Phase I Open-label, Single Dose Study to Investigate the Effect of Hepatic Impairment on the PK of Evobrutinib (M2951)
Phase: PHASE1
Conditions: Hepatic Impairment
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

M2951
Effect of hepatic impairment on evobrutinib PK
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
Phase I
Open-label, Single Dose Study to 
Investigate the Effect of Hepatic Impairment on the 
Pharmacokinetics (PK) of Evobrutinib (M2951)
Study Number:
MS200527_0059
Amendment Number
Not Applicable
Merck Compound Number:
M2951
Study Phase:
Phase I
Short Title:
Effect of hepatic impairment on evobrutinib PK
Principal Investigator:
Sponsor Name and Legal Registered 
Address:
Merck Healthcare KGaA
an affiliate of Merck KGaA, Darmstadt, Germany
Frankfurter Str. 250
Darmstadt, Germany
Medical Responsible:
Name:
Address: As above
General Merck Phone Number:
Mobile: 
General Merck Fax Number: Not applicable
Email:
Regulatory Agency Identifying 
Numbers:
EudraCT: 2020-001920-32
Protocol Version:
22 May 2020/Version 1.0
Replaces Version:
Not applicable
Approval Date:
22 May 2020
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Medical Monitor Name and Contact 
Information:
Phone: 
Mobile: 
Email: 
Protocol History
Version Number
Type
Version Date
1.0
Original Protocol
22-May-2020
- Confidential –
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2020 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................3
1
Protocol Summary ................................................................................6
1.1
Synopsis................................................................................................6
1.2
Schema..................................................................................................8
1.3
Schedule of Activities...........................................................................9
2
Introduction.........................................................................................11
2.1
Study Rationale...................................................................................11
2.2
Background.........................................................................................11
2.3
Benefit/Risk Assessment ....................................................................12
2.3.1
Risk assessment ..................................................................................13
2.3.2
Benefit Assessment.............................................................................14
2.3.3
Overall Benefit: Risk Conclusion.......................................................14
3
Objectives and Endpoints ...................................................................15
4
Study Design.......................................................................................15
4.1
Overall Design....................................................................................15
4.2
Scientific Rationale for Study Design ................................................17
4.3
Justification for Dose..........................................................................17
4.4
End of Study Definition......................................................................18
5
Study Population.................................................................................18
5.1
Inclusion Criteria ................................................................................18
5.2
Exclusion Criteria...............................................................................20
5.3
Lifestyle Considerations .....................................................................23
5.3.1
Meals and Dietary Restrictions...........................................................23
5.3.2
Caffeine, Alcohol, Tobacco, and Cannabinoid...................................23
5.3.3
Activity ...............................................................................................23
5.4
Screen Failures....................................................................................23
6
Study Intervention(s) ..........................................................................24
6.1
Study Intervention(s) Administration.................................................24
6.1.1
Medical Device(s)...............................................................................24
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6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................24
6.3
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................25
6.3.1
Study Intervention Assignment ..........................................................25
6.3.2
Blinding ..............................................................................................26
6.3.3
Emergency Unblinding.......................................................................26
6.4
Study Intervention Compliance..........................................................26
6.5
Concomitant Therapy .........................................................................26
6.5.1
Rescue Medicine.................................................................................26
6.5.2
Permitted Medicines...........................................................................26
6.5.3
Prohibited Medicines..........................................................................27
6.5.4
Other Interventions.............................................................................27
6.6
Dose Selection and Modification........................................................28
6.7
Study Intervention after the End of the Study ....................................28
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................28
7.1
Discontinuation of Study Intervention................................................28
7.2
Participant Discontinuation/Withdrawal from the Study ...................28
7.3
Lost to Follow-Up...............................................................................29
8
Study Assessments and Procedures....................................................29
8.1
Efficacy Assessments and Procedures................................................30
8.2
Safety Assessments and Procedures ...................................................30
8.2.1
Physical Examinations........................................................................30
8.2.2
Vital Signs ..........................................................................................30
8.2.3
Electrocardiograms.............................................................................31
8.2.4
Clinical Safety Laboratory Assessments ............................................31
8.2.5
Suicidal Ideation and Behavior Risk Monitoring...............................31
8.3
Adverse Events and Serious Adverse Events.....................................31
8.3.1
Time Period and Frequency for Collecting Adverse Event and
Serious Adverse Event Information....................................................32
8.3.2
Method of Detecting Adverse Events and Serious Adverse Events...32
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............32
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8.3.4
Regulatory Reporting Requirements for Serious Adverse Events .....33
8.3.5
Pregnancy ...........................................................................................33
8.4
Treatment of Overdose .......................................................................34
8.5
Pharmacokinetics................................................................................34
8.6
Pharmacodynamics.............................................................................36
8.8
Biomarkers..........................................................................................36
8.9
Immunogenicity Assessments ............................................................36
8.10
Health Economics...............................................................................36
9
Statistical Considerations....................................................................37
9.1
Statistical Hypotheses.........................................................................37
9.2
Sample Size Determination ................................................................37
9.3
Populations for Analyses ....................................................................38
9.4
Statistical Analyses.............................................................................38
9.4.1
Efficacy Analyses ...............................................................................38
9.4.2
Safety Analyses ..................................................................................39
9.4.3
Other Analyses....................................................................................40
9.4.3.1
Analysis of Pharmacokinetics.............................................................40
9.4.4
Sequence of Analyses.........................................................................40
10
References...........................................................................................41
11
Appendices .........................................................................................42
Appendix 1
Abbreviations......................................................................................43
Appendix 2
Study Governance...............................................................................45
Appendix 3
Contraception......................................................................................52
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................54
Appendix 5
Clinical Laboratory Tests ...................................................................60
Appendix 7
Sponsor Signature Page......................................................................62
Appendix 8
Principal Investigator Signature Page.................................................63
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1
Protocol Summary
1.1
Synopsis
Protocol Title: 
Phase I, Open-label, Single Dose Study to Investigate the Effect of Hepatic Impairment on the 
Pharmacokinetics (PK) of Evobrutinib (M2951)
Short Title: 
Effect of hepatic impairment on evobrutinib PK
Rationale: 
The purpose of the study is to describe the evobrutinib pharmacokinetics (PK) in participants with 
different stages of hepatic impairment compared to a control group of participants with normal 
hepatic function. The results of this study will contribute to the understanding of the evobrutinib 
metabolism and inform recommendations on dose adjustments in participants with hepatic 
impairment.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To investigate the PK of evobrutinib after a 
single dose to participants with hepatic 
impairment compared to participants with 
normal hepatic function
AUC0-∞, and Cmax
Secondary
To assess the safety and tolerability of 
evobrutinib when administered as a single 
dose to participants with normal hepatic 
function and with impaired hepatic function
Occurrence of treatment-emergent adverse 
events (TEAEs), changes from Baseline in 
laboratory safety tests, 12-lead 
electrocardiogram (ECG) morphology and 
time intervals (PR, QRS, RR, QT, and QTcF), 
and vital signs from time of first dose to the 
End of Study
To characterize the effect of hepatic function 
on the PK of evobrutinib through secondary 
PK endpoints
tmax, t½, AUC0-12 and AUC0-24, AUC0-t, CL/f, 
VZ/f, unbound fraction in plasma (fu), AUC 
for unbound drug from time zero to infinity 
(AUC0-∞,u), unbound Cmax (Cmax,u), and 
unbound apparent oral clearance (CL,u/f)
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Overall Design: 
This is an open-label, nonrandomized, parallel-group, single-center, single oral dose, Phase I study 
to investigate the PK and safety of evobrutinib in participants with different degrees of hepatic 
impairment compared to participants with normal hepatic function. Participants will be assigned 
to one of 3 groups: normal hepatic function (Group 1), mild hepatic impairment (Group 2), or 
moderate hepatic impairment (Group 3). Participants of Group 2 (8 participants with mild hepatic 
impairment) will be recruited in parallel with participants of Group 3 (8 participants with moderate 
hepatic impairment). After completion of enrollment of both Group 2 and Group 3, Group 1 
consisting of 8 healthy participants will be recruited to match the group mean value to the 
participants of Group 2 and Group 3 regarding age (± 10 years; ≥ 18 years old and ≤ 79 years old), 
and weight (± 10%; ≥50 kg and ≤ 120 kg). Efforts will also be made to have adequate sex
representation in Group 1 (+ 2/- 2 male or female participants) that is similar to Groups 2 and 3. 
Up to 4 additional participants may be recruited in Group 1 for matching purpose.
Disclosure Statement:
This is an open-label, parallel group PK study with 3 arms.
Number of Arms: 3
Blinding: No blinding
Number of Participants: 
A maximum of 28 participants will be assigned to study intervention such that approximately 24 
to 28 evaluable participants complete the study. Each of the 3 groups is planned to include 
8 participants. Up to 4 additional participants may be added into Group 1 for matching purpose.
Based on the observed total variability of the primary PK endpoints for similar doses of evobrutinib 
in the most recent Phase I studies, the coefficient of variation (CV) of the geometric mean for AUC 
and Cmax is expected to be between 30% and 60%.
Study Intervention Groups and Duration: 
The duration of the study will be up to 33 days: Participants will be screened between Day -28 to 
Day -2, dosing will occur on Day 1, PK sampling and safety assessments will occur on Day 1 
through to Day 2 and the Follow-Up visit between Day 4 and Day 6.
Involvement of Special Committee(s): No
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1.2
Schema
Abbreviations: PK= Pharmacokinetics
Hepatic 
Impairment
Moderate (Child-
Pugh Class B) (N=8)
Healthy participants matched to participants with 
mild and moderate hepatic impairment  
(N=8-12)
Mild (Child-Pugh 
Class A) (N=8)
Study Day
1              2
Evobrutinib
Administration
30 mg fed
30 mg fed
Evobrutinib
PK sampling
Safety
Confinement 
Days
-1 to 2
-1 to 2
1              2
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1.3
Schedule of Activities
Assessments & Procedures
Screening
(Baseline 
if Day -1 
value not 
available)
Study Day
Follow-Up/ 
Discontinuation
Notes
Study Day
-28 to -2
-1 
1 
2 
4 to 6
Day -1 value will be used as baseline if 
available. For ECG and vital sign, Day 1 
predose value will be used as baseline.
Informed Consent
X
Prior to any screening activity
Inclusion and Exclusion Criteria
X
X
Demography
X
Hospitalization
X
X
X
Participants may be discharged 32 hours after 
administration of study intervention
Full Physical Examination 
X
X
Medical History (includes substance 
usage)
X
Substances: drugs, smoking history, alcohol 
intake, use of caffeine or xanthine-containing 
beverages
Ultrasound and Assessment of
Encephalopathy
X
For participants with hepatic impairment only
Serum Pregnancy Test (WOCBP only)
X
X
X
Drug and Alcohol Test
X
X
See Appendix 5
Clinical Laboratory Tests
X
X
X
X
See Appendix 5
12-lead ECG
X
X
X
Single ECG assessments will be conducted;
Day 1: at predose (as baseline) and 1 hour
postdose
Vital Signs
X
X
X
X
X
Includes height & weight collected at Screening 
only
Day 1: at predose (as baseline) and 1 hour
postdose; Day 2 at 32 hours postdose. 
See Section 8.2.2.
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Assessments & Procedures
Screening
(Baseline 
if Day -1 
value not 
available)
Study Day
Follow-Up/ 
Discontinuation
Notes
Study Day
-28 to -2
-1 
1 
2 
4 to 6
Day -1 value will be used as baseline if 
available. For ECG and vital sign, Day 1 
predose value will be used as baseline.
Administration of Study Intervention
X
Administration will occur 30 mins after starting a 
standard breakfast
AE & SAE Review
X
X
X
X
X
Concomitant Medication Review
X
X
X
X
PK sampling
X
X
Predose, 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 
8.0, 10.0, 12.0, 16.0, 24.0, 32.0 hours postdose. 
See Section 8.5.
PK sampling for free fraction
X
1.5, 4, and 12 hours postdose. No separate 
blood collected. Backup samples will be used 
See Section 8.5
Abbreviations: AE = Adverse event; ECG = Electrocardiogram; PK= Pharmacokinetics; SAE = Serious adverse event; WOCBP = woman of childbearing potential
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2
Introduction
Evobrutinib is an oral, selective, irreversible inhibitor of Bruton’s tyrosine kinase (BTK) which is 
in clinical development for the treatment of autoimmune diseases, e.g., multiple sclerosis (MS), 
rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE).
Detailed information on the chemistry, pharmacology, efficacy, and safety of evobrutinib is in the
current version of the Investigator’s Brochure (IB).
2.1
Study Rationale
The purpose of the study is to describe the evobrutinib pharmacokinetics (PK) in participants with 
different stages of hepatic impairment compared to a control group of participants with normal 
hepatic function. The results of this study will contribute to the understanding of the evobrutinib 
metabolism and inform recommendations on dose adjustments in participants with hepatic 
impairment.
2.2
Background
Evobrutinib (also known as M2951 and MSC2364447C) is an oral, selective, irreversible inhibitor 
of BTK. Bruton’s tyrosine kinase is a crucial intracellular kinase in the B cell antigen receptor 
(BCR) signaling pathway. The mode of action of evobrutinib and nonclinical data support clinical 
development in a broad spectrum of autoimmune and inflammatory disorders involving aberrant 
B cell and myeloid cell activity. Inhibition of BTK is expected to achieve profound B cell silencing. 
Thus, BTK inhibition could provide clinical benefit in the treatment of multiple autoimmune 
diseases including RA, SLE, and MS. 
 
 
 
 
 
 
 
 
Additional details of the safety, efficacy, and PK of evobrutinib may be found in the current version 
of the IB.
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2.3
Benefit/Risk Assessment
As of July 31, 2019, approximately 1,214 adults have been exposed to evobrutinib including 
healthy participants, participants with relapsing multiple sclerosis (RMS), SLE, or RA, and 
participants with renal impairment. Evobrutinib was generally well tolerated in all participants. 
The treatment-emergent adverse events (TEAE)s have been primarily mild to moderate in severity.
The aim of the study is to describe PK of evobrutinib in participants with different stages of hepatic 
impairment compared to a healthy control group. The results of this study will contribute to the 
understanding of the evobrutinib metabolism and inform recommendations on dose adjustments 
in participants with hepatic impairment. 
 
 
 
 
 
 
 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AE)s of evobrutinib may be found in Section 4.2 and the IB. 
Based on the available nonclinical and clinical data to date, the conduct of the study, as specified 
in this protocol, is considered justifiable.
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2.3.1
Risk assessment
Identified and Potential 
Risks of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Intervention(s) [evobrutinib]
Identified risks:
Elevated liver transaminases.
Elevated liver transaminases 
have been observed in 
patients treated with 
evobrutinib across the 
program and is considered an 
important identified risk (for 
details see current IB). 
Elevations of liver 
transaminases were frequent, 
generally mild (Grade 1), 
asymptomatic and reversible, 
and occurred within 6 months 
of treatment. However, more 
severe cases were reported. 
This has not been observed in 
healthy participants after a 
single dose nor in patients 
within a week of treatment 
with evobrutinib.
As a single low dose of 
evobrutinib will be 
administered in this study, 
and given the short half-life 
of evobrutinib, worsening of 
liver function is unlikely to 
occur. Study participants will 
be confined, and liver tests 
will be monitored during the 
study.
Potential risks:
Embryo-fetal toxicity
Based on nonclinical 
findings, embryo-fetal 
toxicity is considered as an 
important potential risk in 
participants exposed to 
evobrutinib. 
Female participants of 
childbearing potential must 
not be pregnant, must have a 
negative pregnancy test at the 
time of enrollment and use 
highly effective contraception 
(Section 5.1) during the study 
period and for 120 days after 
the last dose and agree not to 
donate eggs for reproduction.
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Identified and Potential 
Risks of Clinical 
Significance
Summary of Data/Rationale 
for Risk
Mitigation Strategy
Study Procedures
Blood draw
Blood draws have the 
potential to cause discomfort 
and adverse events such as 
fainting or hematoma.
Amount of blood drawn will 
be strictly controlled. 
Participants will be in a 
hospital setting with support 
from highly trained 
professionals.
Electrocardiogram (ECG)
Contact allergies can develop 
during ECG procedures.
Participants with known 
contact allergies will not be 
included in the study. During 
ECG participants will be 
monitored by highly trained 
professionals.
Other
Not applicable.
2.3.2
Benefit Assessment
The aim of the study is to describe the PK of evobrutinib in participants with different stages of 
hepatic impairment compared to a healthy control group. The results of this study will contribute 
to the understanding of the evobrutinib metabolism and inform recommendations on dose 
adjustments in participants with hepatic impairment. Therefore, participants will contribute to the 
process of developing new therapies in areas of unmet need where evobrutinib could be used.
2.3.3
Overall Benefit: Risk Conclusion
The risk minimization proposed in this study includes a low dose of evobrutinib, single dosing and 
site admission of the study participant for the duration of the study to allow continuous safety 
monitoring. This clinical study will be conducted in compliance with the clinical study protocol, 
International Council for Harmonization and Good Clinical Practices (ICH GCP), and any 
additional applicable regulatory requirements.
Considering the potential risks and the measures taken to minimize risk to participants in this study, 
the conduct of the study is considered as justified in the participants with hepatic impairment. 
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3
Objectives and Endpoints
Objectives
Endpoints
Primary
To investigate the PK of evobrutinib after a 
single dose to participants with hepatic 
impairment compared to participants with 
normal hepatic function
AUC0-∞, and Cmax
Secondary
To assess the safety and tolerability of 
evobrutinib when administered as a single 
dose to participants with normal hepatic 
function and with impaired hepatic function
Occurrence of treatment-emergent adverse 
events (TEAEs), changes from Baseline in 
laboratory safety tests, 12-lead ECG 
morphology and time intervals (PR, QRS, 
RR, QT, and QTcF), and vital signs from time 
of first dose to the End of Study
To characterize the effect of hepatic function 
on the PK of evobrutinib through secondary 
PK endpoints
tmax, t½, AUC0-12 and AUC0-24, AUC0-t, CL/f, 
VZ/f, unbound fraction in plasma (fu), AUC 
for unbound drug from time zero to infinity 
(AUC0-∞,u), unbound Cmax (Cmax,u), and 
unbound apparent oral clearance (CL,u/f)
Tertiary/Exploratory
Not applicable.
4
Study Design
4.1
Overall Design
This is an open-label, nonrandomized, parallel-group, single-center, single oral dose, Phase I study 
to investigate the PK and safety of evobrutinib in participants with different degrees of hepatic 
impairment compared to participants with normal hepatic function.
Participants with hepatic impairment will be assigned to a group of mild (Child-Pugh class A) or 
moderate (Child-Pugh class B) hepatic impairment at Screening by use of the Child-Pugh system 
(Table 1 and Table 2) and, in addition to participants with normal hepatic function, assigned to 
one of the following groups:
! Group 1: normal hepatic function
! Group 2: mild hepatic impairment
! Group 3: moderate hepatic impairment
Participants of Group 2 (8 participants with mild hepatic impairment) will be recruited in parallel 
with participants of Group 3 (8 participants with moderate hepatic impairment). After completion 
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of enrollment of both Group 2 and Group 3, Group 1 consisting of 8 healthy participants will be 
recruited to match the group mean value to the participants of Group 2 and Group 3 regarding age 
(± 10 years; ≥ 18 years old and ≤ 79 years old), and weight (± 10%; ≥50 kg and ≤ 120 kg). Efforts 
will also be made to have adequate sex representation in Group 1 (+2/-2 male or female 
participants) that is similar to Groups 2 and 3. Up to 4 additional participants may be recruited in 
Group 1 for matching purpose.
Table 1
Child-Pugh Grades/Class of Hepatic Impairment
Child-Pugh Score 
Child-Pugh Grade/Class
Severity of Hepatic Impairment
5-6 
A
Mild
7-9 
B
Moderate
10-15 
C
Severea
a
Participants with severe hepatic impairment will not be included in this study. 
Table 2
Child-Pugh Criteria (FDA – Guidance for Industry, 2003)
Points Scored for Observed Findings
1
2
3
Encephalopathy gradea
none
1 or 2
3 or 4
Ascitesb
absent
slight
moderate
Serum bilirubin (mg/dL) 
< 2
2 to 3
> 3
Serum albumin (g/dL) 
> 3.5
2.8 to 3.5
< 2.8
Prothrombin time, sec prolonged 
< 4
4 to 6
> 6
a
Encephalopathy will be assessed by an experienced physician at Screening using the following criteria: 
!
Grade 0: normal consciousness, personality, neurological examination, electroencephalogram 
!
Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cycles per second 
waves 
!
Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
!
Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves 
!
Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2 to 3 cycles per second delta 
activity. 
b
Ascites will be assessed by an experienced physician by physical examination as well as ultrasound examination 
at Screening using the following criteria: 
!
Absent: No ascites is detectable by manual and also not by ultrasound investigation. 
!
Slight: Ascites palpitation doubtful, but ascites measurable by ultrasound investigation. 
!
Moderate: Ascites detectable by palpitation and by ultrasound investigation. 
Grading of hepatic impairment with the Child-Pugh system, including ultrasound examination for 
detection and classification of ascites as well as assessment of hepatic encephalopathy, will only 
be performed on participants with hepatic impairment.
The duration of the study will be up to 33 days: Participants will be screened between Day -28 to 
Day -2, dosing will occur on Day 1, PK sampling and safety assessments will occur on Day 1 
through to Day 2 and the Follow-Up visit between Day 4 and Day 6.
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4.2
Scientific Rationale for Study Design
A parallel design with a small number of participants with hepatic impairment and controls with 
normal hepatic function is the standard design for hepatic impairment studies, in line with the FDA 
and EMA guidance/guidelines (FDA Guidance for Industry 2003, EMA Guideline 
CPMP/EWP/2339/02 2005). 
In a CYP3A4 drug-drug interaction (DDI) study with evobrutinib (study MS200527-0054, a 
Phase I, open-label, single-sequence, three-period trial to investigate the effect of CYP3A4 
inhibitors on the PK of M2951 in 16 healthy participants), an approximately 3-fold decrease of 
clearance was observed in participants receiving evobrutinib concurrently with the moderate 
(fluconazole) and the strong (itraconazole) CYP3A4 inhibitor. Assuming similar magnitude of 
increase in half-life for evobrutinib in the moderate hepatic impairment group, the predicted half-
life would be 6 hours (increased 3 folds from 2 hours under normal condition) for the moderate 
hepatic impairment group. Therefore, sampling until 32 hours is sufficient for this study. Since 
evobrutinib showed concentration independent protein binding in human plasma, limited samples 
will be taken for free fraction measurement at 1.5 hours (anticipated peak concentration) and 
12 hours (anticipated trough concentration when given BID). Considering the PK profile of 
evobrutinib, free trough concentration at 12 hours (anticipated trough concentration when given 
BID) may not be measurable, therefore one additional sample will be taken at 4 hours in order to 
have measurable free concentration at lower concentration range. Since there is no 
pharmacologically active metabolite, metabolite PK profile will not be evaluated in this study.
4.3
Justification for Dose
Evobrutinib exposure increased when given with either a high-fat or low-fat meal. Mean AUC0-∞
and Cmax following administration of the tablet formulation increased by 70% and 27%, 
respectively, following a high-fat meal, and 50% and 25%, respectively, following a low-fat meal. 
The oral dose of 30 mg evobrutinib 30 minutes after a standard meal in this study is expected to 
have an exposure similar to the exposure achieved at 50 mg dosed under fasted condition, which 
was the dose used in the moderate (fluconazole) CYP3A4 inhibitor group in the CYP3A4 DDI 
study. Based on published data (de Jong 2015, de Jong 2017, de Jong 2018) for ibrutinib (a similar 
BTK inhibitor), the effect of mild/moderate hepatic impairment on exposure (~4-fold higher AUC 
for mild hepatic impairment and ~10-fold higher AUC for moderate hepatic impairment) was 
similar to the effect of a moderate CYP3A4 inhibitor (6-fold higher AUC with voriconazole). 
Therefore, assuming a similar effect for evobrutinib, the CYP3A4 DDI study outcome can be used 
to predict the change of exposure in participants with impaired hepatic function for evobrutinib. 
Given the ~3-fold increase in evobrutinib exposure observed with concurrent administration of a 
moderate CYP3A4 inhibitor (fluconazole) (MS200527-0054), a similar fold increase in 
evobrutinib exposure is expected in the mild/moderate hepatic impairment groups. The dose of 
30 mg under fed conditions is lower than the intended commercial dose (45 mg under fed 
conditions). It was selected for this study in consideration of the potential 3-fold increase of 
exposure in mild/moderate hepatic impairment participants to ensure evobrutinib exposure 
remains below the level observed at the highest single dose of 500 mg and the highest multiple 
dose of 200 mg under fasted conditions in the first in human study.
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4.4
End of Study Definition
A participant has completed the study if he/she has completed all study parts, including the last 
scheduled procedure shown in Section 1.3.
The end of the study is defined as the date of the last scheduled procedure shown in Section 1.3
for the last participant in the study.
A clinical study protocol may not be considered closed as long as:
! Any participant is still receiving any study intervention.
! Visits specified by the protocol are still taking place.
! Procedures or interventions according to the protocol are still being undertaken in any 
participant.
! The postintervention follow-Up period, defined in the clinical study protocol as being part 
of the study, has not yet been completed for any participant.
5
Study Population
The criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are appropriate 
for the study; thereby, ensuring the study fulfills its objectives. All relevant medical and 
nonmedical conditions are considered when deciding whether a participant is suitable for this 
study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant has provided written informed consent, as 
indicated in Appendix 2.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1.
Are between 18 and 79 (inclusive) years of age at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2.
For participants with normal hepatic function only: Are overtly healthy as determined by 
medical evaluation, including no clinically significant abnormality identified on physical 
examination or laboratory evaluation and no active clinically significant disorder, condition, 
infection or disease that would pose a risk to participant safety or interfere with the study 
evaluation, procedures, or completion. 
OR
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For participants with moderately impaired hepatic function only: Is considered to have 
moderately (Child-Pugh class B and confirmed liver cirrhosis) impaired hepatic function and 
has been clinically stable for at least 1 month prior to Screening.
OR
For participants with mildly impaired hepatic function only: Is considered to have mildly 
(Child-Pugh class A and confirmed liver cirrhosis) impaired hepatic function and has been 
clinically stable for at least 1 month prior to Screening.
Weight
3.
Have a body weight within 50.0 and 120.0 kg (inclusive) and body mass index (BMI) within 
the range 19.0 and 36.0 kg/m2 (inclusive).
Sex
4.
Are male or female
Contraceptive use by females will be consistent with local regulations on contraception methods 
for those participating in clinical studies.
a.
Female Participants:
!
Are not pregnant or breastfeeding, and at least one of the following conditions 
applies:
o
Not a woman of childbearing potential (WOCBP)
OR
o
If a WOCBP, use a highly effective contraceptive method (i.e., with a failure rate 
of <1% per year), preferably with low user dependency, as described in
Appendix 3 for the following time periods:

Before the first dose of the study intervention(s), if using hormonal 
contraception:
 Has completed at least one 4-week cycle of an oral contraception pill and 
either had or has begun her menses
OR
 Has used a depot contraceptive or extended-cycle oral contraceptive for 
least 28 days and has a documented negative pregnancy test using a 
highly sensitive assay.
AND
 A barrier method, as described in Appendix 3.

During the intervention period

After the study intervention period (i.e., after the last dose of study 
intervention is administered) for at least 120 days after the last dose of study 
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intervention and agree not to donate eggs (ova, oocytes) for reproduction 
during this period.
The investigator evaluates the effectiveness of the contraceptive method in 
relationship to the first dose of study intervention.
o
Have a negative serum pregnancy test, as required by local regulations, within 24 
hours before the first dose of study intervention.
!
Additional requirements for pregnancy testing during and after study intervention are 
in Section 8.2.4.
!
The investigator reviews the medical history, menstrual history, and recent sexual 
activity to decrease the risk for inclusion of a female with an early undetected 
pregnancy
Informed Consent
5.
Capable of giving signed informed consent, as indicated in Appendix 2, which includes 
compliance with the requirements and restrictions listed in the informed consent form (ICF) 
and this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1.
Clinical history of autoimmune disorder with hepatic influence (Hashimoto thyroiditis and 
rheumatic diseases allowed).
2.
Diseases and surgeries of the gastrointestinal tract, which could influence the gastrointestinal 
anatomy and mobility. Prior history of cholecystectomy or inflammatory bowel disease, and 
any clinically relevant surgery within 6 months prior to Screening.
3.
History of any malignancy.
4.
History of chronic or recurrent acute infection or any bacterial, viral, parasitic or fungal 
infections within 30 days prior to Screening and at any time between Screening and admission, 
or hospitalization due to infection within 6 months prior to Screening.
5.
History of shingles within 12 months prior to Screening.
6.
History of drug hypersensitivity, ascertained or presumptive allergy/hypersensitivity to the 
active drug substance and/or formulation ingredients; history of serious allergic reactions 
leading to hospitalization or any other hypersensitivity reaction in general, which may affect 
the safety of the participant and/or outcome of the trial per the Investigator’s discretion.
7.
History of alcoholism within 6 months prior to Screening or drug abuse within 2 years prior 
to Screening.
8.
History of heavy smoking (more than 10 cigarettes a day) within 3 months prior to Screening.
9.
Renal dysfunction (estimated glomerular filtration rate < 60 mL/min/1.73 m2 according to the 
Modification of Diet in Renal Disease equation).
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10. History of residential exposure to tuberculosis, or a positive QuantiFERON® or T SPOT® 
test within 4 weeks prior to Screening.
11. Administration of live vaccines or live-attenuated virus vaccines within 3 months prior to 
Screening.
12. Significant central nervous system disease (e.g., seizures) which the Investigator considers 
will interfere with the informed consent, conduct, and completion of the study or constitutes 
an unacceptable risk to the participants.
13. History of Grade >2 esophagus varices with gastrointestinal bleeding within 3 months prior 
to Screening.
14. For participants with impaired hepatic function: Primary and secondary biliary cirrhosis.
15. For participants with impaired hepatic function: Clinical evidence of severe ascites.
16. For participants with impaired hepatic function: Hepatic encephalopathy Grade >1.
Prior/Concomitant Therapy
17. Moderate or strong inhibitors or inducers of CYP3A4 and substrates of CYP3A4 within 
4 weeks prior to the first administration of study intervention.
18. H2-blocker and proton pump inhibitors within 48 hours of the first study intervention 
administration.
19. Inhibitor or inducers of P-gp, BCRP, OATPs and OCT1 within 5 days prior to the first study 
intervention administration.
20. For participants with normal hepatic function: Use of any prescribed medicine or over-
the-counter drug (other than occasional paracetamol or ibuprofen) or dietary supplement 
including herbal remedies, vitamins, and minerals within 2 weeks or 5 times the half-life of 
the respective drug, whichever is the longer, prior to the first administration of study 
intervention.
21. For participants with impaired hepatic function: Addition of new prescribed medicine or 
over-the-counter drug (other than occasional paracetamol or ibuprofen) or dietary supplement 
including herbal remedies, vitamins, and minerals within 2 weeks or 5 times the half-life of 
the respective drug, whichever is the longer, prior to the first administration of study 
intervention. 
Prior/Concurrent Clinical Study Experience
22. Use of any investigational drug in any clinical study within 30 days or 5 half-lives of the 
investigational drug, whichever is longer, prior to Study Day 1 administration, or have used 
an experimental monoclonal antibody within the past 1 year prior Study Day 1, or have 
participated in any study evaluating a BTK inhibitor, regardless of duration since 
participation, or are on extended follow-up in a clinical study, even if last administration of a 
study intervention was more than 60 days ago, or 5 half-lives of the investigational drug, 
whichever is longer, prior to Screening.
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Diagnostic Assessments
23. For participants with normal hepatic function: Supine systolic blood pressure 
> 139 mmHg or < 95 mmHg if ≤65 years old or > 159 mmHg or < 95 mmHg if > 65 years 
old, diastolic blood pressure > 90 mmHg or < 50 mmHg and pulse rate > 100 or ≤ 50 bpm, at 
admission (Day -1) (Any abnormal blood pressure 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).
24. For participants with impaired hepatic function: Supine systolic blood pressure 
> 170 mmHg or < 95 mmHg, diastolic blood pressure > 95 mmHg or < 50 mmHg and pulse 
rate > 100 or ≤ 50 bpm, at admission (Day -1) (Any abnormal blood pressure 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).
25. For participants with normal hepatic function: 12-Lead ECG showing a QTcF > 470 ms, 
PR > 220 ms, or QRS > 120 ms.
26. For participants with impaired hepatic function: 12-Lead ECG showing a QTcF > 480 ms, 
PR > 220 ms, or QRS > 120 ms.
27. Platelet count less than 50 x 109 L.
28. Positive for human immunodeficiency virus 1 and 2 antibodies at Screening.
29. Positive QuantiFERON® or T SPOT® test within 4 weeks prior to Screening.
30. For participants with normal hepatic function: Liver function tests (i.e., ALT, AST, GGT,
total bilirubin, lipase and amylase) > 1.5x upper limit of normal (ULN). 
31. For participants with normal hepatic function: Positive for hepatitis B surface antigen 
(HBsAg), hepatitis B core antibody, hepatitis C antibody at Screening.
32. For participants with impaired hepatic function: Evidence of recent infection with hepatitis 
B and/or hepatitis C within 6 months. Participants with chronic hepatis B or C (duration > 
6 months) are eligible for enrollment.
Other Exclusions
33. Consumption of an average weekly intake of > 14 drinks/week for men or > 7 drinks/week 
for women. One drink is equivalent to (12 g alcohol) = 5 ounces (150 mL) of wine or 
12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of 80 proof distilled spirits.
34. Positive for drugs of abuse or alcohol on Screening or at admission (Day -1).
35. Excessive consumption of xanthine-containing food or beverages (> 5 cups of coffee a day or 
equivalent) or inability to stop consuming caffeine, from 48 hours prior to study intervention 
administration.
36. Herbal supplements including, but not limited to, St. John’s wort, grapefruit, Seville oranges, 
cranberries, or juices of these fruits within 14 days prior to the first administration of study 
intervention.
37. Donation or loss of more than 250 mL of blood in the 60 days prior to Screening.
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38. Inability to communicate reliably with the Investigator or considered by the Investigator to be 
unable to or unlikely to cooperate with the requirements of the study.
39. Any condition, including findings in the laboratory tests, medical history, or other screening 
assessments, that in the opinion of the Investigator constitutes an inappropriate risk or a 
contraindication for participation in the trial or that could interfere with the trial’s objectives, 
conduct, or evaluation.
5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice, cranberries 
or cranberry juices, and St. John’s wort from 14 days before the start of study intervention until 
after the final dose.
5.3.2
Caffeine, Alcohol, Tobacco, and Cannabinoid
! During each dosing session, participants will abstain from ingesting caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, and chocolate) for 48 hours before the start 
of dosing until after collection of the final PK and/or pharmacodynamic (PD) sample.
! During each dosing session, participants will abstain from alcohol for 24 hours before the start 
of dosing until after collection of the final PK and/or PD sample and will abstain from 
cannabinoid-containing products from Screening until after collection of the final PK and/or 
PD sample.
! Participants who use tobacco products will be instructed that use of nicotine-containing
products (including nicotine patches) will not be permitted while they are in the clinical unit.
5.3.3
Activity
Participants will abstain from strenuous exercise for 72 hours before each blood collection for 
clinical laboratory tests. Participants may participate in light recreational activities (e.g., watching 
television or reading). This restriction lasts until the Follow-Up/Discontinuation visit.
5.4
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Rescreened participants will be assigned a new participant number.
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6
Study Intervention(s)
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol.
6.1
Study Intervention(s) Administration
ARM name
Group 1: normal hepatic function
Group 2: mild hepatic impairment
Group 3: moderate hepatic impairment
Intervention Name
Evobrutinib
Type
Drug
Dose Formulation
Film-coated tablet
Unit Dose Strength(s)
10 mg
Dose Amount
Participants will receive a single evobrutinib dose of 30 mg 
as three 10 mg film-coated tablets.
For further details, see Section 6.6.
Frequency
Single dose
Route of Administration
Oral
Use
Experimental
Investigational Medicinal 
Product (IMP) and Non-
Investigational Medicinal 
Product (NIMP)
IMP: evobrutinib
Manufacturer/supplier:
The Sponsor will supply evobrutinib.
Packaging and Labeling:
Evobrutinib will be provided in PE-bottles. Each PE-bottle
will be labeled per country requirement.
6.1.1
Medical Device(s)
Not applicable.
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is responsible 
for study intervention accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
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! Upon receipt of the study intervention(s), the Investigator or designee will confirm appropriate 
temperature conditions have been maintained during transit and any discrepancies are reported 
and resolved before use. Also, the responsible person will check for accurate delivery. Further 
guidance and information for study intervention accountability are provided in the Pharmacy
manual.
! Only participants enrolled in the study may receive study intervention(s) and only authorized 
site staff may supply it. All study intervention(s) will be stored in a secure, environmentally
controlled, and monitored (manual or automated) area, per the labeled storage conditions, and 
with access limited to the Investigator and authorized site staff.
! Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit.
! Study intervention(s) accountability records at the study site will include the following:
! Confirmation of receipt, in good condition and in the defined temperature range.
! The inventory provided for the clinical study and prepared at the site.
! The dose(s) each participant used during the study.
! The disposition (including return, if applicable) of any unused study intervention(s).
! Dates, quantities, batch numbers, container numbers, expiry dates, and the participant 
numbers.
! The Investigator site will maintain records, which adequately documents that participants were 
provided the doses specified in this protocol, and all study intervention(s) provided were fully 
reconciled.
! Unused study intervention(s) will not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a participant may be re-dispensed to a 
different participant.
! A Study Monitor will periodically collect the study intervention(s) accountability forms.
! Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the Pharmacy manual.
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding
6.3.1
Study Intervention Assignment
On Day 1 participants will be assigned a unique number (participant number) in ascending 
numerical order at the study site. The participant number encodes the participant’s assignment to 
one of the 3 arms of the study. Participants will be assigned to each of the treatment groups based 
on their level of hepatic function and, thus, no randomization procedures will be applied.
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6.3.2
Blinding
Blinding Method
Not applicable as this is an open-label study.
Assignment Method Retention
Not applicable.
6.3.3
Emergency Unblinding
Not applicable as this is an open-label study.
6.4
Study Intervention Compliance
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date and time of each dose administered
in the clinic will be recorded in the source documents and recorded in the Case Report Form (CRF). 
The dose of study intervention and study participant identification will be confirmed at the time of 
dosing by a member of the study site staff other than the person administering the study 
intervention. The Investigator will ensure that the information entered into the electronic Case 
Report Form (eCRF) regarding study intervention administration is accurate for each participant. 
Any reason for noncompliance should be documented.
Noncompliance is defined as a participant missing 1 dose of study intervention.
6.5
Concomitant Therapy
Record in the CRF all concomitant therapies (e.g., medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
Additional information on prohibited medicines is provided in Section 6.5.3.
6.5.1
Rescue Medicine
The study site will not supply rescue medication.
6.5.2
Permitted Medicines
The only permitted medications are the following:
! Paracetamol up to 1,500 mg daily or ibuprofen up to 800 mg daily, at the discretion of the 
Investigator.
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Any medicines that are considered necessary to protect the participant’s welfare in emergencies
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation.
For participants with mild and moderate hepatic impairment, treatment with chronic stable 
medications necessary for maintaining the clinical status of the participant will be permitted if 
prescribed by the participant’s personal physician and approved by the Investigator, in consultation 
with the Sponsor or designee as needed. Administration of medications should be withheld for at 
least 2 hours predose and 4 hours postdose as clinically appropriate, except for the prohibited 
medications as described in Section 6.5.3.
The Investigator will record all previous/concomitant medications taken by the participant during 
the study, from the date of signature of informed consent, in the appropriate section of the eCRF.
6.5.3
Prohibited Medicines
The following treatments and therapies are not permitted during this study:
! H2-blocker and proton pump inhibitors within 48 hours prior to the first study intervention 
administration until 6 hours after study intervention administration.
! Antacids within 2 hours of dosing (2 hours prior to dosing and 2 hours after the dosing).
! Herbal supplements including, but not limited to, St. John’s wort; grapefruit, Seville oranges, 
cranberries, or juices of these fruits within 2 weeks prior to the first study intervention 
administration until the Follow-Up visit.
! Moderate or strong inhibitors or inducers of CYP3A4 within 4 weeks prior to the first 
administration of study intervention until the Follow-Up visit.
! Inhibitor or inducers of P-gp, BCRP, OATPs and OCT1 within 5 days prior to the first study 
intervention administration until the Follow-Up visit.
! For participants with normal hepatic function: The participants are prohibited from using 
prescription or over-the-counter medications (apart from paracetamol or ibuprofen, as judged 
appropriate by the Investigator) or dietary supplement including herbal remedies, vitamins, and 
minerals within 2 weeks or 5 half-lives, whichever is longer, prior to the first study intervention 
administration during the study, and until the Follow-Up visit. 
! For participants with impaired hepatic function: Addition of any medication is prohibited, 
which includes prescribed medicine, over-the-counter drug (other than occasional paracetamol
or ibuprofen) or dietary supplement including herbal remedies, vitamins, and minerals within 2 
weeks or 5 times the half-life of the respective drug, whichever is the longer, prior to the first 
administration of study intervention and until the Follow-Up visit. 
6.5.4
Other Interventions
Additional restrictions that study participants should adhere to from Day -1 until the 
Follow-Up/Discontinuation visit are detailed in Section 5.2.
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6.6
Dose Selection and Modification
The participants will receive the following treatment during the study:
! A single oral administration of 3 x 10 mg film-coated tablets of evobrutinib under fed conditions
All participants will receive the study intervention after they have completed a standard breakfast. 
Drug administration will be 30 minutes after start of the intake of a standard breakfast with 240 mL 
of water. Participants should eat this meal within 25 minutes. The participants will remain fasting 
for 2 hours when a standardized snack will be provided and at 4 hours a standardized lunch will 
be served. 
The standard breakfast will contain approximately 500 calories and will be balanced in 
macronutrients (approximately 50% carbohydrates, 25% protein, and 25% fat). The menu must be 
approved by the Sponsor. The participant will be expected to eat the entire meal. The percentage 
consumed will be recorded for all participants. A deviation will be recorded if the participant eats 
less than 90% of the meal. Participants will not be excluded from dosing if they are unable to 
complete the entire meal.
6.7
Study Intervention after the End of the Study
After a participant with hepatic impairment has completed the study or has withdrawn early, the 
pre-study treatment will be continued, if required, in accordance with generally accepted medical 
practice. In the healthy participants, no further treatment or medical care is planned or required 
after the end of the study.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
Not applicable since evobrutinib is administered only once in the study.
7.2
Participant Discontinuation/Withdrawal from the Study
! A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons.
! At the time of discontinuing from the study, if possible, a discontinuation visit will be 
conducted, as listed in the Schedule of Activities (SoA). The SoA specifies the data to collect 
at study discontinuation and follow-up, and any additional evaluations that need to be 
completed.
! If the participant withdraws consent for future involvement in the study, any data collected up 
to that point may still be used, but no future data can be generated, and any biological samples 
collected will be destroyed.
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! A participant has the right at any time to request destruction of any biological samples taken. 
The investigator will document this in the site study records.
In case a participant must be withdrawn from the study, the Medical Monitor and clinical study 
leader for the Sponsor will be informed immediately.
If there is a medical reason for the withdrawal, appropriate medical care will be provided.
Participants who withdraw from the study prior to the first administration of study intervention or 
for any reason do not have a full PK dataset may be replaced. A discussion should occur between 
the Investigator and the Sponsor regarding whether a replacement may be considered.
7.3
Lost to Follow-Up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions will be taken if a participant fails to return to the clinic for a required study 
visit:
! The site will attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wants to or should continue in the study.
! Before a participant is deemed “lost to follow-up”, the Investigator or designee will make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts will be documented 
in the participant’s medical record.
! If the participant continues to be unreachable, he/she will be deemed “lost to follow-up”.
8
Study Assessments and Procedures
! Study assessments and procedures and their timing are summarized in the SoA (Section 1.3).
! No protocol waivers or exemptions are allowed.
! Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study intervention.
! Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
! All screening evaluations will be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of 
all participants screened, to confirm eligibility, and if applicable, record reasons for screening 
failure.
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! Prior to performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will obtain written informed consent as specified in Appendix 2.
! Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA (Section 1.3).
! A maximum of 200 mL of blood will be collected in any one-month period from each 
participant in the study, including any extra assessments that may be required.
8.1
Efficacy Assessments and Procedures
Not applicable.
8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting and 
analysis of baseline medical conditions, AEs, physical examination findings, vital signs, and 
laboratory tests.
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1.
8.2.1
Physical Examinations
! A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems.
! A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen).
! Investigators will pay special attention to clinical signs related to previous serious illnesses.
! Any physical examination abnormality findings which are clinically significant, before the ICF 
is signed, will be captured on the eCRF. After the ICF is signed, new physical exam abnormality 
findings will be captured on the AE form.
8.2.2
Vital Signs
! Height and weight will be measured at Screening and recorded.
! Tympanic temperature, pulse rate, respiratory rate, and blood pressure will be assessed.
! Blood pressure and pulse measurements will be assessed in a semi-supine position with a 
completely automated device. Manual techniques will be used only if an automated device is 
not available.
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! Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones).
! Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded on 
the CRF.
8.2.3
Electrocardiograms
! Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals. ECG
assessments will be done after 5 minutes rest in supine position.
8.2.4
Clinical Safety Laboratory Assessments
Blood samples will be collected in a fasted condition (after a fast of at least 8 hours). 
! Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 5
at the time points listed in the SoA. All samples will be clearly identified. 
! Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations.
! The tests will be performed by the local laboratory.
! The Sponsor will receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study will be forwarded to the Sponsor or 
designated organization.
! The Investigator will review each laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports will be filed with the source documents.
! Additional serum or highly sensitive urine pregnancy tests may be conducted, as determined 
necessary by the investigator or required by local regulation, to establish the absence of 
pregnancy at any time during the study.
8.2.5
Suicidal Ideation and Behavior Risk Monitoring
Not applicable.
8.3
Adverse Events and Serious Adverse Events
! The definitions of an AE and a Serious Adverse Event (SAE) are in Appendix 4.
! The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for 
detecting, documenting, and recording events that meet the definition of an AE or SAE. The 
Investigator remains responsible for following up AEs that are serious or that caused the 
participant to discontinue the study, as specified in Section 8.3.3.
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! Requests for follow-up will usually be made via the Study Monitor, although in exceptional 
circumstances the global patient safety department may contact the Investigator directly to 
obtain further information or to discuss the event.
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
! All SAEs will be collected from the signing of the ICF until the Follow-Up 
Visit/Discontinuation Visit at the time points specified in the SoA (Section 1.3). Beyond this 
reporting period, any new unsolicited SAEs that the Investigator spontaneously reports to the 
Sponsor will be collected and processed.
! All AEs will be collected from the signing of the ICF until Follow-Up Visit/Discontinuation 
Visit at the time points specified in the SoA.
! AEs/SAEs that begin before the start of study intervention but after obtaining ICF will be 
recorded on the Medical History/Current Medical Conditions CRF, not on the AE CRF.
! All SAEs will be recorded and reported to the Sponsor or designee immediately and under no 
circumstance will this exceed 24 hours, as indicated in Appendix 4. The Investigator will submit 
any updated SAE data to the Sponsor within 24 hours of it being available using the same 
procedure that was used for the initial report.
! Investigators are not obligated to actively solicit AEs or SAEs after the end of study 
participation. However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator will promptly 
notify the Sponsor.
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in his or her condition. 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrences.
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are in Appendix 4.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the Investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Reasonable 
attempts to obtain this information will be made and documented. It is also the Investigator’s 
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responsibility to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. Further information on follow-up procedures is in Appendix 4.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the Investigator to the Sponsor of an SAE (particularly life-threatening and 
deaths) is essential so that legal obligations and ethical responsibilities towards the safety of 
participants and the safety of a study intervention under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
Sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, Institutional Review Boards (IRB)/Independent Ethics Committees 
(IEC), and Investigators.
Individual Case Safety Reports will be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy and forwarded 
to Investigators, as necessary.
An Investigator who receives an Individual Case Safety Report describing a SUSAR or other 
specific safety information (e.g., Emerging Safety Issue Report, summary or listing of 
SAEs/SUSARs) from the Sponsor will review and then file it along with the Investigator Brochure 
in the Investigator’s Site File and will notify the IRB/IEC, if appropriate according to local 
requirements.
8.3.5
Pregnancy
! Details of all pregnancies in female participants will be collected after the start of study 
intervention and until the end of the reporting period defined in Section 8.3.1.
! If a pregnancy is reported, the Investigator will inform the Sponsor within 24 hours of learning 
of the pregnancy and will follow the procedures specified below for collection of pregnancy 
information.
! Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
Collection of Pregnancy Information
Female Participants who become pregnant
! The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while she is in the study. The initial information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of the pregnancy. 
! The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 
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8 weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure.
! While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE.
! A spontaneous abortion (occurring at < 22 weeks gestational age) or stillbirth (occurring at 
>22 weeks gestational age) is always considered to be an SAE and will be reported as such.
! Any post-study pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as specified in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting.
! Any female participant who becomes pregnant while participating in the study will be 
withdrawn from the study.
8.4
Treatment of Overdose
For this study, any dose of evobrutinib greater than the maximum dose in the study within a 
24-hour time period will be considered an overdose.
The Sponsor does not recommend specific treatment for an overdose.
Even if it not associated with an AE or a SAE, any overdose is recorded in the CRF and reported 
to global patient safety in an expedited manner. Overdoses are reported on a SAE and Overdose 
Report Form, following the procedure in Appendix 4, the section on Reporting SAEs.
8.5
Pharmacokinetics
The following PK parameters will be calculated from the individual plasma concentration-time 
data, when appropriate:
Symbol
Definition
AUC0-tlast
The area under the 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. Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
AUC0-12 and AUC0-24
The area under the concentration-time curve (AUC) from time zero (= dosing time) to 12 
or 24 hours at which the concentration is at or above the lower limit of quantification. 
Calculated using the mixed log-linear trapezoidal rule (linear up, log down).
AUC0-∀
The AUC from time zero (dosing time) extrapolated to infinity, based on the predicted 
value for the concentration at tlast, as estimated using the linear regression from λz
determination. AUC0-∞= AUC0-tlast + Clast pred/ λz.
Cmax
Maximum observed concentration.
tmax
The time to reach the maximum observed concentration collected during a dosing interval 
(i.e., 1st occurrence in case of multiple/identical Cmax values).
t1/2
Apparent terminal half-life. t1/2 = ln (2)/λz.
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Symbol
Definition
CL/F
Apparent total plasma clearance after oral administration.
CL/F = Dose p.o. /AUC0-∞. 
VZ/F
Apparent volume of distribution during terminal phase after oral administration.
Vz/F = Dose/(AUC0-∞*λz) following single dose. 
fu
Free or unbound fraction of evobrutinib calculated as free concentration/total 
concentration (For each participant, 3 samples will be analysed to determine a percent of 
free fraction or unbound evobrutinib. The values from these samples if measurable will be 
used to estimate a mean percentage).
AUC0-∀#u
Calculated as fu * AUC0-∀
Cmax, u
Calculated as fu * Cmax
CL,u/F
Calculated as Dose p.o. /AUC0-∞,u
Whole blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of evobrutinib. Collection times are specified in the SoA (Section 1.3). The actual 
date and time (24-hour clock time) of each sample will be recorded to calculate actual time elapsed 
since the prior dose administration. The sampling timing may be altered during the study based on 
newly available data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure 
appropriate monitoring.
The quantification of evobrutinib in plasma will be performed using a validated LC-MS/MS assay. 
Concentrations will be used to evaluate the PK of evobrutinib. The free fraction of evobrutinib 
sample will not be drawn separately but will be analyzed from the PK back up samples at 1.5, 4 
and 12 hours.
Remaining samples collected for analyses of evobrutinib concentrations may also be used to 
evaluate safety or PD aspects related to concerns arising during or after the study. Full details of 
the bioanalytical methods will be described in a separate bioanalytical report.
Details on processes for collection and handling of these samples are in the Laboratory Manual. 
Retention time and possible analyses of samples after the End of Study are specified in the 
respective ICF.
PK parameters will be derived using noncompartmental methods with the validated computer 
program Phoenix® WinNonlin® (version 6.4 or higher; Certara, L.P., Princeton, New Jersey, 
USA).
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The exact date/time of sample collection and drug administration (24-hour clock time) must be 
recorded in the eCRF and will be used in the calculation of PK parameters. The accepted time 
deviations from planned PK times that will not be considered a protocol violation are listed below:
The predose sample will be considered as if it had been taken simultaneously with the 
administration of study intervention.
8.6
Pharmacodynamics
Not applicable.
8.8
Biomarkers
Not applicable.
8.9
Immunogenicity Assessments
Not applicable.
8.10
Health Economics
Not applicable.
Procedure
Time Point (Relative Time)
Window Allowance
PK
Predose
- 60 min
0.25 to 1 h postdose
- 2 / + 2 min
> 1 h to 12 h postdose
- 5 / + 5 min
> 12 h to 32 h postdose
- 15 / + 15 min
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9
Statistical Considerations
Details of the statistical analyses will be described in a separate Integrated Analysis Plan.
9.1
Statistical Hypotheses
No formal statistical hypothesis will be tested, as the study is designed to be descriptive.
9.2
Sample Size Determination
It is of note that the number of participants in special population studies should be limited due to 
feasibility constraints, since participants with hepatic impairment are in general difficult to recruit. 
Thus, the sample size is partially based on experience from previous Phase I studies with other 
candidate drugs to obtain adequate safety, tolerability, and PK data to achieve the objectives of the 
study while exposing as few participants as possible to the study intervention and procedures.
The aim of the comparison between participants with moderate (or mild) hepatic impairment and 
healthy participants is to characterize possible differences in the PK primary endpoints AUC0-∞
and Cmax in the hepatic impaired and normal participants.
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A maximum of 28 participants will be assigned to study intervention such that approximately 24
to 28 evaluable participants complete the study. Each of the 3 groups is planned to include 
8 participants. Up to 4 additional participants may be added into Group 1 for matching purpose.
9.3
Populations for Analyses
The analysis populations are specified below. The final decision to exclude participants from any 
analysis population will be made during a data review meeting prior to database lock.
Analysis Set
Description
Screening (SCR) 
All participants, who provided informed consent, regardless of the participant’s randomization 
and study intervention status in the study.
Safety (SAF)
All participants, who were administered any dose of any study intervention. Analyses will 
consider participants as treated.
PK
The PK Analysis Population is a subset of the Safety Analysis Population and will consist of 
all participants who receive at least one dose of active IMP and provide at least one 
measurable postdose concentration. A measurement below lower limit of quantification 
(BLQ) is considered a valid measurement. Participants will be analyzed according to the 
actual treatment they received. All PK analyses will be based on the PK Analysis Population.
9.4
Statistical Analyses
Statistical analysis will be performed using the computer program package SAS® System for 
Windows™(release 9.4 or later version; SAS Institute, Cary NC, USA). 
All data will be evaluated as observed; no imputation method for missing values will be used.  If 
not otherwise specified, ‘baseline’ refers to the last scheduled measurement before administration 
of the study intervention. If no baseline exists, then the baseline value will be treated as missing. 
All data recorded during the study will be presented in individual data listings performed on the 
Safety Analysis Set, as appropriate.
Further details on the statistical analysis will be presented in the Integrated Analysis Plan that will 
be finalized prior to database lock.
9.4.1
Efficacy Analyses
Not applicable.
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9.4.2
Safety Analyses
In general, for the evaluation of safety parameters, the numerical values will be summarized 
descriptively (N, arithmetic mean, median, standard deviation, minimum and maximum values). 
Categorical variables will be presented in frequency tables by the number of observations and 
percentages.
Adverse event counts and participants with AEs will be summarized for each treatment by system 
organ class and preferred term. In addition, AEs will be tabulated and listed per participant and 
analyzed by severity and relationship to study intervention. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) terminology.
Participants who prematurely withdrew from the study will be displayed in a by-participant listing, 
and summarized by primary withdrawal reason.
Safety laboratory parameters will be listed for each participant including changes from baseline 
and flags for measurements outside the reference ranges, where applicable. Laboratory parameters 
(hematology, coagulation and clinical chemistry) will be summarized by time point including both 
absolute values and changes from baseline. Urinalysis parameters will be listed. 
Vital signs and ECG parameters will be listed by participant including changes from baseline, and 
summarized by treatment and time point using descriptive statistics. 
All safety analyses will be performed on the Safety Analysis population (Section 9.3).
Endpoint
Statistical Analysis Methods
Primary
No primary safety endpoints
Secondary
Nature, occurrence, and 
severity of treatment-
emergent adverse events 
(TEAEs)
The number and percentage of participants experiencing at least 1 TEAE will be 
summarized by treatment as well as the number of events. Tables by relationship 
to study drug and by severity will be generated. AEs will be coded using Medical 
Dictionary for Regulatory Activities terminology.
Absolute values and 
changes in safety laboratory 
tests
All laboratory data will be reported with SI units. Laboratory parameters will be 
summarized using descriptive statistics for absolute values and data listings of 
abnormalities.
12-lead electrocardiograms 
(ECGs) (morphology and 
time intervals [PR, QRS, RR, 
QT and corrected QT 
intervals based on Fridericia 
formula, QTcF])
ECG data will be summarized by changes-from-baseline values by treatment 
using descriptive statistics. Clinical noteworthy ECG findings for individual 
participants will be listed and summarized as appropriate.
Vital signs assessed from 
time of first dose to end of 
study participation
Vital signs data will be summarized by changes-from-baseline values using 
descriptive statistics.
Tertiary/Exploratory
Not applicable
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9.4.3
Other Analyses
Details on the PK analyses will be specified in the Integrated Analysis Plan that will be finalized 
before database lock. Integrated analyses across studies, such as the population PK analysis and 
PD analyses will be presented separately from the main clinical study report (CSR).
9.4.3.1
Analysis of Pharmacokinetics 
An analysis of variance (ANOVA) model including hepatic function group as a fixed effect will 
be applied to log-transformed PK parameters AUC0-∞, and Cmax of evobrutinib of the hepatic 
impairment groups (Child-Pugh class A and Child-Pugh class B) and control group (normal 
hepatic function). Separate models will be fitted for the comparison between the hepatic 
impairment groups (Child-Pugh class A and Child-Pugh class B) and the control group. For each 
parameter, differences between the hepatic impairment groups and the control group will be 
estimated on the log scale (group mean ratio) together with corresponding 90% CIs. The geometric 
least square means together with corresponding 95% CIs by hepatic function group will also be 
estimated. Point estimates and CIs will be back-transformed to the original scale.
The relationship between AUC0-∞ and Cmax of evobrutinib and the hepatic function parameters 
(e.g., albumin-bilirubin score as continuous variable) will additionally be explored with a linear 
regression.
For secondary PK endpoints such as CL/f, AUC0-∞,u, Cmax,u, and CL,u/f, the same ANOVA and 
linear regression analyses like for the primary endpoints will be performed.
All primary and secondary PK endpoints (parameters) will be listed and will be descriptively 
summarized by hepatic impairment group using: number of non-missing observations (N), 
arithmetic mean (Mean), standard deviation (SD), coefficient of variation (CV%), minimum 
(Min), median (Median) and maximum (Max), geometric mean (Geomean), geometric coefficient 
of variation (GeoCV%) and graphically displayed. Individual plasma and mean concentration time 
plots will be provided for each treatment using linear (± SD) and semi-logarithmic scales. 
The analysis of all primary and secondary PK endpoints of evobrutinib will be performed using 
the PK Analysis population.
9.4.4
Sequence of Analyses
All final, planned analyses identified in the Clinical Study Protocol will be performed only after 
the last participant has completed the last visit, i.e., Follow-Up/Discontinuation visit with all study 
data in-house, all data queries resolved, and the database locked.
There are no planned formal interim analyses.
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10
References 
de Jong J, Skee D, Murphy J, et al. Mannaert E. Effect of CYP3A perpetrators on ibrutinib 
exposure in healthy participants. Pharma Res Per. 2015;3:e00156.
de Jong J, Skee D, Hellemans P, et al. Single-dose pharmacokinetics of ibrutinib in subjects with 
varying degrees of hepatic impairment. Leukemia & Lymphoma. 2017;58:185-94.
de Jong J, Hellemans P, de Wilde S, et al. A drug–drug interaction study of ibrutinib with 
moderate/strong CYP3A inhibitors in patients with B-cell malignancies. Leukemia & Lymphoma. 
2018;59:2888-95.
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11
Appendices
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Appendix 1
Abbreviations 
AE
Adverse event
ANOVA
Analysis of variance
BCR
B cell antigen receptor
BMI
Body mass index
BTK
Bruton’s tyrosine kinase
CRF
Case Report Form
CRO
Clinical Research Organization
CSR
Clinical Study Report
CI
Confidence interval
CV
Coefficient of variation
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICH
International Council for Harmonization
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IRB
Institutional Review Board
MedDRA
Medical Dictionary for Regulatory Activities
MS
Multiple sclerosis 
PD
Pharmacodynamics
PK
Pharmacokinetics
RA
Rheumatoid arthritis
RMS
Relapsing multiple sclerosis
SAE
Serious Adverse Event
SLE
Systemic lupus erythematosus
SoA
Schedule of activities
SUSAR
Suspected unexpected serious adverse reactions
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TEAE
Treatment-emergent adverse event
WOCBP
Woman of childbearing potential
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with enough, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial certification 
or disclosure statements to the appropriate regulatory authorities. This information is required 
during the study and for 1 year after completion of the study.
Informed Consent Process
! The Investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions on the study.
! Participants will be informed that their participation is voluntary.
! Participants or their legally-authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50; local regulations; ICH guidelines; 
Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable; 
and the IRB/IEC or study center.
! The medical record will include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. The 
authorized person obtaining the informed consent will also sign the ICF.
! If the ICF is updated during their participation in the study, participants will be re-consented to 
the most current, approved version.
! A copy of the ICF(s) will be provided to the participant.
! The original signed and dated consent will remain at the Investigator’s site and will be safely 
archived so that it can be retrieved at any time for monitoring, auditing and inspection purposes.
! A participant who is rescreened is not required to sign another ICF if the rescreening occurs 
within 30 days from the previous ICF signature date
Data Protection
! The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. Any participant records or datasets that are transferred to the Sponsor will contain the 
identifier only; participant names or any identifiable information will not be transferred.
! The Sponsor will inform participants that their personal study-related data will be used per local 
data protection and privacy laws. The level of disclosure will also be explained to the participant
and pregnant partners (if applicable), who will be required to give consent for their data to be 
used, as specified in the informed consent.
! The participant will be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by appropriate 
IRB/IEC members, and by regulatory authority inspectors. All such persons will strictly 
maintain participants’ confidentiality.
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Study Administrative
The study is planned to be conducted at a single site in Germany. This site is a clinical 
pharmacology unit.
The Principal Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Principal Investigator will provide expert medical 
input and advice on the study design and execution and is responsible for the review and signoff 
of the clinical study report.
The study will appear in the following clinical studies registries: EU Clinical Trials Register and 
ClinicalTrials.gov.
Details of structures and associated procedures will be defined in a separate Standard Operation 
Procedures. The Clinical Research Organization (CRO), Covance, will be responsible for the 
following activities:
! Site management
! Data management
! Statistical programming and analysis
! PK analysis
! Medical writing
! Independent monitoring
! Medical monitoring
! Project management
! Regulatory services
! Safety management
Regulatory and Ethical Considerations
! This study will be conducted in accordance with the protocol and the following:
! Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines
! Applicable ICH Good Clinical Practice (GCP) Guidelines
! Applicable laws and regulations
! The Investigator will submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and 
the IRB/IEC will review and approve them before the study is initiated.
! Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
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eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities.
! The Investigator will be responsible for the following:
! Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures.
! Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures
! Providing oversight of the study conduct at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations
! The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
! The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any information 
about this participation that may be needed to determine the course of medical treatment for the 
participant. The information on the Emergency Medical Support card may include the process 
for emergency unblinding (if applicable).
! The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant.  Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators.
! When the Investigator is not available, the Phase I facility will provide the appropriate means 
to contact a physician. This includes the provision of a 24-hour contact number at the facility, 
whereby the health care providers will be given access to an appropriate physician to assist with 
the medical emergency and to provide support for the potential unblinding of the participant 
concerned.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions will meet good local standards, as applicable.
Clinical Study Report
After study completion, the Sponsor will write a clinical study report in consultation with the 
Principal Investigator.
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Publication
! The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments. 
! The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by agreement.
! Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
A summary of data will be provided to www.ClinicalTrials.gov as well as to the European Clinical 
Trial Database, if applicable. Participants might be provided with the results of the medical 
examinations at request. After finalization of the study, healthy participants might be provided 
with the information published on ClinicalTrials.gov and/or the European Clinical Trial database 
at request.
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Principal Investigator following the guidance in ICH Topic E3 and will be submitted in accordance 
with local regulations.
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to such of the Investigator’s employees and staff who had 
been made aware that the information is confidential and who are bound to treat it as such and to 
whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than for determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study.
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study drug and therefore may be 
disclosed as required to other clinical Investigators, to the US Food and Drug Administration, 
EMA, and to other government agencies. The Investigator also understands that, to allow for the 
use of the information derived from the clinical study, the Investigator has the obligation to provide 
the Sponsor with complete test results and all data developed in the study. No publication or 
disclosure of study results will be permitted except under the terms and conditions of a separate 
written agreement.
Data Quality Assurance
! All participant study data will be recorded on printed or electronic CRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
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verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the CRF. Details for managing CRFs are in the Data Management Plan.
! The Investigator will maintain accurate documentation (source data) that supports the 
information in the CRF.
! The Investigator will permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and source 
data.
! Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan.
! The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. Details will be outlined in Data 
Management documents and procedures.
! Study Monitors will perform ongoing source data verification to confirm that data in the CRF 
are accurate, complete, and verifiable; that the safety and rights of participants are being 
protected; and that the study is being conducted per the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
! The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 15 years after study completion, unless local regulations, institutional 
policies, or the Sponsor requires a longer retention. No records may be destroyed during the 
retention period without the Sponsor’s written approval. No records may be transferred to 
another location or party without the Sponsor’s written notification.
Source Documents
! Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.
! The Investigator will keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file will identify each participant, contain the following 
demographic and medical information for the participant, and will be as complete as possible:
! Participant’s full name, date of birth, sex, height, and weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the study)
! Study identifier (i.e., the Sponsor’s study number) and participant’s study number.
! Dates of entry into the study (i.e., signature date on the informed consent) and each visit to 
the site
! Any medical examinations and clinical findings predefined in the protocol
! All AEs
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! Date that the participant left the study, including any reason for early withdrawal from the 
study or study intervention, if applicable.
! All source data will be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document will have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records will be performed, documented, signed and dated by the Investigator. 
! Data recorded on printed or electronic CRFs that are transcribed from source documents will
be consistent with the source documents or the discrepancies will be explained. The Investigator 
may need to request previous medical records or transfer records, depending on the study. Also, 
current medical records will be available.
! The Study Monitors will use printouts of electronic files for source data verification. These 
printouts will be signed and dated by the Investigator and kept in the study file.
! Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator ensures
that no destruction of medical records is performed without the Sponsor’s written approval.
! Definition of what constitutes source data is found in Source Data Identification Form.
Study and Site Start and Closure
First Act of Recruitment
! The study start date is the date when the clinical study will be open for recruitment.
! The first act of recruitment is when the site is opened and will be the study start date.
Study Closure and Site Termination
! The Sponsor reserves the right to close the study site or terminate the study at any time and for 
any reason. Study sites will be closed upon study completion. A study site is considered closed 
when all required documents and study supplies have been collected and a site closure visit has 
been completed.
! The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination.
! Reasons for the early closure of a study site by the Sponsor or Investigator may include:
! Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or
local health authorities, the Sponsor's procedures, or GCP guidelines
! Inadequate recruitment of participants by the Investigator
! Discontinuation of further development of the Sponsor’s compound
! If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
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the applicable regulatory requirements. The Investigator will promptly inform the participants 
and assure appropriate participant therapy and/or follow-up.
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Appendix 3
Contraception
Definitions:
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below.
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, consider additional evaluation.
A WOCBP is not:
1. Premenarchal
2. A premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Documentation can come from the site personnel’s review of the female’s medical records, 
medical examination, or medical history interview.
For a female with permanent infertility due to an alternate medical cause other than the 
above, (e.g., mullerian agenesis, androgen insensitivity), investigator discretion applies to 
determine study entry.
3. A postmenopausal female
! A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.
! A high follicle-stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in a female not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, more than 1 FSH measurement is required in the postmenopausal range.
! A female on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if she wishes to 
continue her HRT during the study. Otherwise, she must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
Bilateral tubal occlusion
!
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation
!
Oral
!
Intravaginal
!
Transdermal
!
Injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulation
!
Oral
!
Injectable
!
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence is evaluated in relation 
to the duration of the study.
Acceptable Methods
!
Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary mode of action
!
Male or female condom with or without spermicide.  Male condom and female condom cannot be used 
together (due to risk of failure with friction)
!
Cervical cap, diaphragm, or sponge with spermicide
!
A combination of male condom with either cervical cap, diaphragm, or sponge with spermicide (double-barrier 
methods)
Contraceptive use by men or women is consistent with local regulations regarding the use of contraceptive 
methods for those participating in clinical studies.
Highly effective methods have a failure rate of <1% per year when used consistently and correctly. Typical use 
failure rates differ from those when used consistently and correctly.
Hormonal contraception may be susceptible to interaction with the study intervention(s), which may reduce the 
efficacy of the contraceptive method. As such, male condoms must be used in addition to hormonal 
contraception. If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, 
acceptable contraceptive methods are limited to those which inhibit ovulation as the primary mode of action.
Acceptable methods are considered effective, but not highly effective (i.e., have a failure rate of ≥1% per year).  
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception.
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
AE Definition
AE Definition
!
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether considered related to the 
study intervention or not.
!
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with 
the use of study intervention.  For surgical or diagnostic procedures, the condition/illness 
leading to such a procedure is considered as the AE rather than the procedure itself.
! Events Meeting the AE Definition
!
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g., ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (i.e., not related to progression of underlying 
disease).
!
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition.
!
New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study.
!
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.
!
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication.
!
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or a SAE.  However, the signs, symptoms, and/or clinical sequelae 
resulting from lack of efficacy will be reported as an AE or a SAE if they fulfil the 
definition of an AE or SAE.
! Events NOT Meeting the AE Definition
!
Unless judged by the Investigator to be more severe than expected for the participant’s 
condition, any clinically significant abnormal laboratory findings, other abnormal safety 
assessments that are associated with the underlying disease, the disease/disorder being 
studied, or expected progression, signs, or symptoms of the disease/disorder being studied.
!
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to 
the procedure is the AE.
!
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
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!
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
SAE Definition
If an event is not an AE per the definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease).
A SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant 
was at risk of death at the time of the event. It does not refer to an event, which hypothetically 
might have caused death, if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
!
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
will be considered serious.
!
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
!
However, all events leading to unplanned hospitalizations or unplanned prolongation of an 
elective hospitalization (i.e., undesirable effects of any administered treatment) must be 
documented and reported as SAEs.
d.
Results in persistent disability/incapacity
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions.
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
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f.
Other situations:
!
Medical or scientific judgment will be exercised in deciding whether SAE reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These events are usually considered as serious.
!
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions 
that do not result in hospitalization, or development of drug dependency or drug abuse.
Any suspected transmission of an infectious agent via a study intervention is also considered an 
SAE for reporting purposes, as specified below for reporting SAEs.
Recording and Follow-Up of AE and/or SAE
AE and SAE Recording
!
When an AE/SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event.
!
The Investigator will then record all relevant AE/SAE information in the CRF.
!
As needed, the Sponsor or its designee may ask for copies of certain medical records (e.g., 
autopsy reports, supplemental lab reports, documents on medical history/concomitant 
medications, discharge letters), as supporting source documentation. All participant 
identifiers, except the participant number, will be redacted on these copies before 
submission to the Sponsor or its designee.
!
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not the 
individual signs/symptoms) will be documented as the AE/SAE.
!
Specific guidance is in the CRF Completion and Monitoring Conventions.
Assessment of Intensity
The Investigator will assess the intensity of each AE and SAE reported during the study and 
assign it to 1 of the following categories:
!
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities.
!
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities.
!
Severe: An event that prevents normal everyday activities.  Do not confuse an AE that is 
assessed as severe with a SAE. Severe is a category used to rate the intensity of an event; 
both AEs and SAEs can be assessed as severe.
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An event is defined as “serious” when it meets at least 1 of the predefined criteria specified 
in the definition of an SAE, NOT when it is rated as severe.
If death occurs, the primary cause of death or event leading to death will 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 (e.g., sudden 
death, unexplained death), the death per se might then be reported as an SAE.
Assessment of Causality
!
The Investigator will assess the relationship between study intervention and each AE/SAE 
occurrence:
!
Unrelated: Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention. A reasonable 
alternative explanation will be available.
!
Related: Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention.
!
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out.
!
The Investigator will use clinical judgment to determine the relationship.
!
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated.
!
The Investigator will also consult the Investigator Brochure (IB) and/or Product 
Information, for marketed products, in his/her assessment.
!
For each AE/SAE, the Investigator will document in the medical notes that he/she has 
reviewed the AE/SAE and assessed causality.
!
There may be situations when an SAE has occurred, and the Investigator has minimal 
information to include in the initial report to the Sponsor or its designee.  To meet the 
reporting timeline, the causality assessment is not required for the initial report.
!
The Investigator may change his/her causality assessment after considering follow-up 
information and send a SAE follow-up report with the updated causality assessment.
!
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
Follow-up of AEs and SAEs
!
The Investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations, as medically indicated or as requested by the Sponsor or its designee to 
elucidate the nature and/or causality of the AE or SAE, as fully as possible. This may 
include additional laboratory tests or investigations, histopathological examinations, or 
consultation with other health care professionals.
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!
If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide Sponsor or its designee with a copy of any 
post-mortem findings including histopathology, if possible.
!
New or updated information will be recorded in the originally completed CRF.
!
The Investigator will submit any updated SAE data to Sponsor or its designee within 24 
hours of receipt of the information.
Reporting of SAEs
SAE Reporting by an Electronic Data Collection Tool
!
The primary mechanism for reporting an SAE to the Sponsor or its designee will be the 
electronic data collection tool.
!
If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool, specified below, to report the event within 24 hours.
!
The site will enter the SAE data into the electronic system as soon as it becomes available.
!
After the study is completed at a site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data.
!
If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken off-
line, then the site can report this information on a paper SAE form or to the Sponsor’s 
safety department.
!
By exception, an SAE (or follow-up information) may be reported by telephone.  The site 
will complete the electronic SAE data entry immediately thereafter.
SAE Reporting by a Paper Form
!
SAE reporting on a paper report form is used as a back-up method for an EDC system 
failure. The form includes completion instructions for the Investigator, names, addresses, 
and telephone and fax numbers. All information from the paper form will be transcribed 
into the electronic form as soon as the system becomes available.
!
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee.
!
In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the form sent by overnight mail or courier service.
!
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the form within 24 hours after becoming aware of the event.
!
Additional documents (e.g. laboratory reports, autopsy report, hospital discharge letter) and 
relevant pages from the CRF may be required in addition (e.g. medical history, 
concomitant medication). The data provided will be consistent with the information in the 
CRF.
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Reporting of Pregnancies
!
Pregnancy will be reported whether related to the study intervention using the applicable paper 
form.
!
The applicable form will be used to report if an abnormal outcome of the pregnancy occurs 
and the child/fetus sustains an event.
!
Facsimile transmission (fax to mail) of the paper form or any follow-up information is the 
preferred method for transmission and will be done within 24 hours to the Sponsor or its 
designee.
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Appendix 5
Clinical Laboratory Tests
Table 4
Protocol-Required Clinical Laboratory Assessments
Laboratory Assessments
Parameters
Hematology
Platelets
Mean Corpuscular 
Volume (MCV)
WBC Count with 
Differential:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes
Hemoglobin
MCH
Hematocrit
Red blood cell count
White blood cell counts
Biochemistry
Blood Urea 
Nitrogen
Potassium
Aspartate 
Aminotransferase
Bilirubin
Creatinine
Sodium
Alanine 
Aminotransferase
Total Protein
Glucose
Calcium
Alkaline 
phosphatase
Cholesterol
Uric acid
Chloride
γ-Glutamyl-
transferase
Triglycerides
C-reactive 
protein
Inorganic 
Phosphate
Lactate 
dehydrogenase
Amylase
Albumin
Urea
Magnesium
Creatinine
phosphokinase
Lipase
Coagulation
!
INR
!
PT
Routine Urinalysis
!
Specific gravity
!
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, 
leukocyte esterase by dipstick
!
microscopic examination (if blood or protein is abnormal)
Pregnancy Testing
Serum at Screening, Day -1, and Follow-Up/Discontinuation assessment. 
Other Tests
!
Follicle -stimulating hormone (FSH) and estradiol (as needed if not a 
WOCBP only)
!
Serum human chorionic gonadotropin (hCG) pregnancy test (as 
needed for a WOCBP). 
!
Urine drug screen (to include at minimum: amphetamines, 
methamphetamines, barbiturates, ecstasy, cocaine, opiates, 
cannabinoids, benzodiazepines, methadone, phencyclidine, 
oxycodone, and tricyclic antidepressants)
!
Urine Microscopy, only if blood, protein, nitrite, or leukocyte esterase 
are positive on the dipstick
!
Serology (HIV I and II antibodies, hepatitis B surface antigen, hepatitis 
B core antibody, hepatis C antibody, Quantiferon® Test)
!
Thyroid stimulating hormone (TSH)
!
Alcohol breath test
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