Clinical trial NCT03628339
Conditions: Healthy
Keywords: Tepotinib Midazolam Cytochrome P450 Pharmacokinetics
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-08-20; Completion date: 2018-10-30
Enrollment: 12 participants; Allocation: NA; Intervention model: SEQUENTIAL

Brief summary:
The study investigated the effect of tepotinib on the pharmacokinetics (PK) of the Cytochrome P450 (CYP) 3A substrate midazolam determined from concentrations of midazolam and its main metabolite 1-hydroxymidazolam in healthy participants.

Detailed description:

Arms: arm 1: Participants received single oral dose of 7.5 milligrams (mg) midazolam tablet on Day 1 of treatment period 1. The washout period between midazolam administrations in Period 1 and Period 2 was 12 days. arm 2: All participants who received 7.5 mg midazolam tablet in treatment period 1 received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 along with 7.5 mg midazolam tablet on Day 11 in treatment period 2.
Interventions: intervention 1: Midazolam intervention 2: Tepotinib
Intervention descriptions: intervention 1: Participant received single oral dose of 7.5 mg midazolam tablet on Day 1 of treatment period 1 and Day 11 in treatment period 2. intervention 2: Participants received single oral dose of 500 mg tepotinib film-coated tablet from Day 1 to 11 in treatment period 2.

Protocol documents:
Prot_000.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 P K of C Y P 3 A S u bstr ate Mi d az ol a m
M S 2 0 0 0 9 5- 0 0 3 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/ 7 1
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 0
Title
P hase 1, O pe n -la bel, Si n gle Se q ue nce, T w o -Peri o d 
Cr oss o ver Trial t o E val uate t he Effect of Te p oti ni b 
o n C y t oc hr o me P 4 5 0 ( C Y P) 3 A b y  In vesti gati n g t he 
P har mac o ki netics 
of 
t he 
C Y P 3 A 
S u bstrate 
Mi daz ola m i n Healt h y  S u bjects
P h ase
1
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 5 0 5 5- 9 2
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
1 2 J u ne 2 0 1 8 / Versi o n 1. 0
Re pl aces Versi o n
N ot a p plica ble
- 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 su 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 2f 5 2 1 v 1. 0
0 9 0 0 ba be 8 0fc b 3 d d
Pa ge 2 of 7 2
PI
PI
PI
PI
PI
PI
PI


Tepotinib (MSC2156119J)
Effect of Tepotinib on PK of CYP3A Substrate Midazolam
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................5
Table of In-Text Figures......................................................................................................5
List of Abbreviations ...........................................................................................................6
1
Synopsis..............................................................................................10
2
Sponsor, Investigators and Trial Administrative Structure ................18
3
Background Information.....................................................................18
3.1
Trial Rationale ....................................................................................21
4
Trial Objectives ..................................................................................22
4.1
Primary Objective...............................................................................22
4.2
Secondary Objectives .........................................................................22
4.3
Exploratory Objective.........................................................................22
5
Investigational Plan ............................................................................22
5.1
Overall Trial Design and Plan ............................................................22
5.2
Discussion of Trial Design .................................................................24
5.2.1
Inclusion of Special Populations ........................................................24
5.2.2
Scientific Rationale for Trial Design..................................................24
5.2.3
Justification for Dose..........................................................................26
5.2.4
Rationale for Endpoints......................................................................26
5.3
Selection of Trial Population..............................................................26
5.3.1
Inclusion Criteria ................................................................................27
5.3.2
Exclusion Criteria...............................................................................27
5.4
Criteria for Initiation of Trial Treatment ............................................29
5.5
Criteria for Subject Withdrawal..........................................................29
5.5.1
Withdrawal from Trial Treatment ......................................................29
5.5.2
Withdrawal from the Trial..................................................................29
5.6
Premature Termination of the Trial ....................................................30
5.7
Definition of End of Trial...................................................................31
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................31
6.1
Description of the Investigational Medicinal Product........................31
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6.2
Dosage and Administration ................................................................31
6.3
Assignment to Treatment Groups.......................................................33
6.4
Non-investigational Medicinal Products to be Used ..........................33
6.5
Concomitant Medications and Procedures .........................................33
6.5.1
Permitted Medicines...........................................................................33
6.5.2
Prohibited Medicines..........................................................................34
6.5.3
Permitted/Prohibited Procedures ........................................................34
6.5.4
Other Interventions.............................................................................35
6.5.5
Special Precautions.............................................................................35
6.5.6
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................35
6.6
Packaging and Labeling of the Investigational Medicinal Product....35
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................35
6.8
Investigational Medicinal Product Accountability.............................36
6.9
Assessment of Investigational Medicinal Product Compliance .........36
6.10
Blinding ..............................................................................................37
6.11
Emergency Unblinding.......................................................................37
6.12
Treatment of Overdose .......................................................................37
6.13
Medical Care of Subjects after End of Trial.......................................37
7
Trial Procedures and Assessments......................................................37
7.1
Schedule of Assessments....................................................................37
7.1.1
Screening Examination.......................................................................38
7.1.2
Treatment Periods...............................................................................38
7.1.3
End of Trial Visit................................................................................41
7.2
Demographic and Other Baseline Characteristics ..............................42
7.3
Efficacy Assessments .........................................................................42
7.4
Assessment of Safety..........................................................................42
7.4.1
Adverse Events ...................................................................................43
7.4.2
Pregnancy and In Utero Drug Exposure.............................................47
7.4.3
Clinical Laboratory Assessments .......................................................48
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............50
7.5
Pharmacokinetics................................................................................51
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7.5.1
Blood Sampling ..................................................................................51
7.5.2
Calculation of Pharmacokinetic Variables .........................................52
7.6
Biomarkers..........................................................................................53
7.7
Pharmacogenomics.............................................................................53
7.8
Other Assessments..............................................................................53
8
Statistics..............................................................................................53
8.1
Sample Size ........................................................................................53
8.2
Randomization....................................................................................53
8.3
Endpoints............................................................................................54
8.3.1
Primary Endpoint................................................................................54
8.3.2
Secondary Endpoints ..........................................................................54
8.3.3
Exploratory Endpoint..........................................................................54
8.4
Analysis Sets.......................................................................................54
8.5
Description of Statistical Analyses.....................................................55
8.5.1
General Considerations.......................................................................55
8.5.2
Analysis of Primary Endpoint ............................................................55
8.5.3
Analysis of Secondary Endpoints.......................................................56
8.5.4
Analysis of Safety and Other Endpoints.............................................56
8.5.5
Analysis of Exploratory Endpoint ......................................................57
8.6
Interim and Additional Planned Analyses ..........................................57
9
Ethical and Regulatory Aspects..........................................................57
9.1
Responsibilities of the Investigator ....................................................57
9.2
Subject Information and Informed Consent .......................................57
9.3
Subject Identification and Privacy......................................................58
9.4
Emergency Medical Support and Subject Card..................................58
9.5
Clinical Trial Insurance and Compensation to Subjects.....................58
9.6
Independent Ethics Committee...........................................................59
9.7
Health Authorities...............................................................................59
10
Trial Management...............................................................................59
10.1
Case Report Form Handling...............................................................59
10.2
Source Data and Subject Files............................................................60
10.3
Investigator Site File and Archiving...................................................60
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................61
10.5
Changes to the Clinical Trial Protocol................................................61
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 .........................................................................................64
Appendix I
Signature Pages and Responsible Persons for the Trial......................65
Signature Page – Protocol Lead.........................................................................................66
Signature Page – Principal Investigator.............................................................................67
Sponsor Responsible Persons not Named on the Cover Page ...........................................68
Appendix II
Planned Numbers of Blood Samples for Clinical Laboratory, PK, 
and PGx and Total Blood Sampling Volume .....................................69
Appendix III
Contraception Guidance .....................................................................70
Table of In-Text Tables
Table 1
Schedule of Assessments - Period 1 (Administration of 
Midazolam Alone)..............................................................................14
Table 2
Schedule of Assessments - Period 2 (Administration of Tepotinib 
and Midazolam)..................................................................................16
Table 3
Safety Laboratory Evaluations ...........................................................49
Table 4
PK Blood Sampling - Allowed Time Windows .................................51
Table 5
Definition of PK Parameters for Midazolam and 1-
Hydroxymidazolam after Single Dose Administration ......................52
Table of In-Text Figures
Figure 1
Treatment Overview ...........................................................................23
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List of Abbreviations
Abbreviation
Definition of Terms
AE
Adverse event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
Alu
Aluminum
anti-HCV
Hepatitis C virus antibody
AST
Aspartate aminotransferase
AUC
Area under the plasma concentration-time curve
AUC0-∞
Area under the plasma concentration-time curve from time zero (= dosing 
time) extrapolated to infinity
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
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞ in percent
beta-HCG
Beta-human chorionic gonadotropine 
BMI
Body mass index
CI
Confidence interval
Cmax
Maximum plasma concentration observed
c-Met
Mesenchymal-epithelial transition factor
CRO
Contract research organization
CTCAE
Common Terminology Criteria for AEs
CTFG
Clinical Trial Facilitation Group
CV
Coefficient of variation
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Abbreviation
Definition of Terms
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DDI
Drug-drug interaction
ECG
Electrocardiogram 
eCRF
Electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
FDA
Food and Drug Administration
FSH
Follicle-stimulating hormone 
GABA
Gamma-aminobutyric acid
GCP
Good Clinical Practice
GeoCV%
Geometric coefficient of variation in percent
GeoMean
Geometric mean
h
Hour(s)
HBsAg
Hepatitis B surface antigen
HCC
Hepatocellular carcinoma
HGF
Hepatocyte growth factor
HIV1/HIV2
Human immunodeficiency virus 1 and 2 
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
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Abbreviation
Definition of Terms
LLOQ
Lower limit of quantification
Min
Minute(s)
MR
Metabolic ratio
NCI
National Cancer Institute 
NSCLC
Non-small cell lung cancer
PD
Pharmacodynamics
PGx
Pharmacogenetics
PK
Pharmacokinetics
QTcF
Corrected QT interval per Fridericia’s formula
RP2D
Recommended Phase 2 dose
SAE
Serious adverse event
SAP
Statistical analysis plan 
SBP
Systolic blood pressure
SD
Standard deviation 
SmPC
Summary of Product Characteristics
SOP
Standard operational procedures
SUSAR
Suspected unexpected serious adverse reactions
T/R ratio
Test/Reference ratios
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
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Abbreviation
Definition of Terms
TPR
Translocated promoter region
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal range
λz
Terminal rate constant
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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 P K of C Y P 3 A S u bstr ate Mi d az ol a m
M S 2 0 0 0 9 5- 0 0 3 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 0 /7 1
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 0
Title
P hase 1 , O pe n-la bel, Si n gle Se q ue nce, T w o-
Peri o d Cr oss o ver Trial t o E val uate t he Effect of 
Te p oti ni b o n C y t oc hr o me P 4 5 0 ( C Y P) 3 A b y 
I n vesti gati n g t he P har mac o ki netics of t he C Y P 3 A 
S u bstrate Mi daz ola m i n Healt h y S u bjects
Tri al P h ase
1
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 5 0 5 5- 9 2
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 3- Q 4 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 m ulti ple d oses of te p oti ni b o n A U C 0-t, A U C 0- ∞, a n d C ma x of 
t he C Y P 3 A s u bstrate mi daz ola m i n healt h y  s u bjects.
Sec o n d ar y O bjecti ves:

T o f urt her i n vesti gate effects of m ulti ple d oses of te p oti ni b o n t he P K of mi daz ola m

T o i n vesti gate t he effect of m ulti ple d o ses of te p oti ni b o n t he P K of t he mai n 
mi daz ola m meta b olite 1 -h y dr o x y m i daz ola m

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 
mi daz ola m .
E x pl or at or y O bjecti ve :

T o e x pl ore t he effect of p har mac o ge netics ( P G x) a n d variati o ns of ass ociate d ge nes o n 
t he P K pr ofile of te p oti ni b a n d/ or mi daz ola m.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0f 2f 5 2 1 v 1. 0
0 9 0 0 ba be 8 0fc b 3 d d
Pa ge 1 1 of 7 2
PI
PI
PI


Tepotinib (MSC2156119J)
Effect of Tepotinib on PK of CYP3A Substrate Midazolam
MS200095-0030
C O N F I D E N T I A L
I N F O R M A T I O N
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Methodology: Phase 1, open-label, 2-period, crossover trial.
The trial will be divided into 2 periods. Period 1 will evaluate the PK of midazolam and 
1-hydroxymidazolam after single dose administration of midazolam over a sampling period of 
48 h post-dose. In Period 2, tepotinib will be administered alone for 10 days. On Day 11 of 
Period 2, midazolam and tepotinib will be co-administered and the PK of midazolam and 
1-hydroxymidazolam will be evaluated again over 48 h post-dose. Dosing of tepotinib will be 
performed after completion of breakfast. Midazolam will be administered 4 h after tepotinib 
administration, when tepotinib systemic exposure is building up, and a quasi-fasted condition 
is reached to minimize for food effects on midazolam absorption. Day 1 of Period 2 will be 
2 days after midazolam administration in Period 1.
The subjects will be admitted to the trial site on Trial Day -1. They will be resident at the trial
site under medical supervision from Day -1 of Period 1 until Day 13 of Period 2 (Trial
Day 15). The End of Trial Visit is planned 7 days (± 1 day) after the last drug administration in 
Period 2 (Trial Day 20 ± 1).
After the first 6 subjects completed administration up to Day 11 of Period 2, safety and PK 
data will be reviewed by the responsible functional representatives. 
Planned number of subjects: Overall, 12 healthy subjects are planned to be included.
Primary endpoint:

AUC0-t, AUC0-∞and Cmax of midazolam (at Day 1 of Period 1 and Day 11 of Period 2 
from time zero to 48 h post-dose).
Secondary endpoints: 

tmax and t1/2 of midazolam

AUC0-t, AUC0-∞, Cmax, tmax and t1/2 of 1-hydroxymidazolam; metabolic ratio (MR)

Occurrence of treatment emergent adverse events (TEAEs; incidence, frequency, 
intensity and causality), occurrence of changes in clinical laboratory assessments, 12-
lead electrocardiograms (ECGs) and vital signs in subjects receiving tepotinib alone 
and together with midazolam assessed from Day 1 of Period 2 until the End of Trial
Visit.
Exploratory endpoint: 

Genetic variants and mutations in genes that potentially influence PK of tepotinib 
and/or midazolam.
Pharmacokinetics: 
Blood samples for the determination of plasma concentrations of midazolam and 
1-hydroxymidazolam will be taken on Day 1 of Period 1 and Day 11 of Period 2 from time 
pre-dose to 48 h post midazolam dosing. Blood samples for determination of tepotinib and its 
metabolites trough levels will be taken before tepotinib administration on Days 9, 10 and 11. 
PK parameters will be calculated using non-compartmental analysis. 
Other assessments: Not applicable.
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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.
Midazolam: commercially available midazolam, ie Dormicum® 7.5 mg film-coated tablets.
Treatment A (Period 1): On Day 1 of Period 1, a single oral dose of 7.5 mg midazolam as 
tablet will be administered in a quasi-fasted state 4 h after completion of a standardized 
breakfast together with 240 mL water.
Treatment B (Period 2): On Days 1 to 10 of Period 2, 500 mg tepotinib will be administered 
together with 240 mL of water after a continental breakfast (about 30 min after start of 
breakfast). Some flexibility of the continental breakfast is allowed, but the breakfast should be 
not high caloric. On Day 11 of Period 2, the subjects will receive a standardized breakfast, 
which must be consumed completely within 25 min. The standardized breakfast must match 
with the breakfast on Period 1, Day 1, with regard to composition and content. 30 min after 
start of the breakfast, 500 mg tepotinib will be administered together with 240 mL of water. A 
single oral dose of 7.5 mg midazolam will be administered 4 h after tepotinib administration 
together with 240 mL water.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable.
Planned trial and treatment duration per subject:
About 6 weeks from Screening to End of Trial Visit, treatment on Day 1 of Period 1 
(Treatment A) and on Days 1-11 of Period 2 (Treatment B).
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Statistical methods:
A general linear model with a fixed effect for TREATMENT and a random effect for 
SUBJECT will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞of 
midazolam based on the PK analysis set. Treatment differences on the log scale of midazolam 
with tepotinib vs midazolam 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. For the statistical analysis of AUC0-t of midazolam data, a-priori ordered 
hypotheses will be tested The confidence intervals for AUC will be compared to acceptance 
ranges for moderate effects [0.2 ; 5.0] (to be tested first) and mild effects [0.5 ; 2.0].
Individual estimates of relative bioavailability and MR of midazolam will be calculated for 
each subject and summarized. Summary statistics will be provided for all parameters.
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Table 1
Schedule of Assessments - Period 1 (Administration of Midazolam Alone)
Assessment / Activity
Screening
Period 1
Day of Period 1
Day -21 to -2
-1
1
2
Trial Day
-1
1
2
Written informed consent a
Hospitalization
X --------------------------------------------------------------------------------------------X
Ambulatory visit
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 b
Pulse oximetry
X c
12-lead ECG
X
X
X b
X b
Clinical laboratory (hematology, biochemistry, urinalysis)
X
X
Serology (HIV/hepatitis)
X
Pregnancy test
X d
X d
Drugs of abuse, Alcohol breath test
X
X
Administration of midazolam
X
PK blood sampling midazolam and 
1-hydroxymidazolam
X e
X e
PGx blood sampling (mandatory)
X f
Adverse event monitoring
X --------------------------------------------------------------------------------------------------------------X g
Prior and concomitant medication
X --------------------------------------------------------------------------------------------------------------X g
BMI = Body Mass Index; ECG = electrocardiogram, FSH: Follicle-stimulating hormone, HIV = human immunodeficiency virus, PGx = pharmacogenetics, 
PK = pharmacokinetics.
a
Written informed consent must be obtained prior to any Screening activities 
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b 
Vital signs and ECG will be measured after at least 5 min rest at pre-dose (within 60 min prior to dosing) as well as 4, 8, 24 and 48 h post-dose (48 h post-
dose midazolam administration = pre-dose tepotinib administration in Period 2) 
c
Pulse oximetry will be performed from about 30 min before until 6 h after midazolam administration
d
Women of non-childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day -1 of 
Period 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, bilateral oophorectomy or bilateral salpingectomy
e
PK blood samples for determination of midazolam and 1-hydroxymidazolam will be collected at pre-dose (within 60 min prior to administration of midazolam ) 
and 15, 30, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36 and 48 h post-dose after administration of midazolam (48 h post-dose = pre-dose tepotinib administration 
in Period 2)
f
PGx blood samples of 2 x 2 mL to be drawn at pre-dose on Day 1 of Period 1
g
Adverse events and concomitant medication will be assessed from signing of the informed consent form (ICF) throughout the whole trial until the End of Trial
Visit.
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Table 2
Schedule of Assessments - Period 2 (Administration of Tepotinib and Midazolam)
Assessment / Activity
Period 2
End of Trial
Visit
Day of Period 2
1
2 - 10
11
12
13
Day 18 (1)
Trial Day
3
4 - 12
13
14
15
Day 20 (1)
Hospitalization
X
X
X
X
X
Ambulatory visit
X
Physical examination
X
X
Vital signs (blood pressure, pulse 
rate, body temperature)
X a
X a
X b
X b
X b
X
Pulse oximetry
X c
12-lead ECG
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
Pregnancy test (serum)
X
Administration of tepotinib
X
X
X
Administration of midazolam
X
PK blood sampling for tepotinib and 
its metabolites
X f
X f
PK blood sampling for midazolam and 
1-hydroxymidazolam
X g
X h
X h
X h
Adverse event monitoring
X i
X i
X i
X i
X i
X
Concomitant medication
X i
X i
X i
X i
X i
X
ECG = electrocardiogram, PK = pharmacokinetics
a
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 at Days 1, 2, 5, 8 and 10 of Period 2
b
Vital signs will be measured after at least 5 min rest before (within 60 min prior to dosing) as well as 4, 8, 24 and 48 h after midazolam administration at 
Day 11 of Period 2
c
Pulse oximetry will be performed from about 30 min before until 6 h after midazolam administration
d
12-lead ECGs will be recorded and printed out after at least 5 min rest before each time point 
On Days 1, 2, 5, 8 and 10 of Period 2: within 60 min prior to dosing and 6 h after each tepotinib administration; 
On Day 11 of Period 2: within 60 min prior to dosing, as well as 4, 8, 24, and 48 h after midazolam administration
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e
Laboratory assessments will be performed prior to tepotinib administration on Days 1, 2, 5, 8 and 11 of Period 2, on Day 12 of Period 2 and at the End of Trial
visit (on Day 2 of Period 2 biochemistry only) 
f
PK blood samples for determination of trough levels of tepotinib and its metabolites will be collected pre-dose (within 60 min prior to tepotinib administration) 
on Days 9, 10 and 11
g
48 h PK blood sampling for determination of midazolam and 1-hydroxymidazolam of Period 1
h
PK blood samples for determination of midazolam and 1-hydroxymidazolam will be collected at pre-dose (within 60 min prior to administration of midazolam) 
and 15, 30, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36 and 48 h post-dose after administration of midazolam
i
Adverse events and concomitant medication will be assessed from signing of the ICF throughout the whole trial until the End of Trial Visit.
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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 P K of C Y P 3 A S u bstr ate Mi d az ol a m
M S 2 0 0 0 9 5- 0 0 3 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 8 /7 1
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 c o nsiste nt wit h t he I nter nati o nal C o u ncil f or Har m o nisati o n 
(IC H) T o pic E 6 G o o d Cli nical Practice ( G C P; hereafter referre d t o as I C H G C P) [ 1 4].
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 n s or 
res p o nsi ble pers o ns f or t he trial are i n A p pe n di x I .
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 c o ntract researc h or ga nizati o n
( C R O), 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 ysis, 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  ap 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 N u 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 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 uc ts (I M Ps) te p oti ni b a n d 
mi daz ola m . 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 nd 
metastasis.
I n pri mar y  phar mac o d y n a mic ( Pd ) st u dies, te p oti ni b ( M S C 2 1 5 6 1 1 9J) p ote ntl y  in 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 
was acti vate d i n a li ga n d i n de pe n de nt ma n ner, ie i n cells har b ori n g c-Met ge ne a m plificati o n or 
e x pressi n g t he o nc o ge nic f usi o n pr otei n tra nsl ocate d pr o m oter re gi o n ( T P R) Met.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0f 2f 5 2 1 v 1. 0
0 9 0 0 ba be 8 0fc b 3 d d
Pa ge 1 9 of 7 2
PI
PI


Tepotinib (MSC2156119J)
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Until 30 September 2017, 452 subjects have been exposed to tepotinib. 60 subjects of these have 
been exposed to a tepotinib + gefitinib combination. 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 1 or 
Phase 1b/2 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. The recommended Phase 2 dose (RP2D) is 500 mg tepotinib once daily.
Single oral doses of 500 mg tepotinib have been administered 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 500 mg tepotinib in crossover) and was 
found safe and well tolerated. Refer to the Investigator’s Brochure for further information about 
the nonclinical and clinical programs and the implemented Guidance for the Investigator.
During the development of tepotinib, in all 3 studies performed in healthy subjects (n = 79), the 
subjects have well tolerated single doses of tepotinib at different dose levels up to 500 mg. All 
treatment emergent adverse events (TEAEs) were mild to moderate, except one Grade 3 
asymptomatic lipase elevation in 1 subject. Treatment emergent adverse events 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 the only identified risks for subjects 
administered tepotinib so far. These elevations were observed in 5 of 79 (6.3%) healthy subjects 
exposed to tepotinib and were mild to moderate in severity (exception: one Grade 3 lipase 
elevation), transient
and without apparent dose dependency. All increases of serum 
amylase/lipase were asymptomatic and not associated with pancreatitis.
Following the nonclinical observation that tepotinib and its metabolite MSC2571109A were 
identified as inducers of cytochrome P450 (CYP) 3A4, and that MSC2571109A was identified as 
a mechanism-based inhibitor of CYP3A4/5, the need to investigate tepotinib clinically for any 
potential to cause CYP3A-mediated drug-drug interaction (DDI) was triggered. In this DDI trial
multiple doses of the RP2D of 500 mg tepotinib will be administered to healthy subjects to 
achieve steady-state levels and robustly evaluate its potential as perpetrator toward the CYP3A 
substrate midazolam.
Short term multi-day administration in this trial of 500 mg tepotinib to healthy subjects is 
expected to be safe and well tolerated, considering the previous clinical experience with 
administration of multiple tepotinib doses up to 1400 mg in patients and of single doses of 
500 mg in healthy volunteers, the preclinical safety pharmacology and toxicity data, in 
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conjunction with the predicted exposures at steady state after multiple dosing of 500 mg/day in 
healthy subjects, and the absence of genotoxicity.
Since loss of c-Met induces teratogenic effects in c-Met knockout mice, and since a pilot 
embryo-fetal development trial in rabbits revealed maternotoxic effects and a dose-dependent 
increased number of skeletal malformations (teratogenicity), stringent criteria are applied to 
ensure exclusion of women of childbearing potential in this trial. Only healthy women that are 
known to be postmenopausal or surgically sterile (ie due to hysterectomy and bilateral 
oophorectomy, or bilateral salpingectomy) will be enrolled in this trial (for details see Section 5, 
Investigational Plan). Male subjects will be required to take precautions with regards to female 
partners.
Close safety monitoring will be implemented. Subjects will be admitted to the trial site and 
remain resident there from Day -1 to Day 2 of Period 1 and from Day 1 to Day 13 of Period 2, to 
allow continuous safety monitoring of the clinical laboratory parameters, ECG vital signs and 
pharmacokinetic (PK) sampling. After the first six subjects have completed their treatment up to 
Day 11 of Period 2, safety and PK data will be reviewed by the responsible functional 
representatives. In addition, frequent monitoring of subjects is ensured by choosing a CRO 
experienced in the conduct of clinical pharmacology trials.
It is recognized that healthy subjects will not benefit by participating in this trial.
For PK of tepotinib refer to Investigator’s Brochure.
Midazolam
Midazolam is a short-acting sedative-hypnotic benzodiazepine, and is metabolized in the liver 
and gut wall by CYP3A4 and CYP3A5 [1, 2] to form the major active metabolite 
1-hydoxymidazolam, which is further glucuronidated and mainly excreted via the kidneys [3].
Midazolam is rapidly absorbed, reaching maximum plasma concentration after about 1 to 2 hours
(h) (time to reach the maximum plasma concentration [tmax]) and eliminated with a half-life of 
approx. 2.5 (1.5 to 5) h. Tmax is delayed after non-fasting administration. The terminal half-life 
(t1/2) of the active metabolite is 8 to 10 h [4]. Its anxiolytic, muscle-relaxant, sedative and 
sleep-inducing effects are mediated via enhancing the effect of the neurotransmitter gamma-
aminobutyric acid (GABA) on the GABAA receptors. It is prescribed as a sleep-inducing agent 
for adults and children in situations requiring sedation or anesthesia. It also exerts anticonvulsant 
effects and is indicated as a treatment of prolonged, acute, convulsive seizures in pediatric 
patients with epilepsy. The sedative effect would last about 7 to 8 h, paralleling the fast decline 
phase. It is available in both oral and intravenous formulations. The recommended clinical oral 
dose for sedation in adults is ranging from 7.5 to 15 mg. 
There is extensive clinical experience of the use of midazolam [5] and full information about the 
potential side effects of midazolam treatment are described in the currently approved Summary 
of Product Characteristics (SmPC) [6]. There are a number of contraindications and precautions 
within the prescribing information (eg contraindication in patients with severe respiratory failure 
or acute respiratory depression, or liver insufficiency, use with caution in patients with impaired 
respiratory function and other patients at higher risk of alteration to vital functions). Respiratory
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depression and severe cardiorespiratory adverse events (AEs) have been reported, including 
respiratory depression, apnea, respiratory arrest and cardiac arrest. Such life-threatening 
incidents are more likely to occur when a high dose is administered or when an intravenous 
injection is given rapidly. Midazolam can also cause anterograde amnesia and paradoxical 
reactions, and long-term use can also lead to tolerance, dependence and withdrawal syndromes. 
There is also the potential for clinically important DDIs between midazolam and a number of 
other medications. Most of these interactions are the result of reduction of midazolam 
metabolism by inhibitors of CYP3A leading to elevated midazolam exposure. If the trial 
compound inhibits CYP3A, the risk for the listed side effects of midazolam could be increased. 
Antidote
Midazolam may cause somnolence, confusion, lethargy, muscle relaxation and paradoxical 
excitation. Treatment, if needed, of overdosing or overreaction of midazolam will be performed 
as per SmPC, ie monitoring of vital signs, symptomatic treatment of cardiorespiratory or central 
nervous adverse events; in case of severe central nervous depression, Flumazenil, a specific 
benzodiazepine-receptor antagonist, is an antidote available at the site for midazolam.
3.1
Trial Rationale
This trial will generate human data on the potential of DDI of tepotinib as potential perpetrator 
toward CYP3A on the PK of the CYP3A probe substrate midazolam at the RP2D of 500 mg. As 
the intended target population, patients suffering from malignancies such as HCC and NSCLC, 
often receives multiple concomitant drugs, including drugs that are metabolized by CYP3A4, 
characterization of the DDI perpetrator potential toward CYP3A4 is clinically relevant.
In vitro, tepotinib caused increases in CYP3A4 mRNA levels of 7-fold in one out of three 
hepatocyte preparations, and its major metabolite MSC2571109A induced 7- and 21-fold 
increases in two out of three hepatocyte preparations. Mechanistic static modeling for tepotinib 
and its metabolite MSC2571109A for CYP3A induction based on maximal exposure observed in 
Trial EMR 200095-001 resulted in an RAUC value of 0.25 for tepotinib and 0.07 for 
MSC2571109A, ie tepotinib is currently meeting the Food and Drug Administration (FDA) 
definition of a potential inducer. This meets the criteria given in the FDA guideline for the 
conduct of a clinical DDI trial using a sensitive index substrate.
In addition, the tepotinib metabolite, MSC2571109A was found to be a mechanism-based 
inhibitor of CYP3A4/5 enzymes based on increased percent of inhibition observed at the highest 
tested concentration of 15 µM (Trial XT155037) after preincubation in vitro in human liver 
microsomes. However, due to limited solubility, Ki and Kinact values could not be determined, 
preventing the proper evaluation of the risk associated with this mechanism based inhibition of 
CYP3A4/5.
The trial design is based on the regulatory guidance of the FDA [7, 8] and of the European 
Medicines Agency (EMA) [9]. Midazolam is well characterized [5, 6], and has been established 
as a selective and sensitive probe index substrate for CYP3A commonly used in clinical DDI 
studies and considered as an index substrate in the most recent update of the FDA guidance [7, 8] 
and EMA guideline [9].
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This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP [14] 
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. 
4
Trial Objectives
4.1
Primary Objective

To investigate the effect of multiple doses of tepotinib on AUC0-t, AUC0-∞, and Cmax of
the CYP3A substrate midazolam in healthy subjects.
4.2
Secondary Objectives

To further investigate effects of multiple doses of tepotinib on the PK of midazolam

To investigate the effect of multiple doses of tepotinib on the PK of the main midazolam
metabolite 1-hydroxymidazolam

To assess the safety and tolerability of tepotinib alone and upon co-administration of
midazolam.
4.3
Exploratory Objective

To explore the effect of pharmacogenetics (PGx) and variations of associated genes on
the PK profile of tepotinib and/or midazolam.
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase 1, open-label, single-sequence, 2-period, crossover trial to investigate the effect 
of tepotinib on the PK of the CYP3A substrate midazolam determined from concentrations of 
midazolam and its main metabolite 1-hydroxymidazolam in 12 healthy subjects. A flowchart 
summarizing the overall trial design is shown in Figure 1.
The trial will be divided into 2 periods: Period 1 will evaluate the PK of midazolam and 
1-hydroxymidazolam after single dose administration of midazolam over a sampling period of 
48 h post-dose, which covers > 5 times the geometric mean (GeoMean) t1/2 of about 2.5 h [6]. In 
Period 2, tepotinib will be administered alone for 10 days. On Day 11 of Period 2, midazolam 
and tepotinib will be co-administered and the PK of midazolam and 1-hydroxymidazolam will 
be evaluated again over 48 h post-dose (see Figure 1). Dosing of tepotinib will be performed 
after completion of breakfast. Midazolam will be administered 4 h after tepotinib administration, 
when tepotinib systemic exposure is building up, and a quasi-fasted condition is reached to 
minimize for food effects on midazolam absorption. 
Day 1 of Period 2 will be 2 days after midazolam administration in Period 1.
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Figure 1
Treatment Overview
A Screening period is implemented from Trial Day -21 to Day -2.
The subjects will be admitted to the trial site on Trial Day -1. They will be resident at the trial
site under medical supervision from Day -1 of Period 1 until Day 13 of Period 2 (Trial Day 15).
Serial blood and urine samples will be collected for laboratory assessments (hematology, 
biochemistry, urinalysis), which will be performed at Screening, during the inpatient period and 
for the End of Trial Visit as explained in detail in Table 1 and Table 2 (see also Figure 1).
Serial blood samples for PK assessment of midazolam and 1-hydroxymidazolam will be 
collected for 48 h after administration of midazolam in Periods 1 and 2.
The End of Trial Visit is planned 7 days (± 1 day) after the last drug administration in Period 2 
(Trial Day 20 ± 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. 
A detailed schedule of trial procedures and assessments is provided in Table 1 and Table 2.
After the first 6 subjects completed administration up to Day 11 of Period 2 (including), safety 
and PK data will be reviewed by the responsible functional representatives before remaining 
subjects will be treated. The decision will be documented and will be filed in the trial 
documentation files.
The following stopping rules apply throughout the trial: 

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
clinical reason for the SAE other than the trial drug
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
The trial will be permanently stopped if 4 or more subjects were withdrawn from the trial
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 occur in at least 50% of subjects which are considered related to the trial drug
by the Investigator.
Primary endpoint:

Area under the plasma concentration-time curve from time zero to the last sampling time
(AUC0-t), area under the plasma concentration-time curve from time zero extrapolated to
infinity (AUC0-∞) and maximum plasma concentration (Cmax) of midazolam (at Day 1 of
Period 1 and Day 11 of Period 2 from time zero to 48 h post-dose).
Secondary endpoints: 

tmax and t1/2 of midazolam

AUC0-t, AUC0-∞, Cmax, tmax and t1/2 of 1-hydroxymidazolam; metabolic ratio (MR)

Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of
changes in clinical laboratory assessments, 12-lead ECGs and vital signs in subjects
receiving tepotinib alone and together with midazolam assessed from Day 1 of Period 2
until the End of Trial Visit.
Exploratory endpoint: 

Genetic variants and mutations in genes that potentially influence PK of tepotinib and/or
midazolam
Note: Pharmacogenetic sample collection is mandatory. 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).
5.2.1
Inclusion of Special Populations
Not applicable.
5.2.2
Scientific Rationale for Trial Design
The trial design and endpoints are typical for a drug interaction trial of this type. The effect of 
tepotinib on CYP3A will be investigated by measurement of the PK of the sensitive CYP3A 
substrate midazolam and its main metabolite 1-hydroxymidazolam. Midazolam will be 
administered as a single dose once alone (Day 1 of Period 1) and once after 11 days of daily 
tepotinib administration (Day 11 of Period 2). Oral administration of the probe drug midazolam 
is expected to be the most sensitive test for CYP interaction as reflects effects on both, 
presystemic and systemic clearance.
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The trial will utilize a crossover design to minimize the influence of covariates, with both 
treatments applied to the same subject. A single-sequence crossover design was chosen as the 
potential effects of tepotinib on CYP3A4, including mRNA induction and mechanism-based 
inhibition, may be long-lasting. Therefore, multiple doses of tepotinib will only be administered 
in the second period of the trial. It is anticipated that a possible period effect is very small and 
negligible compared to relevant treatment effects.
No carryover of midazolam is expected between the periods due to the wash-out time of at least 
12 days between midazolam administrations. In addition, the midazolam plasma concentrations 
are expected to be below the quantification limit at the start of the first tepotinib administration 
in Period 2 (considering an apparent elimination t1/2 of about 2.5 h for midazolam and 8 to 10 h 
for 1-hydroxymidazolam in healthy adult subjects [4, 6]). 
Tepotinib will be administered for 11 days. Considering its apparent half-life of 30 h, exposure 
to tepotinib is expected to be at steady state on Day 11 of Period 2. The apparent half-life of the 
metabolite MSC2571109A is around 45 h. Simulations based on the population-PK model 
indicate that stable trough concentrations for MSC2571109A are reached only beyond 50 days of 
treatment. After 11 daily administrations, 77% of the steady-state exposure are expected. In line 
with tmax and t1/2 only small peak to trough fluctuations around the average concentration values 
were observed at steady state, therefore an interval of 4 h between tepotinib and midazolam 
administration is considered adequate to reach the maximum inhibition/induction by tepotinib.
This trial will be conducted in healthy subjects to standardize the trial population and to 
minimize exposure variability.
Although multiple doses of up to 1400 mg were found safe and well tolerated in patients (Trial
EMR200095-001), tepotinib 500 mg has been administered so far to healthy volunteers only as 
single doses (Trial EMR200095-007, single dose; trial MS200095-0012, two single doses). To 
assess the safety profile of multiple doses of 500 mg tepotinib in healthy subjects, the safety, 
tolerability and PK data from the first 6 subjects up to Day 11 of Period 2 will be reviewed by 
the responsible functional representatives. Only if tepotinib was safe and well tolerated by these 
subjects, the remaining subjects will be treated.
Nonclinical safety investigations did not reveal a genotoxicity potential or other findings with 
relevance for human use. Knowing that tepotinib shows teratogenic effects in animals, only 
healthy women who are postmenopausal or surgically sterile (ie due to hysterectomy, or bilateral 
oophorectomy, or bilateral salpingectomy) will be enrolled in this trial, and male subjects must 
agree to use and have his female partner use highly effective methods of contraception.
Close safety monitoring including clinical laboratory parameters, ECG and vital signs will be 
conducted. Special attention will be paid to the clinical laboratory parameters, including serum 
amylase and lipase. 
Midazolam is a well-established and safe drug with overall low toxicity. Owing to these 
properties, it has been safely used as a sensitive probe substrate in CYP3A4 interaction studies 
and is recommended by the relevant guidelines [7, 9].
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Subjects will be admitted to the trial site and remain resident there until at least 48 h after the last 
administration, to allow continuous safety monitoring. A monitoring period of 48 h after the last 
dose of tepotinib is regarded as sufficient to ensure the safety of the subjects. If there are any 
safety concerns 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.
An open-label design is deemed appropriate as the primary endpoint relates to pharmacokinetic 
parameters.
5.2.3
Justification for Dose
The dose of 500 mg tepotinib has been selected to reflect the RP2D dose for the treatment of 
human malignant tumors and will be administered to the trial subjects for 11 days during 
Period 2 of the trial. Given the lack of genotoxic effects of tepotinib, and the large clinical 
database, which revealed asymptomatic transient increases of amylase and/or lipase as the only 
identified risk, short term multi-day administration in this trial of 500 mg tepotinib in healthy 
subjects is expected to be safe and well tolerated. Up to two single doses of 500 mg (MS200095- 
0012) have been studied in previous studies in healthy s ubjects and were found to be well 
tolerated. Multiple dosing of 500 mg t epotinib was well tolerated in patients (see Section 3). 
Also, multiple doses of tepotinib up to 1400 mg daily have been explored in 7 patients and were 
well tolerated.
The recommended therapeutic dose of midazolam is 7.5 mg to 15 mg for premedication before 
induction of anesthesia or for conscious sedation before and during diagnostic and therapeutic 
procedures. A dose of 7.5 mg midazolam was used in several studies investigating the effect on 
CYP3A and proved to be sensitive enough to detect such an effect [4, 10]. Midazolam will be 
administered as a single oral dose of 7.5 mg midazolam tablet (ie Dormicum® 7.5 mg film-
coated tablet) on Day 1 of Period 1 and Day 11 of Period 2. 
On Day 11 of Period 2, midazolam will be administered 4 h after tepotinib dosing ie about 4 h 
after completion of a standardized continental breakfast. Thus, dosing of midazolam can be 
regarded as quasi-fasted administration.
5.2.4
Rationale for Endpoints
The peak (Cmax) and extent (area under the plasma concentration-time curve [AUC]) of exposure 
of midazolam after single dose administration are considered adequate endpoints to evaluate the 
effect of tepotinib on the PK on the CYP3A probe substrate midazolam. These endpoints are in 
line with the regulatory guidance of the FDA and the EMA (see Section 3.1).
5.3
Selection of Trial Population
Only subjects meeting all inclusion criteria and no exclusion criteria may be enrolled into the 
trial as participants. Prior to performing any trial assessments, the Investigator will ensure that 
the subject has provided written informed consent following the procedure described in 
Section 9.2.
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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 not pregnant, not breastfeeding and 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, bilateral 
oophorectomy, or bilateral salpingectomy
4. A male participant must agree to use and to have his female partners of childbearing potential 
to use highly effective methods of contraception (ie methods with a failure rate of less than 
1% per year) as detailed in the Clinical Trial Facilitation Group (CTFG) recommendations 
[11] during the period of participation in the trial and for at least 3 months after the last 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 
trial evaluation, procedures, or completion (at Screening and Day -1)
6. Subject must have given written informed consent before any trial-related activities are 
carried out and must be able to understand the full nature and purpose of the trial, including 
possible risks and adverse effects 
7. All values for hematology and biochemistry tests of blood and urinalysis should be within the 
normal range (at Screening). Minor (solitary) nonclinically relevant deviation(s) are allowed 
as judged by the Investigator, however amylase, lipase, alanine aminotransferase [ALT] and
aspartate aminotransferase [AST] values should not exceed the upper limit of normal range 
(ULN).
5.3.2
Exclusion Criteria
Subjects are not eligible for this trial if they fulfill any of the following exclusion criteria:
1. Participation in the treatment phase of a clinical trial within 60 days or 5 half-lives after last 
dosing of the previous trial drug, whatever is longer, before administration of trial drug
2. Whole blood donation or loss of > 450 mL within 60 days before administration of trial drug
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3. Any surgical or medical condition, including findings in the medical history or in the 
screening 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 trial or that 
could interfere with the trial objectives, conduct, or evaluation
4. Supine systolic blood pressure (SBP) > 140 or < 90 mmHg, diastolic blood pressure (DBP) 
> 90 or < 50 mmHg, and pulse rate > 90 or < 50 beats per minute 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. In case of a borderline result 
between ≥80 and < 90 mL/min, Cystatin C will be determined in addition, and the subject 
will only be included if the Cystatin C value is below the ULN
7. Subjects with gall bladder removal or other relevant surgery of gastrointestinal tract.
(Appendectomy is not considered as relevant)
8. History of any malignancy except for adequately treated superficial basal cell carcinoma 
9. History of epilepsy
10. Ascertained or presumptive allergy/hypersensitivity to tepotinib or midazolam 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 trial
11. Positive screen for alcohol or drugs of abuse (at Screening and Day -1 of Period 1)
12. 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)
13. Excessive consumption of xanthine-containing food or beverages (> 5 cups of coffee or 
equivalent a day) or inability to stop consuming caffeine (at Screening and Day -1)
14. Receipt of any prescription or nonprescription medication within 14 days or 5 half-lives, 
whatever is longer, before trial drug administration (apart from paracetamol up to 1500 mg 
per day, as judged appropriate by the Investigator)
15. Smoker (cigarettes, pipes, cigars, or others) or former smoker who stopped smoking less than 
6 months before the time of the Screening Visit
16. Intake of grapefruit, Seville orange, cranberry or juices of these fruits, or St. John’s Wort, 
from 14 days prior to Day -1
17. Inability to communicate or cooperate with the Investigator (eg language problem, illiteracy, 
poor mental status) or to comply with the requirements of the entire trial, including dietary 
restrictions 
18. Other factors, which in the opinion of the Investigator may interfere with trial conduct (at 
Screening and Day -1 only)
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19. Legal incapacity or limited legal capacity 
20. Subjects kept in detention
21. Any contraindications according to midazolam label (ie hypersensitivity to the active 
substance, benzodiazepines or to any of the excipients listed in the SmPC, severe respiratory 
insufficiency, sleep apnea syndrome, severe hepatic impairment, myasthenia gravis.
5.4
Criteria for Initiation of Trial Treatment
Inclusion and exclusion criteria will be checked within the screening period and again on Day -1 
of Period 1. Subjects meeting all the inclusion and none of the exclusion criteria will be enrolled 
in the trial.
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 trial assessments).
Withdrawal of a subject from trial drug due to any of the above reasons means that this subject 
prematurely discontinues the trial, 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).
Subjects who dropped out must be replaced. 
5.5.2
Withdrawal from the Trial
Subjects must be withdrawn from the trial by the Investigator at any time for any of the 
following reasons:
Subject withdrew consent
Subject lost to Follow-up
Participation in another clinical trial
Relevant AEs, especially SAEs, occur that do not justify the subject’s continuation in the trial
Pregnancy
Protocol noncompliance judged as significant by the Investigator and/or Sponsor
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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 IMPs 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 ULN, total bilirubin ≥2 x 
ULN), creatinine ˃ 1.5 x (ULN) confirmed by ≥2 repeat measurements
-
Any clinically relevant symptom or sign which in the opinion of the Investigator and/or 
Sponsor warrants subject withdrawal.
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 electronic Case Report Form 
(eCRF) section must be completed.
Subjects who withdraw from the trial must be replaced.
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 IMP. 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.
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Health Authorities and IECs will be informed about the discontinuation of the trial in accordance 
with applicable regulations.
5.7
Definition of End of Trial
The End of 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 trial).
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 treatment or therapy in a clinical trial, including products that have a 
marketing authorization but are formulated, packaged, or administered differently from the 
authorized form, 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 (HCl) hydrate, is 
supplied as 500 mg (oblong, light yellow) film-coated tablets (Tablet Formulation 2, 
TF2) for oral administration 
Tepotinib 500 mg film-coated tablets have a drug load of approximately 50% and 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 (ALU)/ALU blisters and storage at or below 25°C.

Midazolam: Commercially available midazolam will be used, ie Dormicum 7.5 mg film-
coated tablets.
Reference product: Not applicable.
Specific rules for treatment modifications: Not applicable.
6.2
Dosage and Administration
Subjects will receive the following 2 treatments.
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Treatment A (Period 1): Administration of Midazolam Alone
On Day 1 of Period 1, a single oral dose of 7.5 mg midazolam as tablet will be administered in a 
quasi-fasted state 4 h after completion of a standardized breakfast together with 240 mL water. 
Time of breakfast and midazolam administration should be the same as planned for Day 11 of 
Period 2 (eg breakfast from 06:30 h to 06:55 h, midazolam dosing at 11:00 h).
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 can leave the bed without undue physical stress/activity. If necessary subjects may 
stay in bed for a longer period at the discretion of the Investigator.
Standardized meals will be served 4 h (light meal) and 8 h (dinner) after administration of 
midazolam on Day 1 of Period 1; thereafter, meals will be served at customary times during the 
inpatient period.
Treatment B (Period 2): Administration of Tepotinib and Midazolam
On Days 1 to 10 of Period 2, 500 mg tepotinib will be administered together with 240 mL of 
water after a continental breakfast (about 30 min after start of breakfast). Some flexibility of the 
continental breakfast on Days 1 to 10 is allowed, but the breakfast should be not high caloric. 
Cooked egg and Müsli with milk will be allowed on these days.
Standardized meals will be served 4 h (light meal) and 8 h (dinner) after administration of 
tepotinib on Days 1 to 10 of Period 2, while some flexibility is allowed within the range of 
standardization on these days, ie meals should be light, and comparable with regard to 
composition and caloric content. Other meals will be served at customary times during the 
inpatient period.
On Day 11 of Period 2, the subjects will receive a standardized breakfast, which must match with 
the breakfast on Period 1, Day 1, with regard to composition and content, in order to minimize 
potential influence of covariates for the PK profiling of midazolam. The standardized breakfast 
must be consumed completely within 25 min. 30 min after start of the breakfast, 500 mg 
tepotinib will be administered together with 240 mL of water. A single oral dose of 7.5 mg 
midazolam will be administered 4 h after tepotinib administration together with 240 mL water.
On Day 11 of Period 2, subjects will stay in a semi-recumbent position for 4 h after midazolam 
administration, except for use of the toilet, when the subjects will be allowed to leave the bed 
without undue physical stress/activity. If necessary subjects may stay in bed for a longer period 
at the discretion of the Investigator.
Standardized meals will be served 4 h (light meal) and 8 h (dinner) after administration of 
midazolam on Day 11 of Period 2; other meals will be served at customary times during the 
inpatient period.
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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 P K of C Y P 3 A S u bstr ate Mi d az ol a m
M S 2 0 0 0 9 5- 0 0 3 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 3 /7 1
6. 3
Assi g n me nt t o Tre at me nt Gr o u ps
T he s u bjects willi n g t o partici pate i n t he trial a n d si g ni n g t he I nf or me d C o nse nt F or m (I C F) will 
be assi g ne d a s u bject n u m ber. T he y  will o nl y  be i ncl u de d w he n all Scre e ni n g e xa mi nati o n 
pr oce d ures ha ve de m o nstrate d t hat all i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria a p pl y. 
S u bjects eli gi ble f or t he trial will recei ve a n assi g n me nt n u m ber pri or t o t he first a d mi nistrati o n.
Ra n d o mizati o n is n ot a p plica ble i n t hi s trial.
Acc or di n g t o C R O sta n dar d o perati o nal pr oce d ures ( S O Ps), t he s u bjects will be assi g ne d a n
assi g n me nt n u m ber i n t he or der of t heir re gistrati o n t o t he trial (first re gistrati o n res ults i n t he 
l o west a vaila ble assi g n me nt n u m ber, sec o n d re gistrati o n res ults i n t he sec o n d l o west a vaila ble 
assi g n me nt n u m ber, a n d s o o n). H o we ver, prece de nce will be gi ve n t o s u bjects w h o partici pate 
i n a trial at 
 f or t he first ti me a n d f or s u bjects w h o ser ve d as “sta n d-b y ” d uri n g a 
prece di n g trial. 
T he I nvesti gat or will kee p a rec or d (scree ni n g l o g) relati n g t he s u bject n u m bers a n d t he na mes of 
all s u bjects (i ncl u di n g t he N u visa n G m b H I D n u m ber) w h o ha ve gi ve n t heir i nf or me d c o nse nt, t o 
all o w eas y chec ki n g of data i n s u bject files, w he n re q uire d. T his re c or d will als o i ncl u de t he date 
of scree ni n g a n d c o m pleti o n stat us, as well as s u bjects w h o c o ul d n ot be e nr olle d i n t he acti ve 
treat me nt trial part ( defi ne d as scree ni n g fail ures) f or w hate ver reas o n. O n t he e nr ollme nt l o g t he 
s u bject n u m ber, assi g n me nt nu m ber a n d stat us are liste d.
6. 4
N o n- i n vesti g ati o n al Me dici n al Pr o d ucts t o be Use d
N ot a p plica ble.
6. 5
C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures
All c o nc o mita nt me dicati o ns ta ke n b y  the s u bject d uri n g t he trial, fr o m t he date of si g nat ure of 
i nf or me d c o nse nt are t o be rec or de d i n t he a p pr o priate secti o n of t he e C R F, n oti n g t he na me, 
d ose, r o ute, d urati o n, re gi me n, stat us a n d i n dicati o n of eac h dr u g. N o n dr u g i nter ve nti o ns a n d a n y 
c ha n ges t o a c o nc o mita nt me dicati o n or ot her i nter ve nti o n s h o ul d als o be rec or de d i n t he e C R F.
6. 5. 1
Per mitte d Me dici nes
Paraceta m ol is t he o nl y per mitte d me dicati o n. Paraceta m ol will be per mitte d u p t o a ma xi m u m 
dail y  d osa ge of 1 5 0 0 m g .
A n y  me dicati o ns t hat are c o nsi dere d necessar y t o pr otect s u bject welfare a n d t hat will n ot 
i nterfere wit h t he I M Ps ma y  be gi ve n at t he I n vesti gat or’s discreti o n. T he p ote ntial D DI s wit h 
te p oti ni b are still u n der e val uati o n. T heref ore, me dicall y  re q uire d c o nc o mita nt me dicati o n mi g ht 
ha ve t o be a dj uste d base d o n t olera bilit y  a n d t he cli nical res p o nse.
T he I nvesti gat or will rec or d, i n t he a p pr o priate secti o n of t he e C R F, all pre vi o us/c o nc o mita nt 
me dicati o ns ta ke n b y t he s u bject d uri n g t he trial, fr o m t he date of si g nat ure of i nf or me d c o nse nt.
D o c u me nt N o. 
 
O bject N o. 
 
0 9 0 0 ba be 8 0f 2f 5 2 1 v 1. 0
0 9 0 0 ba be 8 0fc b 3 d d
Pa ge 3 4 of 7 2
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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 14 days or 
5 half-lives, whichever is longer, prior to the first IMP 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 (as provided by 
the trial site) and will be reminded regularly.
Throughout the PK profiling days of Periods 1 and 2, the following restrictions must be met:

Subjects should be in the fasted state for at least 10 h before breakfast and at least 4 h 
after midazolam administration (= 8 h after breakfast) on Day 1 of Period 1 and on Day 
11 of Period 2

Drinking is not allowed for 1 h before and after administration of midazolam and for 1 h 
after administration of tepotinib

Chewing gum is not allowed during the PK profile days.
Throughout the trial, the following restrictions must be met:

No smoking or use of tobacco products

No alcohol intake

No intake of food and beverages other than provided to the subjects by the trial site 
during the inpatient period

No intake of caffeine- and xanthine-containing food and beverages (eg coffee, black or 
green tea, cola, cocoa, chocolate or chocolate-containing food or beverages) from 48 h 
before first administration of trial drug until collection of last PK sample of 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 
of Period 1 until final examination

No intake of poppy seeds (eg poppy seed rolls, poppy seed cake, yoghurt containing 
poppy seed etc.) from 72 h before first administration of trial drug until completion of 
final examination

No intake of concomitant medication within 14 days or 5 half-lives, whatever is longer, 
before first administration of trial drug until final examination (except for paracetamol up 
to 1500 mg per day, may be given at the discretion of the Investigator) 

No intake of recreational drugs within 14 days or 5 half-lives, whatever is longer, before 
first administration of trial drug until final examination 
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
No exhausting physical activities (body building, sports) from at least 72 h before the first 
administration of trial drug until the final examination 

No sun baths, solarium or sauna at least 12 h before first administration of trial 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. 
Midazolam 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 midazolam will be supplied 
in ready to use oral formulations. The responsible pharmacist will dispense the necessary amount 
of the IMPs. Detailed guidance will be provided in an IMP handling manual.
The IMP supplies will be recorded in an IMP 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 IMP 
should not be used until authorization has been received from the Sponsor. The preparation, 
handling and storage of the IMP will be documented.
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Detailed recommendations for the use and storage of midazolam are described in the Summary
of Product Characteristics [6].
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 IMP 
accountability, including reconciliation of drugs and maintenance of records. Drug accountability 
will also be confirmed by the Trial Monitor.

Upon receipt of IMPs, 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:
o
Confirmation of IMP receipt, in good condition
o
The inventory of IMPs provided for the clinical trial and prepared at the site
o
The use of each dose by each subject
o
The disposition (including return, if applicable) of any unused IMP
o
Dates, quantities, batch numbers, kit numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject assignment 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. No IMP 
that is dispensed to a subject may be redispensed to a different subject. 
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.
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 
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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
This is an open-label trial by design. Therefore, blinding is not applicable. (Note: the 
bioanalytics will be performed without knowledge of treatment information. Access to treatment 
information will be restricted and defined in a Data Access Plan).
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.
Midazolam may cause somnolence, confusion, lethargy, muscle relaxation and paradoxical 
excitation. Treatment, if needed, of overdosing or overreaction of midazolam will be performed 
as per SmPC, ie monitoring of vital signs, symptomatic treatment of cardiorespiratory or central 
nervous adverse events; in case of severe central nervous depression, Flumazenil, a specific 
benzodiazepine-receptor antagonist, is an antidote available at the site for midazolam.
6.13
Medical Care of Subjects after End of Trial
Not applicable in a trial with healthy subjects.
7
Trial Procedures and Assessments
7.1
Schedule of Assessments
Detailed schedule of trial procedures/assessments is provided in Table 1 (administration of 
midazolam alone) and Table 2 (administration of tepotinib and midazolam).
Prior to performing any trial assessments, the Investigator will obtain written informed consent 
as described in Section 9.2.
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7.1.1
Screening Examination
All subjects will undergo an entry examination to evaluate their health status and their eligibility 
for inclusion in the trial. The Screening examination will be conducted not more than 21 days 
prior to the planned first drug administration, ie between Day -21 to Day -2 before commencing 
to first trial period. Only subjects who meet the inclusion criteria and none of the exclusion 
criteria will be admitted to the trial. 
Prior to Screening examination, the subjects will receive a subject number for identification. 
Eligible subjects will receive an assignment number prior to the first drug administration.
There is a notification on the subject’s card as well as in the electronic subjects’ database 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 ICF. This Screening examination 
will consist of the following:

Demographic information including body height, body weight and BMI

Medical history

Physical examination

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments 

Serological tests for hepatitis B, C, and HIV1/HIV2 

Serum pregnancy test for women 

Urine drugs of abuse screen (including test for cotinine) 

Alcohol breath test

Prior medication and concomitant medication

Assessment of AEs

Preliminary evaluation of inclusion and exclusion criteria.
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. Subjects will be assigned an assignment number within the trial prior to the first 
administration.
For detailed time points and assessments please see Table 1 (Treatment A) and Table 2
(Treatment B).
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Adverse event monitoring is generally assessed between Trial Day -1 and Trial Day 15.
Subjects will be hospitalized from the morning of Trial Day -1 (= Day -1 of Period 1) until 
completion of the assessments of Trial Day 15 (= Day 13 of Period 2). 
Treatment A (Period 1 - Midazolam alone)
Day -1 of Period 1 (admission)
On admission on Day -1 of Period 1 the following will be done:

Physical examination

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments

Pregnancy test for women (in urine)

Urine drugs of abuse screen (including test for cotinine)

Alcohol breath test

Evaluation of inclusion and exclusion criteria

Assessment of AEs

Documentation of concomitant medication.
Days 1 to 2 of Period 1 (inpatient)
Prior to dosing of midazolam on Day 1 of Period 1 the following will be done:

Vital signs

12-lead ECG

Pulse oximetry from about 30 min before until 6 h after midazolam administration

Pre-dose PK blood sample for determination of midazolam and 1-hydroxymidazolam

Blood sample for PGx.
Midazolam will be administered together with 240 mL water, 4 h after completion of a 
standardized breakfast.
After dosing of midazolam on Day 1 of Period 1 the following will be done:

PK blood samples for determination of midazolam and 1-hydroxymidazolam will be 
taken regularly until 48 h post-dose (for time points please see Table 1)

Vital signs will be measured and 12-lead ECGs will be recorded from 4 h until 48 h 
post-dose (for time points please see Table 1)
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
Regular assessment of AEs and documentation of concomitant medication.
Treatment B (Period 2 - Tepotinib and Midazolam)
Days 1 to 10 of Period 2 (inpatient)
Prior to the daily dosing of tepotinib the following will be done on specific days as detailed 
in the Schedule of Assessments (see Table 2):

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments

Pre-dose PK blood sample for determination of trough levels of tepotinib and its
metabolites on Days 9 and 10 of Period 2

Day 1 of Period 2: PK blood sample for determination of midazolam and 1-
hydroxymidazolam (= 48 h sample for Period 1).
After completion of the pre-dose assessments a continental breakfast will be served and 500 mg 
tepotinib will be administered together with 240 mL water 30 min after start of breakfast on 
Days 1 to 10.
Additionally, the following will be done on specific days as detailed in the Schedule 
of Assessments (see Table 2):

Vital signs (6 h post-dose)

12-lead ECG (6 h post-dose)

Regular assessment of AEs and documentation of concomitant medication.
Day 11 of Period 2 (inpatient)
Prior to dosing of tepotinib the following will be done:

Pre-dose PK blood sample for determination of trough levels of tepotinib and its
metabolites is taken

Blood and urine samples for safety laboratory assessments.
Thereafter, 500 mg tepotinib will be administered together with 240 mL of water, 30 min after 
start of a standardized breakfast, which must be consumed completely within 25 min. 
Prior to dosing of midazolam the following will be done:

Vital signs

12-lead ECG

Pulse oximetry from about 30 min before until 6 h after midazolam administration
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
Pre-dose PK blood sample for determination of midazolam and 1-hydroxymidazolam.
After completion of the pre-dose assessments a single oral dose of 7.5 mg midazolam will be 
administered together with 240 mL water 4 h after tepotinib administration.
After dosing of midazolam the following will be done

Vital signs will be measured and 12-lead ECGs will be recorded from 4 h until 48 h
post-dose (for time points please see Table 2).

PK blood samples for determination of midazolam and 1-hydroxymidazolam will be
taken regularly until 12 h post-dose (for time points please see Table 2).

Regular assessment of AEs and documentation of concomitant medication.
Days 12 to 13 of Period 2 (inpatient)
The following activities will be done:

Physical examination (on Day 13 of Period 2 only)

Vital signs

12-lead ECG

Blood and urine samples for safety laboratory assessments (on Day 12 of Period 2 only)

PK blood samples for determination of midazolam and 1-hydroxymidazolam will be
taken regularly from 24 h until 48 h post-dose (for time points please see Table 2)

Regular assessment of AEs and documentation of concomitant medication.
After completion of all assessments on Day 13 of Period 2, the subjects will be discharged.
Details about the measurements are provided in Sections 7.4 and 7.5.1.
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:
A detailed listing of restrictions during the trial is provided in Section 6.5.
7.1.3
End of Trial Visit
The End of Trial examination must verify that all values tested in the Screening have remained 
within a clinically acceptable range. The assessments will be performed 7 ± 1 days 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. 
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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

Serum pregnancy test for women

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)

Smoking status, alcohol intake

Female status (postmenopausal, sterilization).
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the IMP 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.
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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 
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.
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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
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.
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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 d ocumented 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. 
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.
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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.
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 [14], 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 with regards to Safety Report notifications to 
Investigators will be taken into account.
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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 AEs 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 p regnancies 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 c onvention 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.
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.
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7.4.3
Clinical Laboratory Assessments
Fasted blood samples and urine samples will be collected for the clinical laboratory t ests 
(hematology, biochemistry, 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.
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 as summarized in Table 3. 
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMP. Any 
change in laboratory normal ranges during the trial should be forwarded to the Sponsor, 
including laboratory certificates.
For the amount of blood taken in this trial see Appendix II.
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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
Cystatin C (if applicable)
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:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils 
Urinalysis 
pH
Nitrite
Protein 
Glucose
Ketone bodies
Urobilinogen 
Bilirubin
Urine pregnancy 
test, females only
Leucocytes
Blood
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 C antibody
HIV1/HIV2 antibodies 
Follicle stimulating hormone (if applicable), only females
Thyroid stimulating hormone
Serum pregnancy test (beta-HCG), only females
eGFR e
Alcohol breath test
HIV = human immunodeficiency virus, beta-HCG = beta-human chorionic gonadotropine, eGFR = Estimated 
glomerular filtration rate
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.
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7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Blood pressure (SBP [mmHg] and DBP [mmHg]) will be measured according to the 
oscillometric method using an automated device, which also indicates the corresponding pulse 
rate. 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).
Pulse oximetry will be performed continuously from about 30 min before until 6 h after 
midazolam administration. Oxygen will be administered as determined by the Investigator in the 
event of a pulse oximetry reading of < 92% (confirmed by repeat measurement).
Body temperature will be measured auricular (Table 1 and Table 2).
Further vital sign measurements during the trial 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 will be signed and dated electronically 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 trial 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 schedule of assessments (see Table 1 
and Table 2). Further physical examinations during the course of the trial are at the discretion of 
the Investigator. Any relevant findings are to be recorded on the Medical History form in the 
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eCRF (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). 
7.4.4.4
Alcohol Breath Test
A commercially available breath analyzer (Alcotest 6510, Draeger Safety GmbH) will be used to 
determine the concentration of alcohol in the subject’s breath per the schedule of assessments 
(see Table 1 and Table 2). 
Additional alcohol breath tests during the course of the trial are at the discretion of the 
Investigator.
7.5
Pharmacokinetics
7.5.1
Blood Sampling
On the PK profiling days, an indwelling venous catheter will be positioned in a suitable forearm 
vein for blood sampling and should be kept, if possible, until 12 or 24 h after dosing. After 
removing the indwelling venous cannula, samples will be taken by venipuncture. 
Plasma levels of midazolam and 1-hydroxymidazolam (Day 1  o f Period 1 and Day 1 1 of 
Period 2 from time pre-dose to 48 h post midazolam dosing) will be determined. Blood samples 
for determination of tepotinib and its metabolites trough levels will be taken before tepotinib 
administration on Days 9, 10 and 11. The sampling schedule is outlined in Table 1 and Table 2.
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
PK Blood Sampling - Allowed Time Windows
Planned Blood Sampling 
Time Windows (min)
Pre-dose
-60 min
0-1 h post-dose
± 2 min
After 1 h - 12 h post-dose
± 5 min
After 12 h - 48 h post-dose
± 15 min
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.
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 trial see 
Appendix II.
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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 midazolam, 1-hydroxymidazolam and tepotinib (and its metabolites) will be 
measured using validated Liquid Chromatography and Tandem Mass Spectrometry methods at 
Nuvisan. The assays will be carried out in accordance with Good Laboratory Practice 
Regulations and the EMA reflection paper. Separate bioanalytical protocols will be provided 
before the start of the analytical part of the trial. Full details of the bioanalytical methods used 
will be described in separate bioanalytical reports.
7.5.2
Calculation of Pharmacokinetic Variables
The following non-compartmental PK parameters (see Table 5) will be calculated from the 
individual 
plasma 
concentration-time 
data 
using 
commercial 
software 
such 
as 
Phoenix®/WinNonlin® (Certara, L.P., Princeton, New Jersey, Version 6.4 or higher) at Nuvisan 
GmbH.
Table 5
Definition 
of 
PK 
Parameters 
for 
Midazolam 
and
1-Hydroxymidazolam 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 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
AUCextra
The AUC from time tlast extrapolated to infinity
AUCextra%
AUCextra / AUC0-∞x 100
MR
Metabolic ratio of midazolam AUC0-∞and 1-hydroxymidazolam AUC0-∞
Individual PK parameters will be calculated using actual sampling times. The pre-dose sample 
will be considered as if it had been taken simultaneously with the administration of trial drug. PK 
variables will be evaluated and listed for all subjects who provide sufficient concentration-time 
data.
Plasma concentrations below lower limit of quantification (LLOQ) before the last quantifiable 
data point will be taken as zero for calculating the AUC (ie embedded below the limit of 
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quantitation values set to zero). Plasma concentrations below LLOQ after the last quantifiable 
data point will not be considered for the determination of the terminal rate constant (λz).
7.6
Biomarkers
Not applicable.
7.7
Pharmacogenomics 
Pharmacogenetic sample collection is mandatory. An additional separate 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
The sample size consideration and the statistical analysis are primarily aimed at the classification 
of the tepotinib effect (inducer and/or inhibitor of CYP3A) as strong/moderate/mild. 
Nevertheless, the calculated 90% confidence intervals for the treatment ratios will provide a 
more general description of the drug-drug interaction.
8.1
Sample Size
A total of 12 subjects will be treated in this trial. Drop-outs will be replaced.
The coefficient of variation for midazolam AUC0-t has been reported between 31% [12] and 49% 
[13]. 
Assuming a coefficient of variation (CV) of 50% for AUC0-t, a one-sided alpha of 0.05, and a 
treatment ratio for the GeoMeans ranging between 0.85 and 1.18, the power to exclude a 
moderate effect (the 90% confidence interval needs to be within [0.50 – 2.00]) will be 80% with 
12 evaluable subjects. A test to exclude a mild effect (ie to demonstrate bioequivalence) is not 
considered since the required sample size is unacceptably high with around 80 subjects assuming 
a true treatment ratio of 1.00.
8.2
Randomization
Not applicable.
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8.3
Endpoints
8.3.1
Primary Endpoint

AUC0-t, AUC0-∞and Cmax of midazolam (at Day 1 of Period 1 and Day 11 of Period 2 
from time zero to 48 h post-dose).
8.3.2
Secondary Endpoints

tmax and t1/2 of midazolam

AUC0-t, AUC0-∞, Cmax, tmax and t1/2 of 1-hydroxymidazolam; metabolic ratio (MR)

Occurrence of TEAEs (incidence, frequency, intensity and causality), occurrence of 
changes in clinical laboratory assessments, 12-lead ECGs and vital signs in subjects 
receiving tepotinib alone and together with midazolam assessed from Day 1 of Period 2 
until the End of Trial Visit.
8.3.3
Exploratory Endpoint

Genetic variants and mutations in genes that potentially influence PK of tepotinib and/or 
midazolam
Note: Pharmacogenetic sample collection is mandatory. The results of the 
pharmacogenetic analysis, as applicable, will be described in a separate report.
8.4
Analysis Sets
For purposes of analysis, the following populations are defined:
Population
Description
Safety
The Safety Analysis Set will include all subjects who have received at 
least 1 dose of planned IMP. 
Pharmacokinetic
The PK Analysis Set will include all subjects without any relevant 
protocol deviations with respect to PK and absence of factors likely to 
affect the comparability of PK results, who have received at least one dose 
of midazolam and who have at least 3 post-dose concentration 
measurements. 
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.
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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 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, minimum, and maximum) and categorical data will be summarized by 
means of frequency tables (ie count and percentages), if not stated otherwise.
Concentrations of midazolam and 1-hydroxymidazolam 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, standard error of the mean, median, minimum, maximum, 
and CV%. Values below the LLOQ will be taken as zero for descriptive statistics of PK 
concentrations. Descriptive statistics of PK parameters will additionally show the GeoMean, the 
geometric coefficient of variation (GeoCV%), and the 95% confidence interval (CI) for the 
GeoMean. PK data flagged as “invalid” will be handled as missing in the analyses.
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 (SAP) and in the clinical trial report.
8.5.2
Analysis of Primary Endpoint
For the statistical analysis of AUC0-t of midazolam data, a-priori ordered hypotheses will be 
tested. 
Test 1
H01: T/R ratio ≤0.2 or T/R ratio ≥5.0
effect stronger than moderate
versus
HA1: T/R ratio within [0.2 ; 5.0]
moderate effect
Test 2
H02: T/R ratio ≤0.5 or T/R ratio ≥2.0
effect stronger than mild
versus
HA2: T/R ratio within [0.5 ; 2.0]
mild effect.
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A general linear model with a fixed effect for TREATMENT and a random effect for SUBJECT 
will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞of midazolam based 
on the PK analysis set. Treatment differences on the log scale of midazolam with tepotinib vs 
midazolam 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 confidence intervals 
for AUC will be compared to the acceptance ranges for moderate effects [0.2 ; 5.0] and mild 
effects [0.5 ; 2.0].
Individual estimates of relative bioavailability and metabolic ratio (MR) of midazolam will be 
calculated for each subject and summarized.
For tmax of midazolam the Hodges-Lehmann shift estimator will be calculated together with the 
90% CI according to Tukey. PK variables will be evaluated and listed for all subjects of the PK 
Analysis Set.
Graphical displays will be given, where appropriate, individual and mean concentration-time 
plots will be produced in linear and log-linear scale. For the primary endpoints, boxplots will be 
given. Details of the statistical analysis will be described in the SAP.
8.5.3
Analysis of Secondary Endpoints
For tmax of midazolam the Hodges-Lehmann shift estimator will be calculated together with the 
90% CI according to Tukey.
Summary statistics will be provided for all secondary PK parameters in plasma by time point. 
PK variables will be listed for all subjects who provide sufficient concentration-time data. 
Invalid data will be flagged accordingly.
Graphical displays will be given, where appropriate. Details of the statistical analysis will be 
described in the SAP.
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 TEAE 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 postdose 
shifts relative to baseline, and data listings of clinically significant abnormalities/out of the 
normal range.
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.
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8.5.5
Analysis of Exploratory Endpoint
Methods for the pharmacogenetic analysis will be separately planned and results will be 
described in a separate report.
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 [14], 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 
[14] 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.
After the information is provided by the Investigator, the ICF 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 ICF 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 
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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 ICF 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.
In cases where the Investigator is not available, the Phase 1 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.
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9.6
Independent Ethics Committee 
Prior to commencement of the trial, this clinical trial protocol will be submitted together with its 
associated documents (for example, ICF, 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 ICF 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, IMP Dossier, Subject 
Information and ICF) 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.
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.
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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.
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 ICFs. 
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 [14], 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.
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP [14] 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 (non-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.
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 [15].
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoints. The results 
of this trial 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 trial results. 
Posting of data on ClinicalTrials.gov and EU Clinical Trials Register (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. Gorski JC, Hall SD, Jones DR, et al. Regioselective biotransformation of midazolam by 
members of the human cytochrome P450 3A (CYP3A) subfamily. Biochem Pharmacol.
1994;47(9):1643-53.
2. Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of midazolam by the human 
intestine. Clin Pharmacol Ther. 1996;60(1):14-24. 
3. Zhu B, Bush D, Doss GA, et al. Characterization of 1′-hydroxymidazolam glucuronidation 
in human liver microsomes. Drug Metab Dispos. 2008;36(2):331-8.
4. Juif PE, Boehler M, Donazzolo Y, et al. A pharmacokinetic drug–drug interaction trial
between selexipag and midazolam, a CYP3A4 substrate, in healthy male subjects. Eur J 
Clin Pharmacol. 2017;73:1121-8.
5. Reves JG, Fragen RJ, Vinik HR, et al. Midazolam: pharmacology and uses. 
Anesthesiology. 1985;62(3):310-24.
6. Midazolam Summary of Product Characteristics (Fachinformation) Dormicum® 7.5 mg 
film-coated tablets, November 2014.
7. Clinical Drug Interaction Studies - Trial Design, Data Analysis, and Clinical Implications, 
Guidance for Industry, DRAFT GUIDANCE, U.S. Department of Health and Human 
Services Food and Drug Administration, Center for Drug Evaluation and Research 
(CDER), October 2017.
8. Guidance for Industry; Drug Interaction Studies - Trial Design, Data Analysis, 
Implications for Dosing, and Labeling Recommendations, DRAFT GUIDANCE; U.S. 
Department of Health and Human Services Food and Drug Administration, Center for 
Drug Evaluation and Research (CDER), February 2012.
9. EMA Guideline on the investigation of drug interactions, CPMP/EWP/560/95/Rev. 1 
Corr. 2**, 21 June 2012.
10. Zdravkovic M, Olsen AK, Christiansen T, et al. A clinical trial investigating the 
pharmacokinetic interaction between NN703 (tabimorelin), a potential inhibitor of 
CYP3A4 activity, and midazolam, a CYP3A4 substrate. Eur J Clin Pharmacol. 2003;58: 
683-8.
11. 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.
12. Paulson SK, Wood-Horrall RN, Hoover R, et al. The Pharmacokinetics of the CYP3A 
Substrate Midazolam After Steady-state Dosing of Delafloxacin. Clin Therapeut.
2017;39:1182-90.
13. Syed S, Clemens PL, Lathers D, et al. Lack of Effect of Brivanib on the Pharmacokinetics 
if Midazolam, a CYP2A4 Substrate, Administered Intravenously and Orally in Healthy 
Participants. J Clin Pharmacol. 2012;52:914-21.
14. ICH 
Topic 
E6(R2) 
Guideline 
for 
good 
clinical 
practice 
E6(R2). 
EMA/CHMP/ICH/135/1995. London, 1 December 2016. 1-70.
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15. ICH Topic E3. Structure and Content of Clinical Study Reports. CPMP/ICH/137/95,
London July 1996. 1-47.
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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 1 5 6 1 1 9 J) 
M S 2 0 0 0 9 5- 0 0 3 0 
Eff e ct of T e p oti ni b o n P K of C Y P 3 A S u bstr ate Mi d az ol a m 
Si g n at u r e P a g e - P r ot o c ol L e a d 
T ri al Titl e: 
P hase 1, O p e n-l a b el, 
Si n gle S e q u e n c e, T w o- P eri o d 
Cr oss o v er Trial t o E v al u at e t he Eff e ct of T e p oti ni b o n 
C yt oc hr o m e P 4 5 0 ( C Y P) 3 A b y I n v esti g ati n g t he 
P h ar m a c o ki n eti cs of t h e C Y P 3 A S u bstr at e Mi d a z ol a m 
i n H e alt h y S u bj e cts 
E u dr a C T N u m ber: 
2 0 1 7- 0 0 5 0 5 5- 9 2 
Cli ni c al 
T ri al 
P r ot o c ol 
D at e 
/ 1 2 J u n e 2 0 1 8 / V ersi o n 1. 0 
V e rsi o n: 
P r ot o c ol L e a d: 
I a p pr o v e t he d esi g n of t he 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, a c a d e mi c de gree: 
, 
 
F u n cti o n / Title: 
Me dical R es p o nsi bl e / 
 
I nstit uti o n: 
M er c k K G a A 
A d dress: 
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 ber: 
 
E- m ail a d dress: 
 
D o c u m e nt N o. 0 9 0 0 b a b e 8 0f 2f 5 2 I v I. 0 
O bj e ct N o. 0 9 0 0 b a b e 8 0f c b 3 d d 
C O N F
I D E N TI A L 
I N F O R M A TI O N 
6 6/ 7 1 
Pa ge 6 7 of 7 2
PI
PI
PI
PI
PI
PI
PI


T e p oti ni b ( M S C 2 1 5 6 1 1 9 J) 
M S 2 0 0 0 9 5- 0 0 3 0 
Eff e ct of T e p oti ni b o n P K of C Y P 3 A S u bst r at e Mi d a z ol a m 
Si g n at u r e P a g e - P ri n ci p al I n v esti g at o r 
T ri al Titl e 
P h as e I, 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 
Cr oss o v er Tri al t o E v al u at e the Eff e ct of T e p oti ni b o n 
C yt o c hr o m e 
P 4 5 0 ( C Y P) 3 A 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 C Y P 3 A S u bstr at e M i d a zo la m 
i n H e alt h y S u bj e cts 
E u d r a C T N u m b e r 
2 0 1 7- 0 0 5 0 5 5- 9 2 
Cli ni c al 
T ri al 
P r ot o c ol 
D at e 
/ 
1 2 J u n e 2 0 1 8 / V ersi o n 1. 0 
V e rsi o n 
C e nt e r N u m b e r 
P ri n ci p al I n v esti g at o r 
 
 
I, t h e u n d ersi g n e d, a p pr o v e t h e d e s i g n of t h e cli ni c al tri al a n d I u n d er st a n d a n d will c o n d u ct of 
t h e tri al at t his sit e a n d affir m t h at I u n d erst a n d a n d will c o n d u ct t h e tri al a c c or di n g t o the cli ni c al 
tri al pr ot o c ol , a n y a p pr o v e d pr ot o c ol a m e n d m e nts , I nt er n ati o n al C o u n c il f or H ar m o nis ati o n 
G o o d Cli ni c al Pr a cti c e ( T o pi c E 6) a n d all a p pli c a bl e H e alt h A ut h orit y re q uir e m e nts a n d n ati o n al 
l a ws. 
Si g n at ur e 
D at e of Si g n at ur e 
N a m e , a c a d e mi c d e g ree: 
, 
 
F u n cti o n/ Titl e: 
Pri n ci p al I n v esti g at or 
I nstit uti 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: 
 
F a x n u m b er: 
 
E- m ail a d dr ess: 
 
D oc u m e nt N o. 0 9 0 0 b a b e 8 0 1 2f 5 2 I v 1. 0 
O bj e c t N o. 0 9 0 0 b a b e 8 0f c b 3 d d 
C O N FI D E N TI A L 
I N F O R M A TI O N 
6 7/ 7 1 
Pa ge 6 8 of 7 2
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 Te p oti ni b o n P K of C Y P 3 A S u bstr ate Mi d az ol a m
M S 2 0 0 0 9 5- 0 0 3 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 8 /7 1
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 2f 5 2 1 v 1. 0
0 9 0 0 ba be 8 0fc b 3 d d
Pa ge 6 9 of 7 2
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
1 a
6 b
1
9
42.3
Hematology
2.7
1
1 a
5 b
1
8
21.6
PK midazolam
2.0
14 e
14 f
28
56.0
PK tepotinib
2.0
3 g
3
6.0
PGx
2.0
2 h
2
4.0
Total
2
18
28
2
50
129.9
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 trial
that will not be exceeded in this planned trial as by experience of the Investigating Institution:
180
FSH = follicle stimulating hormone, PGx = pharmacogenetics, PK = pharmacokinetics, TSH = thyroid stimulating 
hormone.
Clinical laboratory (biochemistry and hematology) blood samples
a
Period 1: Day -1 = 1 sample
b
Period 2: 
Biochemistry: pre-dose on Days 1, 2, 5, 8, 11 and on Day 12 = 6 samples
Hematology: pre-dose on Days 1, 5, 8, 11 and on Day 12 = 5 samples
Midazolam and 1-hydroxamidazolam PK blood samples
e
Period 1, Day 1: at pre-dose, 15, 30, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36 and 48 h post-dose = 14 samples
f
Period 2, Day 11: at pre-dose, 15, 30, 60, 90 min, and 2, 3, 4, 6, 8, 12, 24, 36 and 48 h post-dose = 14 samples
Tepotinib and its metabolites PK blood samples
g
Period 2: pre-dose on Days 9, 10 and 11 = 3 samples
PGx blood samples
h
PGx blood samples of 2 x 2 mL to be drawn on Day 1 of Period 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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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 P K of C Y P 3 A S u bstr ate Mi d az ol a m  
M S 2 0 0 0 9 5- 0 0 3 0 fi n al  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 3  
 
 
 
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 0  
Title  
P hase 1, O pe n -la b el, Si n gle Se q u e nce, T w o-Peri o d  
Cr oss o ver Trial t o E val u ate t he Effect of T e p oti ni b 
o n C yt oc hr o me P 4 5 0 ( C Y P) 3 A b y I n vesti gati n g t he 
P har mac o ki netics of t he C Y P 3 A S u bstrate 
Mi daz ola m i n Healt h y S u bjects  
Tri al P h ase  
I 
I n vesti g ati o n al Me dici n al 
Pr o d uct(s)  
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  
1 2 J u ne 2 0 1 8 / Versi o n 1. 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 
 
, Nu vi s a n  
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n  
1 4 N o ve m ber 2 0 1 8 / Fi nal  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  
  
, 
, M er c k 
 
,  
 
, M er c k 
 
, M er c k 
 
, M er c k 
 
 
 
 
C o nfi de nti al  
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 de 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 1 5 3
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI
PI


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 P K of C Y P 3 A S u bstr at e Mi d a z ol a m 
M S 2 0 0 0 9 5- 0 0 3 0 fi n al v ersi o n 1. 0 
Si g n at ur e P a g e 
I nt e gr at e d A n al ysis Pl a n: M S 2 0 0 0 9 5- 0 0 3 0 
P h as e 1, O p e n-l a b el, Si n gl e S e q u e nce , T w o- P eri o d Cr oss o v er Tri al t o E v al u at e t h e Eff e ct of 
T e p oti ni b o n C yt o c hr o m e P 4 5 0 ( C YP) 3 A b y I nv es ti g ati n g t h e P h ar m a c o ki n eti c s of t h e C Y P 3 A 
S u bstr at e 
, 
, 
, 
N U VI S A N G m b H , 
W e g e n er str ass e 1 3, 
8 9 2 3 1 N e u- Ul m, G er m a n y 
, 
 
M er c k K G a A , Fra n kft u 1er Str ass e 2 5 0 , 
6 4 2 9 3 D ar mst a dt , G er m a n y 
D at e 
 
C O N F I D E N T
I A L 
I N F O R M A TI O N 
Si g n at ur e 
2/ 2 3 
Pa ge 3 of 1 5 3
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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 o n P K of C Y P 3 A S u bstr ate Mi d az ol a m 
M S 2 0 0 0 9 5- 0 0 3 0 fi n al versi o n 1. 0 
Si g n at u r e P a g e 
I nt e g r at e d A n al ysis Pl a n: M S 2 0 0 0 9 5- 0 0 3 0 
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 Cr oss o v er Tri al t o E v al u at e t h e Eff e ct of 
T e p oti ni b o n C yt o c hr o m e P 4 5 0 ( C Y P) 3 A 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 he 
C Y P 3 A S u bstr at e 
, 
, 
, 
N U VI S A N G m b H, 
W e g e n erstr ass e 1 3, 
8 9 2 3 1 N e u- Ul m, G er m a n y 
, 
 
M er c k K Ga A, 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 
D at e 
C O N FI D E N TI A L 
I N F O R M A TI O N 
Si g n at u r e 
2/ 2 3 
Pa ge 4 of 1 5 3
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Tepotinib (MSC2156119J) 
Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
MS200095-0030 final 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 
3/23 
 
 
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 ..........7 
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 ..........................................8 
9 
General Specifications for Data Analyses ............................................9 
10 
Trial Subjects ......................................................................................10 
10.1 
Disposition of Subjects and Discontinuations ....................................10 
10.2 
Protocol Deviations ............................................................................11 
10.2.1 
Important Protocol Deviations ............................................................11 
10.2.2 
Reasons Leading to the Exclusion from an Analysis Set ...................11 
11 
Demographics and Other Baseline Characteristics .............................12 
11.1 
Demographics .....................................................................................12 
11.2 
Medical History ..................................................................................12 
11.3 
Other Baseline Characteristics ............................................................12 
12 
Previous or Concomitant Medications/Procedures .............................13 
13 
Treatment Compliance and Exposure .................................................13 
14 
Efficacy Analyses ...............................................................................13 
15 
Safety Analyses ..................................................................................13 
15.1 
Adverse Events ...................................................................................14 
15.1.1 
All Adverse Events .............................................................................14 
15.1.2 
Adverse Events Leading to Treatment Discontinuation .....................15 
15.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................16 
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4/23 
 
 
15.2.1 
Deaths .................................................................................................16 
15.2.2 
Serious Adverse Events ......................................................................16 
15.2.3 
Other Significant Adverse Event ........................................................16 
15.2.3.1 
Adverse Events of Special Interest .....................................................16 
15.3 
Clinical Laboratory Evaluation ...........................................................16 
15.4 
Vital Signs ..........................................................................................17 
15.5 
ECG Evaluation ..................................................................................17 
16 
Analyses of Other Endpoints ..............................................................18 
16.1 
Pharmacokinetics ................................................................................18 
General Specifications for Plasma Concentration Data .....................................................18 
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 .................................................................21 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters .......................21 
16.2 
Pharmacogenetics ...............................................................................23 
17 
References ...........................................................................................23 
18 
Appendices .........................................................................................23 
 
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Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
MS200095-0030 final version 1.0 
 
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I N F O R M A T I O N 
5/23 
 
 
2 
List of Abbreviations and Definition of Terms 
AE 
Adverse Event 
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% 
AUCextra / AUC0-∞ x 100 
BMI 
Body Mass Index 
CI 
Confidence Interval 
Cmax 
Maximum plasma concentration observed 
CSR 
Clinical Study Report 
CV% 
Coefficient of Variation 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
GeoCV% 
Geometric Coefficient of Variation 
GeoMean 
Geometric Mean 
IAP 
Integrated Analysis Plan 
ICH 
International Conference on Harmonization 
LCI 
Lower Confidence Interval Bound 
LLOQ 
Lower Limit of Quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Metabolic Ratio 
NCI-CTCAE 
National Cancer Institute – Common Terminology Criteria for Adverse 
Events 
PD 
Pharmacodynamics 
PGx 
Pharmacogenetics 
PK 
Pharmacokinetics 
PT 
Preferred Term 
Q1 
25th Percentile 
Page 7 of 153


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 P K of C Y P 3 A S u bstr ate Mi d az ol a m  
M S 2 0 0 0 9 5- 0 0 3 0 fi n al  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 3  
 
 
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 A E  
Seri o us A d verse E v e nt  
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  
t1/ 2 
Ter mi nal half -lif e 
T E A E  
Treat me nt E mer ge nt A d v erse E ve nt  
tlast 
T he  last  sa m pli n g  ti me  at  w hic h  t he  c o nce ntrati o n  is  at  or  a b o ve  t he 
l o wer li mit of q ua ntificati o n 
tma x  
Ti me t o reac h t he m a xi m u m plas ma c o nce ntrati o n  
U L O Q  
U p per Li mit of Q ua ntificati o n  
U CI  
U p per C o nfi de n ce I nter v al  B o u n d  
 
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  
1 4 -N O V -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 0 . 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 res 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 par e d i n c o m plia nce wit h I C H E 9.  
 
 
Pa ge 8 of 1 5 3
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Tepotinib (MSC2156119J) 
Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
MS200095-0030 final 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 
7/23 
 
 
5 
Objectives and Endpoints 
 
Objective 
Endpoint 
IAP 
section 
Primary 
Objective 
To investigate the effect of 
multiple doses of tepotinib on 
AUC0-t, AUC0-∞, and Cmax of 
the CYP3A substrate midazolam 
in healthy subjects. 
AUC0-t, AUC0-∞, and Cmax of midazolam 
 
 
 
 
 
Secondary 
Objective 
To further investigate effects of 
multiple doses of tepotinib on the 
PK of midazolam 
tmax and t1/2 of midazolam 
 
 
To investigate the effect of 
multiple doses of tepotinib on the 
PK of the main midazolam 
metabolite 1-hydroxymidazolam 
AUC0-t, AUC0-∞, Cmax, tmax and t1/2 of 1-
hydroxymidazolam; metabolic ratio (MR) 
 
To assess the safety and 
tolerability of tepotinib alone and 
upon co-administration of 
midazolam. 
Occurrence of treatment emergent adverse events 
(TEAEs; incidence, frequency, 
intensity and causality), occurrence of changes in 
clinical laboratory assessments, 12-lead 
electrocardiograms (ECGs) and vital signs in 
subjects receiving tepotinib alone and together with 
midazolam assessed from Day 1 of Period 2 until 
the End of Trial Visit. 
 
Exploratory 
Objective 
To explore the effect of 
pharmacogenetics (PGx) and 
variations of associated genes on 
the PK profile of tepotinib and/or 
midazolam. 
Genetic variants and mutations in genes that 
potentially influence PK of tepotinib 
and/or midazolam. 
 
 
 
 
 
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, ie, end of trial visit/early 
termination visit with all trial data in-house, all data queries resolved, and the database locked.  
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.  
Boxplots of the primary endpoints have been replaced with scatter plots (16.1.1).   
 
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Tepotinib (MSC2156119J) 
Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
MS200095-0030 final version 1.0 
 
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I N F O R M A T I O N 
8/23 
 
 
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 
• 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) 
In addition for the definition of the PK analysis set (see section 8.2) factors likely to affect the 
comparability of PK results will be identified. Important events to be considered are: 
• Vomiting or diarrhea following oral dosing (these instances will be discussed on a case-
by-case basis) 
• 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 and factors likely to affect the comparability of PK results 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: 
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Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
MS200095-0030 final version 1.0 
 
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I N F O R M A T I O N 
9/23 
 
 
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 without any relevant 
protocol deviations with respect to PK and absence of factors likely to 
affect the comparability of PK results, who have received at least one dose 
of midazolam and who have at least 3 post-dose concentration 
measurements. 
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). 
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 [n] and percentage of observations, 
number and percentage of missing observations, arithmetic mean [Mean], standard deviation 
[SD], median, 25th and 75th percentiles [Q1 and Q3], minimum [Min], and maximum [Max]) 
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.  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 within the same period pre-dose could become 
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I N F O R M A T I O N 
10/23 
 
 
the baseline value. 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 dosing or event 
then = event start date – date of dose administration + 1 
• Rel. Day in period of AE = start date of the event – date of First Admin in period + 1 (for AEs 
on or after the day of dosing)  
• Rel. Day of pre-treatment AE = start date of the event – date of First Admin (for pre-treatment 
AEs before first treatment administration of the study only)  
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, eg due to technical reasons, and needed to be replaced by an unscheduled repeat 
measurement). 
In this phase 1 PK 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 
to the last planned observation in a trial period will be included in the analyses up to the time of 
discontinuation. 
The following treatment labels will be used in listing and tables: 
• midazolam 
• tepotinib + midazolam 
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 
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Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
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I N F O R M A T I O N 
11/23 
 
 
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) 
• Number and percentage of subjects who discontinued 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 the PK  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. 
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Tepotinib (MSC2156119J) 
Effect of Tepotinib on PK of CYP3A Substrate Midazolam 
MS200095-0030 final version 1.0 
 
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I N F O R M A T I O N 
12/23 
 
 
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 CRF pages.  
Demographic characteristics: 
• Sex: male, female  
• Race: Black or African American, American Indian or Alaska Native, Asian, Native 
Hawaiian or other Pacific Islander, White, Other 
• Ethnic origin: Hispanic or Latino , Not Hispanic or Latino  
• Age (years): summary statistics 
• Height (cm) at Baseline: summary statistics 
• Weight (kg) at Baseline: summary statistics 
• 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 
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• 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. 
 
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. In addition a listing of the midazolam plasma 
concentrations will be provided. 
  
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.  
 
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14/23 
 
 
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. 
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 midazolam 
• Any TEAE related to tepotinib  
• Any serious TEAE  
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• Any trial treatment related serious TEAE  
• Any midazolam related serious TEAE  
• Any tepotinib related serious TEAE  
• Any TEAE of grade >=3 
• Any trial treatment related TEAE of grade >=3  
• Any midazolam related TEAE of grade >=3  
• Any tepotinib related TEAE of grade >=3 
• Any TEAE leading to death 
• Any trial treatment related TEAE leading to death 
• Any midazolam related TEAE leading to death 
• Any tepotinib related 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. Group/SOC terms will be sorted alphabetically and PTs 
within each group/SOC term will be sorted by descending frequency.  
• 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. 
In addition the following tables will be provided. 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):  
• 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 (related to any treatment, related to midazolam, and 
related to tepotinib) with the number and percentage of subjects by treatment with at least one 
TEAE and the number of events by SOC and PT.  
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. 
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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. 
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. 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 
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- 
End of Trial versus Screening 
- 
Discharge versus Pre-dose (Tepotinib admistration) for period 2 only. 
 
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, Version 5.0 (publication date: 
27 Nov 2017),  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 
• Biochemistry 
• Urinalysis 
• Other tests 
 
Tables will be produced for the groups Hematology, and Biochemistry.  
 
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 by 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 =
 
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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. 
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 will be descriptively summarized using nominal times: n, Mean, SD, 
standard error of the mean (SEM), coefficient of variation (CV%), Min, Median and Max. 
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  
Values below the lower limit of quantification of the assay (LLOQ) will be taken as zero for 
summary statistics of PK concentration data. 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 
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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 hours, as if 
the sample had been taken simultaneously with the study drug administration. 
General Specifications for PK Parameter Data  
PK parameter data will be descriptively summarized: n, Mean, SD, SEM, CV%, Min, Median, 
Max, geometric mean (GeoMean), the geometric coefficient of variation (GeoCV) and the 95% 
confidence interval for the GeoMean (LCI 95% GeoMean, UCI 95% 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 digits. In export datasets, as well as in the SDTM PP 
domain, PK parameters will be provided with full precision, and will not be rounded. 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, MR) 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 PK data will be listed. Data of subjects not in the PK analysis 
set or invalid data will be flagged accordingly. 
In this phase 1 PK 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 
to the last planned observation in a trial period will be included in the analyses up to the time of 
discontinuation. 
 
 
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16.1.1 
Primary Endpoints 
Statistical hypotheses 
For the statistical analysis of AUC0-t of midazolam data, a-priori ordered hypotheses will be 
tested. 
Test 1  
H01: T/R ratio ≤ 0.2 or T/R ratio ≥ 5.0 effect stronger than moderate 
 
versus 
 
HA1: T/R ratio within [0.2 ; 5.0] moderate effect 
Test 2  
H02: T/R ratio ≤ 0.5 or T/R ratio ≥ 2.0 effect stronger than mild 
 
versus 
 
HA2: T/R ratio within [0.5 ; 2.0] mild effect, 
where R is midazolam and T is tepotinib + midazolam 
A general linear model with a fixed effect for TREATMENT and a random effect for SUBJECT 
will be applied to log-transformed PK parameters Cmax, AUC0-t, and AUC0-∞ of midazolam based 
on the PK analysis set. Treatment differences on the log scale of midazolam with tepotinib vs. 
midazolam 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 confidence intervals 
for AUC will be compared to the acceptance ranges for moderate effects [0.2 ; 5.0] and mild 
effects [0.5 ; 2.0]. 
PK variables will be evaluated and listed for all subjects of the PK Analysis Set. 
The primary endpoints will be descriptively summarized. Scatter plots will be produced for each 
primary endpoint by treatment group indicating the geometric means within each treatment 
group. 
16.1.2 
Secondary Endpoints 
Summary statistics will be provided for tmax and t1/2 and the relative bioavailabilities 
(Frel,test/reference) of midazolam. For tmax, the Hodges-Lehmann shift estimates will be calculated 
together with the 90% confidence intervals according to Tukey.  
Summary statistics will be provided for AUC0-t, AUC0-∞, Cmax, tmax and t1/2 of 1-
hydroxymidazolam and the metabolic ratio (MR). 
PK variables will be evaluated for all subjects of the PK population, but listed for all subjects 
with available data. 
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16.1.3 
Exploratory Endpoints 
Pharmacogenetic analyses will be presented in a separate report. 
16.1.4 
Plasma Concentration Data 
Concentrations of midazolam and its metabolite 1-hydroxymidazolam will be tabulated and 
displayed graphically. Summary statistics will be provided by treatment and nominal timepoint. 
The following figures will be produced, separately for midazolam and 1-hydroxymidazolam: 
• 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 
Trough concentrations of Tepotinib and its metabolite will be descriptively summarized by 
treatment and nominal time point. Scatter plots will be produced for each of the days 9, 10 and 
11 for the trough concentrations indicating the geometric mean within each treatment group. 
 
The following listing will be produced: 
• Plasma concentrations will be listed for each analyte by treatment, subject, and nominal 
time. Excluded plasma concentrations will be flagged. 
• Trough concentrations will be listed for Tepotinib and its metabolite by treatment, 
subject, and nominal time. Excluded trough concentrations will be flagged. 
 
16.1.5 
Estimation of Individual Pharmacokinetic Parameters 
The following non-compartmental PK parameters (see Table 1) will be calculated from the 
individual plasma midazolam and 1-hydroxymidazolam concentration-time data using 
commercial software such as Phoenix®/WinNonlin® (Version 6.4 or higher) at Nuvisan GmbH. 
 
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Table 1 
Definition of PK Parameters for Midazolam and 1-Hydroxymidazolam  
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 observed 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 
AUCextra 
The AUC from time tlast extrapolated to infinity 
AUCextra% 
AUCextra / AUC0-∞ x 100. 
MR 
Metabolic ratio of midazolam AUC0-∞ and 1-hydroxymidazolam AUC0-∞ 
Frel,test/reference Relative bioavailability (test versus reference), defined as AUC0-∞, reference 
/AUC0-∞, test, where AUC0-∞, test is AUC0-∞ for tepotinib+midozalam and AUC0-∞, 
reference is AUC0-∞ for midazolam. 
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 below the limit of quantification values set to zero). 
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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.   
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 the 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, and t1/2) will be included in the parameter listings and will be discussed 
appropriately in alignment with the protocol lead and quantitative pharmacology representative. 
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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