Set. All available concentration/PK data will be listed. Data of subjects not in 
the PK analysis set or invalid data will be flagged accordingly. 
16.1.1 
Primary Endpoints 
A general linear model with TREATMENT and SUBJECT as fixed effects will be applied to 
log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ of dabigatran (measured as total 
dabigatran) based on the PK analysis set. Treatment differences on the log scale of dabigatran 
with tepotinib vs dabigatran alone will be estimated for Cmax, AUC0-t, and AUC0-∞ together with 
their 90% CIs. Point estimates and CIs will be back-transformed to the original scale.  
 
The primary endpoints will be descriptively summarized. Scatter plots will be produced for the 
individual PK parameters by treatment group indicating the geometric means within each 
treatment group. 
16.1.2 
Secondary Endpoints 
Summary statistics will be provided for all secondary PK parameters by treatment.  
Individual 
estimates 
of 
relative 
bioavailability 
of 
dabigatran 
(dabigatran 
with 
tepotinib/dabigatran alone) will be calculated for each subject and listed and summarized. 
For tmax of dabigatran the Hodges-Lehmann shift estimator (dabigatran with tepotinib - 
dabibatran alone) will be calculated together with the 90% confidence interval according to 
Tukey. 
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PK variables will be evaluated for all subjects of the PK population. PK variables will be listed 
for all subjects with available data in the safety set. 
 
16.1.3 
Exploratory Endpoints 
Summary statistics will be provided for all exploratory PK parameters.  
16.1.4 
Plasma Concentration Data for Dabigatran, Tepotinib and 
Metabolites  
Summary statistics will be provided by treatment and nominal timepoint. 
The following tables will be produced separately for dabigatran, tepotinib and the metabolites: 
• Summary of plasma concentrations by treatment and nominal time 
The following figures will be produced for the dabigatran plasma concentrations: 
• Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear and 
semi-logarithmic scale 
• Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear scale 
including SD error bars 
• Individual plasma concentration-time profiles overlaying subjects, for each treatment 
separately on linear and semi-logarithmic scale 
• Individual plasma concentration-time profiles overlaying all treatments, separately for each 
subject on linear and semi-logarithmic scale 
The following listing will be produced: 
• Plasma concentrations will be listed by nominal time by treatment. Excluded plasma 
concentrations will be flagged. 
 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters 
The following non-compartmental PK parameters (see Table 1 and Table 2) will be calculated 
from the individual plasma total dabigatran (unconjugated plus conjugated), tepotinib and 
metabolites concentration-time data using commercial software such as Phoenix®/WinNonlin® 
(Version 6.2 or higher) at Nuvisan GmbH. 
 
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Table 1 
Definition of PK Parameters for Dabigatran after Single Dose 
Administration 
Symbol 
Definition 
AUC0-t 
Area under the plasma concentration-time curve (AUC) from time zero (= 
dosing time) to the last sampling time (tlast) at which the concentration is at or 
above the lower limit of quantification (LLOQ), calculated per the mixed log 
linear trapezoidal rule (ie, linear up/log down) 
AUC0-∞ 
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity, calculated as AUC0-t + AUCextra. AUCextra 
represents the extrapolated part of AUC0-∞ calculated by Clastpred/λz, where 
Clastpred is the predicted plasma concentration at the last sampling time point, 
calculated from the log-linear regression line for λz determination at which the 
measured plasma concentration is at or above LLOQ 
Cmax 
Maximum plasma concentration observed 
tlast 
The last sampling time at which the plasma concentration is at or above the 
lower limit of quantification 
tmax  
Time to reach the maximum plasma concentration 
t1/2 
Terminal half-life, calculated as ln(2)/λz 
λz  
Terminal rate constant determined from the terminal slope of the log-
transformed plasma concentration curve using linear regression on t erminal 
data points of the curve 
CL/f  
Apparent total body clearance of drug from plasma following extravascular 
administration, calculated as dose/AUC0-∞ 
Vz/f  
Apparent volume of distribution during the terminal phase following 
extravascular administration 
AUCextra% 
The AUC from time tlast extrapolated to infinity given as percentage of AUC0-
∞. AUCextra% = (extrapolated area/AUC0-∞) x100. 
 
 
 
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Table 2 
Definition of PK Parameters for Tepotinib and Metabolites 
MSC2571109A and MSC2571107A after Multiple Dose Administration 
Symbol 
Definition 
AUCτ 
The area under the plasma concentration-time curve (AUC) at steady state 
over the dosing interval from 
T1 = 0 h to T2 = τ h. Calculated using the mixed log linear trapezoidal rule 
(linear up, log down), τ = 24 h 
CLSS/f 
Apparent total body clearance of drug at steady state following extravascular 
administration, considering the fraction of dose absorbed. CLSS/f = Dose p.o. / 
AUCτ (parent drug only) 
Cmax,SS 
Maximum observed plasma concentration during a complete dosing interval 
at steady state 
Cmin,SS 
Minimum observed plasma concentration during a complete dosing interval at 
steady state 
tmax,SS 
The time to reach the maximum observed plasma concentration collected 
during a dosing interval (unless otherwise defined, take the 1st occurrence in 
case of multiple/identical Cmax values) 
Frel,test/reference 
Relative bioavailability, defined as AUC0-∞,test/AUC0-∞,reference,  
F = 
reference
AUC
,
0
 test
,
-
0
AUC
∞
−
∞
 * 100 
Individual PK parameters will be calculated using actual sampling times. The predose sample 
will be considered as if it had been taken simultaneously with the administration of study drug. 
PK variables will be evaluated and listed for all subjects who provide sufficient concentration-
time data. 
Plasma concentrations below LLOQ before the last quantifiable data point will be taken as zero 
for calculating the AUC (ie, embedded BLQ values set to zero). Plasma concentrations below 
LLOQ after the last quantifiable data point will not be considered for the determination of λz. 
The following PK parameters will be calculated for diagnostic purposes and listed, but will not 
be summarized: 
• The time interval (h) of the log-linear regression (λz low, λz upp) to determine λz.  
• Number of data points included in the log-linear regression analysis to determine λz. 
• Goodness of fit statistic (Rsq) for calculation of λz.   
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The regression analysis should contain data from at least 3 different time points in the terminal 
phase consistent with the assessment of a straight line on t he log-transformed scale. Phoenix 
WinNonlin best fit methodology will be used as standard. The last quantifiable concentration 
should always be included in the regression analysis, while the concentration at tmax and any 
<LLOQ concentrations that occur after the last quantifiable data point should not be used.  
The coefficient of correlation (R²) should be ≥0.8 and the observation period over which the 
regression line is estimated should be at least twofold the resulting t1/2 itself. If these criteria are 
not met, then the corresponding values should be flagged in the listing displaying Individual 
Plasma Pharmacokinetic Diagnostic Parameters for Each Treatment. Any flags should be 
included in the study specific SDTM. Then the rate constants and all derived parameters (e.g. 
AUC0-∞, %AUCextra, CL/f, t1/2, and VZ/f) will be included in the parameter listings and will be 
discussed appropriately in alignment with the protocol lead and quantitative pharmacology 
representative. 
Partial areas AUCτ should be calculated using the scheduled dosing interval, as defined in the 
Clinical Trial Protocol. The actual dosing interval calculated from eCRF time data should not be 
used. The following rules apply when calculating the partial area AUCτ within the observed time 
interval fromT1 to T2:  
• If the start time of the interval (T1) occurs before the first observation, the observation at 
T1 will be estimated using the linear interpolant between the first datapoint and C0. For 
single dose data C0= 0 when the drug was administered via an extravascular route. For 
steady state models, C0 is the minimum concentration value occurring within the time 
interval T1 to T2. 
• If either T1 or T2 falls within the time range in which samples were taken, but does not 
coincide with an observed data point, then a linear or logarithmic interpolation is 
performed to estimate the corresponding concentration value. Whether a linear or 
logarithmic interpolation is used will depend on the method of AUC calculation e.g. 
linear up log down.  
• If the end time of the interval (T2) occurs after the last measurable concentration and the 
terminal regression (λz) is estimable, then λz is used to estimate the concentration at time 
T2. The log trapezoidal rule will be used to calculate the area from the last observation 
time to the end time of the partial area (T2). If λz cannot be estimated the partial area will 
not be calculated. 
The IMP dose administered is given for the monohydrate hydrochloride salt (ie, 500 mg IMP). A 
conversion factor for the freebase IMP was calculated and will be applied when ‘dose’ is used in 
deriving PK parameter formulas needing a dose value (CL/f). 
Conversion factor = Molecular weight (MW) of base IMP divided by MW of salt form IMP = 
492.574 g/mol / 547.05 g/mol = 0.9004  
Amount of dose * conversion factor = actual dose of IMP:  500 mg * 0.900 = 450 mg 
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The Phoenix WinNonlin NCA Core Output will be provided in a separate listing. 
 
16.2 
Pharmacogenetics 
The results of the pharmacogenetic analysis, as applicable, will be described in a separate report. 
 
17 
References 
None. 
 
18 
Appendices 
None. 
 
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