A Single-Dose, Randomized, Double-Blind, Placebo- and Positive-Controlled, 4-Way Crossover Study to Evaluate the Effect of Evobrutinib on the QTc (Corrected QT) Interval in Healthy Adult Participants
Phase: PHASE1
Conditions: Healthy
Sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Evobrutinib (M2951)  
 
A TQT Study of Effect of Evobrutinib on Cardiac Repolarization 
MS200527_0070 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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Clinical Study Protocol  
Title Page  
Clinical Study Protocol Title: 
A Single-Dose, Randomized, Double-Blind, 
Placebo- and Positive-Controlled, 4-Way 
Crossover Study to Evaluate the Effect of 
Evobrutinib on the QTc (Corrected QT) Interval in 
Healthy Adult Participants 
Study Number: 
MS200527_0070 
Protocol Version: 
 01 December 2022/Version 3.0 
Merck Compound: 
Evobrutinib 
Merck Registered Compound Name in 
Japan: 
Not applicable 
Study Phase: 
Phase 1 
Brief Title: 
A TQT Study of Effect of Evobrutinib on Cardiac 
Repolarization 
Principal Investigator: 
 
 
Sponsor Name and Legal Registered 
Address: 
Sponsor: 
Affiliates of Merck KGaA, Darmstadt, Germany 
For all countries, except the US and Canada: 
Merck Healthcare KGaA, Darmstadt, Germany  
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Strasse 250 
Darmstadt, 64293, Germany 
In the US and Canada:  
EMD Serono Research & Development Institute, 
Inc.  
an affiliate of Merck KGaA, Darmstadt, Germany  
45A Middlesex Turnpike  
Billerica, MA, 01821, USA 
Regulatory Agency Identifying 
Numbers: 
EudraCT: 2022-002664-78 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
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Keywords 
Not applicable 
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Evobrutinib (M2951)  
 
A TQT Study of Effect of Evobrutinib on Cardiac Repolarization 
MS200527_0070 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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Protocol Amendment Summary of Changes 
Protocol History 
 
Version Number 
Type 
Version Date 
3.0 
Updated Protocol 
01-December-2022 
2.0 
Updated Protocol 
24-October-2022 
1.0 
Original Protocol 
29-August-2022 
Protocol Version 3.0 (01 December 2022) 
Overall Rationale for the Amendment 
This non-substantial protocol amendment was prepared to allow rescreening of participants that 
were not previously enrolled in the study due to personal or logistical reasons or due to minor 
deviations that were not considered clinically relevant. Additional, wording of inclusion criteria 
was changed to have more flexibility regarding ratio of sexes. 
Section # and 
Name 
Description of Change 
Brief Rationale 
5.1 Inclusion 
Criteria 
Wording regarding enrolment of women 
changed form ‘at least 30% of each sex’ 
to ‘approx. 30% or more of each sex’ 
Wording of inclusion criteria was changed to have 
more flexibility regarding ratio of sexes. 
5.4 Screen 
Failures 
Four exceptions for rescreening were 
introduced. 
To allow rescreening of participants that were not 
previously enrolled in the study due to personal or 
logistical reasons or due to minor deviations that 
were not considered clinically relevant. 
 
- 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 © 2022 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved. 
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Evobrutinib (M2951)  
 
A TQT Study of Effect of Evobrutinib on Cardiac Repolarization 
MS200527_0070 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
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Table of Contents  
Title Page 
 ..............................................................................................................1 
Table of Contents  ..............................................................................................................4 
1 
Protocol Summary ................................................................................8 
1.1 
Synopsis ................................................................................................8 
1.2 
Schema ................................................................................................10 
1.3 
Schedule of Activities .........................................................................10 
2 
Introduction .........................................................................................13 
 
 
2.2 
Background .........................................................................................13 
2.3 
Benefit/Risk Assessment ....................................................................14 
2.3.1 
Risk Assessment .................................................................................15 
2.3.2 
Benefit Assessment .............................................................................17 
2.3.3 
Overall Benefit: Risk Conclusion .......................................................17 
3 
Objectives and Endpoints ...................................................................18 
4 
Study Design .......................................................................................18 
4.1 
Overall Design ....................................................................................19 
4.2 
Scientific Rationale for Study Design ................................................19 
4.2.1 
Use of Moxifloxacin ...........................................................................20 
4.2.2 
Participant Input into Design ..............................................................20 
4.3 
Justification for Dose ..........................................................................20 
4.4 
End of Study Definition ......................................................................20 
5 
Study Population .................................................................................21 
5.1 
Inclusion Criteria ................................................................................21 
5.2 
Exclusion Criteria ...............................................................................22 
5.3 
Lifestyle Considerations .....................................................................26 
5.3.1 
Meals and Dietary Restrictions ...........................................................26 
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoid ...................................27 
5.3.3 
Activity ...............................................................................................27 
5.4 
Screen Failures ....................................................................................27 
5.5 
Criteria for Temporarily Delaying Administration of Study 
Intervention .........................................................................................28 
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6 
Study Intervention(s) and Concomitant Therapies .............................28 
6.1 
Study Intervention(s) Administration .................................................28 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................30 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................31 
6.3.1 
Study Intervention Assignment ..........................................................31 
6.3.2 
Blinding ..............................................................................................32 
6.3.3 
Emergency Unblinding .......................................................................32 
6.4 
Study Intervention Compliance ..........................................................33 
6.5 
Dose Modification ..............................................................................33 
6.6 
Continued Access to Study Intervention After the End of the 
Study ...................................................................................................33 
6.7 
Treatment of Overdose .......................................................................33 
6.8 
Concomitant Therapy .........................................................................33 
6.8.1 
Rescue Medicine .................................................................................34 
6.8.2 
Permitted Medicines ...........................................................................34 
6.8.3 
Prohibited Medicines ..........................................................................34 
6.8.4 
Other Interventions .............................................................................34 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................34 
7.1 
Discontinuation of Study Intervention................................................35 
7.1.1 
Liver Clinical Safety Laboratory Tests Stopping Criteria ..................35 
7.1.2 
Cardiac Safety Stopping Criteria ........................................................35 
7.1.3 
Hypersensitivity/Allergic Reactions Stopping Criteria ......................36 
7.2 
Participant Discontinuation/Withdrawal from the Study ...................36 
7.3 
Lost to Follow-Up...............................................................................36 
8 
Study Assessments and Procedures ....................................................37 
8.1 
Efficacy Assessments and Procedures ................................................37 
8.2 
Safety Assessments and Procedures ...................................................37 
8.2.1 
Physical Examinations ........................................................................38 
8.2.2 
Vital Signs ..........................................................................................38 
8.2.3 
Electrocardiograms .............................................................................38 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
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8.2.4 
Clinical Safety Laboratory Tests ........................................................38 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting ............................................................................................39 
8.3.1 
Method of Detecting Adverse Events and Serious Adverse Events ...39 
8.3.2 
Follow-up of Adverse Events and Serious Adverse Events ...............40 
8.3.3 
Regulatory Reporting Requirements for Serious Adverse Events .....40 
8.3.4 
Pregnancy ...........................................................................................40 
8.3.5 
Cardiovascular and Death Events .......................................................41 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs ................................................................41 
8.3.7 
Adverse Events of Special Interest .....................................................41 
8.4 
Pharmacokinetics ................................................................................42 
8.4.1 
Blood Sampling and Bioanalysis ........................................................42 
8.4.2 
PK Parameters ....................................................................................44 
8.4.3 
Electrocardiograms .............................................................................44 
8.5 
Pharmacogenetics ...............................................................................46 
8.6 
Biomarkers ..........................................................................................46 
8.7 
Immunogenicity Assessments ............................................................46 
8.8 
Medical Resource Utilization and Health Economics ........................46 
9 
Statistical Considerations ....................................................................46 
 
..46 
 
47 
9.3 
Analysis Sets .......................................................................................47 
9.4 
Statistical Analyses .............................................................................47 
9.4.2 
Other Analyses (QTc and PK analyses) ..............
.49 
9.4.3 
Sequence of Analyses .........................................................................49 
10 
References ...........................................................................................50 
11 
Appendices .........................................................................................51 
Appendix 1 
Abbreviations ......................................................................................52 
Appendix 2 
Study Governance ...............................................................................54 
Appendix 3 
Contraception and Barrier Requirements ...........................................60 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ................................................61 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
C O N F I D E N T I A L 
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Appendix 5 
Liver Safety: Suggested Actions and Follow-up Assessments ...........67 
Appendix 6 
Clinical Laboratory Tests ...................................................................68 
Appendix 7 
Protocol Amendment History .............................................................70 
Appendix 8 
Sponsor Signature Page ......................................................................71 
Appendix 8 
Principal Investigator Signature Page .................................................72 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
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1 
Protocol Summary  
1.1 
Synopsis  
Clinical Study Protocol Title: A Single-Dose, Randomized, Double-Blind, Placebo- and 
Positive-Controlled, 4-Way Crossover Study to Evaluate the Effect of Evobrutinib on the QTc 
(Corrected QT) Interval in Healthy Adult Participants 
Brief Title: A TQT Study of Effect of Evobrutinib on Cardiac Repolarization 
 This study is being conducted to assess potential effects of evobrutinib on cardiac 
repolarization (i.e. prolongation of QT interval). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Evobrutinib (M2951)  
 
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MS200527_0070 
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Objectives and Endpoints:  
Objectives 
Endpoints 
Ref. # 
Primary
To evaluate whether evobrutinib 
administered as a single oral 
dose (as solution) of 45 mg or 
225 mg prolongs QT/QTc in 
comparison to placebo control 
ǻǻQTcF (placebo-corrected change from baseline QTcF) for 
evobrutinib; with concentration-QTc analysis as primary analysis
1
Secondary
To demonstrate QTc assay 
sensitivity 
ǻǻQTcF (placebo-corrected change from baseline QTcF) for 
moxifloxacin 
2
To assess the safety and 
tolerability of evobrutinib 
Nature, occurrence, and severity of TEAEs 
3
Absolute values and changes in safety laboratory tests 
Vital signs assessed from time of first dose to end of study 
participation
Single 12-lead ECGs evaluated by Investigator 
To assess the effect of 
evobrutinib on other ECG 
parameters 
QT, QTcB, QTcI, PR, QRS, RR, HR, cardiologist assessment 
including T-wave morphology, and U-wave 
4
To determine the PK of 
evobrutinib 
 
 at 45 mg and 225 mg 
oral dose (solution) under fasting 
conditions and moxifloxacin at 
400 mg oral dose 
AUC0-24, AUC0-, Cmax, and tmax for evobrutinib and major metabolite 
AUC0-24, AUC0-, Cmax, and tmax for moxifloxacin 
5
Overall Design: This will be a Phase 1, single-center, randomized, double-blinded, placebo- and 
positive-(moxifloxacin) controlled, single-dose, 4-period crossover study.
Brief Summary: The purpose of this study is to assess potential effects of evobrutinib on cardiac 
repolarization (i.e. prolongation of QT interval). Study details include: 
x Study Duration: up to 57 days 
x Treatment: Single oral dose of 45 or 225 mg evobrutinib, 400 mg moxifloxacin or placebo 
administered in fasted state at Study Day 1 of each period. 
x The washout between administrations of study intervention between each period will be at least 
7 days. 
x Visit Frequency: Screening visit will be within 28 to 2 days prior to first administration of study 
intervention. Participants will be resident in the Clinical Research Unit from Day -1 to Day 2 
of each period.  
Study Intervention Groups and Duration: Single-dose, 4-way crossover study, up to 57 days
Data and Safety Monitoring /Other Committee: No 
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Evobrutinib (M2951)  
 
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1.2 
Schema  
 
a End of Treatment assessment 
Treatment A, B, C, and D are used to denote placebo (solution, fasted), moxifloxacin 400 mg (tablet, fasted), evobrutinib 45 mg 
(solution, fasted) and evobrutinib 225 mg (solution, fasted), but not necessarily in that respective order. The assignment of actual 
treatments to the labels will be made when generating the randomization list. 
1.3 
Schedule of Activities  
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
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Assessments & 
Procedures 
Screening 
Treatment 
Safety 
Follow-up 
call 
Comments 
P1 
P2 
P3 
P4 
Study Day(s) 
-28 to -2 
-1 
1 
2 
7a 
8 
9 
14a 
15 
16 21a 
22 23b 
29 
a Assuming 7 days washout between treatment periods. 
b End of Treatment assessment. 
Period-specific Day(s) 
-28 to -2 
-1 
1 
2 
-1 
1 
2 
-1 
1 
2 
-1 
1 
2 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior to any screening activity 
Participants resident at 
CRU 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Discharge on Day 2 of each period 
Eligibility criteria 
X 
Xc 
 
 
Xc 
 
 
Xc 
 
 
Xc 
 
 
 
c Recheck of health status on Day -1. 
Demography, height & 
weight  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography to include, at minimum age (year of birth), sex, 
race, and ethnicity. 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum pregnancy test 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Viral serology, TSH, 
eGFR, QuantiFERON® 
test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cotinine, alcohol and 
drugs of abuse testing, 
SARS-CoV-2 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Brief examination on Days -1 of each period to recheck 
eligibility/ healthy state after return to CRU and on the End of 
Treatment assessment visit. 
Vital signs 
Xd 
X 
Xd 
X 
X 
Xd 
X 
X 
Xd 
X 
X 
Xd 
Xd 
Vital signs will be assessed on Day -1 of each period and on 
the days of dosing (Day 1 of each period) at predose and 1, 2, 
6, and 24 h postdose.  
d Body temperature will be assessed at Screening, predose, 
and the End of Treatment assessment visit. 
At visits where assessment time points coincide with each 
other, the following sequence of activities will be followed: 
safety ECG followed by vital signs within 30 minutes before 
the specified time point preceding the PK sampling, which will 
be performed at the specified time point.  
Safety ECGs 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Safety ECG at 2 h postdose in each period. 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
C O N F I D E N T I A L 
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Assessments & 
Procedures 
Screening 
Treatment 
Safety 
Follow-up 
call 
Comments 
P1 
P2 
P3 
P4 
Study Day(s) 
-28 to -2 
-1 
1 
2 
7a 
8 
9 
14a 
15 
16 21a 
22 23b 
29 
a Assuming 7 days washout between treatment periods. 
b End of Treatment assessment. 
Period-specific Day(s) 
-28 to -2 
-1 
1 
2 
-1 
1 
2 
-1 
1 
2 
-1 
1 
2 
 
 
Holter recordings 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Holter recordings starting 1 hour prior to first timepoint on 
Day 1 and lasting at least until last timepoint of PK sampling 
on Day 2 (24 h postdose) of each period. 
Triplicate ECGs from 
Holter recordings 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
On each dosing day 12-lead ECGs extracted in triplicates 
from Holter recordings at 3 timepoints before dosing 
(-1 h, -30 min, and -10 min), and at 15 and 30 min and 1, 1.5, 
2, 2.5 3, 4, 6, 8, 12,16 h and at 24 h postdose. 
Clinical laboratory safety 
tests 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
X 
 
Blood samples for the clinical laboratory safety assessments 
will be collected in a fasted condition. 
PK sampling (evobrutinib, 
evobrutinib major 
metabolite, and 
moxifloxacin) 
 
 
X 
X 
 
X 
X 
 
X 
X 
 
X 
X 
 
Plasma samples for PK analysis will be collected on the days 
of dosing (i.e., Days 1, 8, 15, and 22) at predose and 15 and 
30 min, and 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16 and 24 h 
postdose. 
At visits where assessment time points coincide with each 
other, the following sequence of activities will be followed: PK 
sample to be collected shortly (within time windows specified) 
after ECG. 
Study intervention 
administration 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Previous/concomitant 
medication monitoring 
X 
<=======================================================> Section 6.8. 
AE monitoring 
X 
<=======================================================> Section 8.3. 
CRU=clinical research unit; ECG=electrocardiogram; eGFR=estimated glomerular filtration rate; FSH=follicle stimulating hormone; PK=pharmacokinetics; 
SARS-CoV-2=severe acute respiratory syndrome coronavirus 2; TSH=thyroid stimulating hormone. 
 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
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2 
Introduction  
Evobrutinib is an oral, selective, irreversible inhibitor of BTK that is in clinical development for 
the treatment of autoimmune diseases, e.g. RMS. Detailed information on the chemistry, 
pharmacology, efficacy, and safety of evobrutinib is in the current IB. 
 
  
This study is being conducted to assess potential effects of evobrutinib on cardiac repolarization 
(i.e., prolongation of QT interval). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.2 
Background  
Evobrutinib 
Evobrutinib (also known as M2951 and MSC2364447C) is an oral, selective, irreversible inhibitor 
of BTK. Evobrutinib inhibits primary B cell responses, such as proliferation and antibody and 
cytokine release, without directly affecting T cells. Indirect effects on T cells can be mediated by 
BTK inhibition by blocking the B cell antigen presentation function. In addition, BTK inhibition 
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Evobrutinib (M2951)  
 
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I N F O R M A T I O N 
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blocks the activation of innate immune cells by immune complexes downstream of Fc receptor 
activation. All 3 mechanisms may play a role in the pathogenesis of various autoimmune diseases. 
Thus, BTK inhibition could provide clinical benefit in the treatment of multiple autoimmune 
diseases including RMS. 
In clinical studies with healthy participants, evobrutinib was rapidly absorbed with a tmax of 0.5 to 
1.5 hours under fasted conditions. Evobrutinib demonstrated dose-proportional PK (i.e. Cmax and 
AUC0-) over the evaluated dose range of 25 to 500 mg single dose and 25 to 200 mg once daily 
multiple dose. Median t1/2 was approximately 2 hours (range 1.8 to 2.6 hours) at relevant plasma 
concentrations following a single oral dose of 25 to 200 mg. Accumulation of evobrutinib is 
minimal with daily dosing (refer to IB). 
Moxifloxacin 
Moxifloxacin 400 mg film-coated tablets are indicated for the treatment of bacterial infections in 
patients 18 years and older caused by bacteria susceptible to moxifloxacin. Following oral 
administration, moxifloxacin is rapidly and almost completely absorbed. The absolute 
bioavailability is approximately 91%. Its pharmacokinetics are linear in the range of 50 to 800 mg 
single dose and up to 600 mg once daily dosing over 10 days. Following a 400 mg oral dose, peak 
concentrations of 3.1 mg/L are reached within 0.5 to 4 h after dosing. Moxifloxacin is frequently 
used in thorough QT studies as a positive control because it induces small and consistent 
prolongations of QT/QTc but is not considered as having a proarrhythmic activity (refer to 
moxifloxacin approved product information). 
QT Interval 
The QT interval (time from the beginning of the QRS complex to the end of the T wave) of the 
ECG is a measure of the duration of ventricular depolarization and repolarization. When 
ventricular repolarization is delayed and the QT interval is prolonged, there is an increased risk of 
ventricular tachyarrhythmia, which can, usually in conjunction with other factors (e.g. 
hypokalemia, atrial fibrillation and structural heart disease), lead to TdP, a frequently fatal form 
of polymorphic ventricular tachyarrhythmia. Hence, much emphasis has been placed on the 
potential proarrhythmic effects of pharmaceuticals associated with QT interval prolongation. 
2.3 
Benefit/Risk Assessment  
As of 31 July 2021, approximately 2,041 adult participants in 16 completed and 4 ongoing clinical 
studies have been exposed to evobrutinib, including healthy participants (243), participants with 
RMS (943), systemic lupus erythematosus (437), or rheumatoid arthritis (363), and participants 
with renal impairment (31) and hepatic impairment (24). Evobrutinib was generally safe and well 
tolerated in all participants. The TEAEs have been primarily mild to moderate in severity. 
Evobrutinib treatment will be administered as a single dose of 45 mg or 225 mg (oral solution) 
under fasting conditions. These doses are within the range of doses that were previously tested in 
healthy participant studies and do not exceed exposures reached in first-in-human clinical Study 
EMR200527-001, where single doses of evobrutinib from 25 up to 500 mg and 14 days of dosing 
with 25, 75, and 200 mg/day were tested and shown to be well tolerated. 
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Evobrutinib (M2951)  
 
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MS200527_0070 
 
 
C O N F I D E N T I A L 
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The positive control used, single-dose moxifloxacin, should induce a QTc prolongation of more 
than 5 ms as evidenced by the lower bound of the two-sided 90% CI in the mean placebo-corrected 
change from baseline in QTcF (ǻǻQTcF) exceeding 5 ms at the mean peak moxifloxacin 
concentration. The risk to induce a dysrhythm or TdP by moxifloxacin is very low and this risk is 
known and is considered acceptable in the scientific community.
 
 
 
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of evobrutinib may be found in the current IB. 
 
 
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 risk: 
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 refer to 
current IB Section 6.1). 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 receiving short treatment 
with evobrutinib. 
Participants with known history of 
hepatic disorder will not be included 
in the study. Study participants will 
be confined, and liver tests (e.g. 
ALT, AST) will be adequately 
monitored during the study. 
Important potential risk: 
Embryo-fetal toxicity 
Based on nonclinical findings, 
embryo-fetal toxicity is considered 
as an important potential risk in 
women of childbearing potential 
exposed to evobrutinib.  
Only women of nonchildbearing 
potential are included in this study. 
Moxifloxacin 
Aortic aneurysm and dissection 
This risk applies for the long-term 
use of the medicine only. 
Not applicable as this is single-dose 
use only. 
Prolonged, disabling and potentially 
irreversible serious adverse drug 
reactions (musculoskeletal, 
nervous, psychiatric and senses) 
This risk applies for the long-term 
use of the medicine only. 
Exclusion of participants with 
medical history of psychiatric 
disorders. 
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Evobrutinib (M2951)  
 
A TQT Study of Effect of Evobrutinib on Cardiac Repolarization 
MS200527_0070 
 
 
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Hypersensitivity and allergic 
reactions 
Hypersensitivity and allergic 
reactions have been reported for 
fluoroquinolones including 
moxifloxacin after first 
administration. Anaphylactic 
reactions can progress to a 
life-threatening shock, even after 
the first administration. 
Suitable emergency treatment will 
be available (e.g. treatment for 
shock). 
ECG: QTc interval prolongation 
QTc prolongations can result in 
clinically relevant arrhythmias. 
Suitable emergency treatment will 
be available. 
Liver: hepatitis 
Cases of fulminant hepatitis 
potentially leading to life-threatening 
liver failure have been reported with 
moxifloxacin. 
Liver enzyme monitoring and strict 
stopping rules. 
CNS: seizures 
Quinolones are known to trigger 
seizures. 
Exclusion of participants with 
medical history of seizures. 
Photosensitivity reactions 
Quinolones have been shown to 
cause photosensitivity reactions in 
patients. 
Participants should be advised to 
avoid exposure to either UV 
irradiation or extensive and/or 
strong sunlight during treatment with 
moxifloxacin. 
Study Procedures 
Blood draw 
Blood draws have the potential to 
cause AEs 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. 
ECG 
Contact allergies can develop 
during ECG procedures. 
Participants with known contact 
allergies will not be included in the 
study.  
Other 
Not applicable 
 
 
2.3.1.1.1 
Potential Risks associated with the COVID-19 Pandemic 
Situation  
As for the general population, there is a risk of a SARS-CoV-2 infection for study participants as 
long as COVID-19 pandemic situation is ongoing. 
Evobrutinib is a BTK inhibitor and, as such, works as an immunomodulator. There was some 
decrease in IgM, an increase in IgA, and some modest changes in IgG following long-term 
treatment with evobrutinib; these changes were not clinically significant. In addition, duration of 
the evobrutinib treatment in this study will be limited to 2 days. Although BTK is not required to 
clear viral infections, apart from enteroviruses, no information is available regarding BTK 
inhibitors as a class or evobrutinib specifically regarding the risk for either contracting 
SARS-CoV-2 or severity of COVID-19 at this point. The published data on approved BTK 
inhibitors (e.g. ibrutinib and acalabrutinib) used in oncology suggest a protective effect of BTK 
inhibitors for severity and mortality of COVID-19 (Scarfò 2020, Thibaud 2020, Treon 2020).  
During the entire study, all recommendations issued by the Robert Koch Institute as well as local 
guidelines with respect to the minimization of the risk of disease spreading, e.g. social distancing, 
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disinfection, hygiene, and wearing of mouth-nose masks will be followed. During the pandemic 
situation, further measures according to recommendations and requirements from local Health 
Authorities may become necessary and will be followed within the context of this study as far as 
applicable, in order to ensure full implementation of the principles of GCP with priority on 
participant safety in this study also during the COVID-19 pandemic situation. These measures are 
described in a preventive action plan implemented at the Investigator site. 
To minimize the risk coming from a current infection and the risk of getting infected by other 
participants during the in-house period (covering the whole treatment phase) of the study, the 
following measures are implemented: Only participants without any symptoms of a respiratory 
disease and without contact to any known SARS-CoV-2 positive patient or COVID-19 patient in 
the previous 7 days will be included into the study. Furthermore, as a part of the clinical study 
procedures, participants will be closely monitored (including for signs of COVID-19) during the 
entire study duration. Continuation of the study in case of a SARS-CoV-2 infection in the study 
participant or an identified contact to a SARS-CoV-2 positive participant or COVID-19 patient 
will be done at the Investigator’s discretion and agreement with the medical monitoring team. The 
Sponsor will monitor the events related to any SARS-CoV-2 infection reported following 
evobrutinib regularly and update the recommendations, if necessary. 
2.3.2 
Benefit Assessment  
The healthy volunteers participating in this study will not obtain any clinical benefit from the 
treatments. The data obtained from this study will guide further development of evobrutinib. 
2.3.3 
Overall Benefit: Risk Conclusion  
Risk minimization measures routinely implemented in early phase clinical studies are considered 
adequate, including exclusion criteria (see Sections 5.1 and 5.2), adequate biochemical and 
hematology laboratory monitoring (see Section 8.2.4), and observation of vital signs and ECGs 
(see Sections 8.2.2 and 8.2.3). Participants will be admitted to the study site for the duration of the 
study to allow continuous safety monitoring. Considering the measures taken to minimize risk to 
participants in this study, the potential risks identified in association with evobrutinib and 
moxifloxacin are justified in healthy participants. 
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3 
Objectives and Endpoints  
Objectives 
Endpoints 
Ref. # 
Primary 
 
To evaluate whether evobrutinib 
administered as a single oral 
dose (as solution) of 45 mg or 
225 mg prolongs QT/QTc in 
comparison to placebo control 
ǻǻQTcF (placebo-corrected change from baseline QTcF) for 
evobrutinib; with concentration-QTc analysis as primary analysis 
1 
Secondary 
 
To demonstrate QTc assay 
sensitivity 
ǻǻQTcF (placebo-corrected change from baseline QTcF) for 
moxifloxacin 
2 
To assess the safety and 
tolerability of evobrutinib  
Nature, occurrence, and severity of TEAEs 
3 
Absolute values and changes in safety laboratory tests 
Vital signs assessed from time of first dose to end of study 
participation 
Single 12-lead ECGs evaluated by Investigator 
To assess the effect of 
evobrutinib on other ECG 
parameters 
QT, QTcB, QTcI, PR, QRS, RR, HR, cardiologist assessment 
including T-wave morphology, and U-wave. 
4 
To determine the PK of 
evobrutinib and its major 
metabolite at 45 mg and 225 mg 
oral dose (solution) under fasting 
conditions and moxifloxacin at 
400 mg oral dose 
AUC0-24, AUC0-, Cmax, and tmax for evobrutinib and major metabolite 
AUC0-24, AUC0-, Cmax, and tmax for moxifloxacin 
5 
4 
Study Design  
This is a Phase 1, single-center, randomized, double-blinded, placebo- and positive-(moxifloxacin) 
controlled, single-dose, 4-period crossover thorough QT study. There will be a at least 7-day 
washout period between successive doses.
 
Eligible participants will be randomized to 1 of 
4 treatment sequences in which each of the 4 treatments will be administered sequentially during 
4 treatment periods. The 4 treatments are: 
x Therapeutic dose, double-blind: single oral dose of evobrutinib (45 mg) solution, 
administered under fasted conditions; 
x Supratherapeutic dose, double-blind: single oral dose of evobrutinib (225 mg) solution, 
administered under fasted conditions; 
x Placebo control, double-blind: single oral dose of placebo solution, administered under 
fasted conditions; 
x Positive control, open-label: single oral dose of 1 moxifloxacin tablet (400 mg), 
administered under fasted conditions. 
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4.1 
Overall Design  
Study Design 
Single-dose, 4-way crossover 
Control Method 
Placebo- and positive-controlled 
Single or Multicenter 
Single center 
Study Population Type 
Healthy participants 
Level and Method of 
Blinding 
Double-blind for evobrutinib and placebo 
Bias Minimalization 
Method(s) 
Randomization, blinding 
Study Intervention 
Assignment Method 
Randomization 
Data and Safety 
Monitoring /Other 
Committee: 
No  
Total Duration of Study 
Participation per 
Participant 
Up to 57 days, including the Screening Period (maximum of 
28 days), 23 days of intervention period with at least a 7-day 
washout between each study period, and the Safety Follow-up call 
on Day 29, 1 week after the last dose of study intervention. A 
study schema and a detailed Schedule of Assessments are 
provided in Section 1.2 and Section 1.3, respectively. 
Provisions for Study 
Extension or Entry into 
Roll-Over Studies 
Not applicable 
Adaptive Aspects of 
Study Design 
Not applicable  
A study design schema and a detailed Schedule of Activities are provided in Section 1.2 and 
Section 1.3, respectively. 
4.2 
Scientific Rationale for Study Design  
The design of this thorough QT study, a randomized, assessor-blinded, placebo- and positive-
(moxifloxacin) controlled, single-dose, 4-period crossover study, is the standard design for this 
type of QT assessment study. 
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4.2.1
Use of Moxifloxacin  
A positive control is recommended by regulatory authorities to be able to detect a ~ 5 ms change 
from baseline- and placebo-corrected QTc duration (ǻǻQTc) to confirm the sensitivity of the 
study. Moxifloxacin is frequently used in thorough QT studies because it induces small and 
consistent prolongations of QT/QTc but is not considered as having a proarrhythmic activity (as 
outlined in ICH E14/S7B Q&A 2020). A pooled analysis of 14 crossover thorough QT studies 
with 400 mg single oral dose of moxifloxacin demonstrated a largest mean ǻǻQTcF effect of 
12.3 ms at 3 h postdose (Yan 2010). In this study, a single 400 mg dose of moxifloxacin will be 
administered orally to the participants (refer to approved product information). 
4.2.2
Participant Input into Design  
Not applicable. 
4.3
Justification for Dose  
Evobrutinib 
The evobrutinib therapeutic dose to be used in this study 
 is 
expected to result in Cmax similar to those in the Phase 3 studies in patients dosed with 45 mg 
tablets (fed) BID, and the supratherapeutic dose 
 is expected 
to result in 5-fold higher Cmax. A 
 higher Cmax is expected to provide adequate coverage for 
the clinically relevant high-exposure scenario for evobrutinib Cmax, if administered with a moderate 
or strong CYP3A4 inhibitor 
 
Moxifloxacin 
Moxifloxacin is frequently used in thorough QT studies because it induces a small and consistent 
QT/QTc prolongation with a low incidence of inducing proarrhythmic activity. A single oral dose 
of 400 mg given in a fasted state is the standard dose used for this type of study.  
4.4
End of Study Definition  
The end of the study is defined as the date of last contact (related to this study) with the last 
participant who participates in this study (last participant’s Safety Follow-up Assessment/Early 
Termination Assessment). 
A participant has completed the study if he/she has completed all study parts including the Safety 
Follow-up Assessment shown in Section 1.3. 
Study Termination Criteria 
The study will be discontinued or terminated if: 
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x unacceptable risk, any relevant toxicity, or a negative change in the risk/benefit assessment 
is identified. This might include the occurrence of AEs which character, severity or 
frequency is new in comparison to the existing risk profile. 
x any data derived from other clinical trials or toxicological studies become available which 
negatively influence the risk/benefit assessment. 
General information on study termination is specified in Appendix 2. 
5 
Study Population  
The criteria in Sections 5.1 and 5.2 are designed to enroll only individuals who are appropriate for 
the study; thereby, ensuring the study fulfills its objectives. All relevant medical and nonmedical 
conditions are considered when deciding whether an individual 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 individual’s routine medical care, 
the Investigator will confirm that the individual 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: 
Category 
Criterion 
Age 
1.  Are between 18 and 55 (inclusive) years of age at the time of 
signing the informed consent. 
Type of Participant 
and Disease 
Characteristics 
2. 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.  
Weight 
3. Have a body weight within 50.0 and 100.0 kg (inclusive) and 
BMI within the range 19.0 and 30.0 kg/m2 (inclusive). 
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Category 
Criterion 
Sex and 
Contraception/ 
Barrier Requirements 
4. 
 
x Male 
o No contraception and barrier requirements needed. 
x Female 
o Is 
not 
a 
woman 
of 
childbearing 
potential 
(Appendix 3). 
Note: Study to include approx. 30% or more of each sex 
Informed Consent 
5. Are capable of giving signed informed consent, as indicated in 
Appendix 2, which includes compliance with the requirements 
and restrictions listed in the ICF and this protocol. 
Smoking 
6. Are stable nonsmokers for at least 3 months preceding the first 
administration of study intervention. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Category 
Criterion 
Medical Conditions 
1. History or presence of clinically relevant respiratory, 
gastrointestinal, renal, hepatic, hematological, lymphatic, 
neurological, cardiovascular, musculoskeletal, genitourinary, 
immunological, dermatological, connective tissue, psychiatric 
(due to rare risk of hallucinations, agitation and activation of 
psychosis), and other diseases or disorders, and epilepsy, as 
determined by medical evaluation. 
2. Individuals with diagnosis of hemochromatosis, Wilson´s 
disease, alpha 1 antitrypsin deficiency, or any other chronic 
liver disease including Gilbert’s disease will be excluded 
from the study. 
Prior history of cholecystectomy or splenectomy, and any 
clinically relevant surgery within 6 months prior to the first 
administration of study intervention. 
3. History of any malignancy. 
4. History of seizures. 
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Category 
Criterion 
5. History of pharmacologically treated psychiatric disease. 
6. 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 the first administration of study intervention. 
7. History of shingles within 12 months prior to Screening. 
8. History of drug hypersensitivity (e.g. quinolones and 
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 including contact 
hypersensitivity to ECG electrodes, which may affect the 
safety of the participant and/or outcome of the study per the 
Investigator’s discretion. 
9. History of alcoholism or drug abuse within 2 years prior to 
the first administration of study intervention, or positive for 
drugs of abuse, nicotine/cotinine or alcohol by the laboratory 
assays conducted during Screening and Study Day -1. 
10. History of residential exposure to tuberculosis, or a positive 
QuantiFERON® test within 4 weeks prior to or at the time of 
Screening. 
11. Positive for a) hepatitis B surface antigen, hepatitis B core 
antibody, hepatitis C antibody, or human immunodeficiency 
virus I and II tests at Screening; b) SARS CoV-2 at Screening 
or Study Day -1. 
12. Any condition, including findings in the laboratory tests, 
medical history (e.g. heart failure, hypokalemia, family 
history of Long QT Syndrome), or other Screening 
assessments, that in the opinion of the Investigator constitutes 
an inappropriate risk or a contraindication for participation in 
the study or that could interfere with the study’s objectives, 
conduct, or evaluation. 
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Category 
Criterion 
13. Administration of live vaccines or live-attenuated virus 
vaccines within 3 months prior to Screening. Administration 
of other types of vaccines (e.g. SARS-CoV-2 vaccines) is 
allowed until 42 days before the first administration of study 
intervention, thereafter it is prohibited until the end of the 
study. 
Note: In case of clinical symptoms, the participant should be 
symptom-free for at least 1 week prior to the first 
administration of study intervention. 
Prior/Concomitant 
Therapy 
14. Moderate or strong inhibitors or inducers of CYP3A4/5 or 
P-gp within 4 weeks prior to the first administration of study 
intervention. 
15. Use of any prescribed medicine or over-the-counter drug or 
dietary supplement, including herbal remedies, vitamins, and 
minerals, antacids and dietary supplements such as fish oils 
within 2 weeks or 5 times the half-life of the respective drug, 
whichever is longer, prior to the first administration of study 
intervention.  
Occasional paracetamol (acetaminophen) up to 2 g per day is 
permitted. 
Prior/Concurrent 
Clinical Study 
Experience 
16. Use of any investigational drug in any clinical study within 
60 days prior to Study Day 1 administration, or have used an 
experimental monoclonal antibody within the past 1 year 
prior to Study Day 1, or have participated in a study 
evaluating a BTK inhibitor within 60 days, 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 the first administration of study intervention. 
Diagnostic Assessments 17. Medical history and physical examination results that include 
any ongoing clinically relevant findings as judged by the 
Investigator. 
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Category 
Criterion 
18. Clinically relevant findings (excluding minor, not clinically 
relevant excursions from normal ranges, as judged by the 
Investigator) at Screening in biochemistry, hematology, 
coagulation, and urinalysis examinations for the age of the 
participant, as judged by the Investigator: 
• 
Alanine aminotransferase, aspartate aminotransferase: 
above ULN 
• 
Creatinine: above normal limits 
• 
Absolute lymphocyte count, absolute neutrophil count: 
below limit of reference range. 
• 
Amylase and lipase above normal ranges, minor deviations 
are allowed, if not clinically relevant. 
• 
Abnormal, low levels of potassium levels 
19. Estimated glomerular filtration rate according to the Chronic 
Kidney Disease Epidemiology Collaboration Creatinine 
Equation (2009) < 90 mL/min at Screening. In case of a 
borderline result between  80 and < 90 mL/min, Cystatin C 
will be determined in addition, and the participant will only 
be included if the Cystatin C value is below the upper limit of 
normal. 
20. Semi-supine systolic blood pressure > 140 mmHg or 
< 90 mmHg, diastolic blood pressure > 90 mmHg or 
< 50 mmHg, and pulse rate > 90 or < 50 bpm at Screening. 
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. 
21. 12-Lead ECG showing a QT interval corrected for heart rate 
according to Fridericia’s formula (QTcF) > 450 ms, 
PR > 215 ms, or QRS > 110 ms at Screening. 
22. Any other abnormal laboratory results that the Investigator 
believes should preclude the participant’s participation in the 
study. 
Other Exclusions 
23. Consumption of an average weekly alcohol intake of 
> 14 units/week for men or > 7 units/week for women. 1 unit 
(12 g) of alcohol equals ½ pint (285 mL) of beer or lager, 
1 glass (125 mL) of wine, or 1/6 gill (25 mL) of spirits. 
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Category 
Criterion 
24. Contraindication to moxifloxacin (refer to approved product 
information moxifloxacin). 
25. 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 until after collection of the final 
PK sample in each period. 
26. Consumption of alcohol from 48 hours prior to first 
administration of study intervention. 
27. Herbal supplements including, but not limited to, St. John’s 
wort (hypericum perforatum), grapefruit, Seville oranges, 
cranberries, or juices of these fruits within 14 days prior to 
the first administration of study intervention. 
28. Donation or loss of more than 450 mL of blood in the 60 days 
prior to the first administration of study intervention, 
donation of plasma from 2 weeks prior to the first 
administration of study intervention, or platelets from 
6 weeks prior to the first administration of study intervention. 
29. Travel to a country with a high prevalence of tropical 
diseases within 3 months prior to the first administration of 
study intervention. 
30. 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. 
5.3 
Lifestyle Considerations  
5.3.1 
Meals and Dietary Restrictions  
x Participants will abstain from consuming Seville oranges, grapefruit or grapefruit juice, 
pomelos, exotic citrus fruits, grapefruit hybrids, or fruit juices from these fruits from 14 days 
before the start of study intervention until after the final dose. 
x Participants will receive standardized meals on Day -1 of each period at customary times.  
x On Day 1 of each period the participants will be fasting (no food, no beverages, only water is 
allowed) from at least 10 hours before and until 4 hours after drug administration. Ingestion of 
water between 1 hour predose and until 1 hour postdose will not be allowed. 4 hours after drug 
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administration, a standardized lunch will be served. An afternoon snack will be provided 
approximately 8 hours and dinner approximately 12 hours postdose. 
5.3.2 
Caffeine, Alcohol, Tobacco, and Cannabinoid  
x During each dosing period 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 sample. 
x In this study the consumption of alcohol is not allowed from 48 hours prior to first 
administration of study intervention (see Section 5.2) until after collection of the final PK 
sample. 
x During the study, participants will abstain from THC or cannabinoid-containing products for 2-
weeks before the start of dosing until after collection of the final PK sample. 
x Participants who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted from at least 3 months preceding 
Screening until after the final follow-up visit. 
5.3.3 
Activity  
Participants will abstain from strenuous exercise for 3 days before each blood collection for 
clinical laboratory tests and PK samples. Participants may participate in light recreational activities 
(e.g. watching television or reading). 
5.4 
Screen Failures  
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
rescreened with the following exceptions: 
x The participant successfully passed the screening procedures but subsequently could not start 
the study on schedule. 
x Initial screening occurred too early to complete the required washout period after any prior 
therapy. 
x The participant was not included due to transient reasons (e.g., an infection at the time of 
screening). 
x Minor (not clinically relevant, as judged by the principal investigator) deviations from the 
in-/exclusion criteria at the previous screening may entitle the participant for rescreening. 
Rescreening will be limited to 2 rescreenings per participant. 
If an individual is to be rescreened, signature of a new ICF will be required. 
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5.5 
Criteria for Temporarily Delaying Administration of Study 
Intervention  
Not applicable. 
6 
Study Intervention(s) and Concomitant Therapies  
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  
Study Intervention(s) Administered 
Intervention 
Label 
Placebo  
Moxifloxacin 
Evobrutinib 
Evobrutinib 
Intervention 
Name 
Placebo 
Moxifloxacin 
Evobrutinib 
Evobrutinib 
Intervention 
Description 
Participants will 
receive an oral 
solution 
of 
placebo  
Participants will 
receive an oral 
400 mg dose of 
moxifloxacin  
Participants will 
receive an oral 
45 mg dose of 
evobrutinib  
Participants will 
receive an oral 
225 mg dose of 
evobrutinib  
Type 
Drug 
Drug 
Drug 
Drug 
Dose 
Formulation 
Solution 
Tablet 
Solution 
Solution 
Unit Dose 
Strength(s) 
N/A 
400 mg 
45 mg 
225 mg 
Dose 
Fasted 
400 mg (fasted) 
45 mg (fasted) 
225 mg (fasted) 
Dosage 
Regimen 
Single dose  
Single dose  
Single dose  
Single dose  
Route of 
Administration 
Oral 
Oral 
Oral 
Oral 
Use 
Placebo-
experimental 
Positive control 
Experimental 
Experimental 
IMP or 
NIMP/AxMP 
IMP 
IMP 
IMP 
IMP 
Sourcing 
Will be provided 
by 
Nuvisan 
GmbH. 
Will be provided 
by 
Nuvisan 
GmbH, 
commercial 
- 
- 
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product 
from 
German market. 
Supplier 
- 
- 
Merck 
Healthcare 
KGaA; 
The powder in 
bottle 
formulation and 
the oral solution 
will 
be 
manufactured by 
Nuvisan. 
Merck 
Healthcare 
KGaA; 
The powder in 
bottle 
formulation and 
the oral solution 
will 
be 
manufactured by 
Nuvisan. 
Packaging and 
Labeling 
Study 
intervention will 
be provided in 
bottles. 
Each 
bottle 
will 
be 
labeled 
per 
country 
requirement. 
Additional 
details 
of 
packaging 
and 
labeling of study 
intervention will 
be defined in a 
separate 
IMP 
Handling 
Manual. 
Study 
Intervention will 
be provided in 
the 
original, 
commercial 
packaging. 
Commercial 
blisters 
and 
original folding 
cartons will be 
labeled as per 
country 
requirement.  
Study 
Intervention will 
be provided in 
bottles. 
Each 
container will be 
labeled 
per 
country 
requirement. 
Additional 
details 
of 
packaging 
and 
labeling of study 
intervention will 
be defined in a 
separate 
IMP 
Handling 
Manual. 
Study 
Intervention will 
be provided in 
bottles. 
Each 
container will be 
labeled 
per 
country 
requirement. 
Additional 
details 
of 
packaging 
and 
labeling of study 
intervention will 
be defined in a 
separate 
IMP 
Handling 
Manual. 
 
Study Arm(s) 
Arm Name 
Placebo: double-
blind period 
Moxifloxacin: 
400 mg open-
label period 
Evobrutinib: 
45 mg double-
blind period 
Evobrutinib: 
225 mg double-
blind period 
Arm Type 
Placebo-
experimental 
Active control  
Experimental 
Experimental 
Arm 
Description 
Single dose  
Single dose  
Single dose  
Single dose 
Associated 
Intervention 
Labels 
Placebo 
Moxifloxacin 
Evobrutinib  
Evobrutinib  
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x Evobrutinib and placebo solution will be administered after reconstituting API (or placebo) in 
100 mL buffer. A second bottle of buffer will be used to rinse the bottle with reconstituted API 
(or placebo) twice (50 mL each time). The participants will then receive 40 mL of water to 
reach a total volume of 240 mL. Further details are provided in the IMP handling manual. 
x All treatments will be administered following an overnight fast (10 h). Subjects will not be 
allowed any liquid from 1 h predose until 1 h postdose, except for the 240 mL water and buffer 
required to consume the dose with. Subjects will remain fasting until 4 h postdose.  
x To mask the taste of the active compound, both the active compound and placebo will contain 
orange flavor to allow identical taste. The placebo oral solution will be matched for appearance 
and volume in order to maintain the blind. 
x Moxifloxacin dose will be administered together with a total amount of 240 mL water in a 
standing position. 
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). 
x 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 IMP 
Handling Manual. 
x 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. 
x Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit. 
x Study intervention(s) accountability records at the study site will include the following: 
o 
Confirmation of receipt, in good condition and in the defined temperature range. 
o 
The inventory provided for the clinical study and prepared at the site. 
o 
The dose(s) each participant used during the study. 
o 
The disposition (including return, if applicable) of any unused study intervention(s). 
o 
Dates, quantities, batch numbers, medication numbers, expiry dates, and the participant 
numbers. 
x 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. 
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x 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. 
x A Study Monitor will periodically collect the study intervention(s) accountability forms. 
x Further guidance and information for the final disposition of unused study intervention(s) are 
provided in the IMP Handling Manual. 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding  
6.3.1 
Study Intervention Assignment  
Study using 
Pre-Coded 
Randomization 
provided to site 
On Study Day 1 participants will be assigned a unique number 
(randomization number) in ascending numerical order. The 
randomization number encodes the participant’s assignment to one 
of the 4 treatment sequences of the study, per the randomization 
schedule generated prior to the study by Nuvisan GmbH CTS 
Department. 
x Sequence 1: A-B-C-D  
x Sequence 2: B-D-A-C  
x Sequence 3: C-A-D-B  
x Sequence 4: D-C-B-A 
A, B, C, and D are used to denote placebo (solution, fasted), 
moxifloxacin 400 mg (tablet, fasted), evobrutinib 45 mg (solution, 
fasted) and evobrutinib 225 mg (solution, fasted), but not 
necessarily in that respective order. 
Each participant is identified by the study site’s unique participant identification code (Nuvisan 
GmbH identification code). After informed consent procedure, every participant is given a 
screening number. Only participants who comply with all selection criteria (Sections 5.1 and 5.2) 
can be included into the study. 
The Investigator will keep a record relating the participant numbers (Nuvisan GmbH identification 
code, screening and randomization number) and the names of all participants who have given their 
informed consent, to allow easy checking of data in participant files, when required. This record 
will also include the date of participant’s study enrollment and completion, as well as participants 
who could not be assigned to study intervention for whatever reason. 
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6.3.2 
Blinding  
Blinding Method 
Randomization codes will be kept strictly confidential, accessible only to authorized staff (i.e. 
randomization statistician, unblinded reconstitution team, bioanalytical laboratories responsible 
for analyses of the PK samples and unblinded monitor), until the time of unblinding. All other 
study-related individuals, ancillary site staff, clinical research associates/monitors, the 
Investigator, Sponsor, ECG core lab, and clinical research organization staff will remain blinded 
to study intervention. 
Since moxifloxacin will be administered open-label, and evobrutinib and placebo administered 
double-blinded, the treatment sequences will not be displayed in this protocol. Placeholders 
(‘Treatment A’, ‘Treatment B’, ‘Treatment C’, and ‘Treatment D’) will be used to refer to the 
study interventions. Only authorized staff mentioned above will be aware of the sequences actually 
used. 
The procedures of database lock and unblinding statistical analyses will be documented in the Data 
Management Plan and Unblinding Plan.  
Confirmation of the Indistinguishability of the Study Interventions: evobrutinib and placebo 
solutions will be identical in volume and appearance. 
The analytical laboratories responsible for analysis of the PK samples will be unblinded to study 
treatment codes to enable sample testing of evobrutinib and moxifloxacin prior to database lock. 
Masked participant identifiers will be used to support association of PK data with treatment codes 
while preventing association of treatment codes with any other clinical data, such as safety and 
clinical response data. 
Evobrutinib and moxifloxacin information that would unblind the study participants will not be 
reported with participant identifiers to investigative sites or blinded personnel until the study has 
been unblinded. 
Assignment Method Retention 
Unblinding may be done in the event of an emergency necessary for participant safety or the 
reporting of SUSARs using code break envelopes provided to the site by the CTS department. 
6.3.3 
Emergency Unblinding  
In an emergency, the Investigator is solely responsible for determining if unblinding of a 
participant’s study intervention assignment is warranted. Participant safety is always the first 
consideration in this decision. If the Investigator decides that unblinding is warranted, the 
Investigator makes every effort to contact the Sponsor prior to the unblinding, unless this could 
delay emergency treatment. The Sponsor will be notified within 24 hours after unblinding. The 
Investigator will provide the Sponsor the reason for unblinding without revealing the study 
intervention, except to the designated global patient safety representative via the Emergency 
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Unblinding Notification Form. The date of and reason for unblinding will be recorded in the source 
documents and CRF. Contact information for unblinding in an emergency is given on the 
participant emergency card provided to each participant, as noted in Appendix 2. 
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 CRF. A member of the 
study site staff other than the person administering the study intervention will confirm the study 
intervention dose and study participant identification at the time of dosing. Study site personnel 
will examine each participant’s mouth to ensure that the study intervention was ingested. 
6.5 
Dose Modification  
Doses will not be modified. 
6.6 
Continued Access to Study Intervention After the End of the Study  
The Sponsor will not provide any additional care to participants after they leave the study because 
such care would not differ from what is normally expected for healthy participants. 
6.7 
Treatment of Overdose  
For this study, any dose of study intervention greater than maximum dose that is considered safe 
and well-tolerated within a 24 hour time period will be considered an overdose. 
The Sponsor has no specific recommendation for treating an overdose of evobrutinib or 
moxifloxacin. The Investigator will use his/her clinical judgment to manage any overdose, 
considering the symptoms and any site procedures or standards. 
Even if not associated with an AE or SAE, any overdose is recorded in the CRF and reported to 
global patient safety in an expedited manner. Overdoses are reported on an SAE and Overdose 
Report Form, following the procedure in Appendix 4. 
6.8 
Concomitant Therapy  
Record in the CRF all concomitant therapies (e.g. medicines or nondrug interventions) used from 
the signing of the ICF until the end of treatment assessment at the timepoints specified in the SoA, 
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. 
For nondrug interventions, record the name, the indication, and dates administered. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
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Paracetamol/Acetaminophen, at doses of  2 g/24 hours, is permitted for use any time during the 
study, at the discretion of the Investigator. Other concomitant medication may be considered on a 
case-by-case basis by the Investigator in consultation with the Medical Monitor if required. 
6.8.1 
Rescue Medicine  
No specific antidote is available for evobrutinib. Symptomatic treatment will be provided in case 
of a medical emergency. Any kind of toxicity occurring during the study will be treated 
symptomatically.  
In case of toxicity during moxifloxacin, refer to the approved product information. 
6.8.2 
Permitted Medicines  
The only permitted medicines are the following: 
Acetaminophen (paracetamol) up to 2 g per day, at the discretion of the Investigator. 
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. 
6.8.3 
Prohibited Medicines  
Prohibited medicines at study entry are indicated in the exclusion criteria (Section 5.2). 
The participants are prohibited from using prescription or over-the-counter medications (apart 
from those described above) within 2 weeks or 5 terminal half-lives, whichever is longer, prior to 
the first administration of study intervention, during the study, and until the Safety Follow-Up 
assessment (this includes herbal remedies, vitamins, minerals, antacids, and dietary supplements 
such as fish oils). 
Inhibitors or inducers of CYP3A4/5 or P-gp within 4 weeks prior to the first administration of 
study intervention, and until after the Safety Follow-Up assessment, are prohibited. Also, drugs 
mainly metabolized by CYP3A4/5 and that have a narrow therapeutic index should be avoided. 
6.8.4 
Other Interventions  
Additional restrictions that study participants should adhere to from Day -1 until the Final 
assessment are detailed in Section 5.2. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
Discontinuation of specific sites or of the entire study is specified in Appendix 2. 
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7.1 
Discontinuation of Study Intervention  
A participant must be withdrawn from administration of study intervention if any of the following 
occur:  
x Participant withdraws consent.  
x A participant is enrolled but is subsequently discovered not to have met inclusion/exclusion 
criteria at Screening.  
x AEs, if discontinuation of study intervention is considered necessary by the Investigator and/or 
desired by the participant. This includes in particular AEs of severe intensity and SAEs 
regardless of the relationship to study intervention. 
x Pregnancy (see Section 8.3.4). 
x Protocol noncompliance judged as significant by the Investigator (after discussion with the 
Sponsor). 
x Use of a nonpermitted concomitant drug if clinically relevant as agreed by Sponsor and 
Investigator, as defined in Section 5.2, where the predefined consequence is withdrawal from 
study intervention. 
x Any events that unacceptably endanger the safety of the participant.  
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for safety assessments: The SoA indicates data to be collected at the time of 
discontinuation of study intervention and follow-up and for any further evaluations that need to be 
completed. 
The SoA specifies the data to collect at study intervention discontinuation and follow-up, and any 
additional evaluations that need to be completed. 
7.1.1 
Liver Clinical Safety Laboratory Tests Stopping Criteria  
The Investigator will consider discontinuation of study intervention for abnormal liver function 
when a participant meets one of the conditions outlined in the algorithm or if the Investigator 
believes that it is in best interest of the participant. 
All confirmed events of ALT or AST  5 × ULN triggers stopping criteria. 
All confirmed events of ALT or AST  3 × ULN and total bilirubin  2 × ULN triggers stopping 
criteria. 
All liver related events will be reported as AESI according to the risk profile of evobrutinib.  
7.1.2 
Cardiac Safety Stopping Criteria  
If a clinically significant finding is identified (including changes from baseline in QT interval 
corrected using Fridericia’s formula [QTcF > 60 ms and QT/QTcF > 500 ms]) after start of study 
intervention, the Investigator or qualified designee will determine if the participant can continue 
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in the study and if any change in participant management is needed. This review of the ECG at the 
time of collection will be documented. Any new clinically relevant finding is reported as an AE. 
7.1.3 
Hypersensitivity/Allergic Reactions Stopping Criteria  
Hypersensitivity, allergic reactions and Severe Cutaneous Adverse Reactions have been reported 
for fluoroquinolones, including moxifloxacin, after first administration. In cases of clinical 
manifestations of severe hypersensitivity reactions or signs and symptoms of severe skin reactions 
Participant should be discontinued from the study. 
7.2 
Participant Discontinuation/Withdrawal from the Study  
x A participant may discontinue from the study at any time, at his/her own request or at the 
discretion of the Investigator for safety, behavioral, compliance, or administrative reasons (e.g. 
disruption of operations due to natural disasters, interruption of lab or facility accreditation, 
participant moving to another country, resignation of key staff”). 
x At the time of study discontinuation, if possible, a discontinuation visit will be conducted, as 
listed in the SoA. The SoA specifies the data to collect at study discontinuation and follow-up, 
and any additional evaluations that need to be completed. 
x If the participant revokes consent for 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. 
x If a participant requests the destruction of any biological samples still remaining, the 
Investigator will document this in the site study records and inform the Sponsor. The samples 
will be destroyed. 
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: 
x 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 will continue in the study. 
x 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 or caretaker (where allowed by local regulations) for 
information. These contact attempts will be documented in the participant’s medical record. 
x If the participant continues to be unreachable, he/she will be deemed as “lost to follow-up”. 
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8 
Study Assessments and Procedures  
x Study assessments and procedures and their timing are summarized in the SoA. 
x No protocol waivers or exemptions are allowed. 
x Immediate safety concerns are discussed with the Sponsor immediately upon occurrence or 
awareness to determine if the participant will continue or discontinue study intervention. 
x Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
x 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. 
x 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. 
x 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, were performed within the time frame defined 
in the SoA, and if reviewed and approved by the Sponsor. 
x Any data (including Safety, PK and ECG data) that could unblind the study will not be reported 
to investigative sites or other blinded personnel until the study has been unblinded. 
x About 450 ml of blood total will be taken throughout the study. Up to 100 ml of blood may be 
drawn at certain visits. These blood samples will be used for the following purposes: clinical 
laboratory tests and PK analyses. 
Where allowed by local law/regulations, samples collected during this clinical study may be 
transferred to a biobank and used for future research outside the clinical protocol when additional 
consent for this purpose is given. Transfer to the biobank will be documented and any testing of 
coded biobank samples will not be reported in the CSR. 
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, 
electrocardiograms, 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. 
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8.2.1 
Physical Examinations  
x A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. 
x A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen). 
x Investigators will pay special attention to clinical signs related to previous serious illnesses. 
8.2.2 
Vital Signs  
x Blood pressure and participant’s position during measurement; pulse; respiratory rate; 
temperature and location of measurement, weight, and height (at Baseline only) will be 
measured and recorded. 
Vital signs will be measured in supine position. 
x 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) and measured 
with an automated device. Manual techniques will be used only if an automated device is not 
available. 
8.2.3 
Electrocardiograms  
Single 12-lead ECG will be obtained as outlined in the SoA and will be preceded by at least 
5 minutes of rest for the participant in a quiet setting without distractions (e.g. television, cell 
phones).  
Together with the ECG recorders also laptops, a server laptop and printer will be provided by the 
ECG core lab. With the aid of this setup, site personnel will be able to trigger and print 12-lead 
safety ECGs directly from the Holter devices using the laptops. A detailed manual for this process 
will be supplied by the ECG core lab. An on-site training will be done prior to study start. 
Detailed information on Holter ECGs is given in Section 8.4.3. 
8.2.4 
Clinical Safety Laboratory Tests  
x Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 6 
at the timepoints listed in the SoA. All samples will be clearly identified.  
x Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations. 
x The tests will be performed by Nuvisan GmbH laboratory; the QuantiFERON® Test will be 
performed by Synlab, Augsburg, Germany. 
x The Investigator will review each laboratory report, document this review, and record any 
clinically significant changes occurring during the study as an AE, unless it does not meet the 
AE definition, as specified in Appendix 4. The laboratory reports will be filed with the source 
documents. 
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x Laboratory results that could unblind the study will not be reported to investigative sites or 
other blinded personnel until the study has been unblinded (see Section 6.3.2 and 6.3.3). 
8.3 
Adverse Events, Serious Adverse Events, and Other Safety 
Reporting  
x The definitions of an AE and SAE are in Appendix 4. 
x The Investigator and any qualified designees (e.g. Subinvestigators) 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, considered related to 
the study intervention or study procedures, or that caused the participant to discontinue the 
study intervention or study, as specified in Section 8.3.2. 
x Requests for follow-up will usually be made via the Sponsor or CRO-designated study team 
member, although in exceptional circumstances the global patient safety department may 
contact the Investigator directly to obtain further information or to discuss the event. 
x 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. 
x All AEs and SAEs will be collected from the signing of the ICF until the safety follow-up call 
at the timepoints 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. 
x 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. 
x Investigators are not obligated to actively solicit information on 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. 
8.3.1 
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. 
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8.3.2 
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, and AESIs (as defined in Section 8.3.7), 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 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. 
8.3.3 
Regulatory Reporting Requirements for Serious Adverse 
Events  
x 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 toward the safety of 
participants and the safety of a study intervention under clinical investigation are met. 
x 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, IRB/IEC, and Investigators. 
x Individual Case Safety Reports will be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators within 15 days. 
x An Investigator or Subinvestigator 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 read it and confirm completion of this activity. 
This information will be filed in the Investigator’s Site File, and the IRB/IEC will be notified, 
if appropriate, according to applicable local laws/regulations and site SOPs. 
8.3.4 
Pregnancy  
x Details of all pregnancies in female participants will be collected after the start of study 
intervention and until the Safety Follow-up. Note: In this study, only women of nonchildbearing 
potential will be included. 
x If a pregnancy is reported, the Investigator will record the pregnancy information on the 
appropriate form and submit it to the Sponsor within 24 hours of female participant pregnancy. 
x While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy will be reported as an AE or SAE. Adverse pregnancy 
outcomes (e.g. spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic 
pregnancy) are considered and reported as SAEs. 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. 
x 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 for a healthy newborn. In case of a congenital 
anomaly or other illness of the newborn, follow-up will continue until the illness has resolved 
or there is a definite outcome of the event. 
x 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 8.3.3. 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. 
x Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention or be withdrawn from the study. 
8.3.5 
Cardiovascular and Death Events  
Not applicable. 
8.3.6 
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs  
Not applicable. 
8.3.7 
Adverse Events of Special Interest  
For this study, AESI(s) include only the following: 
x Infections (serious, severe, and opportunistic,  Grade 3)  
As per its mechanism of action, evobrutinib may impair B cell function which might lead to a 
decreased humoral immunity and consequently an increased risk of infection. Overall, in 
completed studies in participants the Medical Dictionary for Regulatory Activities SOC 
infection was one of the most reported SOCs (e.g. in the MS200527_0086 RMS study 
approximately 18% to 32% of participants treated with evobrutinib reported infection; a similar 
rate was reported in the placebo group in the 0 to 24 week period), the individual events were 
of low grade, mainly Grade 1, nonserious and did not lead to study intervention discontinuation. 
Treatment of infections must be prompt and done in accordance with local standard of care 
depending on considerations such as the nature and severity of the infection and participant’s 
overall health status. Any Common Terminology Criteria for Adverse Events Grade  3 or 
SAEs of infection and opportunistic infection are considered as an AESI. 
x Seizures 
Seizures are more common in patients with MS than in the general population, occurring in 2% 
to 3% of patients with MS (Poser 2003). Convulsions were observed in early studies of 
evobrutinib in dogs, however the plasma concentration of evobrutinib was approximately 
140-fold greater than it is predicted for the dose used in this study. 1 participant with RMS with 
significant brain lesion load reported seizure of unclear clinical picture. The PK data for this 
participant did not exceed the expected values and was similar to other participants in the study. 
Anticonvulsant therapy was started, and the participant continued treatment with evobrutinib 
with no reoccurrence. The Investigator did not consider the event to be related to evobrutinib. 
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No event of convulsion/seizure was reported in other indications. Evobrutinib has been 
administered to approximately 800 patients with MS, rheumatoid arthritis and systemic lupus 
erythematosus. Moreover, an electroencephalogram study in healthy volunteers did not show 
an epileptogenic potential for evobrutinib. Any type of seizures/epilepsy of any grade or its 
consequences are classified as AESIs. 
x Elevated lipase, elevated amylase, pancreatitis 
Asymptomatic elevations in amylase or lipase or both in participants treated with evobrutinib 
have been observed at a variety of time points and reported as TEAEs or noted as laboratory 
abnormalities. In RMS Study MS200527_0086, the incidence of TEAEs of lipase increased 
was slightly higher in evobrutinib 75 mg once daily and 75 mg twice daily arms (5 [9.4%] and 
5 [9.3%], respectively) when compared to other arms (approximately between 4% to 6%). 
However, shifts from Baseline to highest grade on treatment were similar across all treatment 
arms for both amylase and lipase. In evobrutinib studies in other indications and in healthy 
participants, the incidence of TEAEs of increased amylase or lipase, or both was infrequent and 
no clinically meaningful differences were observed across treatment arms. Any elevation of 
> 2 × ULN of lipase or amylase and any type of pancreatitis are classified as AESIs. 
x Liver related events  
The elevations of transaminases observed in participants treated with evobrutinib were frequent, 
asymptomatic, and reversible on discontinuation of evobrutinib. The mechanism is unknown.  
Evobrutinib liver AESIs will include transaminases (> 3 × ULN), bilirubin elevations 
(> 1.5 × ULN), biological Hy’s Law cases based on laboratory data, any type of acute or chronic 
hepatitis (any grade), suspected drug-induced liver injury, acute or chronic hepatic failure, 
fibrosis, cirrhosis, and other liver damage-related conditions. 
AESIs have to be reported immediately (within 24 hours). For reporting of AESIs, see Appendix 4. 
8.4 
Pharmacokinetics  
8.4.1 
Blood Sampling and Bioanalysis  
x Samples are collected only where allowed by local law/regulations. 
x The actual date and time (24-hour clock time) of: 
o Each sample collection 
o Study intervention administration prior to sample collection 
will be recorded in the eCRF to determine the elapsed time of sampling in relation to the 
administration of study intervention. 
x Blood samples for measurements of plasma evobrutinib 
 
 and moxifloxacin concentrations will be collected. Collection times are 
specified in the SoA. 
x The actual date and time (24-hour clock time) of: 
o start and end of each blood collection interval  
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o study intervention administration prior to sample collection 
o the volume of each blood collection fraction 
will be recorded in the eCRF, in order to determine the elapsed time of sampling in relation to 
the administration of study drug. The accepted time deviations from planned PK sampling times 
that will not be considered a protocol violation are listed in Table 1. 
x The quantification of evobrutinib and moxifloxacin in plasma will be performed using a 
validated assay method. 
 
 
 
 
 
. Retention time and possible analyses of samples after the end of study are 
specified in the respective ICF. 
x Details on processes for collection and handling of these samples are in the Laboratory Manual. 
Table 1 
Time Deviations from PK sampling times  
Procedure 
Time Point (Relative Time) 
Window Allowance 
PK 
Predose 
- 15 min 
15 min 
± 2 min 
30 min 
± 2 min 
1 hr 
± 2 min 
1.5 hr 
± 5 min 
2 hr 
± 5 min 
2.5 hr 
± 5 min 
3 hr 
± 5 min 
4 hr 
± 5 min 
6 hr 
± 5 min 
8 hr 
± 5 min 
12 hr 
± 5 min 
16 hr 
± 15 min 
24 hr 
± 15 min 
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8.4.2 
PK Parameters  
x The following PK parameters for evobrutinib, its major metabolite, and moxifloxacin will be 
calculated, when appropriate: 
Symbol 
Definition 
AUC0-24 
The partial AUC from time zero (= dosing time) to 24 hours. 
AUC0-tlast 
The AUC from time zero (= dosing time) to the time of the last quantifiable concentration (tlast). 
AUC0- 
The AUC from time zero (= dosing time) up to infinity with extrapolation of the terminal phase. 
AUCextra% 
The AUC from time tlast extrapolated to infinity given as percentage of AUC0-. 
Cmax 
Maximum observed concentration. 
CL/F 
The apparent total body clearance following extravascular administration (parent only). 
ȁz 
Terminal first order (elimination) rate constant. 
Tmax 
The time to reach the Cmax in a dosing interval. 
T1/2 
The terminal half-life. 
Vz/F 
The apparent volume of distribution during the terminal phase following extravascular 
administration (parent only). 
Other PK parameters might be added based on emerging data. Details will be in the IAP. 
x Concentration data may be used for integrated data analyses across studies, such as population 
PK and exposure-response analyses of PD biomarker, QTc, efficacy and/or safety analyses and 
reported separately from the main CSR. 
8.4.3 
Electrocardiograms  
In this study, ECGs will be recorded using standard 12-lead ECG devices and 12-lead Holter 
recorders for the following purposes: 
x Check of eligibility of a participant for the study during screening using standard 12-lead ECG 
machines (single ECGs). 
x Immediate safety assessment at the site using safety single 12-lead ECGs that are being printed 
from the Holter recordings.  
x Extraction of triplicate 10 s ECGs from continuous Holter recordings for central evaluation and 
statistical analyses of possible drug effects on cardiac safety parameters. 
The standard ten seconds 12-lead ECGs will be recorded by devices (CardioPerfect, Hillroom, 
Chicago, USA) supplied by the site at times indicated in the Flow Chart. These ECGs will be 
acquired using Goldberger/Einthoven and Wilson leads in supine position (small pillow under 
head allowed) and after a rest for at least 15 min. The devices will print the ECGs for immediate 
evaluation by the investigator or his/her designee. The following automatically calculated 
parameters will be used: Ventricular rate, PR interval, QRS duration, QT interval (uncorrected) 
and QTcB and QTcF. 
The evaluation by the Investigator includes an overall assessment (normal, description of 
abnormality including clinical relevance) which will be entered into the eCRF system. 
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The 12-lead Holter ECGs will be recorded using devices (CM3000 or Seer 12, getemed AG, 
Berlin, Germany), supplied by the ECG core lab (nabios GmbH, Munich, Germany). All devices 
will be tested prior to shipment and installed at the site. An on-site training will be performed for 
the site staff. Details of the ECG recordings and data transfer procedure will be supplied in 
manuals. 
For these continuous recordings modified Goldberger/Einthoven (so-called Mason-Likar) lead 
positions and Wilson chest leads will be used. The recordings will be started approximately 2 h 
before the corresponding time point of the planned time of administration on Day -1 and will end 
shortly after the 24 h time point postdose. At least 15 min prior to the extraction time points the 
participants have to be in supine position in a quiet environment. This resting period is followed 
by another 3 min term during which the participant should be at complete rest with no 
interventions. At the end of this period, the study staff will press the marker button on the recorder 
to flag this electronically on the ECG signal. Immediately afterwards, further planned 
measurements and blood samplings will be performed. After the recordings are done, the data will 
be transferred to the core lab using one of the laptops and a pre-installed and tested data transfer 
program. At the core lab, triplicate 10 s ECGs with approximately 1-minute time difference 
between 2 successive ECGs will be extracted from the 12-lead Holter recordings guided by the 
electronic markers. The timing of the markers will be tested by the core lab staff by checking the 
markers with the respective nominal times of the individual medication times. In case 
inconsistencies are detected, the core lab will query the site. 
After the ECG have been extracted at the core lab, they will be measured for cardiac intervals RR, 
PR(Q), QRS, and QT from 4 preferably consecutive heart beats in lead II. If lead II is not evaluable 
in an ECG lead V or lead I will be used. All ECGs of a particular participant will be measured in 
the same lead. The measurement will be done using the core labs validated semi-automated 
programs and procedures. The end of the T wave will be determined using the so-called slope (or 
tangent) method. This method approximates the downslope of the T wave by a linear function. The 
end of the T wave is then defined as the crossing point between this straight and the isoelectric 
line. All fiducial point markings will be reviewed by trained technicians. 
Within the ECG laboratory, the staff involved with ECG interval measurements and morphological 
analyses will be blinded with regard to treatment, date and time as well as time points of the ECG 
measurements. No more than 2 blinded readers will evaluate all ECGs of the study. The interval 
measurements for a given participant will be performed in random and blinded sequence by a 
single reader. For quality assurance and control of the measurements, all ECGs of an individual 
participant will be subsequently reviewed by the ECG technician supervisor or his/her designee to 
assess the overall variance of the measured intervals and to detect accidental switching of leads 
and/or false participant assignments of the ECGs. 
In addition to the measurements of the intervals, one randomly selected ECG at each time point 
will be evaluated by a board-certified cardiologist. This evaluation will include an overall 
assessment as well as specific findings regarding rhythm, conduction, ST-T segment and 
T/U-wave, morphology, and myocardial infarction. Standard CDISC terms will be used for this 
interpretation of the ECG. The cardiologist will review the ECGs one by one and in random order. 
Thus, she/he is practically blinded to the sequence of the ECG within a participant. After 
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evaluation of the ECGs, the results will be submitted to the data management company using a 
predefined data transfer method and specification The transfer will include for any ECG recording 
classified as “abnormal” the description of the abnormality in addition to the clinical relevance 
(yes/no). 
8.5 
Pharmacogenetics  
Not applicable.  
8.6 
Biomarkers  
Not applicable.  
8.7 
Immunogenicity Assessments  
Not applicable. 
8.8 
Medical Resource Utilization and Health Economics  
Healthcare resource utilization data are not collected in this study. 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
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There will be no other formal statistical hypotheses testing. 
 
  
 
 
 
 
 
 
 
 
 
 
 
9.3 
Analysis Sets  
The analysis sets are specified below. 
Analysis Set 
Description 
SCR  
All participants, who provided informed consent, regardless of the participant’s 
enrollment and study intervention status in the study. 
SAF 
All participants, who were administered any dose of any study intervention. 
Analyses will consider participants as treated. 
PK 
The PK Analysis Set is a subset of the SAF, and the PK population will include all 
participants: 
Who have completed the study without any relevant protocol deviations and factors 
likely to affect the comparability of PK results. 
With adequate study intervention compliance. 
With evaluable PK data, i.e. nonmissing values for primary endpoints. 
If participants received prohibited concomitant therapy or medicines, as specified in 
Section 6.8, they will be excluded from the PK population. 
All PK analyses will be based on this analysis set. 
ECG 
The ECG Analysis Set will be the basis of the C-QTc analysis and will be a subset of 
the SAF. Only participants who had a baseline Holter ECG in triplicate and at least one 
post-baseline Holter ECG in triplicate with a time-matched concentration will be 
retained for C-QTc analysis. Participants with protocol deviations likely to affect the 
comparability of ECG measurements or PK concentrations will not be considered in the 
C-QTc analysis. 
9.4 
Statistical Analyses  
  
 
 
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handling of 
concentration values below the limit of quantification will be described in the IAP. 
9.4.1 
Safety Analyses  
All safety analyses will be performed on the Safety Analysis set. 
Reference #  
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable 
 
 
Secondary 
3 
Nature, occurrence, 
and severity of 
TEAEs 
AE counts and participants with Aes will be summarized for each 
treatment by SOC and PT.  
In addition, Aes will be tabulated and listed per participant and analyzed 
by severity and relationship to study intervention. 
3 
Absolute values and 
changes in safety 
laboratory tests 
Safety laboratory parameters will be listed for each participant including 
flags for measurements outside the reference ranges, where applicable.  
Laboratory parameters (hematology and clinical chemistry) will be 
summarized by time point including absolute values. 
3 
Vital signs assessed 
from time of first 
dose to end of study 
participation 
Vital signs by participant, including changes from Baseline, will be listed 
and summarized by treatment and time point using descriptive statistics. 
3 
Single 12-lead ECGs 
evaluated by 
Investigator 
Electrocardiogram data will be summarized by absolute values and 
changes from Baseline values by treatment using descriptive statistics. 
Clinical noteworthy ECG findings for individual participants will be listed 
and summarized as appropriate. 
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9.4.2 
Other Analyses (QTc and PK analyses) 
Reference #  
Endpoint 
Statistical Analysis Methods 
Primary 
 
 
1 
ǻǻQTcF 
(evobrutinib) 
A mixed-effects model with repeated measures will be used to analyze 
the relationship between evobrutinib concentrations and ǻǻQTcF. Based 
on this model, the predicted ǻǻQTcF at clinically relevant concentrations 
will be calculated, with two-sided 90% confidence intervals. Model 
selection, including consideration of linear and nonlinear function to 
describe the C-QTc relationship, will be based on graphical exploration, 
along with standard goodness-of-fit plots., Additionally, the effects of 
evobrutinib on ¨¨QTcF will be descriptively summarized at each 
postdose timepoint (by timepoint analysis). Number and frequency of 
QTcF values within specified ranges will be summarized. Further details 
will be described in the IAP. 
Secondary  
 
 
2 
ǻǻQTcF 
(moxifloxacin) 
Assay sensitivity will be demonstrated by showing that the lower bound of 
the 90% CI of the predicted ǻǻQTcF (from C-QTc model) for moxifloxacin 
at the observed geometric mean Cmax at 400 mg dose exceeds 5 ms. 
Further details will be described in the IAP. 
4 
ǻǻHR, ǻǻPR, 
ǻǻRR, ǻǻQRS, 
T-wave morphology 
and U-wave 
The effects of evobrutinib on these endpoints will be evaluated at each 
postdose timepoint (by timepoint analysis). Further details will be 
described in the IAP. 
5 
PK parameters (in 
Section 8.4) 
Summary statistics of PK parameters will be provided. 
All PK analyses will be performed on the PKAS. 
9.4.3 
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. Safety Follow Up with all study data in house, all 
data queries resolved, and the database locked. 
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10 
References  
Huang DP, Chen J, Dang Q, et al. Assay sensitivity in “Hybrid thorough QT/QTc (TQT)” study. 
J Biopharm Stat. 2019;29(2):378-384.  
Mu S, Darpo B, Tang Z, et al. No QTc Prolongation With Zanubrutinib: Results of Concentration-
QTc Analysis From a Thorough QT Study in Healthy Subjects. Clin Transl Sci. 2020;13(5):923-
931.  
Mueller MS, Sidharta PN, Voors-Pette C, et al. The effect of the glucosylceramide synthase 
inhibitor lucerastat on cardiac repolarization: results from a thorough QT study in healthy subjects. 
Orphanet J Rare Dis. 2020;27;15(1):303.  
Poser CM, Brinar VV. Epilepsy and multiple sclerosis. Epilepsy Behav. 2003. 4:6-12.  
Scarfò L, Chatzikonstantinou T, Rigolin GM, et al. COVID-19 severity and mortality in patients 
with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on 
CLL, and CLL Campus. Leukemia. 2020;1-10.  
Thibaud S, Tremblay D, Bhalla S, et al. Protective role of Bruton tyrosine kinase inhibitors in 
patients with chronic lymphocytic leukaemia and COVID-19. Br J Haematol. 2020;1-3.  
Treon SP, Castillo JJ, Skarbnik AP, et al. The BTK inhibitor ibrutinib may protect against 
pulmonary injury in COVID-19-infected patients. Blood. 2020;135(21):1912-15.  
Ucpinar S, Darpo B, Neale A, et al. A thorough QTc study to evaluate the effects of oral 
rilzabrutinib administered alone and with ritonavir in healthy subjects. Clin Transl Sci. 
2022;15(6):1507-1518.  
Yan LK, Zhang J, Ng MJ, Dang Q. Statistical characteristics of moxifloxacin-induced QTc effect. 
J Biopharm Stat. 2010.20(3):497-507.  
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11 
Appendices  
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Appendix 1 
Abbreviations  
 
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
API 
Active Pharmaceutical Ingredient 
AxMP 
Auxiliary Medicinal Product 
BMI 
Body Mass Index 
BTK 
Bruton’s Tyrosine Kinase 
CDISC 
Clinical Data Interchange Standards Consortium 
CNS 
Central Nervous System 
COVID-19 
Coronavirus Disease 2019 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRU 
Clinical Research Unit 
CSR 
Clinical Study Report 
CYP3A4/5 
Cytochrome P450 3A4/5 
ECG 
Electrocardiogram 
eCRF 
electronic Case Report Form 
EudraCT 
European Clinical Trials Database 
FIH 
First In Human 
FSH 
Follicle Stimulating Hormone 
GCP 
Good Clinical Practice 
HRT 
Hormone Replacement Therapy 
IAP 
Integrated Analysis Plan 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product  
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
MS 
Multiple Sclerosis 
NIMP 
Noninvestigational Medicinal Product 
PD 
Pharmacodynamic 
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PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic Analysis Set  
QTc 
Corrected QT interval 
QTcB 
Corrected QT interval by Bazett’s formula 
QTcF 
Corrected QT interval by Fridericia’ formula 
QTcI 
Individual corrected QT interval 
QTL 
Quality Tolerance Limit 
RMS 
Relapsing Multiple Sclerosis 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe Acute Respiratory Syndrome Coronavirus 2 
SCR 
Screening 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TEAE 
Treatment-Emergent Adverse Event 
TdP 
Torsade de Pointes 
THC 
Tetrahydrocannabinol  
TQT 
Thorough QT 
ULN 
Upper Limit of Normal 
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Appendix 2 
Study Governance  
Financial Disclosure 
Investigators and Subinvestigators will provide the Sponsor with sufficient, 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 
x The Investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions on the study. 
x Participants will be informed that their participation is voluntary. 
x Participants will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50; local regulations; ICH guidelines; privacy and data protection requirements, 
where applicable; and the IRB/IEC or study center. 
x 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. 
x If the ICF is updated during their participation in the study, participants will be reconsented to 
the most current, approved version. 
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Data Protection 
x 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. 
x 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. 
x 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. 
Study Administrative 
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. 
o The study will be conducted at a single center, the Clinical Pharmacology Unit of Nuvisan 
GmbH, Neu-Ulm, Germany. Nuvisan GmbH will be responsible for the following activities: 
o Clinical conduct and laboratory services 
o Data management 
o Statistical programming and analysis 
o PK analysis 
o Medical writing 
o Independent monitoring 
o Medical monitoring 
o Project management 
o Regulatory services 
Clinical trial supplies will be provided by Thermo Fisher. 
The12-lead Holter recorders, accessories and laptops will be supplied by the ECG core lab 
nabios GmbH, Munich, Germany. 
Primary and secondary hypothesis evaluation with regard to ECG will be conducted by Certara. 
Details of structures and associated procedures will be defined in separate Operations Manuals. 
Regulatory and Ethical Considerations 
x This study will be conducted in accordance with the protocol and the following: 
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o Consensus ethical principles derived from international guidelines, including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines 
o Applicable ICH GCP Guidelines 
o Applicable laws and regulations 
x The protocol, protocol amendments (if applicable), ICF, Investigator Brochure, and other 
relevant documents (e.g. advertisements) will be submitted to an IRB/IEC for review and 
approve before the study is initiated. 
x 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 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
x 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 
x 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). 
x 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 1 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 and any other relevant study-appointed experts of the Sponsor and 
Nuvisan GmbH. 
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Publication 
x 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.  
x 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. 
x Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
x A summary of data will be provided to ClinicalTrials.gov as well as to the European Clinical 
Trial Database, as applicable, and will occur 12 months after the last clinic visit of the final 
study participant or another appropriate date to meet applicable requirements. Healthy 
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. 
x 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. 
x 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. 
x 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 intervention and therefore 
may be disclosed as required to other clinical Investigators, to the FDA, 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 
x 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. 
x The Investigator will maintain accurate documentation (source data) that supports the 
information in the CRF. 
x 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. 
x QTLs will not be predefined in this study because study duration is too short and number of 
study participants is too small to allow for meaningful QTL data collection. 
x Monitoring details describing strategy, including definition of study critical data items and 
processes (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. 
x 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. 
x 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. 
x The Investigator will retain records and documents, including signed ICFs, pertaining to the 
conduct of this study for 25 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 
x Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 
x The Investigator will maintain source documents that support the data recorded in the CRFs. 
x Data recorded on 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. 
x 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. 
x Definition of what constitutes source data and its origin is found in Source Data Location Form. 
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Study and Site Start and Closure 
The study start date is when the first participant signs the Informed Consent Form. 
Study and Site Closure 
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
enough notice is given in advance of the intended closure. 
Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
x 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. 
x Inadequate recruitment of participants by the Investigator. 
x Discontinuation of further development of the Sponsor’s compound. 
x Sponsor discontinuation of the study due to an unacceptable risk, any relevant toxicity, or 
negative change in the risk/benefit assessment. 
If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any third-party service providers of 
the reason for termination or suspension, as specified by 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 and Barrier Requirements  
Note:  
This study includes women of nonchildbearing potential only (Section 5.1). However, please see 
the definition for a woman of childbearing potential below for information on criteria to be used. 
Definitions: 
Woman of childbearing potential: 
A woman is of childbearing potential (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. 
Postmenopause: 
Postmenopause is defined as no menses for 12 months without an alternative medical cause. 
x A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state 
in a female not using hormonal contraception or HRT. However, in the absence of 12 months 
of amenorrhea, confirmation with more than 1 FSH measurement is required. 
x A female on HRT and whose menopausal status is in doubt will be required to use one of the 
nonestrogen 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.  
Permanent sterilization: 
For this study, permanent sterilization includes: 
x Documented hysterectomy 
x Documented bilateral salpingectomy 
x Documented bilateral oophorectomy 
Documentation can come from the site personnel’s review of the individual’s medical records, 
medical examination, or medical history interview. 
For individuals 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. 
 
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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
AE Definition 
AE Definition 
x 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. 
x 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 
x Any abnormal laboratory test results (e.g. hematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, radiological scans, vital signs measurements), including 
those that worsen from baseline and are judged to be more severe than expected for the 
participant’s condition per the Investigator’s medical and scientific judgment, are considered 
clinically significant in the medical and scientific judgment of the Investigator (e.g. not 
related to progression of underlying disease, but may be leading to study intervention 
discontinuation). 
x Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition. 
x New conditions detected or diagnosed after study intervention administration even though it 
may have been present before the start of the study. 
x Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
x Signs, symptoms, or the clinical sequelae of a suspected overdose of either study intervention 
or a concomitant medication. 
x “Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported 
as an AE or SAE. However, the signs, symptoms, and/or clinical sequelae resulting from lack 
of efficacy will be reported as an AE or SAE if they fulfil the definition of an AE or SAE. 
Events NOT Meeting the AE Definition 
x 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 within the expectedness for participant’s condition, as judged by the Investigator. 
x Medical or surgical procedure (e.g. endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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x Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
x 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). 
 
An 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 
x 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 fulfils 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. 
x Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
x However, all events leading to unplanned hospitalizations or unplanned prolongation of an 
elective hospitalization 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. 
f. Other situations 
x 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 
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require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events are usually considered as serious. 
x 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 and AESIs. 
Recording and Follow-Up of AE and/or SAE 
AE and SAE Recording 
x 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. 
x The Investigator will then record all relevant AE/SAE information in the CRF. 
x As needed, Sponsor/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/designee. 
x 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. 
x 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: 
x Mild: A type of adverse event that is usually transient and may require only minimal 
treatment or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
x Moderate: A type of adverse event that is usually alleviated with additional specific 
therapeutic intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research participant. 
x Severe: A type of adverse event that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
Do not confuse an AE that is assessed as severe with an SAE. Severe is a category used to 
rate the intensity of an event; both AEs and SAEs can be assessed as severe. An event is 
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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. 
 
Assessment of Causality 
x The Investigator will assess the relationship between study intervention and each AE/SAE 
occurrence: 
o 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. 
o Related: Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention. 
x 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. 
x The Investigator will use clinical judgment to determine the relationship. 
x 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. 
x The Investigator will also consult the IB and/or Product Information, for marketed products, 
in his/her assessment. 
x For each AE/SAE, the Investigator will document in the medical notes that he/she has 
reviewed the AE/SAE and assessed causality. 
x 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. 
x The Investigator may change his/her causality assessment after considering follow-up 
information and send an SAE follow-up report with the updated causality assessment. 
x The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
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Follow-up of AEs and SAEs 
x The Investigator will perform or arrange for the conduct of supplemental measurements 
and/or evaluations, as medically indicated or as requested by the Sponsor/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. 
x If a participant dies during participation in the study or during a recognized follow-up period, 
the Investigator will provide the Sponsor/designee with a copy of any post-mortem findings 
including histopathology. 
x New or updated information will be recorded in the originally completed CRF. 
x The Investigator will submit any updated SAE data to the Sponsor/designee within 24 hours 
of receipt of the information. 
Reporting of SAEs 
SAE Reporting by a Paper Form 
x SAE reporting on a paper report form may be used in single center studies in addition to the 
standard electronic CRF and 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. 
x 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. 
x 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. 
x 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. 
x 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. 
Reporting of AESIs 
x For a nonserious AESI, the site will complete the specific AESI report form and notify the 
Sponsor immediately (within 24 hours), using the same process for reporting SAEs, as 
specified above. 
x For a serious AESI, the site will complete an SAE report form, using the SAE reporting 
process, specified above. 
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Reporting of Pregnancies 
x Pregnancy will be reported whether related to the study intervention using the applicable 
paper form. 
x The applicable form will be used to report if an abnormal outcome of the pregnancy occurs 
and the child/fetus sustains an event. 
x 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 
Liver Safety: Suggested Actions and Follow-up Assessments  
The Investigator will consider discontinuation of study intervention for abnormal liver function 
when a participant meets one of the conditions outlined in the algorithm or if the Investigator 
believes that it is in best interest of the participant. 
All confirmed events of ALT or AST  5 × ULN triggers stopping criteria. 
All confirmed events of ALT or AST  3 × ULN and total bilirubin > 2 × ULN triggers stopping 
criteria.  
All AEs involving the liver or the gall bladder will be reported as AESI according to the risk profile 
of evobrutinib.  
 
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Appendix 6 
Clinical Laboratory Tests  
The protocol-required clinical laboratory assessments are in the following table: 
Laboratory 
Assessment 
Parameter 
Notes 
Biochemistry 
Albumin 
 
Alanine Aminotransferase 
 
Alkaline Phosphatase 
 
Amylase 
 
Aspartate Aminotransferase 
 
Bicarbonate 
 
Total Bilirubin 
 
Blood Urea Nitrogen 
 
Calcium 
 
Chloride 
 
Cholesterol 
 
Creatinine 
 
Creatine Phosphatase 
 
Glomerular Filtration Rate, Estimated 
Refer to SoA 
Gamma Glutamyl Transferase 
 
Glucose 
 
Inorganic Phosphate 
 
Lactate Dehydrogenase 
 
Lipase 
 
Magnesium 
 
Potassium 
 
Sodium 
 
Triglycerides 
 
Urate 
 
Coagulation 
x 
Prothrombin Intl. Normalized Ratio 
x 
Activated partial thromboplastin time 
 
Hematology 
Hematocrit 
 
Hemoglobin 
 
Leukocytes with Differential: 
Neutrophils (absolute/%) 
Lymphocytes (absolute/%) 
Monocytes (absolute/%) 
Eosinophils (absolute/%)  
Basophils(absolute/%) 
 
Mean Corpuscular Hemoglobin (MCH) 
 
Mean Corpuscular Volume (MCV) 
 
Platelets 
Erythrocytes 
 
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Laboratory 
Assessment 
Parameter 
Notes 
Hormonal 
Thyroid stimulating Hormone 
 
Routine Urinalysis 
Specific gravity, pH, glucose, protein, 
blood, ketones, bilirubin, urobilinogen, 
nitrite, leukocyte esterase by dipstick. 
 
Microscopic examination (if blood or 
protein is abnormal with positive dipstick). 
 
 
In case of a positive result for 
hemoglobin, leukocyte esterase, protein 
or nitrite, a flow cytometry count and 
classification will be performed. 
 
Pregnancy Testing 
Serum human Choriogonadotropin Beta 
pregnancy test  
At all timepoints listed in the SoA (see 
Section 1.3). 
Other Screening 
Tests 
x 
Follicle stimulating hormone  
All study-required laboratory assessments 
will be performed by a central laboratory 
(Nuvisan’s clinical laboratory) 
x 
Urine drug screen (to include at 
minimum: amphetamine, 
methamphetamine, barbiturates, 
3,4-methylenedioxymethamphetamine 
[ecstasy], cocaine, opiate, 
cannabinoids, benzodiazepine, 
methadone, phencyclidine, 
oxycodone, and tricyclic 
antidepressants,) 
x 
Serology (HIV-1/2 Antibody, hepatitis 
B virus surface antigen, hepatitis B 
virus core antibody, hepatitis C virus 
antibody, QuantiFERON test)  
At Screening and Day -1 of each period. 
x 
SARS-CoV-2 antigen 
At Screening and Day -1 of each period. 
According to local regulations at the time of 
study conduct. 
x 
Thyrotropin (thyroid stimulating 
hormone)  
 
x 
Cotinine  
At Screening and Day -1 of each period. 
x 
Ethanol (Alcohol breath test)  
At Screening and Day -1 of each period. 
x 
Estimated Glomerular Filtration Rate 
based on Chronic Kidney Disease 
Epidemiology Collaboration 
Creatinine Equation (2009)  
 
MCH= Mean corpuscular hemoglobin; MCV=Mean corpuscular volume, SARS-CoV-2=severe acute respiratory 
syndrome coronavirus type 2. 
 
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Appendix 7 
Protocol Amendment History  
The information for the current amendment is on the title page. 
Protocol Version 2.0 (24 October 2022) 
Overall Rationale for the Amendment 
This non-substantial amendment was prepared to correct a typographical error in the schedule of 
activities. The PK sampling at 16 h postdose is not included in the schedule of activities, although 
the corresponding ECG measurement is included in the schedule of activities. The 16 h postdose 
blood sampling is present in Table 1 (Time Deviations from PK sampling times, Section 8.4.1) 
and is also consistently displayed in the ICF. 
Additionally, in Section 7.1 there was a harmonization with the preexisting next sentence. It was 
clarified, that if study intervention is permanently discontinued, the participant will remain in the 
study to be evaluated for safety assessments. 
Section # and 
Name 
Description of Change 
Brief Rationale 
1.3 Schedule of 
Activities 
The PK sampling at 16 h postdose was 
included. 
To correct a typographical error, the PK sampling 
at 16 h postdose was included. 
7.1 
Discontinuation 
of Study 
Intervention 
It was clarified, that if study intervention 
is permanently discontinued, the 
participant will remain in the study to be 
evaluated for safety assessments. 
No content change – just harmonization with the 
preexisting next sentence. 
 
 
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Appendix 8 
Sponsor Signature Page  
Study Title: 
A Single-Dose, Randomized, Double-Blind, Placebo- and 
Positive-Controlled, 4-Way Crossover Study to Evaluate 
the Effect of Evobrutinib on the QTc (Corrected QT) 
Interval in Healthy Adult Participants 
Regulatory Agency Identifying 
Numbers: 
EudraCT: 2022-002664-78 
Clinical Study Protocol Version: 
01 December 2022/Version 3.0 
I approve the design of the clinical study: 
___ 
____________________________ 
Signature 
Date of Signature 
 
Name, Academic Degree: 
 MD 
Function/Title: 
 
Institution: 
Merck Healthcare KGaA, Darmstadt, Germany an affiliate of 
Merck KGaA, Darmstadt, Germany 
Address: 
Frankfurter Str. 250, 64293 Darmstadt, Germany 
General Merck Phone 
Number: 
Office: +49 6151 72 3564 
 
General Merck Fax 
Number: 
Not applicable 
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Electronically signed by:
Date: Dec 1, 2022 14:59 GMT+1
Dec 1, 2022
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