Conditions: Relapsing Multiple Sclerosis
Keywords: Evobrutinib Teriflunomide Aubagio® Relapsing Multiple Sclerosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1124
Healthy volunteers: no

Brief summary:
The study is to evaluate the efficacy and safety of evobrutinib administered orally twice daily versus Teriflunomide (Aubagio®), administered orally once daily in participants with Relapsing Multiple Sclerosis (RMS). Participants who complete the double-blind treatment period (DBTP) and double-blind extension period (DBEP) prior to approval of a separate long-term follow-up study in their country will get an option for evobrutinib treatment continuation through a 96-week open-label extension (OLE) period.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Teriflunomide intervention 2: Evobrutinib
Intervention descriptions: intervention 1: Participants received Teriflunomide at a dose of 14 milligrams (mg) orally once daily up to 156 weeks in Double blind treatment period (DBTP) followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in double blind extension (DBE) period and followed by once daily oral doses of Teriflunomide 14 mg up to 96 weeks in open label extension (OLE) period. intervention 2: Participants received Evobrutinib at a dose of 45 mg orally twice daily up to 156 weeks in Double blind treatment period (DBTP) followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in double blind extension (DBE) period and followed by twice daily oral doses of Evobrutinib 45 mg up to 96 weeks in open label extension (OLE) period.

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol  
Title Page  
Clinical Study Protocol Title: A Phase III, Multicenter, Randomized, Parallel Group, 
Double Blind, Double Dummy, Active Controlled Study of 
Evobrutinib Compared with Teriflunomide, in Participants 
with Relapsing Multiple Sclerosis to Evaluate Efficacy and 
Safety. 
Study Number: 
MS200527ˍ0080  
Merck Compound Number: 
M2951 
Study Phase: 
III 
Short Title: 
Phase III Study of Evobrutinib in RMS 
Acronym: 
Evolution RMS 1 
Coordinating 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 
an affiliate of Merck KGaA, Darmstadt, Germany 
Frankfurter Str. 250 
Darmstadt, 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 
Medical Responsible: 
Name: 
 
Address: Ares Trading SA,  
an affiliate of Merck Serono GmbH  
Route de Crassier 1, 1262 Eysins, Switzerland  
Phone: 
 
Fax: Not Applicable 
E-mail: 
  
Regulatory Agency 
Identifying Numbers: 
EudraCT: 2019-004972-20 
US IND: 129428 
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Protocol Version: 
26 April 2023/Version 6.0 
Replaces Version: 
06 December 2022/Version 5.0 
Approval Date: 
26 April 2023 
 
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Protocol Amendment Summary of Changes 
Protocol History 
Version Number 
Type 
Version Date 
1.0 
Original Protocol 
13 February 2020 
1.1-CAN 
Local amendment Canada 
03 July 2020 
1.2-DEU 
Local amendment Germany 
04 August 2020 
1.3-BEL 
Local amendment Belgium 
12 August 2020 
2.0 
Amendment 1 - Global 
27 November 2020 
2.1-CAN 
Local amendment Canada 
04 December 2020 
3.0 
Amendment 2 - Global 
19 May 2021 
3.1-CAN 
Local amendment Canada 
26 May 2021 
3.2-ISR 
Local amendment Israel 
07 June 2021 
3.3-GBR 
Local amendment United Kingdom 
11 June 2021 
4.0 
Amendment 3 - Global 
03 April 2022 
4.1-CAN 
Local amendment Canada 
19 April 2022 
4.2-ISR 
Local amendment Israel 
25 April 2022 
4.3-GBR 
Local amendment United Kingdom 
25 April 2022 
5.0 
Amendment 4 - Global 
06 December 2022 
5.1-ISR 
Local amendment Israel 
14 December 2022 
5.2-GBR 
Local amendment United Kingdom 
18 December 2022 
5.3-CZE 
Local amendment Czech Republic 
16 March 2023 
6.0 
Amendment 5 - Global 
26 April 2023 
Protocol Version 6.0 (26 April 2023)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is: 
• To reflect the recent update to the risk profile of evobrutinib (i.e. important identified risk of 
drug-induced liver injury) by adapting liver-related eligibility criteria, monitoring, and 
discontinuation criteria as well as language on tolerability and safety of evobrutinib across the 
protocol. 
• To allow participants to stay on blinded IMP after DBTP in a DBE period to delay the switch 
of participants naïve to evobrutinib treatment to the OLE period. This will also allow to generate 
additional data on efficacy and safety over an extended period of time. 
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A high-level description of each change with rationale is summarized below. 
Section # and Name 
Description of Change and Brief Rationale, if applicable 
1.1 Synopsis 
• 
Updated to include relevant information for 
DBE period including DBE objectives and 
endpoints, information on transitions after 
the DBTP, and involvement of special 
committees 
• 
To enable continuous 
treatment of participants with 
IMP 
• 
Generation of additional data 
on efficacy and safety 
1.2 Schema 
• 
Updated to include the optional DBE 
period 
• 
To ensure continuous 
treatment of participants with 
IMP 
• 
Generation of additional data 
on efficacy and safety 
1.3.1 Schedule of 
Activities – Double-blind 
Treatment Period 
• 
Week 3, 5, 7, 9, and 11 have been added 
to allow weekly LFT monitoring until after 
Study Day 70 
• 
To enhance liver function 
monitoring plan 
1.3.2 Schedule of 
Activities – Double-blind 
Extension Period 
• 
New SoA has been added for the DBE 
period 
• 
To ensure participants’ safety 
and continuous treatment of 
participants with IMP 
• 
Generation of additional data 
on efficacy and safety 
1.3.3 Schedule of 
Activities – Open-label 
Extension Period 
• 
SoA has been updated 
• 
Week 3, 5, 7, 9, and 11 have been added 
to allow weekly LFT monitoring until after 
Study Day 70 
• 
To enhance liver function 
monitoring plan 
2.2 Background 
• 
Rephrased based on updated risk profile 
• 
To reflect recent update to risk 
profile of evobrutinib 
2.3 Benefit/Risk 
Assessment 
• 
Updated important identified risks to 
include the asymptomatic DILI cases. 
• 
Updated important potential risks to 
include weekly monitoring of liver 
enzymes first 12 weeks of DBTP and OLE 
and Hepatology Assessment Committee 
(HAC) review 
• 
To reflect recent update to risk 
profile of evobrutinib 
3 Objectives and 
Estimands 
• 
Added objectives and endpoints for the 
DBE period (primary, secondary, and 
tertiary/exploratory) 
• 
To specify objectives and 
endpoints for the newly added 
DBE period 
4.1 Study Design 
• 
Updated description of transition into the 
DBE period; transition into OLE period; 
transition into the long-term follow-up 
study 
• 
To ensure continuous 
treatment of participants with 
IMP 
4.4 End of Study 
Definition 
• 
Added definition of treatment completion 
for the DBE period 
• 
Added information on study termination 
• 
To define treatment completion 
for newly added DBE period 
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Section # and Name 
Description of Change and Brief Rationale, if applicable 
5.3 Criteria for Entry into 
Open-label Extension 
Period 
5.3.1 Inclusion Criteria 
for Open-label Extension 
Period 
5.3.2 Exclusion Criteria 
for Open Label Extension 
Period 
• 
Added criteria for entry into DBE period  
• 
OLE exclusion criteria have been updated 
for liver enzymes and to accommodate the 
new DBE period 
• 
To specify inclusion and 
exclusion criteria for newly 
added DBE period 
• 
To ensure exclusion of 
participants with abnormal 
blood tests into OLE period 
• 
To ensure participants’ safety 
5.5.2 Caffeine, Alcohol, 
and Tobacco 
• 
Description specified for 
additionalhepatotoxic effects associated 
with IMPs (teriflunomide and evobrutinib) 
• 
To reflect risk of alcohol 
consumption associated with 
IMPs  
6.3.2 Blinding 
• 
Blinding during the DBE period specified 
• 
Clarification on blinding in the 
newly added study period 
6.5.3 Prohibited 
Medicines 
• 
Clarification regarding use of • CYP2C8 
substrates 
• 
Content related to the newly 
added DBE period was 
included 
7.1 Discontinuation of 
Study Intervention 
• 
Liver function test-related monitoring and 
discontinuation further specified 
• 
Liver function testing criteria updated 
• 
HCV RNA by PCR was added 
• 
To enhance safety monitoring 
of liver function 
 
• 
For clarification 
8 Study Assessments 
and Procedures 
• 
Update with information regarding the 
addition of the DBE period 
• 
Updated requirements for AEP adapted to 
DBE period 
• 
AEP (at Screening Visit for OLE only) was 
updated 
• 
Clarification added as related 
to the newly added DBE period 
8.1.2 Brain Magnetic 
Resonance Imaging 
Scans 
• 
Added clarification that the Investigator 
will have full access to the results of the 
MRI scans during the OLE period, starting 
with the first MRI assessment in the OLE 
period at Week 48 
• 
Updated text to clarify that the 
Investigator will have access to 
the full MRI reports including 
MS pathology during the OLE 
period. As the End-of-DBE MRI 
is used as baseline for OLE 
period, this MRI will remain 
blinded to MS pathology to 
ensure the integrity of the 
blinded periods of the study. 
8.2.8 Independent Data 
Monitoring Committee, 
Hepatology Assessment 
Committee, Endpoint 
Adjudication Committee, 
and Study Steering 
Committee 
• 
Description of Hepatology Assessment 
Committee was added 
• 
DBE period added to Endpoint 
Adjudication Committee 
• 
To include involvement of 
newly formed Hepatology 
Assessment Committee 
8.5 Pharmacokinetics 
• 
Description for DBE period added 
• 
Content related to the newly 
added DBE period was 
included 
8.8 Biomarkers 
 
• 
Update on repurposing of blood samples 
and update of blood volumes 
• 
Content related to the newly 
added DBE period was added 
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Section # and Name 
Description of Change and Brief Rationale, if applicable 
8.8.1 Biomarkers of 
Disease, Disease Activity 
and Progression, Drug-
related Outcomes, and 
Treatment Response 
8.8.1.2 Novel Liver 
Function Biomarkers  
8.8.3 OLE Blood 
Biomarker PD Substudy 
– Biomarkers of Disease 
Activity, Progression and 
Response to Drug 
8.8.4 Gene Expression 
• 
DBE added and OLE description updated 
• 
Content related to the newly 
added DBE period was added 
9.3 Populations for 
Analyses 
 
• 
Analysis sets for the DBE Period were 
specified 
• 
Clarified that the subgroups 
were defined specifically for 
the PA 
9.4.3.5 Analysis of Open 
Label Extension Period 
Endpoints 
• 
New Section 9.4.3.5 added for analysis of 
DBE period endpoints  
• 
Analysis of Open Label Extension Period 
Endpoints moved to Section 9.4.3.6 
• 
Content related to the newly 
added DBE period was added 
9.4.4 Sequence of 
Analyses 
 
• 
Additional analysis was added for DBE 
• 
Content related to the newly 
added DBE period was added 
9.4.4.2 Primary Analysis 
• 
Specified that all data until PA trigger will 
be analyzed 
• 
Specified that the PA will be 
performed on all data until the 
PA trigger date. 
Appendix 2 Study 
Governance 
• 
Hepatology Assessment Committee 
added to the list of committees 
• 
To include newly formed 
Hepatology Assessment 
Committee 
Appendix 5 
• 
Parameters added to 
Hepatic/Autoimmune Panel 
• 
Content related to the newly 
added DBE period, 
consistency and clarity. 
Appendix 8 Procedure for 
Accelerated Elimination 
of Teriflunomide 
• 
Updated text on mandatory AEP for OLE 
period  
• 
Content related to the newly 
added DBE period was added 
Throughout the 
document 
• 
Minor editorial and document formatting 
revisions 
• 
Minor changes to accommodate addition 
of DBE, e.g., addition of the word ‘DBE’ in 
the respective sections 
• 
Minor; therefore, have not 
been summarized. 
• 
Content related to the newly 
added DBE period was added 
 
- 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 © 2023 by Merck KGaA, Darmstadt, 
Germany, or its subsidiary. All rights reserved. 
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Table of Contents  
Title Page 
 ..............................................................................................................1 
Table of Contents  ..............................................................................................................7 
Table of Tables 
 ............................................................................................................12 
Table of Figures 
 ............................................................................................................12 
1 
Protocol Summary ..............................................................................13 
1.1 
Synopsis ..............................................................................................13 
1.2 
Schema ................................................................................................20 
1.3 
Schedule of Activities .........................................................................21 
1.3.1 
Schedule of Activities - Double-blind Treatment Period ...................21 
1.3.2 
Schedule of Activities – Double-Blind Extension Period ..................42 
1.3.3 
Schedule of Activities Open-label Extension Period ..........................47 
2 
Introduction .........................................................................................58 
2.1 
Study Rationale ...................................................................................58 
2.2 
Background .........................................................................................59 
2.3 
Benefit/Risk Assessment ....................................................................61 
3 
Objectives and Estimands ...................................................................64 
4 
Study Design .......................................................................................74 
4.1 
Overall Design ....................................................................................74 
4.2 
Scientific Rationale for Study Design ................................................75 
4.3 
Justification for Dose ..........................................................................77 
4.4 
End of Study Definition ......................................................................78 
5 
Study Population .................................................................................79 
5.1 
Inclusion Criteria ................................................................................79 
5.2 
Exclusion Criteria ...............................................................................81 
5.3 
Criteria for Entry into Double-blind Extension Period .......................87 
5.4 
Criteria for Entry into Open-label Extension Period ..........................87 
5.4.1 
Inclusion Criteria for Open-label Extension Period ...........................87 
5.4.2 
Exclusion Criteria for Open Label Extension Period .........................87 
5.5 
Lifestyle Considerations .....................................................................88 
5.5.1 
Meals and Dietary Restrictions ...........................................................88 
5.5.2 
Caffeine, Alcohol, and Tobacco .........................................................88 
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5.6 
Screen Failures ....................................................................................88 
6 
Study Intervention(s) ..........................................................................89 
6.1 
Study Intervention(s) Administration .................................................89 
6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability .....................................................................................90 
6.3 
Measures to Minimize Bias: Study Intervention Assignment and 
Blinding ..............................................................................................91 
6.3.1 
Study Intervention Assignment ..........................................................91 
6.3.2 
Blinding ..............................................................................................92 
6.3.3 
Emergency Unblinding .......................................................................93 
6.4 
Study Intervention Compliance ..........................................................94 
6.5 
Concomitant Therapy .........................................................................94 
6.5.1 
Rescue Medicine .................................................................................95 
6.5.2 
Permitted Medicines ...........................................................................95 
6.5.3 
Prohibited Medicines ..........................................................................95 
6.5.4 
Other Interventions .............................................................................97 
6.6 
Dose Selection and Modification ........................................................97 
6.7 
Study Intervention after the End of the Study ....................................97 
6.8 
Special Precautions .............................................................................97 
6.9 
Management of Adverse Events of Interest ........................................97 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal ...............................................................99 
7.1 
Discontinuation of Study Intervention................................................99 
7.1.1 
Temporary Discontinuation ..............................................................104 
7.1.2 
Rechallenge .......................................................................................104 
7.2 
Participant Discontinuation/Withdrawal from the Study .................104 
7.3 
Lost to Follow-Up.............................................................................105 
8 
Study Assessments and Procedures ..................................................105 
8.1 
Efficacy Assessments and Procedures ..............................................109 
8.1.1 
Neurological Assessment ..................................................................109 
8.1.1.1 
Qualified Relapse ..............................................................................110 
8.1.1.2 
Disability Progression and Expanded Disability Status Scale ..........111 
8.1.1.3 
Confirmed Disability Improvement ..................................................111 
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8.1.1.4 
Timed Twenty-Five Foot Walk ........................................................111 
8.1.1.5 
Nine Hole Peg Test ...........................................................................111 
8.1.1.6 
Symbol Digit Modalities Test ...........................................................112 
8.1.2 
Brain Magnetic Resonance Imaging Scans ......................................112 
8.1.3 
Patient Reported Outcomes ..............................................................113 
8.1.3.1 
Patient Reported Outcomes Measurement Information System .......114 
8.1.3.2 
Medical Outcomes Study 36-Item Short Form Survey Instrument ..115 
8.1.3.3 
EuroQoL 5 Dimension 5 Levels .......................................................115 
8.1.3.4 
WPAI: MS v2.0 (for OLE Period Only) ...........................................116 
8.2 
Safety Assessments and Procedures .................................................116 
8.2.1 
Physical Examinations ......................................................................117 
8.2.2 
Vital Signs ........................................................................................117 
8.2.3 
Electrocardiograms ...........................................................................117 
8.2.4 
Clinical Safety Laboratory Assessments ..........................................118 
8.2.5 
Pregnancy .........................................................................................118 
8.2.6 
Immunoglobulin levels .....................................................................119 
8.2.7 
Columbia-Suicide Severity Rating Scale ..........................................119 
8.2.8 
Independent Data Monitoring Committee, Hepatology 
Assessment Committee, Endpoint Adjudication Committee, and 
Study Steering Committee ................................................................119 
8.3 
Adverse Events and Serious Adverse Events ...................................121 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ..................................................121 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse Events .121 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events .............122 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse Events ...122 
8.3.5 
Pregnancy .........................................................................................123 
8.4 
Treatment of Overdose .....................................................................124 
8.5 
Pharmacokinetics ..............................................................................124 
8.6 
Pharmacodynamics ...........................................................................125 
8.7 
Pharmacogenetics .............................................................................126 
8.8 
Biomarkers ........................................................................................126 
8.8.1 
Biomarkers of Disease, Disease Activity and Progression, Drug-
related Outcomes, and Treatment Response .....................................127 
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8.8.1.1 
Neurofilament Light Chain ...............................................................127 
8.8.1.2 
Novel Liver Function Biomarkers ....................................................128 
8.8.2 
DBTP PD Substudy - Bruton’s Tyrosine Kinase Occupancy, 
Cellular Function, and Cytokines .....................................................128 
8.8.3 
OLE Blood Biomarker PD Substudy – Biomarkers of Disease 
Activity, Progression and Response to Drug ....................................128 
8.8.4 
Gene Expression ...............................................................................129 
8.9 
Health Resource Utilization ..............................................................130 
8.10 
Immunogenicity Assessments ..........................................................130 
9 
Statistical Considerations ..................................................................130 
9.1 
Statistical Hypotheses .......................................................................130 
9.1.1 
Statistical Hypotheses Related to Primary Objective .......................130 
9.1.2 
Statistical Hypotheses Related to Secondary Objectives ..................130 
9.2 
Sample Size Determination ..............................................................131 
9.2.1 
Sample Size for Primary Endpoint: ARR .........................................131 
9.2.2 
Sample Size for Secondary Endpoint: 12-week CDP.......................133 
9.2.3 
Sample Size Considerations due to the Currently Escalating Crisis 
in Eastern Europe ..............................................................................133 
9.2.4 
Sample Size of PK/PD Substudy ......................................................134 
9.3 
Populations for Analyses ..................................................................135 
9.4 
Statistical Analyses ...........................................................................136 
9.4.1 
Efficacy Analyses .............................................................................136 
9.4.1.1 
Efficacy Analyses Related to Primary Objective .............................139 
9.4.1.2 
Efficacy Analyses Related to Secondary Objectives ........................141 
9.4.1.3 
Sensitivity Analyses ..........................................................................145 
9.4.2 
Safety Analyses ................................................................................147 
9.4.2.1 
Adverse Events .................................................................................147 
9.4.2.2 
Clinical Laboratory Test Values .......................................................148 
9.4.2.3 
Vital Signs ........................................................................................148 
9.4.2.4 
Electrocardiogram Parameters ..........................................................148 
9.4.2.5 
Immunoglobulin Levels ....................................................................149 
9.4.2.6 
Concomitant Medication and Procedures .........................................149 
9.4.2.7 
Columbia-Suicide Severity Rating Scale ..........................................149 
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9.4.2.8 
Sensitivity Analyses ..........................................................................150 
9.4.3 
Other Analyses ..................................................................................150 
9.4.3.1 
Pharmacokinetic Parameters, Pharmacodynamic Parameters, 
Biomarkers ........................................................................................150 
9.4.3.2 
Demographics, Baseline Characteristics, Disposition, and 
Compliance .......................................................................................150 
9.4.3.3 
Patient Reported Outcome Analyses ................................................151 
9.4.3.4 
Health Resource Utilization ..............................................................151 
9.4.3.5 
Analysis of Double-Blind Extension Period Endpoints ...................151 
9.4.3.6 
Analysis of Open Label Extension Period Endpoints.......................151 
9.4.4 
Sequence of Analyses .......................................................................151 
9.4.4.1 
Optional Interim Analysis for Blinded Sample Size Re-estimation .152 
9.4.4.2 
Primary Analysis ..............................................................................152 
9.4.4.3 
Multiplicity .......................................................................................153 
10 
References .........................................................................................156 
11 
Appendices .......................................................................................161 
Appendix 1 
Abbreviations ....................................................................................161 
Appendix 2 
Study Governance .............................................................................166 
Appendix 3 
Contraception ....................................................................................173 
Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ..............................................176 
Appendix 5 
Clinical Laboratory Tests .................................................................181 
Appendix 6 
Pharmacogenetics .............................................................................183 
Appendix 7 
Guidance for Diagnosis of PML .......................................................184 
Appendix 8 
Procedure for Accelerated Elimination of Teriflunomide ................186 
Appendix 9 
Teriflunomide Drug-Drug Interactions .............................................187 
Appendix 10 
Structured Interview at Telephone Contact ......................................189 
Appendix 11  
Guidance on Clinically Relevant CYP Inducers, Inhibitors, and 
Substrates ..........................................................................................190 
Appendix 12 
Protocol Amendment History ...........................................................191 
Appendix 13 
Sponsor Signature Page ....................................................................260 
Appendix 14 
Coordinating Investigator Signature Page ........................................261 
Appendix 15 
Principal Investigator Signature Page ...............................................262 
 
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Table of Tables  
Table 1 
Primary and Secondary Objectives, Endpoints and Estimands for 
the Double-blind Treatment Period ....................................................64 
Table 2 
Tertiary/Exploratory Objectives and Endpoints for the 
Double-blind Treatment Period ..........................................................66 
Table 3 
Objectives and Endpoints for the Double-Blind Extension Period ....70 
Table 4 
Objectives and Endpoints for the Open Label Extension Period .......72 
Table 5 
Protocol-Required Clinical Laboratory Assessments .......................181 
 
Table of Figures  
Figure 1 
Study Schema .....................................................................................20 
Figure 2 
Participant Transition Schema ............................................................75 
Figure 3 
Multiplicity Graph ............................................................................155 
Figure 4 
Diagnostic Algorithm for PML – Suggested Diagnostic Algorithm 185 
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Objectives 
Estimand Attributes 
To demonstrate the efficacy of 
evobrutinib relative to that of 
teriflunomide on patient 
reported symptoms and 
functional status 
Endpoints:  
• Change from Baseline (CFB) in Patient Reported 
Outcomes 
Measurement 
Information 
System 
(PROMIS) Physical Function (PF) score over 
96 weeks 
• CFB in PROMIS Fatigue score over 96 weeks 
Population: 
Patients 
with 
RMS 
as 
defined 
by 
inclusion/exclusion criteria 
Treatment: Evobrutinib versus teriflunomide 
Intercurrent Event Strategy:  
• Treatment discontinuation: Treatment policy 
• Death (any cause): While Alive 
• Ukraine crisis: Hypothetical 
Population-Level 
Summary: 
difference 
of 
average 
leastsquares means of score CFB (average over Weeks 72, 84, 
and 96 for PROMIS PF and average over Weeks 48, 60, 72, 
84, and 96 for PROMIS Fatigue) and CI (Mixed effect model 
for repeated measures [MMRM] model), with test of treatment 
effect based on difference of average leastsquares means 
To demonstrate the efficacy of 
evobrutinib relative to that of 
teriflunomide on magnetic 
resonance imaging (MRI) 
lesion parameters 
Endpoints:  
• Total number of T1 Gd+ lesions based on all available 
MRI scans 
• Number of new or enlarging T2 lesions on the last 
available MRI scan relative to the baseline MRI scan  
Population: 
Patients 
with 
RMS 
as 
defined 
by 
inclusion/exclusion criteria 
Treatment: Evobrutinib versus teriflunomide 
Intercurrent Event Strategy:  
• Treatment discontinuation: Treatment policy 
• Death (any cause): While Alive 
• Ukraine crisis: Hypothetical 
Population-Level Summary: lesion rate ratio and CI (NB 
model), with test of treatment effect based on test of lesion rate 
ratio 
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Study Intervention Groups and Duration: The Treatment Period of up to 156 weeks (minimum 
24 weeks) will be preceded by a 4-week Screening Period (may be extended after discussion with 
the Medical Monitor but cannot exceed 12 weeks) and followed by a 4-week Safety Follow-up 
after treatment completion or early discontinuation.  
Transition Into the DBE Period 
Participants who complete the DBTP Period, or who are still under study treatment when the PA 
is triggered, will be considered completers and will be eligible to continue in the DBE Period for 
continuation of treatment as assigned at randomization. Those participants who have not reached 
the Week 156 visit when the PA is triggered, need to undergo an End-of-DBTP Visit, which is 
also their first visit in the DBE. Participants who do not wish to enter the DBE period will have a 
Safety Follow-up Visit occurring after the End-of-DBTP visit. 
Transition Into OLE Period 
Participants who complete the DBE period, or who are still under study treatment once the 
Sponsor– upon agreement with Health Authorities / Ethics Committees – will have notified sites 
(i.e. the OLE is open for enrollment), will be eligible for transition into the OLE period. 
Participants entering the OLE period need to undergo an End-of-DBE Visit, which is also their 
first visit in the OLE period. All participants previously treated with teriflunomide, or with an 
unknown exposure status, entering the OLE will be required to complete the AEP prior to 
dispensation of the IMP in the OLE period. Participants who do not wish to transition into OLE, 
will have a Safety Follow-up Visit after the End of the DBE Period. The treating physician may 
consider conducting the AEP for participants coming off the IMP and prior to initiation of 
alternative DMTs. 
Transition Into Long-term Follow-up Study (MS200527_0123, LONGEVO) 
Once the long-term follow-up study (MS200527_0123, LONGEVO) is open for enrollment (i.e., 
once the sponsor – upon agreement with Health Authorities / Ethics Committees – will have 
notified sites), participants of the OLE will switch into the long-term follow-up study at the nearest 
transition visit (at Weeks 24, 48, 72, or 96 of the OLE period). Participants who do not wish to 
transition into the long-term follow-up study, will have a Safety Follow-up Visit after the End of 
Treatment visit in the OLE Period. 
In case the long-term follow-up study is open for enrollment while participants are still under study 
treatment in the DBE period, they will be offered to transition into that study by default. For 
participants entering the long-term follow-up study, their last visit in the current study (i.e. 
End-of-DBE Visit) is also their first visit in the long-term follow-up study. Participants who do 
not wish to transition into the long-term follow-up study will have a Safety Follow-up Visit after 
the End-of-DBE Visit. 
Involvement of Special Committee(s): Yes. Independent Data Monitoring Committee, 
Hepatology Assessment Committee (HAC), Endpoint Adjudication Committee (for the DBTP and 
DBE Period), and Study Steering Committee.
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1.2 
Schema  
Figure 1 
Study Schema  
 
AEP = accelerated elimination procedure, BID = twice daily, DBE = Double-Blind Extension, DBTP = Double-Blind Treatment Period, OLE = Open-Label 
Extension, PA = primary analysis, QD = once daily, SFU = Safety Follow-up. 
a Screening may be extended to 12 weeks after approval by the Medical Monitor (see Section 8). 
b Treatment Period of up to 156 weeks with a minimum treatment duration of 24 weeks. 
c 
Once PA is triggered, participants who have not reached Week 156 will undergo an End-of-DBTP visit 
d Once the primary analysis is triggered participants have the option to extend their treatment in the DBE for up to 96 weeks, until the Sponsor, upon agreement 
with Health Authorities/Ethics Committees, notifies sites that the OLE and/or the long-term follow-up study is open for enrolment. At that point, participants who 
have not reached Week 96, will need to undergo an End-of-DBE visit. The long-term follow-up study is covered by a separate study protocol. 
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9-HPT = 9-Hole Peg Test, AE = adverse event; AEP= accelerated elimination procedure, AESI = adverse event of special interest, ALP = alkaline phosphatase, 
ALT = alanine aminotransferase, AST = aspartate aminotransferase, C-SSRS = Columbia-Suicide Severity Rating Scale, D = Day, DBE = Double-blind Extension, 
DBTP = double-blind treatment period, DNA = deoxyribonucleic acid, ECG = electrocardiogram, ED = Early Discontinuation, EDSS = Expanded Disability Status 
Scale, EOT = End-of-Treatment, EQ-5D-5L = EuroQoL 5 Dimension 5 Level, GGT = γ-glutamyl-transferase, HBV = hepatitis B virus, ICF = Informed Consent 
Form, Ig = Immunoglobulin, IWRS = Interactive Web Response System, LFT = Liver Function Test, MRI = Magnetic Resonance Imaging, MS = multiple sclerosis, 
OLE = Open-label Extension, PRO = Patient Reported Outcomes, PROMIS = Patient Reported Outcomes Measurement Information System, SAE = Serious 
Adverse Event, SDMT = Symbol Digit Modalities Test, TB = Tuberculosis, T25-FW = Timed 25-Foot Walk, W = Week, WOCBP = Women Of Childbearing 
Potential, WPAI:MS = Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis. 
 
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2 
Introduction  
Evobrutinib is a potent, orally administered, highly selective, irreversible inhibitor of BTK that is 
being developed for the treatment of RMS. 
Complete information on the chemistry, pharmacology, efficacy, and safety of evobrutinib is in 
the current Investigator’s Brochure. 
2.1 
Study Rationale  
The purpose of this study is to characterize the efficacy and safety of evobrutinib 45 mg 
administered orally twice daily versus teriflunomide (Aubagio®; 14 mg once a day orally) in 
participants with RMS. 
Evobrutinib inhibits activation of B cells via the B cell receptor. In addition, evobrutinib inhibits 
activation of myeloid cells by immune complexes via Fc receptors as well as the differentiation of 
proinflammatory macrophages. Thus, evobrutinib may be suitable for the treatment of MS. 
The main randomized, double-blind, placebo-controlled Phase II study of evobrutinib with a 
parallel, open label, active control group (dimethyl fumarate [Tecfidera®]), in patients with RMS 
to evaluate efficacy, safety, tolerability, PK, and biological activity (MS200527_0086) is 
completed; the OLE part of the study is ongoing. The study consisted of first a 24-week period, in 
which 267 participants were randomized to evobrutinib 25 mg once daily (n = 52), 75 mg once 
daily (n = 53), 75 mg twice daily (n = 54), dimethyl fumarate 240 mg twice daily (provided open 
label) (n = 54), or placebo (n = 54). Data from the first 24-weeks were analyzed for the primary 
analysis (PA). Following the 24-week period, all remaining participants continued to be treated 
for an additional 24-week period as follows: participants who received previously evobrutinib 
25 mg once daily, 75 mg once daily, 75 mg twice daily, or dimethyl fumarate, continued to be 
treated with their original treatment, and participants who received placebo for the first 24-weeks 
were switched to evobrutinib 25 mg once daily. Treatment assignment remained blinded with the 
exception of dimethyl fumarate which was open label throughout the study. The first 48 weeks 
analysis is referred to as the BEA. For the PA, efficacy analysis consisted of the comparison 
between the placebo and evobrutinib treatment groups. No formal comparison between the 
dimethyl fumarate and the evobrutinib treatment groups was performed for either the PA or the 
BEA. 
In the PA, the primary efficacy endpoint of the Phase II study was the total number of 
gadolinium-enhancing T1 lesions at Weeks 12, 16, 20, and 24. The primary efficacy analysis was 
a comparison of each evobrutinib dose arm versus placebo based on lesion rate (lesions per scan) 
ratio, adjusted for Baseline lesion activity. The primary endpoint of the study was met, and both 
evobrutinib 75 mg once daily (lesion rate ratio 0.30, 95% CI: 0.14, 0.63; p = 0.0015 [unadjusted], 
p = 0.046 [adjusted according to Hochberg]) and evobrutinib 75 mg twice daily (lesion rate ratio 
0.44, 95% CI: 0.21, 0.93; p = 0.0313 [unadjusted], p = 0.0648 [adjusted according to Hochberg]) 
were associated with a reduction in T1 Gd+ lesion rate compared to placebo (Montalban 2020).  
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The first key secondary endpoint was ARR at 24-weeks. A trend towards a reduction in ARR 
(unadjusted [95% CI]) was seen with evobrutinib 75 mg once daily (0.13 [0.03, 0.38]; p = 0.09) 
and evobrutinib 75 mg twice daily (0.08 [0.01, 0.30]; p = 0.06) versus placebo (0.37 [0.17, 0.70]), 
with evidence of a dose response (p = 0.014). 
In the BEA, results showed an unadjusted ARR at 48 weeks of 0.11 (95% CI: 0.04, 0.25) for 
evobrutinib 75 mg twice daily and 0.25 (95% CI: 0.12, 0.44) for evobrutinib 75 mg once daily 
indicating that the efficacy trend observed during the first 24-week period was sustained during 
the second 24-week period, with greater clinical sustained efficacy in the 75 mg twice daily group. 
The results of the Phase II OLE (cutoff 26 September 2019) indicate that the participants from the 
evobrutinib 75 mg twice daily arm had an ARR of 0.11, consistent with what was observed at the 
end of the main study (Week 48, cutoff 13 July 2018). 
Evobrutinib at 45 mg twice daily in the fed state is expected to be similar to the tested 75 mg twice 
daily dose in the fasted state based on the available exposure/response data (see Section 4.3). 
These results provide evidence of evobrutinib’s efficacy compared to placebo. Clinical 
development efforts in the MS indication will focus specifically on RMS, with potential expansion 
into progressive MS (and SPMS) with subclinical CNS inflammation. 
Reversible elevations in transaminases (ALT and AST) have been observed in participants 
randomized to evobrutinib in the RMS Phase II study (MS200527_0086). This finding, and the 
overall safety and risk-benefit assessment of evobrutinib are discussed further in Section 2.3 and 
Section 4.3. 
Taken together, efficacy and safety data from this study support progression into Phase III. 
Refer to the Investigator’s Brochure for further information about the nonclinical and clinical 
programs and Guidance for the Investigator. 
2.2 
Background  
Currently there is no cure for MS, but the course of the disease can be altered favorably with DMT 
with varying levels of efficacy, and distinct safety and tolerability profiles. Most active RMS 
patients initiate treatment with an interferon-beta or glatiramer acetate therapy. Oral DMTs 
including dimethyl fumarate and teriflunomide are also used as first-line agents. If responding 
suboptimally, patients can be treated with an alternative, second-line oral therapy such as 
cladribine and fingolimod, or infusion agents such as natalizumab and ocrelizumab. Generally, 
DMTs perceived to be more efficacious have also been shown to be associated with more 
significant adverse effects, ranging from serious infections (i.e., PML) to autoimmunity and 
cancer. Switching among these DMTs occurs primarily due to perceived lack of efficacy or the 
occurrence of AEs, as well as individual patient preferences. 
Despite the recent approvals of newer therapies for the treatment of MS, there remains an unmet 
need for highly effective and disease-modifying therapies that address not only inflammation but 
also disability progression within the CNS for patients with MS at all stages of the disease. Early 
treatment with a highly efficacious and safer DMT could be advantageous for long-term quality of 
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life for MS patients and might slow the process of brain atrophy, which accompanies axonal 
damage and loss of grey and white matter. 
Evobrutinib is a highly specific, oral inhibitor of BTK that inhibits B cell activation and 
B cell/T cell interaction, decreasing plasma cell formation and autoantibody production 
(Investigator Brochure, Haselmayer 2017). In addition, evobrutinib was shown to inhibit M1 
macrophage survival and proinflammatory cytokine release and promotes M2 polarization of 
reparative human monocytes in vitro (Alankus 2018). In line with the in vitro data, evobrutinib 
demonstrated pharmacological efficacy in both B cell and T cell dependent mouse models of MS, 
by reducing CNS inflammation and amelioration of disease severity (Boschert 2017, Torke 2018). 
Since B cell depletion studies have shown that antibody independent B cell functions play an 
important role in MS pathogenesis (Bar-Or 2010, Fraussen 2016, Jelcic 2018) and an altered innate 
immune system contributes to disability progression and repair in MS (Vogel 2013, Rawji 2016), 
evobrutinib may offer advantages over current approved DMTs. 
Clinical efficacy was recently demonstrated with B cell depleting anti-CD20 therapies in Phase II 
and Phase III clinical studies in RMS and progressive MS (Hauser 2008, Hawker 2009, 
Montalban 2016, Wolinsky 2016). Ocrelizumab (Ocrevus®) inhibited the formation of new 
inflammatory MRI lesions up to 90% (Hauser 2008) in Phase II RMS studies and high efficacy on 
MRI (-94%), ARR (-46%), and 24-week disease progression (-40%) was also reached in OPERA 
Phase I, II, and III studies against interferon-beta. Translational mechanism of action studies in 
anti-CD20 treated RMS patients show diminished proliferation and proinflammatory 
differentiation of T cells (Bar-Or 2010), pointing towards abrogation of antigen presenting cell 
function as the primary mechanism. In addition to the role of anti-CD20 in B cell antigen 
presentation, a recent publication of Li et al (Li 2015) describes a diminished proinflammatory 
myeloid cell response in ocrelizumab treated MS participants. Evobrutinib shows inhibition of 
myeloid cell activation by immune complexes. 
Preclinical proof of concept with evobrutinib has been demonstrated for SLE/lupus nephritis, 
experimental autoimmune encephalomyelitis, RA and passive cutaneous anaphylaxis. Oral 
evobrutinib does not deplete B cells in the studies carried out to date and, upon withdrawal, 
restoration of immune function can be achieved in days. This is less than treatment with anti-CD20 
therapies, where restoration of the immune system can take months, and is important should the 
need to interrupt or stop therapy arise. This suggests that a more favorable benefit to risk balance 
with respect to infections for evobrutinib versus anti-CD20 therapies may be observed. In addition, 
BTK inhibitors might have broader efficacy than agents that cause B cell depletion, due to the 
importance of BTK activation downstream of various receptors expressed in myeloid cells, 
suggesting an additional direct effect of evobrutinib on innate immune cell activation induced by 
immune complexes, cytokines/chemokines, or TLR activation (Block 2012, López-Herrera 2014, 
Whang 2014). A direct myeloid inhibition activity also best explains the significant reduction of 
clinical score, relapse rate, and time to first relapse in T cell dependent experimental autoimmune 
encephalomyelitis models, in which anti-CD20 antibodies do not work. 
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2.3 
Benefit/Risk Assessment  
Benefit 
In the PA of the MS200527_0086 study, evobrutinib significantly decreased the number of T1 Gd+ 
lesions at Weeks 12, 16, 20, and 24 in participants with RMS. Similar to the relationship seen for 
the MRI endpoints, evobrutinib 75 mg once and twice daily was associated with a lower ARR 
compared to placebo. In the OLE, the ARR remained low and similar to those observed in the PA 
and BEA. These results show evobrutinib is efficacious in participants with RMS, and 
consequently warrant further investigation in Phase III clinical studies.  
Important Identified Risks 
As of July 2022, more than 2,490 participants in completed and ongoing clinical studies have been 
exposed to evobrutinib including healthy volunteers, participants with RMS, SLE, or RA, and 
participants with renal and hepatic impairment. The incidence of SAEs and TEAEs leading to 
withdrawal of study intervention was ≤ 10% in completed SLE, RA, or RMS studies. 
Overall, evobrutinib demonstrated manageable tolerability based on the completed and ongoing 
clinical studies across various indications. Observed TEAEs resolved after treatment 
discontinuation and did not result in permanent disabilities. In the ongoing blinded phase 3 studies, 
cases of DILI have been reported, which were typically asymptomatic and were resolving after 
drug discontinuation. The TEAEs have been primarily mild to moderate in severity.  
Important Potential Risk 
Important Potential Risk: Severe DILI, i.e. Requiring Transplant or Leading to Death 
Based on the important identified risk DILI, there is a theoretical consideration that evobrutinib 
may have the potential to cause severe DILI defined as liver organ failure, i.e. requiring transplant 
or leading to death. Hence, severe DILI, i.e., requiring transplant or leading to death is considered 
an important potential risk for evobrutinib. 
Important Potential Risk: Embryo-fetal Toxicity 
Embryo-fetal toxicity has been classified as an important potential risk based on nonclinical 
experience with evobrutinib (refer to IB), as well as other drugs in the same class. Results of 
nonclinical studies carried out in experimental models show that there is a risk of harm which 
could lead to increased rates of stillbirth, abortion, or cleft palate and limb deformities. While 
nonclinical data suggest no risk for male-mediated developmental effects, female participants of 
childbearing potential must use highly effective contraception and barrier method during the study 
and some period after the study is completed, as specified in the clinical study protocols. 
Given these observations, this protocol excludes participants with hemochromatosis, Wilson’s 
disease, alpha1-antitrypsin deficiency, or any other chronic liver disease including Gilbert’s 
disease and > 1.5 × ULN values for ALT, AST and total bilirubin, > 2 × ULN amylase or lipase 
elevation at Screening. During the study, liver transaminase will be monitored weekly during the 
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first 12 weeks of DBTP and OLE, and every 2 weeks thereafter, for the first 6 months of exposure 
to evobrutinib. The protocol has strict stopping criteria for liver transaminase and total bilirubin 
elevations leading to treatment discontinuation and timely medical management. Also, relevant 
data will be reviewed by a Hepatology Assessment Committee (HAC) with appropriate expertise, 
which will report findings to the IDMC for consideration. 
Investigations on embryo-fetal development in toxicological studies showed an increased 
incidence of malformations (mainly cleft palate) and skeletal variations in mice when compared 
to the control group, and abortions and/or vaginal bleeding during the last period of gestation in 
rabbits. In addition, an increase of resorptions, and a lower mean fetal weight were also seen.  
Based on these investigations, embryo-fetal toxicity is considered as an important potential risk in 
participants exposed to evobrutinib. Therefore, female participants of childbearing potential must 
not be pregnant, must have a negative pregnancy test at the time of enrollment and use highly 
effective contraception (as specified in the clinical study protocol) during the study period and 
after the last dose, and should not donate eggs, as risk mitigation measures (for further details, see 
Section 5.1). 
Adverse Events of Special Interest 
Although no causal relationship has been established, AESIs including infections (serious and 
opportunistic infections), lipase and amylase elevation, and seizure, are under close monitoring.  
Due to the dominant role of CYP3A4/5 in the metabolism of evobrutinib, the compound may be a 
victim of DDI caused by inhibition (competitive/time-dependent) or induction of this enzyme by 
coadministered perpetrator drugs. The results of the completed clinical CYP DDI study 
(MS200527_0054) demonstrated that coadministration of evobrutinib with a moderate (e.g., 
fluconazole) or strong (e.g., itraconazole) CYP3A4 inhibitor resulted in a significant DDI. 
Evobrutinib peak and total exposures were increased by approximately 2.5- to 3.4-fold when 
evobrutinib was dosed concurrently with fluconazole or itraconazole. Based on these observations, 
the coadministration of medications that are moderate or strong inhibitors or inducers of 
CYP3A4/5 is not permitted during ongoing clinical studies. 
No new potential risks emerged from the completed studies: EMR200527_001, MS200527_0019, 
MS200527_0017, MS200527_0022, EMR200527_002, MS200527_0081, MS200527_0060, 
MS200527_0018, MS200527_0073, and MS200527_0074. 
Evobrutinib is a BTK inhibitor and, as such, works as an immunomodulator. There was some 
decrease in IgM, an increase in IgA, and IgG levels remained stable following treatment with 
evobrutinib. There was a decrease in CD19+ B cells and mature-naïve B cells, but no evidence of 
a change in memory B cell levels. The changes in B cells, IgA and IgM levels do not appear to be 
associated with an enhanced risk of infections, but the significance of these changes is not known 
(Montalban 2020). BTK is not required to clear viral infections, apart from enteroviruses. There is 
currently no evidence that evobrutinib treatment leads to a higher risk of SARS-CoV-2 infection, 
or a more severe disease. While no data regarding evobrutinib and COVID-19 are available, 
published data on approved BTK inhibitors (e.g., ibrutinib, acalabrutinib) used in oncology suggest 
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a protective effect of BTK inhibitors for severity and mortality of COVID-19 (Scarfò 2020, 
Thibaud 2020, Treon 2020).  
The evobrutinib data suggest that the risk of infections, including severe and opportunistic 
infections, is not higher than that observed with other disease-modifying treatments in MS, and no 
side effects have been identified that could exacerbate SARS-CoV-2 infection or mask COVID-19 
symptoms.  
Similarly, while teriflunomide is, like evobrutinib, an immunomodulatory agent, published reports 
of patients with MS and COVID-19 while on treatment with teriflunomide do not suggest an 
increased risk to patients, but rather a milder course of disease while on treatment (Ciardi 2020, 
Bollo 2020, Maghzi 2020, Möhn 2020). 
The recommendation by the Multiple Sclerosis International Federation is to continue 
disease-modifying treatment in MS to offset the risk of relapses, as the risk of disease rebound 
outweighs the risk of SARS-CoV-2 infection (MS International Federation 2020). 
To mitigate the risk of contracting COVID-19 during the study, there is flexibility in the timing of 
MRI assessments postscreening on a case-by-case basis. Safety labs, including liver function 
monitoring, may be collected during home visits, if available, and if permitted per local laws and 
regulations. 
In case a SARS-CoV-2 infection occurs during this study, interruption of the study treatment and 
treatment of COVID-19 are recommended as clinically indicated. After recovery, the continuation 
of the study will be at the Investigator’s discretion and in agreement with the medical monitoring 
team.  
The Sponsor will monitor the events related to any SARS-CoV-2 infection regularly. In addition, 
the IDMC will review the impact of any SARS-CoV-2 infection of a study participant as part of 
their activities and will provide recommendations, if required. 
Following the review of the totality of the safety data from the concluded clinical studies with 
evobrutinib, overall, evobrutinib was reported as well tolerated in patients with MS up to 75 mg 
twice daily. The safety profile of evobrutinib has been consistent across doses and indications. No 
dose-related relationship has been observed for the most frequently reported TEAEs. Furthermore, 
evobrutinib at 45 mg twice daily in the fed state is expected to be similar to the tested 75 mg twice 
daily dose in the fasted state based on the available exposure/response data (see Section 4.3). 
Benefit-Risk Conclusion 
Overall, considering the unmet medical need in MS patients, reduction of MS activities (decreased 
the number of T1 Gd+ lesions and lower ARR compared with placebo), convenience of an oral 
therapy and the measures put in place to mitigate the important identified and important potential 
risks, the benefit-risk of evobrutinib 45 mg twice daily fed supports continued clinical 
development of evobrutinib in this population. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of evobrutinib may be found in Section 4.2 and the Investigator’s Brochure. More 
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Objectives 
Estimand Attributes 
To demonstrate the 
efficacy of evobrutinib 
relative to that of 
teriflunomide on 
disability improvement 
Endpoints:  
• Time to first occurrence of 24-week CDI as measured by the 
EDSS up to 156 weeks 
Population: Patients with RMS as defined by inclusion/exclusion 
criteria and who have baseline EDSS ≥ 2.0 
Treatment: Evobrutinib versus teriflunomide 
Intercurrent Event Strategy:  
• Treatment discontinuation: Treatment policy 
• Death (any cause): While Alive 
• Ukraine crisis: Hypothetical 
Population-Level Summary: hazard ratio and CI (Cox model), with 
test of treatment effect based on logrank test 
To demonstrate the 
efficacy of evobrutinib 
relative to that of 
teriflunomide on patient 
reported symptoms and 
functional status 
Endpoints:  
• CFB in PROMIS PF score over 96 weeks 
• CFB in PROMIS Fatigue score over 96 weeks 
Population: Patients with RMS as defined by inclusion/exclusion 
criteria 
Treatment: Evobrutinib versus teriflunomide 
Intercurrent Event Strategy:  
• Treatment discontinuation: Treatment policy 
• Death (any cause): While Alive 
• Ukraine crisis: Hypothetical 
Population-Level Summary: difference of average least-squares 
means of score CFB (average over Weeks 72, 84, and 96 for PROMIS 
PF and average over Weeks 48, 60, 72, 84, and 96 for PROMIS 
Fatigue) and CI (MMRM model), with test of treatment effect based 
on difference of average least-squares means 
To demonstrate the 
efficacy of evobrutinib 
relative to that of 
teriflunomide on MRI 
lesion parameters 
Endpoints:  
• Total number of T1 Gd+ lesions based on all available MRI 
scans 
• Number of new or enlarging T2 lesions on the last available 
MRI scan relative to the baseline MRI scan 
Population: Patients with RMS as defined by inclusion/exclusion 
criteria 
Treatment: Evobrutinib versus teriflunomide 
Intercurrent Event Strategy:  
• Treatment discontinuation: Treatment policy 
• Death (any cause): While Alive 
• Ukraine crisis: Hypothetical 
Population-Level Summary: lesion rate ratio and CI (NB model), with 
test of treatment effect based on test of lesion rate ratio 
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Objectives 
Endpoints (Outcome Measures) 
that of teriflunomide 
on MRI parameters 
• Change in volume of T1 Gd+ lesions from Baseline to Week 96 
based on assessments up to Week 96 
• New or enlarging T2 lesion free status at Week 96 based on 
assessments up to Week 96 
• Change in volume of T2 lesions from Baseline to Week 96 based 
on assessments up to Week 96 
• CUA lesion free status at Week 96 based on assessments up to 
Week 96  
• Total number of CUA lesions based on all available MRI scans  
• Total number of new T1 hypo-intense lesions based on all available 
MRI scans 
• Percentage change in BV from Week 24 to Week 96 based on 
assessments up to Week 96  
• Percentage change in thalamic volume from Week 24 to Week 96 
based on assessments up to Week 96 
• Percentage change in cortical grey matter volume from Week 24 to 
Week 96 based on assessments up to Week 96 
• Change 
in 
normalized 
T1 
intensity 
within 
pre-existing 
nonenhancing T2 weighted lesion volume from Baseline to Week 
96 based on assessments up to Week 96 
• Volume of SELs based on scans at Weeks 24, 48, and 96  
• Change in number of PRL at Weeks 24, 48, and 96 
• Change in CBF in NAWM at Weeks 24, 48, and 96 
To evaluate the effect 
of evobrutinib 
compared to 
teriflunomide on 
functional parameters 
• Time to ≥ 20% increase (confirmed at 12 weeks) in T25-FW  up to 
156 weeks 
• Time to ≥ 20% increase (confirmed at 12 weeks) 9-HPT up to 
156 weeks 
To evaluate the effect 
of evobrutinib 
compared to 
teriflunomide on 
composite parameters 
• NEDA-3 at Week 48, Week 96 defined by: 
o Qualifying relapse-free status 
o T1 Gd+ lesions free status and new or enlarging T2 lesion 
free status 
o 12-week confirmed EDSS progression free status 
• Time to first occurrence of 12-week CDP up to 156 weeks based 
on a composite score defined by: 
o 12-week confirmed EDSS progression (at least 0.5- or 1.0- 
point change, depending on the Baseline EDSS) or; 
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Objectives 
Endpoints (Outcome Measures) 
o 12-week confirmed worsening (≥ 20%) in T25-FW versus 
Baseline or; 
o 12-week confirmed worsening (≥ 20%) in 9-HPT versus 
Baseline 
• NEP at Week 48, Week 96 as defined by: 
o No 12-week CDP on EDSS 
o No 12-week confirmed worsening (≥ 20%) in 9-HPT score 
o No 12-week confirmed worsening (≥ 20%) in T25-FW time 
• NEPAD at Week 48, Week 96 as defined by: 
o No protocol-defined relapses on treatment 
o No 12-week CDP on EDSS 
o No 12-week confirmed worsening (≥ 20%) in 9-HPT score 
o No 12-week confirmed worsening (≥ 20%) in T25-FW time 
o No new or enlarging T2 lesions and no T1 Gd+ lesions on 
MRI 
To evaluate the 
efficacy of 
evobrutinib relative to 
that of teriflunomide 
on progression 
independent of relapse 
activity 
• Time to PIRA, where disability progression is defined for each of 
2 endpoints as follows: 
o 12-week CDP on EDSS 
o 12-week confirmed worsening as a composite of 3 endpoints 
(EDSS, 9HPT, T25-FW) 
To evaluate the 
efficacy of 
evobrutinib relative to 
that of teriflunomide 
on progression 
independent of relapse 
and brain MRI 
activity 
• Time to PIRMA, where disability progression is defined for each 
of 2 endpoints as follows: 
o 12-week CDP on EDSS 
o 12-week confirmed worsening as a composite of the 
3 endpoints (EDSS, 9HPT, T25-FW) 
To evaluate the 
efficacy of 
evobrutinib relative to 
that of teriflunomide 
on cognitive function 
• Change from Baseline in SDMT score at Week 48, Week 96   
To evaluate the 
efficacy of 
evobrutinib relative to 
that of teriflunomide 
on patient reported 
symptoms and 
functional status 
• Change from Baseline in PROMIS PF score at Week 48, Week 96, 
and Week 144  
• Change from Baseline in PROMIS Fatigue score at Week 48, Week 
96, and Week 144  
• Time to first occurrence of 12-week confirmed PF deterioration 
compared to Baseline (decrease of at least 2.7 points on PROMIS 
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Objectives 
Endpoints (Outcome Measures) 
PF score) up to 156 weeks 
• Change from Baseline in Patient Reported Outcome scores at 
Week 48, Week 96, and Week 144: 
o Medical Outcomes SF-36v2 
o EQ-5D-5L 
To evaluate the effect 
of evobrutinib on 
HRU relative to that 
of teriflunomide up to 
156 weeks 
• Absolute values of HRU, including but not limited to 
doctor/home/emergency visits, hospitalizations, paid assistance, 
and missed work 
To characterize the 
PK profile of 
evobrutinib in 
participants with MS 
and to describe the 
exposure-response 
relationship between 
evobrutinib and 
efficacy endpoints and 
safety endpoints 
• PK parameters: CL/F, Vz/f, Cmax, and AUC after a single dose 
(Day 1 data), and at steady state (Weeks 2, 4, 8, 12, 24, 48, 72, and 
96 data) 
To describe the 
exposure-response 
relationship between 
evobrutinib and PD 
biomarkers 
• PD biomarker endpoints at Baseline/Screening, Weeks 2, 4, 8, 12, 
and 24 
To assess relationship 
between candidate 
disease biomarker and 
disease activity or 
treatment response 
• Level of biomarkers of disease with disease activity/treatment 
response at Baseline, Weeks 12, 24, 48, 72, 96; and upon 
relapse/disease progression (unscheduled)  
• NfL concentration at Weeks 24, 48, 72, and 96 
To measure the 
antibody levels to 
SARS-CoV-2 vaccine 
administered in 
participants 
• Level of anti-SARS-CoV-2 antibodies to vaccines pre- and post-
vaccination in a subset of participants who have received anti-
COVID vaccinations during the study. 
To evaluate the 
relationship of the 
novel biomarkers of 
liver function e.g., 
protein, miRNA, etc., 
compared to standard 
• Levels of novel biomarkers of hepatic function compared to ALT 
at Baseline, and on treatment 
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mg BID in participants with 
RMS over time 
4 
Study Design  
4.1 
Overall Design  
This is a Phase III, multicenter, randomized, parallel group, double-blind, double-dummy, 
active-controlled study of evobrutinib with an active control group teriflunomide, in participants 
with RMS. 
Eligible participants will be randomized 1:1 to treatment with evobrutinib 45 mg twice daily, or 
teriflunomide 14 mg once daily (oral), stratified by region and Baseline EDSS. Blinding will be 
accomplished using a double-dummy design. The total sample size is planned to be 898 
participants (approximately 449 participants per treatment group). 
The Treatment Period of up to 156 weeks (minimum 24 weeks) will be preceded by a 4-week 
Screening Period (may be extended after discussion with the Medical Monitor but cannot exceed 
12 weeks) and followed by a 4-week Safety Follow-up after treatment completion or early 
discontinuation. 
Transition Into the DBE Period 
Participants who complete the DBTP Period, or who are still under study treatment when the PA 
is triggered, will be considered treatment completers and will be eligible to continue in the DBE 
Period for continuation of treatment as assigned at randomization (Figure 2). Those participants 
who have not reached the Week 156 visit when the PA is triggered, need to undergo an End-of-
DBTP Visit, which is also their first visit in the DBE. Participants who do not wish to enter the 
DBE period will have a Safety Follow-up Visit occurring after the End-of-DBTP visit. 
Transition Into OLE Period 
Participants who complete the DBE period, or who are still under study treatment once the Sponsor 
– upon agreement with Health Authorities/Ethics Committees – will have notified sites (i.e. the 
OLE is open for enrollment), will be eligible for transition into the OLE period. Participants 
entering the OLE period need to undergo an End-of-DBE Visit which is also their first visit in the 
OLE period. All participants previously treated with teriflunomide, or unknown exposure status, 
entering the OLE will be required to complete the AEP prior to dispensation of the IMP in the 
OLE period. Participants who do not wish to transition into OLE, will have a Safety Follow-up 
Visit after the end of the DBE period. The treating physician may consider conducting the AEP 
for participants coming off the IMP and prior to initiation of alternative DMTs. 
Transition Into Long-term Follow-up Study (MS200527_0123, LONGEVO) 
Once the long-term follow-up study (MS200527_0123, LONGEVO) is open for enrollment (i.e. 
once the Sponsor – upon agreement with Health Authorities/Ethics Committees – will have 
notified sites), participants of the OLE will switch into the long-term follow-up study at the nearest 
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transition visit (at Weeks 24, 48, 72, or 96 of the OLE period). Participants who do not wish to 
transition into the long-term follow-up study, will have a Safety Follow-up Visit after the End of 
Treatment visit in the OLE period. 
In case the long-term follow-up study is open for enrollment while participants are still under study 
treatment in the DBE period, they will be offered to transition into that study by default. For 
participants entering the long-term follow-up study, their last visit in the current study (i.e. 
End-of-DBE Visit) is also their first visit in the long-term follow-up study. Participants who do 
not wish to transition into the long-term follow-up study will have a Safety Follow-up Visit after 
the End-of-DBE Visit. 
Figure 2 
Participant Transition Schema  
 
DBE = Double-blind Extension; DBTP = Double-blind Treatment Period; OLE = Open-label Extension; PA = primary 
analysis. 
Per Protocol Version 3, prior to the completion of enrollment, an optional IA for BSSR, based on 
12-week CDP (as measured by EDSS) data pooled from the present study and second Phase III 
study (MS200527_0082), was conducted. Based on this BSSR in August 2021, it was decided that 
the number of participants to be enrolled would not be increased. 
Initial enrollment was closed on 01 October 2021. The actual enrollment figures exceeded the 
original planned enrollment of 930 participants per study. 
The currently escalating crisis that erupted in Ukraine in February 2022, and the countries 
sanctioned as a result, pose a challenge to the successful conduct of the MS200527_0080 and 
MS200527_0082 studies due to the large representation of these countries in the initial enrollment. 
In the worst-case scenario, all data from participants in the regions affected by the crisis (Ukraine, 
Russian Federation, and Belarus) will be unable to be queried for cleaning purposes and will be 
considered unreliable for inclusion in the PA. The impact on study power is discussed in Section 
9.2.3.  
4.2 
Scientific Rationale for Study Design  
This study was designed to determine the efficacy and safety of evobrutinib in participants with 
RMS. The primary objective will focus on reduction of relapses relative to teriflunomide in adult 
participants with RMS based on the ARR up to 156 weeks.  
The findings in Section 2 support the pathogenic contribution of B cells to MS damage. In contrast, 
a failed clinical study with another B cell targeting agent, atacicept, supports the notion that certain 
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B cell subtypes may mediate beneficial anti-inflammatory effects (Kappos 2014). Novel 
nondepleting B cell therapies may deliver a more favorable benefit risk profile than current B cell 
directed therapeutic approaches. In the Phase II study of evobrutinib, the PA showed a clinically 
significant reduction in MRI activity in participants treated with evobrutinib compared to placebo. 
Furthermore, the results indicate that the ARR in the OLE remained low and similar to those 
observed in the PA and BEA. 
There is consensus in the MS community, that the use of placebo in Phase III studies with RMS 
participants is no longer ethical, due to the availability of established and effective therapies 
(Polman 2008). Teriflunomide is an acknowledged therapy that has recently been used in pivotal 
studies as a comparator and is well-suited for the objectives of this study. It is currently widely 
used in the treatment of MS and has a well-established efficacy and safety profile. Teriflunomide 
is administered as a tablet once daily and eliminates the burden of injections specific to other 
standard of care therapies such as interferons. For further information on teriflunomide, refer to 
the locally approved product information (e.g., relevant SmPC or USPI). 
The study will have a double dummy design, to minimize the potential for bias and maintain the 
integrity of the clinical data generated from this study. It also reduces the risk of concluding that 
superiority to the active comparator was driven by participant and assessor bias. 
This study plans to enroll RMS participants according to the McDonald MS 2017 criteria 
(Thompson 2018) with an EDSS score of 0 to 5.5 at Screening and Baseline (Day 1) who had at 
least one or more documented relapses within the 2 years before Screening with either: 
• one relapse which occurred within the last year prior to randomization, OR 
• the presence of at least 1 T1 Gd+ lesion within 6 months prior to randomization 
These criteria have been implemented to further characterize the benefits of treatment with 
evobrutinib in a wide range of RMS participants with varying degrees of disease activity and 
severity. The age range will be limited to ≤ 55 years with the aim to avoid confounding by 
neurological conditions prevalent in older participants. 
The proposed study endpoints are widely accepted as clinically relevant, and have been used in 
numerous pivotal clinical studies in RMS. The primary endpoint for the study will be ARR up to 
156 weeks, based on qualified relapses. Secondary efficacy endpoints will include time to 12- or 
24-week CDP (as measured by EDSS), total number of new or enlarging T2 lesions based on all 
available MRI scans, and total number of T1 Gd+ lesions based on all available MRI scans. 
Prevention of relapses, prevention/delay of accumulation of sustained neurological disability, as 
well as effect on MRI are meaningful goals in the treatment of participants with RMS. 
Time-to-24-week-CDI (as measured by EDSS) is a relatively new clinical endpoint 
complementary to the CDP endpoints. Week 12 NfL concentration is an emerging biomarker 
endpoint thought to reflect the early impact of treatment on reducing neuronal damage 
(Kuhle 2021; see Section 8.8.1.1 for details on NfL). The timepoint at Week 12 was chosen based 
on a post-hoc analysis of the data from a Phase II clinical study with evobrutinib. 
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Patient Reported Outcomes including those assessing fatigue and PF, are included as a secondary 
endpoint and several exploratory endpoints in the current study. Fatigue has been reported as the 
most bothersome symptom for MS patients among other concerns, such as bladder and bowel 
problems, cognitive impairment, visual disorders, musculoskeletal issues e.g., stiffness, spasm, 
walking difficulty and balance problems (Martin 2017, Patti 2011, Brañas 2000). In turn, these are 
associated with impairments in various functional areas, including IADLs, limitations with 
physical activities such as participating in sports, limitations related to ability to work or study, 
and social interactions (Patti 2014, LaRocca 2011). The current data from randomized controlled 
studies support positive treatment effects of currently available DMTs (including, teriflunomide, 
dimethyl fumarate, natalizumab, and ocrelizumab) on HRQoL, i.e., improving or preventing the 
worsening of HRQoL (Jongen 2017). 
Exploratory research of biomarkers of evobrutinib treatment response in MS aims to define 
responders and non-responders to therapy and to better understand disease pathology. Exploratory 
biomarkers will help to define an optimal evobrutinib treatment response in MS and thus be of 
considerable value for taking treatment decisions and ensuring continued benefit from evobrutinib 
therapy. As genetic variation may impact a participant’s response to therapy, susceptibility to 
disease, and severity and progression of disease, pharmacogenomic and pharmacogenetic 
biomarkers will be assessed to explore the long-term effect evobrutinib. In addition to this, blood 
sample assessments are included to test for biomarkers that are thought to play a key role in the 
disease pathology of MS and to be impacted by treatment with evobrutinib. 
The DBE and OLE periods have been introduced for participants completing the DBTP to enable 
an option for treatment continuation and to investigate sustained or long-term efficacy and safety 
of evobrutinib prior to enrollment in the long-term follow-up study. Refer to the Investigator’s 
Brochure for further information about the nonclinical and clinical programs and Guidance for the 
Investigator. 
4.3 
Justification for Dose  
Selection of the Phase III dose was based on PD, efficacy, and safety data from the Phase IIb study 
MS200527_0086, and supported by clinical pharmacology studies where dosing of the tablet was 
included (Studies MS200527_0017 and MS200527_0019). The models describing the exposure-
response relationship between PK and BTK occupancy (target engagement), ARR, number of T1 
Gd+ lesions and number of new or enlarging (active) T2 lesions (efficacy endpoints) were used in 
the selection of the dose. The results of the modeling of evobrutinib concentrations, BTK 
occupancy, ARR, T1 Gd+ and active T2 lesions were used to select the dose of 45 mg twice daily 
(fed) that will deliver efficacy anticipated to be better than 75 mg once daily (fasted) or equal to 
75 mg twice daily (fasted) observed in the RMS Phase IIb study. 
In the exposure-response analysis of Study MS200527_0086 for participants with RMS, a steep 
exposure-response curve was observed with a threshold evobrutinib exposure (AUC0-24,ss) of 
355 ng•h/mL associated with the onset of a reduction in ARR, and a significant reduction in ARR 
observed at evobrutinib exposure of ≥ 400 ng•h/mL. Participants with exposure ≤ 355 ng•h/mL 
had mean ARR values between 0.42 to 0.63, whereas participants with exposure > 355 ng•h/mL 
had mean ARR values between 0.00 to 0.14. The significant reduction in ARR was observed when 
trough BTK occupancy was > 95%, indicating high target engagement over the entire dosing 
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interval. In addition, for the participants with RMS and > 0 T1 Gd+ lesions at Baseline or > 13 cc 
T2 lesion volume at Baseline, a significant reduction in the number of T1 Gd+ lesions, and the 
number of active T2 lesions was observed when evobrutinib exposure was greater than 468 
ng•h/mL. This significant reduction in the number of active T2 lesions was observed when trough 
BTK occupancy was > 96%.  
Thus, the criteria for selection of an efficacious dose to be used in Phase III is based on targeting 
exposure of ≥ 468 ng•h/mL and with a high percentage of participants expected to have > 95% 
trough BTK occupancy. 
One dose of evobrutinib will be utilized in this study. A dose of 45 mg twice daily, when given 
with a meal, is expected to provide a (geometric) mean evobrutinib daily exposure (AUC0-24,ss) of 
840 ng•h/mL, with only 7.6% of the participants expected to have a daily exposure of < 400 
ng•h/mL. The 45 mg twice daily dose will be administered to participants with a meal, where food 
(either a high-fat or low/moderate-fat meal) has been shown to increase evobrutinib exposure by 
50%. Thus, the daily exposure with 45 mg twice daily fed is similar to the exposure observed in 
the Phase IIb study for 75 mg twice daily fasted (835 ng•h/mL), which provided a significant 
reduction in ARR (see Section 2.1). Mean Cmax,ss for 45 mg twice daily fed is expected to be 24% 
less (128 ng/mL) than the observed mean peak exposure (168 ng/mL) for 75 mg twice daily fasted. 
In addition, high BTK occupancy (at least 95% occupancy in 93% of the participants) is expected 
at the end of a dosing interval; therefore, similar efficacy to that of 75 mg twice daily (BTK 
occupancy of at least 95% in 92% of the participants). 
Teriflunomide will be administered orally at the highest approved dose of 14 mg once a day. Refer 
to the locally approved product information (e.g., relevant SmPC or USPI) for further details. 
Additional information about the justification for dose for evobrutinib may be found in the 
Investigator’s Brochure. 
4.4 
End of Study Definition  
A participant has completed the study if he/she has completed all study visits, including the last 
visit (as defined in the SoA in Section 1.3). A participant is considered a study completer if the 
participant has completed the Safety Follow-up Visit, even if the participant discontinued 
treatment prematurely. Treatment completers who do not require a Safety Follow-up Visit per 
protocol are also considered study completers (i.e., participants entering the long-term follow-up 
study at protocol-defined visits). 
• Treatment completion for the DBTP is defined as completing treatment up until the time of 
the PA trigger or 156 weeks post randomization, whichever is earliest.  
• Treatment completion for the DBE period is defined as completing treatment during the DBE 
at protocol-defined visits. 
• Treatment completion for the OLE period is defined as completing treatment during the OLE 
at protocol-defined visits. 
Refer to Section 9.4.4.2 for details on the PA. 
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The end of the study is defined as the date of the last visit of the last participant. 
The Sponsor may terminate the study at any time once access to the study intervention for 
participants still benefiting is provided via the long-term follow up study, expanded access, 
marketed product, or another mechanism of access, as appropriate. 
5 
Study Population  
The criteria in Sections 5.1 and 5.2 are designed to enroll only participants, who are appropriate 
for the study, thereby ensuring the study fulfills its objectives. All relevant medical and nonmedical 
conditions should be taken into consideration when deciding whether a participant is suitable for 
this study. 
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Before performing any study assessments that are not part of the participant’s routine medical care, 
the Investigator will confirm that the participant has provided written informed consent, as 
indicated in Appendix 2 Study Governance. 
5.1 
Inclusion Criteria  
Participants are eligible to be included in the study only if all the following criteria apply: 
Age 
1. Are 18 to 55 years of age at the time of signing the informed consent. 
Type of Participant and Disease Characteristics 
2. Are diagnosed with RMS (RRMS or SPMS with relapses) in accordance with 2017 Revised 
McDonald criteria (Thompson 2018). 
3. One or more documented relapses within the 2 years before Screening with either: 
a. one relapse which occurred within the last year prior to randomization, OR 
b. the presence of at least 1 T1 Gd+ lesion within 6 months prior to randomization. 
4. Have an EDSS score of 0 to 5.5 at Screening and Baseline (Day 1) 
a. Participants with an EDSS score ≤ 2 at Screening and Baseline (Day 1) are only eligible 
for participation if their disease duration (time since onset of symptoms) is no more than 
10 years. 
5. Are neurologically stable for ≥ 30 days prior to both Screening and Baseline (i.e., no new signs 
or symptoms referable to the CNS for ≥ 30 days). 
Sex 
6. Are female or male 
a. Male Participants: 
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Agree to the following during the study intervention period and for at least 2 years after 
study intervention due to the long elimination period for teriflunomide of 2 years, unless 
the participant undergoes an AEP (see Appendix 8) with a confirmed teriflunomide level 
of < 0.02 mg/L after the last dose of study intervention: 
•  Refrain from donating sperm 
PLUS, either: 
• Abstain from intercourse with a woman of childbearing potential. 
OR 
• Use a male condom: 
o When having sexual intercourse with a woman of childbearing potential, who 
is not currently pregnant, and advise her to use a highly effective contraceptive 
method with a failure rate of < 1% per year, as described in Appendix 3, since 
a condom may break or leak. 
b. Female participants  
• Are not pregnant or breastfeeding, and at least one of the following conditions applies: 
o Not a woman of childbearing potential. 
OR 
o If a woman of childbearing potential, use a highly effective contraceptive 
method (i.e., with a failure rate of < 1% per year), preferably with low user 
dependency, as described in Appendix 3 for the following time periods: 
• Before the first dose of the study intervention(s), if using hormonal 
contraception: 
• Has completed at least one 4-week cycle of an oral contraception 
pill and either had or has begun her menses 
OR 
• Has used a depot contraceptive or extended-cycle oral 
contraceptive for at least 28 days and has a documented negative 
pregnancy test using a highly sensitive assay. 
AND 
o A barrier method, as described in Appendix 3 
• Have a negative serum or highly sensitive urine pregnancy test, as 
required by local regulations, within 4 to 8 weeks and a highly sensitive 
urine pregnancy test at Baseline before the first dose of study 
intervention. If a urine test cannot be confirmed as negative (e.g., an 
ambiguous result), a serum pregnancy test is required.  
• During the Intervention Period 
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For at least 2 years after study intervention due to the long elimination 
period for teriflunomide of (up to) 2 years, unless the participant 
undergoes an AEP (see Appendix 8) with a confirmed teriflunomide 
level of < 0.02 mg/L after the last dose of study intervention and agree 
not to donate eggs (ova, oocytes) for reproduction during this period 
(see Appendix 9). The Investigator evaluates the effectiveness of the 
contraceptive method in relationship to the first dose of study 
intervention. 
• Additional requirements for pregnancy testing during and after study intervention are in 
Sections 8.2.4 and 8.2.5. 
• The Investigator reviews the medical history, menstrual history, and recent sexual activity 
to decrease the risk for inclusion of a female with an early undetected pregnancy. 
Informed Consent 
7. 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. 
8. Participants must be contactable by email or telephone throughout the study. 
5.2 
Exclusion Criteria  
Participants are excluded from the study if any of the following criteria apply: 
Medical Conditions 
1. Participants diagnosed with progressive MS, in accordance with the 2017 Revised McDonald 
criteria, as follows: 
o Participants with primary progressive MS. 
o Participants with SPMS without evidence of relapse. 
2. Disease duration > 10 years in participants with an EDSS ≤ 2.0 at Screening and Baseline (Day 
1). 
3. Immunologic disorder other than MS or any other condition requiring oral, IV, intramuscular, 
or intra-articular corticosteroid therapy, with the exception of well-controlled Type 2 diabetes 
mellitus or well-controlled thyroid disease. 
4. History or current diagnosis of other neurological disorders that may mimic MS, including but 
not limited to: neuromyelitis optica, transverse myelitis, bilateral optic neuritis of simultaneous 
onset, Lyme disease, HTLV-1-associated myelopathy, untreated vitamin B12 deficiency, 
neurosarcoidosis, cerebrovascular disorders, documented peripheral neuropathy (including 
polyneuropathy or mononeuropathy). 
5. History or current diagnosis of PML. If a brain MRI has findings suggestive of PML, CSF JCV 
PCR should be performed to rule out PML (see Appendix 7). 
6. Active, clinically significant viral, bacterial, or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks 
before or during Screening, or completion of oral anti-infectives within 2 weeks before or 
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during Screening, or a history of recurrent infections (i.e., 3 or more of the same type of 
infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or 
oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not 
be exclusionary. 
7. The participant: 
• Has a history of or current diagnosis of active TB 
OR 
• Is currently undergoing treatment for LTBI 
OR 
• Has an untreated LTBI as determined by documented results within 3 months of the 
Screening Visit of a positive TB skin test with PPD with induration ≥ 5 mm. 
OR 
• Has current household contacts with active TB, unless prophylaxis treatment has been 
completed and documented evidence that household contacts have completed treatment. 
OR 
• Has a positive QuantiFERON-TB test at Screening, unless the participant has completed 
chemoprophylaxis for LTBI (as per applicable local guidelines) prior to the Screening 
Visit.  
Study participants in high TB burden settings (> 100 cases / 100,000 individuals [WHO, 
2020], based on WHO TB database [WHO TB Burden Estimates]) must repeat TB testing 
at least annually at the visits indicated (see Schedule of Activities Section 1.3), using the 
assay that was negative at Screening or a replacement (see Laboratory Manual) (see 
Exclusion Criterion 8). 
In addition, participants can be tested for TB at any time during the study, at the discretion 
of the Investigator. 
Participants with documented completed appropriate LTBI treatment would not be 
excluded and are not required to be tested. 
Note: TB skin test with PPD will not be performed at Screening. Reference to TB skin 
test results above is in reference to a potential participant’s past results.  
8. Individuals with indeterminate or positive QuantiFERON test results felt to represent a false 
positive result by the Investigator, with no clinical features consistent with active TB, may be 
evaluated with T-SPOT.TB at the request of the Investigator. In this case, if the T-SPOT.TB 
is negative, the individual may be enrolled after approval by the study eligibility team. Sites 
that are not able to process T-SPOT.TB please see Section 8 (Retesting before Baseline). 
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9. Individuals with a 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. 
10. Individuals with: 
a 
Elevated transferrin saturation (> 50% transferrin saturation in males; and > 40% 
transferrin saturation in females) AND elevated ferritin levels > 500 μg/L will be 
excluded. 
b 
Highly elevated ferritin levels > 1,000 μg/L (independent of transferrin saturation) will 
also be excluded 
11. Individuals with sickle cell anemia, thalassemia and/or any chronic blood disorder requiring 
blood transfusions will be excluded from the study.  
12. History of splenectomy at any time, or any major surgery within 2 months prior to Screening. 
13. History of myocardial infarction or cerebrovascular event within 6 months prior to Screening, 
or current active angina pectoris, history of or current congestive heart failure New York Heart 
Association (NYHA) Class III or Class IV, uncontrolled seizures (remote infantile febrile 
seizures are not exclusionary), prolonged untreated hypertension (systolic ≥ 160 mm Hg 
and/or diastolic ≥ 100 mm Hg), active gastrointestinal bleeding, or any other significant active 
medical condition in the Investigator’s opinion or Sponsor’s/designee’s opinion. 
14. Participants who have evidence of serious suicide risk including any history of suicidal 
behavior in the last 6 months and/or any suicidal ideation of type 4 or 5 on the C-SSRS in the 
6 months prior to Screening. 
OR 
Are at significant suicide risk, as determined by the Treating Investigator. 
15. An episode of major depression within the last 6 months prior to Screening (clinically stable 
minor depression is not exclusionary). 
16. History of cancer with the following exceptions: 
• A confirmed history of nonmelanoma skin cancer Stage 0 (in situ) or Stage 1, considered 
cured > 5 years is not exclusionary. 
• A history of in situ cervical cancer, considered cured > 5 years, is not exclusionary. 
• A history of Stage I prostate cancer with normal Prostate-Specific Antigen (PSA), 
considered cured for > 5 years, is not exclusionary. 
Any history of cancer not meeting these exceptions is exclusionary. 
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17. On Screening ECG, any abnormality (e.g., uncontrolled second or third degree atrioventricular 
conduction block, ventricular tachyarrhythmias) that in the Investigator’s opinion may impact 
participation in the study. 
18. Any other clinically significant abnormality per Investigator opinion.  
Prior/Concomitant Therapy 
19. Contraindication to teriflunomide or leflunomide or incompatibility with teriflunomide or 
leflunomide use, including: 
a. Hypersensitivity to teriflunomide, or to any excipients. 
b. Hypersensitivity to leflunomide, or to any excipients. 
c. Cessation of teriflunomide therapy due to poor tolerability or safety concerns, 
or suboptimal response. 
20. Injectable (e.g., IV, intramuscular, intra-articular) or oral glucocorticoids, or ACTH (e.g., 
Acthar gel) within 4 weeks prior to randomization (inhaled and topical corticosteroids are 
allowed) (see Section 8). 
21. Treatment with monthly IV methylprednisolone (see Section 6.5.1). 
22. Prior treatment with beta-interferons or glatiramer acetate is not exclusionary, but these 
treatments must be discontinued at least 1 day prior to randomization. 
23. Treatment with dimethyl fumarate, diroximel fumarate, or other approved fumaric acid esters 
within 4 weeks prior to randomization (see also Exclusion Criterion 37). 
24. Treatment with teriflunomide within 4 weeks with an AEP or 14 weeks without the completion 
of an AEP prior to randomization (see Appendix 8 for AEP). Reason for switch from 
teriflunomide could not have been because of efficacy or safety related considerations. See 
also Exclusion Criterion 19. 
25. Any of the following: 
a. Use of lymphocyte trafficking blockers (e.g., natalizumab) within 2 months prior 
to randomization. Patients whose last dose of natalizumab was within 6 months 
prior to randomization should be evaluated to rule out PML (see Appendix 7). 
b. Use of S1P inhibitors (e.g., fingolimod, ozanimod, ponesimod, siponimod) within 
2 months prior to randomization. 
See also Exclusion Criterion 37. 
26. Use of IV immunoglobulin (Ig) or plasmapheresis within 8 weeks prior to randomization. 
27. Treatment with rituximab, ofatumumab, or ocrelizumab. Participants who have received 
1 dose of rituximab, ofatumumab, or ocrelizumab, and reason for treatment discontinuation 
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was not treatment failure, will be eligible to enter the study if the last dose of rituximab or 
ocrelizumab was at least 48 weeks prior to randomization.  
28. Treatment with any of the following: 
a. Mildly to moderately immunosuppressive medications (e.g. azathioprine, 
methotrexate): within 6 months prior to randomization. 
b. Highly immunosuppressive medications (mitoxantrone, cyclophosphamide, 
cladribine): within 2 years prior to randomization. 
c. Alemtuzumab, lymphoid irradiation, bone marrow transplantation, or other 
strongly immunosuppressive treatments (with effects potentially lasting over 6 
months): at any time. 
d. BTK inhibitors (including evobrutinib): at any time. 
29. Concomitant treatment with medications commonly used for symptom management of MS 
patients will be exclusionary as follows: 
a. Participants taking dantrolene are to be excluded. Participants on other 
antispasticity agents can be included if they have been on a stable dose over the 3 
months prior to randomization. 
b. Participants on dalfampridine (Ampyra®) or fampridine can be included only if they 
have been on a stable dose 3 months prior to randomization.  
c. Medications known to lower the seizure threshold are not permitted unless 
reviewed and the eligibility of the participant is confirmed by the Medical Monitor.  
30. [Criterion removed by Amendment 1] 
31. On anticoagulation, or antiplatelet therapy other than daily aspirin for cardioprotection. Fish 
oil supplements must be stopped prior to randomization (first dose). 
32. Participants currently receiving (or unable to stop using prior to receiving the first dose of study 
intervention) potent (strong to moderate) inducers of CYP3A (must stop at least 3 weeks prior), 
medications or herbal supplements known to be potent (strong to moderate) inhibitors of 
CYP3A (must stop at least 1 week prior), or drugs mainly metabolized by CYP3A with a 
narrow therapeutic index (must be stopped at least 1 day prior; see Section 6.5). CYP2C8 
substrates with a narrow therapeutic index must also be stopped at least 1 day prior to 
randomization. 
Note: CYP2B6 substrates with a narrow therapeutic index, as well as substrates of P-gp, BCRP, 
OCT1, MATE1 and/or MATE2K, while not exclusionary, should be administered with 
caution. 
Prior/Concurrent Clinical Study Experience 
33. Participation in any investigational drug study within 6 months or 5 half-lives of the 
investigational drug, whichever is longest, prior to Screening. 
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Diagnostic Assessments 
34. Any of the following:  
a. History of or positive for HIV at Screening. 
b. History of or positive for HCV antibody and/or HCV RNA by PCR at Screening. 
However, if a participant has a history of HCV infection and has completed and 
documented appropriate treatment at least 1 year prior to Screening AND is negative 
for HCV RNA by PCR at Screening, participants will not be excluded from the study. 
Note: All participants found to be positive for anti-HCV antibody at Screening will 
have reflex testing performed for HCV RNA by PCR to assess study eligibility. 
c. Positive for HBsAg at Screening. 
d. For participants who are negative for HBsAg at Screening but are anti-hepatitis B 
surface antibody positive without history of vaccination for Hepatitis B and/or 
anti-hepatitis B core antibody positive with or without history of vaccination for 
Hepatitis B at Screening, reflex testing for HBV DNA by PCR will be performed: 
i. Hepatitis B antibody positive participants who have detectable HBV DNA ≥ 20 
IU/mL are excluded. 
ii. Hepatitis B antibody positive participants who are HBV DNA negative or have 
detectable HBV DNA < 20 IU/mL are not excluded from the study. However, 
these participants will have HBV DNA monitoring by PCR at visits noted in 
the SoA (see Section 1.3). 
35. eGFR < 60 mL/min/1.73 m2 as calculated by the 4-variable Modification of Diet in 
Renal-Disease equation by the central laboratory or any renal condition that would preclude 
the administration of gadolinium (e.g., acute kidney injury). 
36. ALT, AST, and total bilirubin > 1.5 × ULN of laboratory reference range, amylase, or lipase 
> 2 × ULN, or any other clinically significant laboratory abnormality. 
37. Significant 
cytopenia, 
including 
neutrophil 
count 
< 1,500 / mm3, 
platelet 
count 
< 75,000 / mm3, absolute lymphocyte count < 1,000 / mm3, or a white blood cell count 
< 3,500 / mm3. 
Other Exclusions 
38. Any allergy, contraindication, or inability to tolerate teriflunomide or evobrutinib or any of 
their excipients, including lactose, which is an excipient in the oral Study Intervention (e.g., 
evobrutinib tablets, placebo tablets). 
Note: Individuals with acquired lactose intolerance are not excluded but should be aware that 
the oral study intervention contains lactose and should be monitored for gastrointestinal 
symptoms related to the increased consumption of lactose in the study intervention, and made 
aware of the risks. 
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39. Inability to comply with MRI scanning, including contraindications to MRI such as known 
allergy or other contraindications to gadolinium contrast media, claustrophobia, presence of a 
pacemaker, cochlear implants, ferromagnetic devices or clips, intracranial vascular clips, 
insulin pumps, nerve stimulators. 
40. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening. 
41. Regular alcohol consumption within 6 months prior to the study defined as: an average weekly 
intake of > 14 units for males or > 7 units for females. One unit is equivalent to 8 g of alcohol: 
a half pint (~240 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits. 
5.3 
Criteria for Entry into Double-blind Extension Period  
Participants need to be able and willing to provide written informed consent for the DBE period 
before the first procedure in DBE. 
Investigators need to ensure that participant does not fulfill any permanent discontinuation criteria 
(Section 7.1) based on Week 156/EODBTP assessments. 
5.4 
Criteria for Entry into Open-label Extension Period  
5.4.1 
Inclusion Criteria for Open-label Extension Period  
Participants who meet the following entry criteria may participate in the OLE Period: 
1. Complete the DBE period, or are still under study treatment when enrollment into OLE is 
opened – but not into the long-term follow-up study –, and who, in the opinion of the 
Investigator, may benefit from treatment with evobrutinib. 
2. Are able and willing to provide written informed consent for the OLE period (e.g., before the 
first OLE procedure on OLE Day 1) and to comply with the study protocol. 
3. Have documentation of completed AEP (confirmed blood concentration level of < 0.02 µg/mL 
of teriflunomide as per Appendix 8) before Day 1/Baseline visit (applicable to all participants 
previously treated with teriflunomide, or with an unknown exposure status during the DBTP 
and DBE period).  
4. Women of childbearing potential are willing to continue to use the contraceptive methods as 
described in Section 5.1 (Inclusion Criterion 6) and Appendix 3. 
5.4.2 
Exclusion Criteria for Open Label Extension Period  
Participants will be excluded from the OLE if they meet any of the following exclusion criteria at 
the OLE screening (OLE Day 1):  
1. Participants who did not complete study intervention in DBE period. 
2. Treatment with injectable (e.g., IV, intramuscular, intra-articular) or oral glucocorticoids, or 
ACTH (e.g., Acthar gel) within 30 days before OLE Day 1, with the exception of rescue 
treatment for MS relapse specified by the study protocol.  
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3. History of suicidal ideation or an episode of clinically severe depression (as determined by 
the Investigator) within 12 weeks prior to OLE Day 1.  
4. History of abnormal laboratory results that, in the opinion of the Investigator, are indicative 
of a significant cardiac, endocrine, hematologic, immunologic, metabolic urologic, 
pulmonary, gastrointestinal, dermatologic, psychiatric, renal, neurologic (other than MS), 
and/or other major diseases.  
5. Any of the following abnormal blood tests during the DBE period requiring discontinuation 
of study intervention, and/or at End of DBE visit, within a week before OLE Day 1: 
• ALT/serum glutamate pyruvate transaminase > 1.5 × ULN 
• AST/serum glutamic oxaloacetic transaminase > 1.5 × ULN 
• Total Bilirubin > 1.5 × ULN 
• Amylase > 2 × ULN 
• Lipase > 2 × ULN 
6. eGFR < 60 mL/min/1.73 m2 as calculated by the 4-variable Modification of Diet in 
Renal-Disease equation.  
7. Female participants who have a positive pregnancy test result, are pregnant, or are currently 
breast feeding.  
8. Inability to comply with study requirements. 
5.5 
Lifestyle Considerations  
5.5.1 
Meals and Dietary Restrictions  
Refrain from consumption of Seville oranges, grapefruit or grapefruit juice, pomelos, grapefruit 
hybrids, exotic citrus fruits, cranberries, or their juices from 7 days before the start of study 
intervention until after the final dose (see Section 6.5.4). 
5.5.2 
Caffeine, Alcohol, and Tobacco  
During each dosing session, participants will abstain from alcohol for 24 hours before the start of 
dosing until after collection of the final PK and/or PD sample. Due to a potential for additive 
hepatotoxic effects associated with IMPs (teriflunomide and evobrutinib), alcohol consumption 
should be avoided during participation in the study. 
There are no restrictions on caffeine or tobacco intake. 
5.6 
Screen Failures  
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once with approval by the Medical Monitor. The second Screening Period is a new 28-
day Screening Period. This Screening Period may be extended after approval by the Medical 
Monitor (but cannot exceed 12 weeks) for the reasons described in Section 8. Rescreened 
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participants will be assigned a new identification number. See Section 8 for required testing to be 
redone at rescreening. 
6 
Study Intervention(s)  
Study intervention is any investigational intervention(s), marketed product(s), placebo, or medical 
device(s) intended to be administered to a study participant per the study protocol. 
6.1 
Study Intervention(s) Administration  
 
Study 
Intervention 
Name: 
Evobrutinib  
Teriflunomide  
Dose 
Formulation: 
Tablets 
Tablets 
Unit 
Dose 
Strength(s)/ 
Dosage Level(s): 
45 mg (active or placebo)  
14 mg (active or placebo) 
Route 
of 
Administration: 
Oral 
Oral 
Dosing 
Instructions: 
Evobrutinib (or placebo) to be taken 
with a meal twice per day  
Teriflunomide (or placebo) to be 
taken with a meal once per day 
Study intervention should be administered during the study visit on PK 
sampling days; otherwise, study intervention should be self-administered 
at home at a set time. 
Supplier/ 
Manufacturer: 
Evobrutinib and placebo will be 
supplied by the Sponsor. 
Teriflunomide and placebo will be 
supplied by the Sponsor. 
Packaging 
and 
Labeling 
• Evobrutinib active (45 mg): 1 blister contains 30 × 45 mg tablets. Two 
blisters to be packed in one wallet. One wallet is equivalent to a kit. OR 
• Matching placebo to Evobrutinib (45 mg): 1 blister contains 
30 × matching Placebo to 45 mg tablets. Two blisters to be packed in one 
wallet. One wallet is equivalent to a kit.  
• Teriflunomide active (14 mg): 1 blister contains 30 × 14 mg tablets. 
One blister to be packed in one wallet. One wallet is equivalent to a kit. 
OR 
• Matching placebo to Teriflunomide (14 mg): 1 blister contains 
30 × matching Placebo to 14 mg tablets. One blister to be packed in one 
wallet. One wallet is equivalent to a kit. 
Each kit will be packaged and labeled per all applicable regulatory 
requirements and Good Manufacturing Practice Guidelines. 
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6.2 
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability  
Storage 
All study intervention supplied to each site must be stored in their original containers carefully and 
safely. The storage facility at the study site must be locked and temperature controlled. Evobrutinib 
and its placebo must be stored at no more than 30°C (86°F). For teriflunomide and its placebo 
storage conditions, refer to the teriflunomide approved product label.  
In case there has been a temperature deviation at the clinical site, the site must contact the clinical 
research associate without delay for further evaluation and assessment by the designated quality 
assurance personnel at Merck Healthcare KGaA or delegated personnel at the packaging and 
distribution provider. The medication with the temperature excursion should still be stored at the 
required temperature, but quarantined during the investigations and must be appropriately labeled 
as “quarantine storage”. 
Detailed recommendations for the use of teriflunomide are described in the locally approved 
product information (e.g., relevant SmPC or USPI), as appropriate. 
The preparation, handling and storage of the study interventions will be documented in a separate 
Pharmacy Manual. 
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). 
• Upon receipt of the study intervention(s), the Investigator or designee must confirm 
appropriate temperature conditions have been maintained during transit and any 
discrepancies are reported and resolved before use. Also, the responsible person will 
check for accurate delivery. Further guidance and information for study intervention 
accountability are provided in the Pharmacy Manual. 
• Only participants enrolled in the study may receive study intervention(s) and only 
authorized site staff may supply it. All study intervention(s) must be stored in a secure, 
environmentally-controlled, and monitored (manual or automated) area, in accordance 
with the labeled storage conditions, and with access limited to the Investigator and 
authorized site staff. 
• Dispensing will be recorded on the appropriate accountability forms so that accurate 
records will be available for verification at each monitoring visit. 
• Study intervention(s) accountability records at the study site will include the following: 
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). 
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o Dates, quantities, batch numbers, container numbers, expiry dates, and the 
participant numbers. 
• The Investigator site will maintain records, which adequately documents that 
participants were provided the doses specified in this protocol, and all study 
intervention(s) provided were fully reconciled. 
• Unused study intervention(s) must not be discarded or used for any purpose other than 
the present study. No study intervention that is dispensed to a participant may be 
redispensed to a different participant. 
• A Study Monitor will periodically collect the study intervention(s) accountability forms. 
• Further guidance and information for the final disposition of unused study 
intervention(s) are provided in the Pharmacy Manual. 
6.3 
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding  
6.3.1 
Study Intervention Assignment  
Participants will be randomized in a blinded fashion to either evobrutinib or teriflunomide 
treatment in a 1:1 ratio. The randomization will be stratified by 2 factors: region (4 levels: North 
America, Western Europe, Eastern Europe, Rest of World) and Baseline (Day 1) EDSS (2 levels: 
< 4.0, ≥ 4.0). A unique participant identification number, assigned according to the Pharmacy 
Manual, will be used throughout the study. 
 
Study using IWRS 
After confirmation of participant’s eligibility and at the last practical 
moment prior to study intervention administration, participants will 
be centrally allocated to either evobrutinib or teriflunomide in a 1:1 
ratio using an IWRS and per a computer-generated randomization 
list. 
The IWRS will be used to assign unique participant numbers, 
allocate participants to study intervention group at the randomization 
visit, and study intervention to participants at each study intervention 
visit. 
Before the study is initiated, the log in information and directions for 
the IWRS will be provided to each site. The site will contact the 
IWRS prior to starting study intervention administration for each 
participant. 
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6.3.2 
Blinding  
Blinding Method 
• Study intervention assignment will be randomized and blinded. Blinding will be accomplished 
using a double dummy design given the differences in tablet characteristics between the study 
intervention and the active control. 
• Packaging and labeling will be prepared to protect the blinded nature of the study. Study 
interventions will be provided in a manner that participants or Investigator will not be able to 
distinguish active study intervention from placebo. Each kit will be labeled by the manufacturer 
with a unique kit number; labeling will not indicate whether the medication is study intervention 
(evobrutinib/teriflunomide) or placebo. Blinded treatment kit numbers will be obtained through 
the IWRS. 
• The Treating Investigator is a neurologist and will be the only one to discuss signs and 
symptoms with the participant to prevent unblinding of study personnel, based on associated 
clinical signs and symptoms related to study intervention. The Treating Investigator will be 
blinded to study intervention and will be responsible for: 
o Management of the routine neurological care of the participant, including the 
management of background treatment and associated safety monitoring  
o Assessment (including assignment of causality) and treatment of AEs and MS 
relapses  
o Review of hematology and blood chemistry results from the central laboratory to 
assess whether the participant’s study intervention should be discontinued as per 
the criteria detailed in Section 7.1 
o If the Treating Investigator is not able to perform the C-SSRS and/or HRU tasks, 
they can assign these tasks to a non-neurologist delegate (Treating Investigator 
Designee), as long as the delegate is trained and qualified in performing these tasks. 
• The independent Examining Investigator (assessor) (or their Qualified Examining Designee) 
will perform neurological assessments only, will remain blinded to all study interventions 
(evobrutinib and teriflunomide), all other study-related assessments, and to all laboratory results 
throughout the study. 
• The central MRI reader will be blinded to all study interventions (evobrutinib and 
teriflunomide) throughout the study. 
• The participants, site staff, and the Investigator will be blinded to all study interventions 
throughout the DBTP and the DBE periods. 
• The Contract Research Organization and Sponsor will be blinded to all study interventions until 
the database is locked for the PA (see Section 9.4). 
• Importantly, the Treating Investigator (or designee) and the Examining Investigator (or 
designee) cannot perform the same tests. The Treating Investigator (or designee) performs the 
relapse assessments, AEs, monitors the participant, and performs C-SSRS and is not permitted 
to perform the EDSS, T25-FW, 9-HPT, and SDMT, and vice-versa, in order to maintain the 
blind. The Patient Reported Outcomes: PROMIS (physical function and fatigue), EQ-5D-5L 
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and SF-36v2 can be administered by any site personnel. Study participants will be instructed to 
not discuss AEs, signs, and/or symptoms with the independent Examining Investigator 
(assessor) (or designee). 
• The participants, site staff, and the Investigators will remain blinded to all study interventions 
during the Safety Follow-up. 
• The IDMC and supporting independent statistician will be unblinded to treatment, as described 
in the IDMC charter. 
• The bioanalytical monitors and other study team members responsible for analyses of PK will 
be blinded to study treatment codes prior to database lock for the PA. Analytical laboratories 
will be unblinded to study treatment codes to enable sample testing of study intervention prior 
to database lock. The process by which masked participant identifiers will be used to prevent 
linking PK data with other clinical data will be documented.  
• Subject matter experts and other study team members responsible for analyses of PGx will be 
blinded to study treatment codes prior to database lock for the PA. Analytical laboratories may 
be unblinded to study treatment codes to enable study-treatment-specific PGx testing prior to 
database lock for the PA. If study treatment specific PGx testing is performed, the process by 
which masked participant identifiers are used to maintain blinding will be documented.  
• Study intervention 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. 
• All other staff, other than those identified above, will remain blinded to the evobrutinib and 
teriflunomide study interventions. 
• Only when the last participant completes study intervention up to the PA trigger or a maximum 
of 156 weeks, or discontinues study intervention prematurely, the protocol deviations are 
determined, and the database is locked for the PA, will the drug codes be broken and made 
available for the data analysis. At that point, the Contract Research Organization and Sponsor 
study teams will be unblinded to study intervention, while the PI and study personnel remain 
blinded to the study intervention throughout the DBE. 
• All breaks of the study blind must be adequately documented.  
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 must always be the first 
consideration in this decision. The Sponsor must be notified within 24 hours after unblinding. The 
Investigator must provide the Sponsor the reason for unblinding without revealing the study 
intervention, except to the designated global patient safety representative via the Emergency 
Unblinding Notification Form. The date of and reason for unblinding must 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 (Study 
Governance). 
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The Sponsor’s global patient safety department will submit any SUSAR reports to regulatory 
authorities and ethics committees with unblinded information, per applicable regulations. Only 
blinded information will be provided to the study team. 
6.4 
Study Intervention Compliance  
The study intervention will be administered at the site on study visit days as defined in the SoA 
(see Section 1.3). All other administrations of study intervention will be done by the participant or 
participant’s caregiver at home throughout the rest of the study. Participants or participant’s 
caregiver will be asked to record the date and time of dosing and food intake around dosing (food 
intake to be recorded only on the day prior to PK sampling and the day of PK sampling, and around 
the time of the last dose prior to evobrutinib concentration assessment sampling) in a participant 
diary. 
Participants will be instructed to bring all study intervention, including the used packaging/empty 
boxes and all blisters, to each study visit during which IMP is dispensed as indicated in the SoA 
(see Section 1.3), and to allow for the assessment of compliance with study intervention. Prior to 
discharge from each scheduled visit, participants will be given sufficient study intervention for at-
home administration until the next scheduled visit during the Treatment Period. On study visit 
days during which IMP is dispensed as indicated in the SoA (see Section 1.3), the previous week(s) 
study intervention adherence will be documented using pill counts. 
Insufficient compliance with the protocol-specified dosing regimen is defined as receiving < 80% 
of the required number of scheduled doses of IMP. Noncompliance is further addressed in Sections 
7.1 and 8.4. 
6.5 
Concomitant Therapy  
Record in the CRF all concomitant therapies (e.g., medicines or nondrug interventions) used from 
the time the participant signs the informed consent until completion of the study, including any 
changes. For prescription and over-the-counter medicines, vaccines, vitamins, and herbal 
supplements, record the name, reason for use, dates administered, and dosing information. 
Contact the Medical Monitor for any questions on concomitant or prior therapy. 
Treatment for Symptoms of Multiple Sclerosis 
The Treating Investigator should attempt to maintain therapies or treatments for symptoms related 
to MS (e.g., walking ability, spasticity, incontinence, pain, fatigue) reasonably constant throughout 
the study. However, if such therapies need to be added or modified during the study due to changes 
in the participant’s clinical presentation, then this could be done at the discretion of the 
Investigator, with the exception of those treatments listed in Section 6.5.3 (Prohibited 
Medications). Nonetheless, any medications that are considered necessary for the participant’s 
well-being may be given at the discretion of the Investigator. 
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6.5.1 
Rescue Medicine  
Participants who experience a MS relapse during study intervention may receive rescue medication 
pursuant to the following restrictions:  
1. Up to 1 g daily of methylprednisolone administered intravenous (or orally if high-dose oral 
formulation is locally available) for up to 5 consecutive days. Where possible, the use of 
corticosteroids should be avoided in the 3 weeks prior to a scheduled MRI scan. If 
participants receive corticosteroids for a relapse, every effort will be made to obtain the 
scan prior to the first steroid dose if the presteroid scan is within 1 week of the scheduled 
visit. In all instances, the treatment of the relapse per the Investigator’s clinical judgment 
takes priority over the timing of the MRI scan. 
2. Oral tapering of corticosteroid rescue medication is permitted, with a maximum of 15 days 
of tapering allowed. 
3. In the treatment of acute exacerbations of MS, daily intramuscular or subcutaneous doses 
of Acthar gel (or equivalent, where approved), 80-120 units and not exceeding 3 weeks 
may be administered. An additional taper of up to 2 weeks with less frequent dosing 
frequency will be permitted as indicated.  
6.5.2 
Permitted Medicines  
The only permitted medications are the following: 
• Medications required per the medical history that: 
o Are not specifically prohibited by the protocol during the study,  
o Are considered necessary for the participants’ welfare, and  
o Will not interfere with the study intervention  
Medications under the conditions described above may be given at the Investigator’s discretion. 
There are no restrictions on the use of marijuana, where and as permitted by local regulations. 
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. 
However, as this may impact continued participation in the study, the Medical Monitor must be 
informed that prohibited medication was used. 
6.5.3 
Prohibited Medicines  
Medications prohibited before the study are listed in the exclusion criteria (see Section 5.2). 
The following medications and therapies are not permitted during the study and would require 
discontinuation of the study intervention: 
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• Rituximab, ofatumumab, ocrelizumab, and any other B cell depleting therapy, BTK 
inhibitors (excluding evobrutinib), mitoxantrone, or lymphocyte-depleting therapies (e.g., 
alemtuzumab, anti-CD4, cladribine, cyclophosphamide, azathioprine, total body 
irradiation, bone marrow transplantation).  
• Lymphocyte trafficking blockers (e.g., natalizumab, fingolimod, or siponimod).  
• Intravenous Ig therapy and/or plasmapheresis and immunosuppressive treatments (e.g., 
azathioprine, methotrexate).  
• Beta-interferons or glatiramer acetate.  
• Dimethyl fumarate, diroximel fumarate, other approved fumaric acid esters, or 
leflunomide. 
• Dantrolene. Other antispasticity agents are permitted at study entry if the participant has 
been on a stable dose over the 3 months prior to randomization. During the study, 
antispasticity agents can be added and/or the regimen modified based on the Investigator’s 
clinical judgment in order to manage the participant’s symptoms (see Section 6.5). 
• Medications known to lower the seizure threshold should be avoided. If treatment with 
these medications is required, the Investigator must inform the Medical Monitor. 
• Dalfampridine (Ampyra) or fampridine are not permitted during the DBTP and the 
DBE unless the participant has been on a stable dose for 3 months prior to 
randomization due to the possibility of confounding effects on key study measures. 
During the OLE period of the study, initiation of therapy with dalfampridine 
(Ampyra) is allowed if (1) indicated by the Treating Investigator, (2) no 
contraindication as per local label is present and (3) participant has been exposed 
to evobrutinib for at least 3 months. 
• Anticoagulation (e.g., warfarin), fish oil supplements, or antiplatelet therapy other than 
daily aspirin for cardioprotection. 
• CYP2C8 substrates with a narrow therapeutic index must also be stopped at least 1 day 
prior to randomization in the DBTP and should not be administered throughout the DBTP 
as well as the DBE. Only during OLE period of the study, CYP2C8 substrates with a 
narrow therapeutic index are not prohibited if indicated by the treating Investigator (see 
Appendix 11). 
• Medications known to be potent (strong to moderate) inhibitors of CYP3A, potent inducers 
of CYP3A, or drugs mainly metabolized by CYP3A with a narrow therapeutic index. 
Medications known to be CYP2B6 substrates with a narrow therapeutic index, as well as 
substrates of P-gp, BCRP, OCT1, MATE1 and/or MATE2K, while not prohibited, should 
be administered with caution. 
• Cholestyramine and activated charcoal, for use other than for AEP after discontinuation 
(see Appendix 8).  
• Live or live-attenuated vaccines. 
• Biologic therapies for MS are prohibited. Biologic therapies for other indications must be 
discussed with the Medical Monitor as their use may impact continued participation in the 
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study, with the exception of insulin and antibodies used for bone density (e.g., denosumab), 
which are permitted. 
• Systemic corticosteroids (oral, injected, IV) except as described in Section 6.5.1. Topical, 
intranasal, or inhaled corticosteroids are permitted. 
For further information on teriflunomide-related DDI, see Appendix 9 and refer to the locally 
approved product information (e.g., relevant SmPC or USPI). 
6.5.4 
Other Interventions  
Herbal or nutritional supplements (including, but not limited to, St. John’s wort, grapefruit, Seville 
oranges, cranberries, or juices of these fruits) known to be potent inhibitors of CYP3A must be 
stopped at least 1 week prior to randomization. As resveratrol supplements can significantly inhibit 
CYP3A, intake of resveratrol supplements must be limited to no more than 500 mg/day. 
Teriflunomide has additional potential for drug interactions and due to the blinded treatment 
assignment, these should be considered when treating participants. See Appendix 9 for potential 
teriflunomide DDI, as defined in the locally approved product information (e.g., relevant SmPC 
or USPI). 
6.6 
Dose Selection and Modification  
Not applicable. 
6.7 
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 participants with relapsing forms 
of MS. 
6.8 
Special Precautions  
See Section 7.1 for precautions related to abnormal liver function. 
If any of the MRIs of the brain have findings suggestive of PML, CSF JCV PCR should be 
performed to rule out PML, see Appendix 7 for further details. See Section 7.1 for precautions 
related to suspected PML. 
6.9 
Management of Adverse Events of Interest  
Adverse events of special interests are liver AEs (possible drug-induced, non-infectious, 
non-alcoholic, and immune-mediated), infections (serious and opportunistic infections), lipase and 
amylase elevation, and seizure. All serious and nonserious AESIs must be additionally 
documented and reported as specified in Appendix 4. 
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Liver adverse 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.  
Infections 
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 MedDRA 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 CTCAE Grade ≥ 3 or SAEs of infection and 
opportunistic infection are considered as an AESI. 
Amylase and lipase elevations 
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.  
Seizures 
Seizures are more common in patients with MS than in the general population, occurring in 2% to 
3% of MS patients (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. One 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. No event of 
convulsion/seizure was reported in other indications. Evobrutinib has been administered to 
approximately 800 patients with MS, RA and SLE. Moreover, an electroencephalogram study in 
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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. 
7 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal  
7.1 
Discontinuation of Study Intervention  
In rare instances, it may be necessary for a participant to permanently discontinue (definitive 
discontinuation) study intervention. If study intervention is definitively discontinued, the 
participant will remain in the study to be evaluated for the SFU visit. 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 Investigator should discontinue study intervention when a participant meets one of the 
conditions outlined below or if the Investigator believes that it is in the best interest of the 
participant. Due to the prolonged half-life of teriflunomide, and the possibility that the participant 
received teriflunomide, accelerated elimination with cholestyramine, activated charcoal, or as per 
local standard of care may be considered (for more details see Appendix 8). In cases for which 
permanent discontinuation of study intervention is required, no rechallenge will be allowed. 
Liver function test-related monitoring and discontinuation criteria should be based on both central 
and local laboratory assessments depending on availability (i.e. participants should be discontinued 
if central or local laboratory result fulfills related criterion). The final decision should be based on 
the highest reported values (regardless of central or the local lab evaluation). 
Criteria for Permanent Discontinuation of Study Intervention: 
The Investigator should permanently discontinue study intervention upon confirmation of the 
criteria outlined below. 
For laboratory or assessment related criteria: 
• a neutrophil count < 500 / mm3 
• a neutrophil count 500–999 / mm3 with fever 
• platelet count < 25,000 / mm3 
• platelet count 25,000–49,999 / mm3 with bleeding 
• an increase in lipase to > 5 × ULN 
• an increase in amylase to > 5 × ULN 
• an increase in serum creatinine to > 3 × ULN 
• any other laboratory abnormality of clinical significance, with the exception of 
lymphopenia (see below) 
• QTcF > 500 msec OR an increase in QTcF > 60 msec relative to the participant’s 
Baseline ECG (Day 1) is observed and confirmed (with a second ECG). 
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• Detectable HBV DNA ≥ 20 IU/mL. Should this occur, consultations with specialists, 
such as a hepatologist, can be performed at the discretion of the Investigator and the 
Medical Monitor should be informed. In addition, a comprehensive hepatic/autoimmune 
panel is required (see below). 
 
Note: HBV DNA is assessed only in Hepatitis B antibody-positive participants 
during the study (see SoA [Section 1.3] and Exclusion Criterion 34). 
• Confirmed increase of ALT/AST ≥ 5 ULN (without increased bilirubin values). 
• Confirmed increase of total bilirubin > 2 ULN (without increased ALT/AST values). 
For an increase in AST and/or ALT to > 3 × ULN in combination with an increase in bilirubin to 
> 2 × ULN, the study intervention should be permanently discontinued and the Medical Monitor 
informed. In addition, a comprehensive hepatic/autoimmune panel is required (see below). 
For other reasons: 
• Pregnancy. As a pregnant participant may have received teriflunomide and due to the 
prolonged half-life of teriflunomide, an AEP should be performed and a teriflunomide 
level < 0.02 mg/L should be reached (for more details see Appendix 8). 
• Any events that endanger the safety of the participant. 
• Sponsor decision to end clinical study. 
• Adverse events, if discontinuation of study intervention is desired or considered 
necessary by the Investigator and/or participant. 
• Noncompliance regarding study intervention (see Section 6.4). 
• Extended interruption of the study treatment for more than 30 days for any reason, 
except during AEP (between DBE period and OLE period) where a treatment gap over 
30 days is acceptable if approved by the Medical Monitor. 
• Use of prohibited medications, as defined in Section 6.5.3.  
o Note: Any medications that are considered necessary for the participant’s well-being 
may be given at the discretion of the Investigator. However, as this may impact 
continued participation in the study, the Medical Monitor must be informed that 
prohibited medication was used, and a protocol deviation should be documented.  
• Lack of efficacy and/or progression of MS as defined by Investigator judgment or when 
a medication other than permitted medications (as defined in Section 6.5.2) is needed 
for treatment (see above regarding prohibited medications). 
Criteria for Temporary Discontinuation of Study Intervention: 
The Investigator should temporarily discontinue study intervention for the discontinuation criteria 
outlined below, inform the Medical Monitor, and perform confirmatory testing as instructed. 
Depending on the result of the confirmatory test (i.e., performed centrally or locally), the 
Investigator should follow instructions as outlined below, including permanently discontinuing 
study intervention, when indicated. 
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For any study intervention discontinuation related to laboratory or assessment results, the 
participant should be followed with additional testing as needed until a return to within normal 
limits or an acceptable value. In cases for which permanent discontinuation of study intervention 
is required, no rechallenge will be allowed. 
Liver Function Testing criteria: 
• For an increase in AST or ALT to > 3 × to < 5 × ULN, temporarily interrupt the study 
intervention and recheck the value within 72 hours to confirm the reported elevation. 
• If AST and/or ALT > 3 × ULN to < 5 × ULN are confirmed within 72 hours and have 
increased by more than 50% (compared to latest confirmed value), continue interruption 
of the study intervention with an additional recheck in 72 hours later. 
o If rechecked value in the second recheck has decreased to < ULN or < participant’s 
baseline, rechallenge can be considered in the absence of hyperbilirubinemia. 
o In all other cases, permanently discontinue the study intervention and inform the 
Medical Monitor. 
• If AST and/or ALT > 3 × ULN to < 5 × ULN are confirmed within 72 hours and have 
increased by less than 50% (compared to latest confirmed value), continue interruption 
of the study intervention with an additional recheck in 1 week. 
o If rechecked value in the second recheck has decreased to < ULN or < participant’s 
baseline, rechallenge can be considered in the absence of hyperbilirubinemia. 
o In all other cases, permanently discontinue the study intervention and inform the 
Medical Monitor. 
• For an increase in bilirubin of > 1.5 × to ≤ 2 × ULN, temporarily interrupt the study 
intervention and recheck the value within 72 hours to confirm the reported elevation. 
o If the value is still > 1.5 × to ≤ 2 × ULN upon recheck, continue temporary 
interruption of the study intervention with an additional recheck in 1 week. 
o If the value is still > 1.5 × to ≤ 2 × ULN upon second recheck, the study intervention 
should be permanently discontinued and the Medical Monitor informed. 
o If the value has decreased to ≤ 1.5 × ULN, the Investigator may reinitiate study 
intervention (see Section 7.1). 
Any re-challenge associated with LFT elevations should follow the weekly monitoring for 
12 weeks. 
For participants who temporarily or permanently discontinue study intervention because of 
abnormal liver function or detection of HBV DNA (see Exclusion Criterion 34), consultations with 
specialists, such as a hepatologist and liver imaging such as ultrasound are encouraged to exclude 
potential alternative causes of liver injury. In addition, a comprehensive hepatic/autoimmune panel 
is required, including the following (performed by central laboratory, unless otherwise stated): 
• International normalized ratio (INR), partial thromboplastin time, fibrinogen, high sensitivity 
C reactive protein 
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• Anti-Hepatitis A Virus (anti-HAV) IgM, HBsAg, anti-Hepatitis B Core Antigen (antiHBc) 
IgM, anti-HBsAg, anti-HCV (6 weeks or later post-initial LFTs elevation), anti-Hepatitis E 
Virus (anti-HEV) IgG and IgM, antiviral capsid antigen (anti-VCA) IgG and IgM, anti-early 
antigen 
(anti-EA) 
IgG, 
antiEpstein-Barr 
Nuclear 
Antigen 
(anti-EBNA) 
IgG, 
anti-cytomegalovirus (CMV) IgG and IgM, Epstein-Barr virus (EBV) PCR, and CMV PCR 
• HCV RNA by PCR 
• Antinuclear antibody, antismooth muscle antibody, antibody to liver-kidney microsomes 
• Albumin 
• Alkaline phosphatase 
• Ferritin and transferrin saturation 
Focused genetic testing for variants that confer risk for liver diseases and/or drug-related liver 
injury, including but not limited to: testing for variants in the High Iron Fe (human 
hemochromatosis protein;HFE) gene (C282Y, H63D) in the setting of abnormal ferritin/transferrin 
saturation values as defined in Exclusion Criterion 10. 
Other Laboratory Criteria: 
• For a decrease in neutrophil count to 500 to 999 / mm3 without fever, temporarily discontinue 
study intervention and recheck the value within 1 week.  
• If the value is still < 1,000 / mm3 upon retest, permanently discontinue study 
intervention.  
• For an improvement to 1,000 to 1,499 / mm3 upon retest, continue to hold the study 
intervention and recheck the value within 1 week.  
o If a further downward trend is observed, permanently discontinue study 
intervention.  
o If no further downward trend is observed, the Investigator may reinitiate 
study intervention. 
a. If the neutrophil count returns to ≥ 1,500 / mm3 upon retest, the Investigator may 
reinitiate study intervention. 
• For a decrease in neutrophil count to 1,000 to 1,499 / mm3, temporarily discontinue study 
intervention and recheck the value within 1 week.  
• If a downward trend is observed upon retest, permanently discontinue study 
intervention.  
• If no downward trend is observed, the Investigator may reinitiate study intervention. 
• For a decrease in platelet count to 25,000 to 49,999 / mm3 without bleeding, temporarily 
discontinue study intervention and recheck the value within 1 week.  
• If the value is still < 50,000 / mm3 upon retest, permanently discontinue study 
intervention.  
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• For an improvement to 50,000 to 74,999 / mm3 upon retest, continue to hold the study 
intervention and recheck the value within 1 week.  
o If a further downward trend is observed upon retest, permanently 
discontinue study intervention.  
o If no further downward trend is observed, the Investigator may reinitiate 
study intervention. 
• If the platelet count returns to ≥ 75,000 / mm3 upon retest, the Investigator may 
reinitiate study intervention. 
• For a decrease in platelet count to 50,000 to 74,999 / mm3, temporarily discontinue study 
intervention and recheck the value within 1 week.  
• If a downward trend is observed upon retest, permanently discontinue study 
intervention.  
• If no downward trend is observed upon retest, the Investigator may reinitiate study 
intervention. 
• For an increase in amylase to > 2 to 5 × ULN, temporarily discontinue study intervention and 
recheck the value within 72 hours of receipt in fasting state (and no later than 1 week).  
• If the value is still > 2 × ULN or higher upon retest, permanently discontinue study 
intervention. 
• If the amylase returns to ≤ 2 × ULN upon retest, the Investigator may reinitiate study 
intervention. 
• For an increase in lipase to > 2 to 5 × ULN, temporarily discontinue study intervention and 
recheck the value within 72 hours of receipt in fasting state (and no later than 1 week).  
• If the value is still > 2 × ULN or higher upon retest, permanently discontinue study 
intervention. 
• If the lipase returns to ≤ 2.0 × ULN upon retest, the Investigator may reinitiate study 
intervention. 
• For any increase in serum creatinine > 1.5 × ULN but ≤ 3 × ULN, temporarily discontinue study 
intervention and recheck the value within 72 hours of receipt (and no later than 1 week).  
• If the value does not decrease upon retest, permanently discontinue study 
intervention 
• If a downward trend is observed, the Investigator may reinitiate study intervention. 
• For an absolute lymphocyte count < 200 / mm3, study intervention should be temporarily 
discontinued, and follow-up testing should be conducted as clinically indicated 
• If the absolute lymphocyte count returns to ≥ 500 / mm3, the Investigator may reinitiate 
study intervention. 
• If there is persistent lymphopenia < 200 / mm3, permanently discontinue study 
intervention. 
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• For any other laboratory increase/decrease (as relevant) from Baseline to a clinically significant 
higher severity grade, temporarily discontinue study intervention and recheck the value within 
72 hours of receipt (and no later than 1 week). The Investigator may reinitiate study intervention 
if an improving trend is observed. 
For other reasons: 
• At the first sign or symptom suggestive of PML, or brain MRI suggestive of PML, temporarily 
discontinue the study intervention and check for CSF JCV PCR (performed by central 
laboratory). If positive, permanently withdraw the study intervention (see Appendix 7). 
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 
Temporary Discontinuation  
See Section 7.1 for specific criteria for temporary discontinuation related to abnormal laboratory 
values. 
7.1.2 
Rechallenge  
See Section 7.1 for specific criteria for rechallenge following temporary discontinuation for 
abnormal laboratory values.  
7.2 
Participant Discontinuation/Withdrawal from the Study  
• A participant may withdraw from the study at any time, at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, 
or administrative reasons. 
• If a participant is permanently withdrawn from study intervention due to stopping rules (see 
Section 7.1), the participant should also be withdrawn from the study. 
• At the time it is determined that a participant is withdrawing from the study, the participant 
should, if possible, return for an Early Discontinuation Visit, 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. 
• Subsequent to the Early Discontinuation Visit, the participant should, if possible, enter the 
4-week Safety Follow-Up Period. At the end of that 4-week period, the participant should 
return for the 4-week Safety Follow-up Visit. After completing this visit, the participant 
would be discontinued from the study. 
• If the participant withdraws consent for future involvement in the study, any data collected 
up to that point may still be used, but no future data can be generated, and any biological 
samples collected will be destroyed. 
• A participant has the right at any time to request destruction of any biological samples taken. 
The Investigator must document this in the site study records. 
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Participants who have discontinued after randomization (e.g., due to AEs or lack of efficacy; see 
Section 7.1) will not be replaced. Participants who discontinue from the study should return for 
the Early Discontinuation Visit and the Safety Follow-up Visit 4 weeks from the day of 
discontinuation of study interventions.  
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 must be taken if a participant fails to return to the clinic for a required study 
visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit schedule, 
and ascertain if the participant wants to or should continue in the study. 
• Before a participant is deemed “lost to follow-up”, the Investigator or designee must make every 
effort to regain contact with the participant: 1) where possible, make 3 telephone calls, 2) if 
necessary, send a certified letter (or an equivalent local method) to the participant’s last known 
mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be documented 
in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have withdrawn 
from the study. 
8 
Study Assessments and Procedures  
• Study assessments and procedures and their timing are summarized in the SoA. 
• No protocol waivers or exemptions are allowed. 
• Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
• All screening evaluations must 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. 
• 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 Study 
Governance. 
• Procedures conducted as part of the participant’s routine medical care (e.g., blood count) and 
obtained before signing of the ICF may be used for screening or Baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA, if reviewed and approved by the Sponsor. 
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The following data will be collected:  
• Demography: date of birth, sex (gender), ethnicity, and race, as permitted by local regulations. 
• Medical history (including diagnosis and duration of MS): previous illness and surgeries (e.g., 
all during the past year and only major ones prior to that), concomitant illness, allergies, prior 
therapies for the target indication and reason for switch (i.e., relevant previous medications), 
therapies stopped or changed at entry into the study (includes use of drugs, alcohol, tobacco, 
and caffeine), special diets and, for women, menstrual status. 
• Participants will be asked to record the following information daily in a paper participant diary:  
• dosing date and time 
• food intake around time of dosing (only on the day prior to PK sampling and the day of PK 
sampling, and around the time of the last dose prior to evobrutinib concentration assessment 
sampling). 
All blood and urine tests will be analyzed by a central laboratory, with the following exceptions: 
• Urine testing for β-human chorionic gonadotropin will be conducted at the local laboratories. 
• Urine dipstick results will be interpreted locally. Urine microscopic examination will be 
conducted centrally. Please see the SoA (see Section 1.3) and Appendix 5 for information 
regarding abnormal dipstick results.  
• PK, PD, and biomarker samples will be analyzed by the analytical laboratories specified by the 
Sponsor. 
• HIV testing should be conducted centrally. Where required by local regulations, can be 
conducted, and analyzed locally. 
• T-SPOT test will be conducted at the local laboratories after an indeterminate or positive 
QuantiFERON test. 
• A standard 12-lead ECG will be performed (see Section 8.2.3).  
Screening 
See the SoA (see Section 1.3) for a list of assessments completed at Screening. 
The Screening packet will be reviewed by the Medical Monitor. See Appendix 2 for further details. 
The Screening Period may be extended after approval by the Medical Monitor (but cannot exceed 
12 weeks) when a laboratory test must be repeated or reflex testing must be performed, an 
unanticipated event occurs, or for participants who have used systemic corticosteroids for their MS 
before Screening. For a participant to be eligible, systemic corticosteroids should not have been 
administered between Screening and Baseline. See Appendix 2 for details of the steps to be 
performed. 
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Accelerated Elimination Procedure (At Screening Visit for OLE only) 
All participants previously treated with teriflunomide, or unknown exposure status during the 
DBTP and DBE period, entering the OLE must undergo an AEP for teriflunomide. The AEP is to 
be initiated at the Screening visit upon signing of ICF and initial screening and completed during 
11 consecutive days preferably within a 30-day period before Day 1 of the OLE (refer to Appendix 
8). If justified for clinical or logistical reasons, an extension of the 30-day period for the AEP 
procedure is possible upon approval by the Medical Monitor. The Investigator should dispense 
cholestyramine or activated charcoal and to instruct participant about proper intake. The blood 
concentration of teriflunomide has to be verified upon completion of the AEP via blood sample 
collection between Day 12 to Day 30 at the central laboratory. The Investigator will remain blinded 
to the teriflunomide levels. Please refer to the study-specific central laboratory manual for detailed 
information on the sampling procedures. The Investigator is responsible to ensure proper and 
timely completion of the AEP and will document completion at the Day 1 visit prior to the IWRS 
call and dispensation of the IMP. 
Retesting before Baseline 
In case the Screening laboratory samples are rejected by the central laboratory or the results are 
not assessable or abnormal, the tests need to be repeated once within 4 weeks. Any abnormal 
Screening laboratory value that is clinically relevant should be retested once in order to rule out 
any progressive or uncontrolled underlying condition. The last value before randomization must 
meet study criteria. In such circumstances, the Screening Period may need to be prolonged after 
approval by the Medical Monitor but should not exceed 12 weeks. 
In the event that an initial ferritin and/or transferrin saturation is abnormal and needs to be repeated, 
consider having participants abstain from iron supplements and vitamin C for 1 week prior to 
retest, and perform the retest as a fasting collection. 
For screen failures, see Section 5.6. 
Rescreening 
Participants who are considered screen failures after a first Screening Period may undergo 
rescreening once, after approval by the Medical Monitor. For those participants, the Screening 
Period for rescreening may be extended after approval by the Medical Monitor (but cannot exceed 
12 weeks) for the reasons described above. If a participant is rescreened, all Screening tests will 
need to be repeated except as follows: 
a. Documented TB testing if occurred within 3 months prior to the rescreening visit. 
b. Hepatitis and HIV testing if occurred within 1 month prior to the rescreening visit. 
Unscheduled Visit 
Participants should be instructed that if, at any point during the study, they suspect that they are 
experiencing new or worsening neurological symptoms, including possible relapse, they should 
contact the Investigator as soon as possible after the onset of symptoms. If necessary, the 
participant should be evaluated by the Treating Investigator and if appropriate, the Examining 
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Investigator (assessor), within the clinic and every effort should be made to complete this 
evaluation within 1 week after the start of symptoms. Any assessments needed to confirm the 
relapse (EDSS) should be performed during the same visit. Details should be documented within 
the relevant section(s) of the eCRF. The definition of a qualifying and nonqualifying relapse is 
provided in Section 8.1.1.1. Once the assessments by the Treating Investigator and the Examining 
Investigator (assessor) are completed, the reported relapse will be adjudicated by the EAC. During 
OLE, the full assessments of relapse should be completed by Treating Investigator also at the same 
visit (neurological exams and EDSS). 
If an MRI scan is indicated at an Unscheduled Visit for Neurological Worsening and Relapse 
Assessment, it should be performed prior to initiating corticosteroid therapy, where possible. In 
addition, care should be taken to avoid the participant being exposed to gadolinium more than once 
in a 4-week period, i.e., it may be necessary to cancel the MRI scan at the next scheduled visit (all 
other assessments should be completed at the visit as normal). If the Unscheduled Visit is 
conducted for a safety concern the assessments described below should be completed and any 
additional assessments and further management will be at the discretion of the Investigator. 
The following will be performed at an Unscheduled Visit: 
• Review of concomitant medications and procedures, evaluation of AEs, disease activity 
assessment (relapse assessment, EDSS), complete physical examination, vital signs, and a 
neurologic exam. 
• Blood sample collection for safety assessments (hematology and biochemistry). 
• Urine collection for urinalysis, and, if necessary, microscopy. 
• Additional assessments can be performed at the discretion of the Investigator. 
Telephone Contact 
If a clinic visit is not scheduled, Telephone contacts will be scheduled with participants as indicated 
in the SoA (Section 1.3). During the Telephone contacts, the following should be discussed with 
the participant:  
• Structured Interview (see Appendix 10) 
• Pregnancy, if applicable, including confirm completion of home pregnancy testing and discuss 
results 
Telephone contacts between D1 and W44 are not expected to occur every 4 weeks, since 
participants are scheduled to be on site at least every 4 weeks. However, if a participant is utilizing 
the home visit option, telephone contacts should occur as indicated in the SoA. 
Telephone contacts between W44 and W156 should occur every 4 weeks if a clinic visit is not 
scheduled. 
Participants experiencing new or worsening neurological symptoms, including possible relapse, 
should be evaluated by the Investigator, if necessary, at an Unscheduled Visit. 
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Double-blind Extension Period 
After completing the DBTP (flexible duration up to 156 weeks) or at the time of PA trigger, all 
participants will be considered treatment completers and offered the opportunity to continue 
treatment assigned at randomization in the DBE. Signed consent will also be obtained prior to 
participation in the DBE period.  
Scheduled assessments will be performed according to the SoA (see Section 1.3.2) before 
administration of study intervention. All scheduled visits during the DBE period may take place 
within the visit windows specified in the SoA. Participants who discontinue early must return for 
the End-of-DBE Visit (Week 96/ED/EODBE). For further details see Sections 1.3.2 and 4. 
Open Label Extension Period 
After completing the DBE period (up to 96 weeks) and if the long-term follow-up study is not yet 
open for enrollment, participants will be considered treatment completers and offered the 
opportunity to continue the treatment with evobrutinib in an OLE period under the current 
protocol. Signed consent will also be obtained prior to participation in the OLE period. 
Scheduled assessments will be performed according to the SoA (see Section 1.3.3) before 
administration of the study intervention. All scheduled visits during the OLE period may take place 
within the visit windows specified in the SoA. Participants who discontinue early must return for 
the OLE End of Treatment Visit (Week 96/ED/EOT). For further details see Sections 1.3.3 and 4. 
8.1 
Efficacy Assessments and Procedures  
8.1.1 
Neurological Assessment  
The Examining Investigator should ideally be a neurologist. However, if a neurologist is not 
available to perform the scope of the Examining Investigator’s tasks, other raters can be considered 
for the study as delegates; the delegate assigned for EDSS must be approved on a case-by-case 
basis by the Sponsor. 
The Examining Investigator (assessor) or Qualified Examining Designee will perform the 
neurological examination, document the FSS, and assess EDSS scores. The Examining 
Investigator (assessor) or Qualified Examining Designee will be also responsible for performing 
and documenting results from: T25-FW, 9-HPT and the SDMT. He or she will have access only 
to data from assessments listed above. The Examining Investigator (assessor) or Qualified 
Examining Designee will not be involved with any aspect of medical management of the 
participant and will not have access to participant data. Every effort will be made to ensure that 
there is no change in the Examining Investigator (assessor) or Qualified Examining Designee 
throughout the course of the study for any individual participant. The Examining Investigator 
(assessor) or Qualified Examining Designee will be trained and instructed not to discuss what 
adverse effects (if any) the participant is experiencing from their medication. The Examining 
Investigator (assessor) or Qualified Examining Designee will receive training in performing EDSS 
assessments prior to the beginning of the study and must have successfully passed an examination 
on performance of the Neurostatus EDSS examination, achieving Level C qualification, within 24 
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months of participation. All Examining Investigators (assessors) and Qualified Examining 
Designees will maintain ongoing training on performance of the Neurostatus EDSS examination 
and must maintain Level C qualification throughout the course of the study. 
Prior to being examined by the Examining Investigator (assessor), Treating Investigator and/or 
study coordinators should remind participants not to discuss what (if any) adverse effects they may 
be experiencing; this should be documented in the source documents. 
During the OLE period, the Investigator or Qualified Examining designee will perform 
neurological examination and assess EDSS scores. The Investigator or Qualified Examining 
designee will be also responsible for performing and documenting results from: Timed 25-foot 
Walk (T25-FW), 9-Hole Peg Test (9-HPT) and the Symbol Digit Modalities Test (SDMT). The 
assessor should ideally be a neurologist. However, if a neurologist is not available to perform the 
task, other site personnel can be considered for the study as Qualified Examining designee. 
The Investigator or Qualified Examining Designee must have successfully passed an examination 
on performance of the Neurostatus EDSS examination, achieving Level C qualification, within 
24 months of participation. All assessors and Qualified Examining Designees will maintain 
ongoing training on performance of the Neurostatus EDSS examination and must maintain Level 
C qualification throughout the course of the study. 
8.1.1.1 
Qualified Relapse  
A qualifying relapse is the occurrence of new or worsening neurological symptoms attributable to 
MS (for > 24 hours, no fever, infection, injury, AEs, and preceded by a stable or improving 
neurological state for ≥ 30 days). The relapse should be accompanied by an increase of ≥ 0.5 
EDSS, or 2 points increase on 1 of the FSS, or 1-point increase on ≥ 2 of the FSS. The increase in 
FSS scores must be related to the neurological symptoms which were reported as new or 
worsening. The change must affect the selected FSS (i.e., pyramidal, cerebellar, brainstem, 
sensory, or visual, excluding cerebral, bladder or bowel). 
Episodic spasms, sexual dysfunction, fatigue, and mood change will not suffice to establish a 
relapse. 
Adjudication of qualified relapses during the DBTP and DBE period (regardless of whether they 
are identified during a scheduled or unscheduled visit) will be performed by the EAC based on 
prespecified criteria, applied to data collected by the Treating and Examining Investigator, in a 
blinded fashion. During the OLE period, relapses will be evaluated, reported, and qualified by the 
Investigator only and no further adjudication via EAC will be performed. Any assessments needed 
to confirm the relapse should be performed, and details of the relapse should be documented within 
the relevant section(s) of the eCRF. The criteria for a qualified relapse should be clear and there 
should be documentation of how each potential relapse did or did not meet the criteria. Participants 
who have a documented relapse during treatment are not required to discontinue study intervention 
unless they meet any of the criteria for discontinuation from the study intervention (see Section 7). 
Relapse assessments may be conducted as phone assessments between study site visits. If 
neurological signs and symptoms are identified that are consistent with relapse, the participant 
should be evaluated on site. 
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The annualized relapse rates up to 156 weeks will be calculated based on qualified relapses. 
8.1.1.2 
Disability Progression and Expanded Disability Status Scale  
Disability progression is defined as an increase of ≥ 1.0 point from the Baseline EDSS score that 
is not attributable to another etiology (e.g., fever, concurrent illness, or concomitant medication) 
when the Baseline score is 5.0 or less and an increase of ≥ 0.5 when the Baseline score is 5.5. 
Disability progression is considered sustained when the initial increase in the EDSS is confirmed 
at a regularly scheduled visit at least 12 weeks or 24 weeks, after the initial documentation of 
neurological worsening. 
CDP, sustained for 12 and 24 weeks after the initial documentation of neurological worsening, 
will be analyzed as secondary endpoints. 
8.1.1.3 
Confirmed Disability Improvement  
Disability improvement will be analyzed only for the subgroup of participants with a Baseline 
EDSS score ≥ 2.0 to ensure relevant baseline disability that is potentially amenable to 
improvement. Disability improvement is defined as a reduction of 1 point from Baseline EDSS 
score when the Baseline score is ≥ 2 and ≤ 6 and a reduction of 0.5 point from Baseline EDSS 
score when the Baseline score is ≥ 6.5 and ≤ 9.5. Disability improvement is considered sustained 
when the initial reduction in the EDSS score is confirmed at a regularly scheduled visit at least 24 
weeks after the initial reduction. 
CDI, sustained for 24 weeks after the initial documentation of neurological improvement, will be 
analyzed as a secondary endpoint. 
8.1.1.4 
Timed Twenty-Five Foot Walk  
The T25-FW is a quantitative mobility and leg function performance test based on a timed 25-foot 
walk. The participant is directed to one end of a clearly marked 25-foot course and is instructed to 
walk 25 feet as quickly as possible, but safely. The time is calculated from the initiation of the 
instruction to start and ends when the participant has reached the 25-foot mark. The task is 
immediately administered again by having the participant walk back the same distance. 
Participants may use assistive devices when doing this task. T25-FW will be administered by the 
Examining Investigator (assessor) or Qualified Examining Designee in DBTP/DBE period and by 
qualified non-blinded site personnel during OLE period. 
A worsening of ≥ 20% is considered to have occurred in this task, when the time it takes to 
complete the task is longer by equal to or more than 20% than the time it took at Baseline. The 
worsening is considered confirmed at 12 weeks if the following assessment (at a scheduled visit 
of 12 weeks or more after the initial observed worsening) confirms it. 
8.1.1.5 
Nine Hole Peg Test  
The 9-HPT is a brief, standardized, quantitative test of upper extremity function. Both the 
dominant and nondominant hands are tested twice. The participant is seated at a table with a small, 
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shallow container holding nine pegs and a wood or plastic block containing nine empty holes. On 
a start command when a stopwatch is started, the participant picks up the nine pegs one at a time 
as quickly as possible, puts them in the nine holes, and, once they are in the holes, removes them 
again as quickly as possible one at a time, replacing them into the shallow container. The total time 
to complete the task is recorded. Two consecutive studies with the dominant hand are immediately 
followed by two consecutive studies with the nondominant hand. 9-HPT will be administered by 
the Examining Investigator (assessor) or Qualified Examining Designee in DBTP/DBE period and 
by qualified non-blinded site personnel during OLE period. 
A worsening of > 20% (either hand) is considered to have occurred in this task, when the time it 
takes to complete the task is longer by equal to or more than 20% than the time it took at Baseline. 
The worsening is considered confirmed at 12 weeks if the following assessment (at a scheduled 
visit of 12 weeks or more after the initial observed worsening) confirms it. 
8.1.1.6 
Symbol Digit Modalities Test  
The SDMT has demonstrated sensitivity in detecting not only the presence of cognitive 
impairment, but also changes in cognitive functioning over time and in response to treatment. The 
SDMT is brief, easy to administer, and involves a simple substitution task that normal children 
and adults can easily perform. Using a reference key, the examinee has 90 seconds to pair specific 
numbers with given geometric figures. Responses will be written and administration time is just 5 
minutes. SDMT will be administered by the Examining Investigator (assessor) or Qualified 
Examining Designee in DBTP/DBE period and by qualified non-blinded site personnel during 
OLE period. 
Two different SDMT forms will be used, administered at alternating visits, to overcome learning 
effects. 
8.1.2 
Brain Magnetic Resonance Imaging Scans  
If a participant discontinues the study more than 4 weeks after his or her most recent MRI, during 
the double-blind, double-dummy phase of the Treatment Period, an MRI may be obtained at the 
Discontinuation Visit. The Screening MRI scan should be acquired before randomization and 
dosing to allow baseline evaluation by the central MRI reader (before randomization). 
Magnetic resonance imaging is a useful tool for monitoring CNS lesions in MS. Various MRI 
derived parameters have been related to disease activity, including T1 weighted 
gadolinium-enhancing (T1 Gd+) lesions and new or enlarging hyperintense T2 (active T2) lesions. 
Other MRI readouts such as chronic T1 hypo-intense lesions are reflective of long-term brain 
damage (black holes). Combined unique active lesions are defined as the sum of new T1 Gd+ 
lesions and active T2 lesions (without double counting). It is hypothesized that changes in brain 
volume may reflect brain atrophy as a result of MS-related tissue loss and may thereby correlate 
with long-term clinical outcome in these participants (De Stefano 2002). 
Brain MRI scans will be performed according to a standardized imaging protocol before and after 
the administration of single-dose gadolinium. Further details, including the scans required and the 
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optimal MRI workflow, will be provided in a separate Imaging Manual that will be provided to 
each study site.  
Images will be assessed by an independent, blinded, centralized MRI reading service, provided by 
NeuroRx Research. The assessment will be performed in the absence of clinical information. At 
the site level, the local radiologist assigned to this study will have access to the MRI scans and 
produces the local reports to inform the Treating Investigator of any noted safety issues. The 
Treating Investigator has access to the Screening (baseline) MRI scan in order to evaluate 
eligibility (see Section 5.1, inclusion criterion 3b) and, during the DBTP and DBE period of the 
study, to local MRI reports only in case of safety-related issues (e.g., non-MS pathologies) to 
preserve the blinding of the data. When assessment of the local MRI report is required for safety 
concerns, a blinded report will be provided to the Treating Investigator by the local radiologist 
containing only non-MS pathology information. In addition, the Treating Investigator may inquire 
about an overall increase in new lesions observed, but this information must not be shared 
proactively or in detail by the local radiologist (such as number, type, or location of MS lesions). 
This inquiry should only occur annually and not more frequently. Overall, the Treating Investigator 
should never have access to the detailed MRI report to preserve the integrity of the study data.  
Independent safety-reads of all MRI scans can be obtained from the local radiology centers. 
In addition, if a scheduled MRI scan is delayed or an unscheduled MRI scan is indicated, care 
should be taken to avoid the participant being exposed to gadolinium more than once in a 4-week 
period, i.e., it may be necessary to cancel the MRI scan at the next scheduled visit (all other 
assessments should be completed at the visit as per schedule). For example, if the next scheduled 
visit is the Week 96, the Week 96 MRI scan should be performed as soon as the 4-week period 
since previous exposure to gadolinium has elapsed. 
Gadolinium will be used to enhance T1-weighted lesions and to optimize clarity and accuracy of 
reporting. As gadolinium is excreted renally, participants with acute renal insufficiency (eGFR 
< 60 mL/min/1.73 m2) will be excluded from the study (see Section 5.2). 
In the OLE period, only those participants who have completed Week 96 and DBTP as well as 
DBE End-of-Treatment MRI assessments will be offered participation in a respective OLE MRI 
substudy. The End-of-DBE MRI will also serve as baseline MRI of the OLE and will require to 
preserve the blinding outlined for the DBTP and DBE period as described in the paragraphs above. 
During the OLE period, the Treating Investigator will have access to the full MRI reports including 
MS pathology (starting with the first MRI assessment in the OLE period at Week 48). Irrespective 
of the MRI substudy, all participants in the OLE period will have access to MRI evaluations for 
safety reasons if indicated by the Investigator. 
8.1.3 
Patient Reported Outcomes  
PRO data will be collected at the study visit with an electronic tablet device at specified study 
visits (see the SoA for details, Section 1.3). The tablet with the PRO instruments will be distributed 
by the Investigator staff and completed in their entirety by the participant. In the event of a tablet 
device not being available, an alternative method of data collection may be used. 
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PROs should be completed prior to administration of study intervention and prior to any other 
study assessment(s) to ensure the validity of the instruments is not compromised, and data quality 
meets requirements of the Guidance for Industry Patient-Reported Outcome Measures: Use in 
Medical Product Development to Support Labeling Claims (Food and Drug Administration 
[FDA] 2009). 
PRO data will be elicited from participants in this study to better characterize the clinical profile 
of evobrutinib. These PRO measurements are described in Section 8.1.3. Please note that the 
methods for collecting and analyzing PRO data are different from those for the ascertainment of 
observed or volunteered AEs. Due to these differences, PRO data will not be reported as AEs and 
no attempt will be made to resolve any noticeable severe symptoms or functional status. 
To ensure missing data are minimized, all participants will be given detailed information and 
training about the nature of the PRO assessments and importance of such information for the study, 
at or prior to study start (based on materials provided).  
Further guidance/information for study sites on procedures for collecting electronic PROs 
(ePROs), as well as strategies to ensure complete and high-quality PRO data will be provided in 
the study manual of operations. 
8.1.3.1 
Patient Reported Outcomes Measurement Information 
System  
The NIH PROMIS comprises an extensive set of item banks and short-form measures created from 
the item banks that assess physical, mental, and social aspects of health in adults and children, 
including symptoms such as pain, fatigue, and sleep disturbance, and health domains such as PF 
(Cella 2007). 
The PROMIS PF item bank was identified as having great potential for the evobrutinib program 
due to several factors, despite limited previous use in MS (Amtmann 2018), and lack of an MS-
specific short form. First, the content includes all key aspects of PF domain, such as IADL, lower 
extremity (mobility), back and neck (central), and upper extremity functioning domains 
(Rose 2014). Second, the development process of PROMIS items included a rigorous development 
and calibration process, ensuring the technical quality of items. Further, items capture the full 
continuum of PF, from low to high levels, which is a useful characteristic for capturing changes 
over time. A short form specific to MS was developed with input from MS patients (n = 57) and 
validated in 2 observational studies. Measures from the PF item bank are scored on a T-score 
metric (higher scores = higher PF). An MID estimate of 2.7 is proposed for worsening PF for the 
PROMISnq PF(MS)15a (Kamudoni 2022). 
The PROMIS Fatigue item bank includes 95 items assessing the experience (frequency, duration, 
and intensity) as well as the impacts of fatigue on physical, mental, and social activities (Lai 2011). 
Psychometric properties of this bank have been established across different clinic populations 
(Cella 2016). An 8-item short-form specific to MS, derived based on input from clinicians (n = 36) 
and participants with MS (n = 48), is available (Cook 2012). This short form was further validated. 
Measures from the fatigue item bank are scored on a T-score metric (higher scores= higher 
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fatigue); An MID estimate of 4 is proposed for minimal improvement and minimal worsening in 
the PROMIS Fatigue (MS) 8a scores (Kamudoni 2021). 
The PROMIS approach offers flexibility in the selection of items and how these are administered, 
including use of bespoke measures, fixed short forms, or computerized adaptive testing. PROMIS 
based short forms for physical functioning and fatigue are currently in preparation for FDA 
qualification as a DDT in MS (MS Working Group, 2018; DDT COA, 2018). 
Physical function deterioration is defined as a reduction in PROMIS PF T-score ≥ 2.7 compared 
to Baseline PROMIS PF T-score sustained for at least 12 weeks. 
8.1.3.2 
Medical Outcomes Study 36-Item Short Form Survey 
Instrument  
The Medical Outcomes SF-36v2 is a 36-item questionnaire that measures 8 areas of participant 
reported health rated from 0 to 100 (McHorney 1992, Ware 1992, McHorney 1993, 
McHorney 1994, and Freeman 2000). The areas are:  
• Physical function 
• Role limitations due to health problems 
• Bodily pain 
• Social functioning 
• General mental health 
• Role limitations due to emotional problems 
• Energy/fatigue 
• General health perceptions 
The instrument will be used to calculate a normalized score for each of the 8 health domain scales, 
a PCS score, and a MSC score, with higher scores indicating better health.  
8.1.3.3 
EuroQoL 5 Dimension 5 Levels  
The EQ-5D is a standardized instrument developed as a measure of health-related quality of life 
that can be used in a wide range of health conditions and treatments. The EQ-5D-5L was 
introduced in 2009 to improve the instrument’s sensitivity and to reduce ceiling effects, as 
compared to the EQ-5D-3L. The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive 
system and the EQ VAS. 
The descriptive system comprises five dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The levels of the five 
dimensions can be combined into a 5-digit number that describes the patient’s health state. 
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EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, may be converted into a 
single health utility index value using country specific value sets. Health utility values facilitate 
the calculation of quality-adjusted life years that are used to inform pharmacoeconomic 
evaluations of health care interventions.  
The EQ VAS records the respondent’s self-rated health on a 20 cm vertical, visual analogue scale 
with endpoints labeled ‘the best health you can imagine’ and ‘the worst health you can imagine’. 
This information can be used as a quantitative measure of health as judged by the individual 
respondents. 
Higher scores on both EQ-5D-5L health utility values and EQ VAS represent a better HRQoL. 
8.1.3.4 
WPAI: MS v2.0 (for OLE Period Only)  
Change in disability, fatigue, cognition, and health related quality of life are known to impact 
physical absence from work (i.e., absenteeism) and reduced productivity while working (i.e., 
presenteeism) and by that cause substantial costs. Work productivity and absenteeism is assessed 
to characterize the associations with disability, fatigue, cognition, and health-related quality of life. 
The Work Productivity and Activity Impairment Questionnaire: Multiple Sclerosis, Version 2.0 
(WPAI: MS v2.0) is a validated and reliable 6-item questionnaire developed to measure the effect 
of multiple sclerosis on the ability to work and perform regular activities during the last seven 
days. The instrument yields four types of scores: 
• Absenteeism (work time missed) 
• Presenteeism (impairment at work / reduced on-the-job effectiveness) 
• Work productivity loss (overall work impairment / absenteeism plus presenteeism) 
• Activity Impairment 
WPAI outcomes are expressed as impairment percentages, with higher numbers indicating greater 
impairment and less productivity, i.e., worse outcomes. 
WPAI:MS v2.0 will be assessed in a subset of participants based on questionnaire availability for 
individual countries and languages. 
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, ECGs, 
and laboratory tests including Ig and subclass concentration.  
Comprehensive assessment of any potential toxicity experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1. 
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8.2.1 
Physical Examinations  
• A complete physical examination will include, at a minimum, assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. 
• Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Any physical exam abnormality findings, which are identified as clinically significant before the 
ICF is signed, will be captured on the Medical History eCRF. After the ICF is signed, any new 
physical exam abnormality findings will be captured on the Adverse Event form. 
8.2.2 
Vital Signs  
• Height at Screening and weight will be measured and recorded. Weight will be measured and 
recorded at each visit where vital signs are recorded as noted in the SoA. 
• Temperature (should be measured at the same location throughout the study), pulse rate, 
respiratory rate, and blood pressure will be assessed. 
• Blood pressure and pulse measurements will be assessed semisupine with a completely 
automated device. Manual techniques will be used only if an automated device is not available. 
• Blood pressure and pulse measurements will be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (e.g., television, cell phones). 
• Vital signs will be measured in a semisupine position after 5 minutes rest and will include 
temperature, systolic and diastolic blood pressure, and pulse and respiratory rate. 
8.2.3 
Electrocardiograms  
• Single 12-lead ECG will be obtained as outlined in the SoA using an ECG machine that 
automatically calculates the HR and measures PR, QRS, and QT intervals and RR duration.  
• The 12-lead ECG recordings will be obtained after 10 minutes of rest in a semisupine position. 
• ECG results will be reviewed locally by the Investigator. In the event of findings that could 
represent clinically relevant cardiac issues (including but not limited to new or worsening 
arrhythmia, significant changes in ECG parameters, signs and/or symptoms that could represent 
cardiac events such as syncope, chest pain, etc.), additional evaluations can be performed per 
the Investigator’s clinical judgment (including but not limited to repeat ECGs, 
echocardiography, evaluation by a cardiologist). The printout of the ECG is to be signed, dated, 
and filed in the Investigator’s Site File along with a signed and dated copy (if the printouts are 
not on archive-quality paper). ECG tracings will be sent to the central reader electronically for 
processing. Final interpretation of ECGs may be made by the central ECG vendor. In addition, 
ECGs will also be stored digitally by the Sponsor. 
• In the OLE period, no ECG evaluation by central reader is required; however, ECGs will also 
be transmitted and stored digitally at the central location.  
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8.2.4 
Clinical Safety Laboratory Assessments  
• Blood and urine samples will be collected for the clinical laboratory tests listed in Appendix 5, 
at the time points listed in the SoA. All samples will be clearly identified.  
• Additional tests may be performed at any time during the study, as determined necessary by the 
Investigator or required by local regulations. 
• The tests will be performed by the central laboratory. See Appendix 5 for exceptions. 
• Local laboratory results are only required when central laboratory results are not available in 
time for study intervention administration and/or response evaluation. If a local sample is 
required, it is important that the sample for central analysis is obtained at the same time. 
Additionally, if the local laboratory results are used to make a study intervention decision or 
response evaluation, the results must be entered in the CRF. Immunoglobulin levels should not 
be done locally unless clinically indicated, as these results may lead to unblinding (see Section 
8.2.6). 
• The Sponsor will receive a list of the local laboratory normal ranges before shipment of study 
intervention(s). Any changes to the ranges during the study will be forwarded to the Sponsor or 
designated organization. 
• The Investigator will review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports will be filed with the source documents. 
• Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the study has been unblinded. 
• Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at monthly intervals during study intervention administration. 
• Pregnancy testing (serum or highly sensitive urine, as required by local regulations) will be 
conducted at the end of relevant systemic exposure of the study intervention and correspond 
with the time frame for female participant contraception in Section 5.1. 
• Reflex analysis testing for HBV DNA by PCR will be conducted for participants who are anti-
hepatitis B surface antibody positive and/or anti-hepatitis B core antibody positive at Screening 
(see Exclusion Criterion 34). Whole blood samples of approximately 4 mL will be collected at 
the times specified in SoA. 
8.2.5 
Pregnancy  
Pregnancy testing (urine or serum as required by local regulations) should be conducted as 
summarized in the SoA (see Section 1.3) during intervention. 
Urine pregnancy testing will be performed at home or at the site. Urine pregnancy test kits will be 
provided to the participants at site visits. The Investigator and/or delegated site staff will train the 
relevant participants to self-administer the urine pregnancy test, and will contact the participant by 
telephone to confirm completion of urine pregnancy testing and discuss results. 
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8.2.6 
Immunoglobulin levels  
Blood samples for Ig levels (IgM, IgA, IgG, and IgE) will be collected as noted in the SoA (see 
Section 1.3). 
Samples will be analyzed by the central laboratory selected by the Sponsor. Samples will be 
collected, labeled, processed, stored, and shipped according to the instructions in the Laboratory 
Manual. 
Results will not be disclosed to the sites, Sponsor, or representative prior to database lock relative 
to the PA to avoid unblinding. However, the IDMC will have access to these data as applicable. 
8.2.7 
Columbia-Suicide Severity Rating Scale  
The C-SSRS will be used for prospective suicidality assessment. C-SSRS is a tool used to assess 
the lifetime suicidality of a participant and to track suicidal events through the treatment. The 
structured interview prompts recollection of suicidal ideation, including the intensity of the 
ideation, behavior and attempts with actual/potential lethality. 
The scale will be administered by the Treating Investigator (or designee) at the timepoints 
indicated in the SoA (see Section 1.3). The C-SSRS “Screening/Baseline” will be collected at 
Screening and Baseline and the C-SSRS “since last visit” will be collected at subsequent visits. 
Participants who answer “yes” to any suicidal behavior questions or to suicidal ideation questions 
4 or 5 on the C-SSRS during the study should be referred for appropriate psychiatric care. The 
decision to discontinue the participant from the study should be taken by the Investigator in 
conjunction with the mental health provider. Any mental health issues considered to be life 
threatening should be recorded as appropriate. 
Please note: assessing the risk of suicide is a difficult and complex task when applied to the 
individual participant. Certainly, no single clinical scale can replace a thorough medical 
examination and suicide risk assessment. Ultimately, the determination of the presence of 
suicidality depends on clinical judgment. 
8.2.8 
Independent Data Monitoring Committee, Hepatology 
Assessment Committee, Endpoint Adjudication Committee, 
and Study Steering Committee  
Independent Data Monitoring Committee 
An IDMC will be formed for this study to monitor interim safety and disease activity data on a 
regular basis to ensure ongoing surveillance of participant safety and to monitor the conduct of the 
study to protect its integrity, including recommendations about additional monitoring measures or 
risk mitigation procedures that may be deemed necessary to protect the study participants. After 
consideration, the Sponsor will inform the IDMC of any decision that will be taken in response to 
the IDMC recommendations. The IDMC will consist of a minimum of at least 3 expert members 
who are independent of the Sponsor. The members will be appointed by the Sponsor based on their 
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expertise in biostatistics, MS, and additional members with expertise in hepatology. All IDMC 
members will have experience in the conduct of clinical studies. Members will not be Investigators 
in the study, nor will they have any conflict of interest with the Sponsor. Sponsor representatives 
and study Investigators are not eligible for membership on the IDMC. Details regarding IDMC 
roles, responsibilities, activities, and possible recommendations will be provided in a separate 
IDMC charter. 
Hepatology Assessment Committee 
A HAC was formed to evaluate cases of possible DILI and to render ongoing opinion on overall 
DILI risk for evobrutinib. The DILI cases are to be suspected if at least one of the following criteria 
are met: 
a.) ALT or/and AST elevations > 8 × ULN;  
b.) ALT or/and AST elevations between > 5 × ULN and ≤ 8 × ULN;  
c.) Total bilirubin > 2 × ULN;  
d.) Total bilirubin > 2 × ULN with ALT or AST > 3 × ULN;  
e.) Acute or chronic hepatic failure, fibrosis, cirrhosis, and other liver damage-related conditions;  
f.) Any other case that might point to suspected DILI, based on Investigator assessment.  
HAC members will review case summaries including but not limited to clinician assessment, IMP 
exposure, laboratory assessments, hepatologist reports, medical history, and prior and concomitant 
medication to evaluate cases of suspected DILI. HAC will make recommendation to escalate cases 
to inform the IDMC and will advise IDMC on whether benefit/risk profile of evobrutinib requires 
changes based on their review. The HAC is composed of external hepatologists with the requisite 
scientific, and medical experience in review of suspected DILI cases. HAC members are 
independent from the Clinical Study Team and the development program team and are blinded to 
treatment assignments. Details regarding HAC roles, responsibilities, activities, and possible 
recommendations will be provided in a separate HAC charter. 
Endpoint Adjudication Committee 
An EAC will be formed for centralized, blinded review and determination of qualified relapses 
during DBTP and DBE (see Section 8.1.1.1). The EAC will be comprised of subject matter experts 
convened for the purpose of ensuring consistency across study sites and to allow for an unbiased 
endpoint assessment. Sponsor representatives and study Investigators are not eligible for 
membership on the EAC. The EAC will be managed by a central vendor; the vendor will be under 
contract to the Sponsor. Specific membership, roles, and responsibilities, required source 
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documentation, data format, details about review process, and procedures and timing of meetings 
will be addressed in a separate EAC charter. 
No EAC will be maintained after the DBTP and DBE have ended as relapses will be qualified by 
Treating Investigators in the OLE period. 
Study Steering Committee 
An SSC will provide direction and oversight to the study from an Investigator’s perspective, 
including protocol creation and amendments, study execution, and evaluation of study results at 
the end of study. Investigators in this clinical study and other experts who are not otherwise 
involved in the study may serve on this committee. 
8.3 
Adverse Events and Serious Adverse Events  
The definitions of an AE and a SAE are in Appendix 4. 
The Investigator and any qualified designees (e.g., Sub-Investigators) are responsible for detecting, 
documenting, and recording events that meet the definition of an AE or SAE. The Investigator 
remains responsible for following up AEs that are serious or that caused the participant to 
discontinue study intervention, as specified in Section 8.3.3. 
Requests for follow-up will usually be made via the Study Monitor, although in exceptional 
circumstances the global patient safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
8.3.1 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information  
The AE reporting period for safety surveillance begins when the participant is initially included in 
the study (date of first signature of informed consent/date of first signature of first informed 
consent) and continues until the Safety Follow-up Visit. 
Any SAE assessed as related to study intervention must be recorded and reported, as indicated in 
Appendix 4, whenever it occurs, irrespective of the time elapsed since the last administration of 
study intervention. 
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are in Appendix 4. 
8.3.2 
Method of Detecting Adverse Events and Serious Adverse 
Events  
At each study visit, the participant will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as AEs, 
regardless if reported by the participant or observed by the Investigator. 
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Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the CRF. 
All SAEs and nonserious AESIs must be additionally documented and reported using the 
appropriate Report Form as specified in Appendix 4. 
8.3.3 
Follow-up of Adverse Events and Serious Adverse Events  
AEs are recorded and assessed continuously throughout the study, as specified in Section 8.3.1 
and are assessed for their outcome at the Safety Follow-up Visit. All SAEs ongoing at the Safety 
Follow-up Visit must be monitored and followed up by the Investigator until stabilization or until 
the outcome is known, unless the participant is documented as “lost to follow-up”. Reasonable 
attempts to obtain this information must be made and documented. It is also the responsibility of 
the Investigator to ensure that any necessary additional therapeutic measures and follow-up 
procedures are performed. Further information on follow-up procedures is given in Appendix 4. 
8.3.4 
Regulatory Reporting Requirements for Serious Adverse 
Events  
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations. 
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the IEC/IRB that approved 
the study. 
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of findings that 
could adversely affect the safety of participants, impact the conduct of the study, or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study. In line with respective regulations, 
the Sponsor/designee will inform the Investigator of AEs that are both serious and unexpected and 
considered to be related to the administered product (“suspected unexpected serious adverse 
reactions” or SUSARs). The Investigator should place copies of Safety Reports in the Investigator 
Site File. National regulations regarding Safety Report notifications to Investigators will be 
considered. 
Individual Case Safety Reports will be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators within 15 days. 
An Investigator or sub-investigator who receives an Individual Case Safety Report describing a 
SUSAR or other specific safety information (e.g., Emerging Safety Issue Report, summary or 
listing of SAEs/SUSARs) from the Sponsor will review the safety reports and confirm completion 
of this review. This information will be filed it in the Investigator’s Site File, and the IRB/IEC will 
be notified, if appropriate, according to applicable local laws/regulations and site Standard 
Operating Procedures. 
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
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regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File. 
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents. 
8.3.5 
Pregnancy  
Details of all pregnancies in female participants and female partners of male participants will be 
collected after the start of study intervention and until the Safety Follow-up Visit. 
If a pregnancy is reported, the Investigator will inform the Sponsor within 24 hours of learning of 
the pregnancy and will follow the procedures specified below for collection of pregnancy 
information. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs. 
Collection of Pregnancy Information 
Male participants with partners who become pregnant: 
• The Investigator will attempt to collect pregnancy information on any male participant’s female 
partner, who becomes pregnant while the participant is in this study. This applies only to 
participants who receive study intervention. 
• After obtaining signed consent from the pregnant female partner directly, the Investigator will 
record the pregnancy information on the appropriate form and submit it to the Sponsor within 
24 hours of learning of the pregnancy. The female partner will also be followed to determine 
the outcome of the pregnancy. Information on the status of the mother and child will be 
forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks 
following the estimated delivery date. Any termination of the pregnancy will be reported 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant:  
• The Investigator will collect pregnancy information on any female participant who becomes 
pregnant while she is in the study. The initial information will be recorded on the appropriate 
form and submitted to the Sponsor within 24 hours of learning of the pregnancy. 
• The participant will be followed to determine the outcome of the pregnancy. The Investigator 
will collect follow-up information on the participant and the neonate, and the information will 
be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 
weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, 
regardless of fetal status (presence or absence of anomalies) or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
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• A spontaneous abortion (occurring at <22 weeks gestational age) or stillbirth (occurring at >22 
weeks gestational age) is always considered to be an SAE and will be reported as such. 
• Any poststudy pregnancy related SAE considered reasonably related to the study intervention 
by the Investigator will be reported to the Sponsor as specified in Section 8.3.4. While the 
Investigator is not obligated to actively seek this information in former study participants, he or 
she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will discontinue 
study intervention. Participants who intend to become pregnant during the study will also 
discontinue study intervention. As a pregnant participant may have received teriflunomide and 
due to the prolonged half-life of teriflunomide, an AEP should be performed and a teriflunomide 
level < 0.02 mg/L has to be reached (for more details see Appendix 8).  
8.4 
Treatment of Overdose  
For this study, any dose of study intervention greater than the highest total daily dose included in 
the protocol or planned for a participant in the study within a 24-hour time period - 6 hours will be 
considered an overdose. 
The Sponsor does not recommend specific treatment for an overdose if not associated with any 
clinical signs/symptoms, but assistive/supportive measures, as necessary, should be provided. 
However, if there are clinical signs/symptoms then AEP should be performed as described in 
Appendix 8. 
Even if it not associated with an AE or a SAE, any overdose is recorded in the CRF and reported 
to drug safety in an expedited manner. Overdoses are reported on a SAE Report Form, following 
the procedure in Appendix 4, section on Reporting Serious Adverse Events and Adverse Events 
of Special Interest. 
8.5 
Pharmacokinetics  
The following PK parameters will be calculated, when appropriate: 
 
Symbol 
Definition 
AUC 
Area under the plasma concentration-time curve 
CL/f 
The apparent total body clearance of study intervention following extravascular administration 
Cmax 
Maximum evobrutinib concentration  
Vz/f 
The apparent volume of distribution during the terminal phase following extravascular 
administration 
DBTP  
• Whole blood samples of approximately 2 mL will be collected for measurement of plasma 
concentrations of evobrutinib, as specified in the SoA. The actual date and time (24-hour clock 
time) of each sample will be recorded to calculate actual time elapsed since the prior dose 
administration. The sampling timing may be altered during the study based on newly available 
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data (e.g., to obtain data closer to the time of peak plasma concentrations) to ensure appropriate 
monitoring. 
• The exact date/time of sample collection and drug administration must be recorded in the eCRF 
and will be used in the calculation of PK parameters. Time deviations from planned PK 
sampling times will not be considered a protocol deviation provided the exact date/time of 
sample collection and drug administration are recorded in the eCRF. 
• For the PK substudy, participants (N = 75) must meet the inclusion/exclusion criteria as 
described for other study participants and should complete all safety and efficacy activities as 
described for other study participants. For the PK substudy participants, additional whole blood 
samples (37) of approximately 2 mL will be collected for measurement of plasma 
concentrations of evobrutinib, as specified in the SoA. The actual date and time (24-hour clock 
time) of each sample will be recorded to calculate actual time elapsed since the prior dose 
administration.  
• The quantification of evobrutinib in plasma will be performed using a validated assay method. 
Concentrations will be used to evaluate the PK of evobrutinib. 
• Remaining samples collected for analyses of evobrutinib concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
• Details on processes for collection and shipment of these samples are in the Laboratory Manual. 
Retention time and possible analyses of samples after the end of study are specified in the 
respective ICF. 
• Evobrutinib concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. As samples from 
participants randomized to teriflunomide will not be analyzed for plasma concentrations of 
evobrutinib, measurements of evobrutinib concentration will be performed by unblinded 
analysts as detailed in Section 6.3.2. 
• All samples collected for PK, as noted in the SoA, still within the known stability of the 
evobrutinib at the time of receipt by the bioanalytical laboratory will be analyzed. 
DBE and OLE periods 
• No blood samples for PK analysis will be collected from participants enrolled in the DBE and 
OLE periods. 
See Section 9.4.3.1 for further details of the PK analysis. 
8.6 
Pharmacodynamics  
• DBTP PD Substudy - Blood samples will be collected for measurement of BTK Occupancy, 
cellular function, and cytokines (approximately 50 mL per visit) at the time points specified in 
the SoA from participants at selected sites in the DBTP PD substudy (N = 75). Participation in 
the substudy is mandatory (see Section 8.8 for details. 
• Details on processes for collection and shipment of these samples are in the Laboratory Manual. 
The Sponsor will store the samples in a secure storage space with adequate measures to protect 
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confidentiality. Retention time and possible analyses of samples after the end of study are 
specified in the respective ICF. 
8.7 
Pharmacogenetics  
• Where local regulations and IRB/IEC allow, approximately 4 mL blood (total) sample will be 
collected for DNA analysis from consenting participants. Participation in pharmacogenetic 
research is optional. Participants who do not wish to participate in the pharmacogenetic research 
may still participate in the study. 
• If not collected on Day 1 or a redraw is needed, the pharmacogenetic sample may be obtained 
at any other point of time during the study. 
• In the event of DNA extraction failure, a replacement sample for pharmacogenetic testing may 
be requested from the participant. Additional informed consent will not be required to obtain a 
replacement sample. 
• Appendix 6 provides further information on pharmacogenetic research. 
8.8 
Biomarkers  
• Collection of participant samples for biomarker research is also part of this study and is 
governed by the appropriate ICF. 
• DBTP and DBE: The following participant samples for biomarker research are required and 
will be collected from all participants enrolled in the DBTP and DBE. Collection times are 
specified in the SoA: 
• Blood samples will be tested for biomarkers of disease to evaluate disease activity or 
treatment response. 
• Blood samples may be tested for biomarkers of disease to evaluate the exposure-response 
relationship between PD biomarkers. 
• Blood samples may be tested for novel liver function biomarkers (e.g., protein, miRNA, etc.) 
to evaluate their activity with respect to predictivity and sensitivity of the novel biomarkers 
of hepatic function compared to traditional clinical chemistry endpoints. 
• Blood samples may be tested for gene expression/gene products to evaluate disease activity 
or treatment response. 
• Blood samples may be tested for impact on vaccinal responses 
• In addition, participant samples (i.e. blood and PGx) collected may be analyzed for 
biomarkers thought to play a role in pharmacokinetics, safety endpoints, MS disease 
progression, drug response, and treatment efficacy including, specific candidate 
genes/genome-wide analysis for genetic variations. Also, samples may be re-purposed or 
used for future research studies. 
• OLE  
• Blood Biomarker Substudy:  
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o Blood samples for biomarker analyses will be collected in the Blood Biomarker 
Substudy (see Section 8.8.3).  
• Participants’ blood samples collected during the DBTP, DBE and OLE study may be re-
purposed to evaluate safety endpoints, MS disease progression, drug response, treatment 
efficacy, response to prophylactic vaccines, and/or future research, as specified in the ICF. 
• Up to approximately 840 mL total blood will be collected during the DBTP with an additional 
370 mL collected from participants in the PK/PD substudy. For participants in the DBE, up to 
approximately 420 mL of blood will be collected. For participants in the OLE, up to 
approximately 220 mL of blood will be collected, with an additional approximately 80 mL 
collected from participants in the OLE biomarker substudy. Further details are provided in the 
ICF and Laboratory Manual. 
• Details on processes for collection and shipment of DBTP, DBE and OLE samples are in the 
Laboratory Manual. The Sponsor will store the samples in a secure storage space with adequate 
measures to protect confidentiality. Retention time and possible analyses of samples after the 
end of study are specified in the respective ICF.  
8.8.1 
Biomarkers of Disease, Disease Activity and Progression, 
Drug-related Outcomes, and Treatment Response  
DBTP, DBE and OLE Blood Biomarker Substudy - Blood samples will be collected from all 
participants to assess the relationship between candidate disease biomarkers (e.g., cytokines, etc.) 
and disease activity and progression (e.g., NfL), drug-related outcomes (e.g., impact on vaccinal 
responses), and/or treatment response. Samples will be obtained predose as noted in the SoA. 
Biomarkers of disease may be measured at the analytical laboratory selected by the Sponsor using 
an appropriately validated bioanalytical method. 
8.8.1.1 
Neurofilament Light Chain  
Recently, NfL, a critical component of neurons, has been established as a marker of neuronal 
damage and has become a potential biomarker for treatment monitoring in MS. As 1 of 5 
neurofilament proteins, NfL contributes to the structural support of axons, and the maintenance of 
their size, shape, and integrity. Following axonal damage, NfL is released into the CSF and blood. 
In patients with MS, serum NfL concentrations correlate with relapses, disability worsening, MRI 
disease activity and brain volume loss (Kuhle 2016, Kuhle 2017, Disanto 2017, Piehl 2018, 
Novakova 2017, Barro 2018). Recently, the International Progressive MS Alliance received a 
Letter of Support from the US FDA encouraging additional studies evaluating NfL as a 
pharmacodynamic and/or response biomarker in early clinical trials involving patients with 
progressive MS. Consequently, serum NfL concentrations will be assessed in all participants 
enrolled in this study. 
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8.8.1.2 
Novel Liver Function Biomarkers  
DBTP and DBE 
Blood samples will be collected from all study participants enrolled in the DBTP to evaluate the 
relationship of novel biomarkers (e.g., protein, miRNA, etc.) of hepatic function levels compared 
to standard clinical chemistry endpoints during the DBTP. Levels of novel biomarkers of hepatic 
function may be measured using various methods in samples collected from participants at time 
points noted in the SoA.  
Sampling for novel liver function biomarkers is performed in parallel with liver function test (LFT) 
clinical chemistry monitoring. To enable analysis of a variety of biomarkers, samples are needed 
both prior as well as during the occurrence of elevated liver enzymes. Samples will be collected 
from all participants, stored, and a subset may be analyzed retrospectively, as appropriate. In 
addition, samples (both plasma and serum) may be repurposed to evaluate disease activity and 
progression (e.g., NfL), drug-related outcomes (e.g., impact on vaccinal responses), treatment 
responses, role of EBV in MS and/or future research studies. 
8.8.2 
DBTP PD Substudy - Bruton’s Tyrosine Kinase Occupancy, 
Cellular Function, and Cytokines  
BTK occupancy, cellular function (e.g., B cell activation), and cytokines will be measured as part 
of the DBTP PD substudy (described in Section 8.6) in order to confirm the expected occupancy, 
which has been predicted based on data from healthy participants and participants from the 
Phase II RMS study (MS200527_0086) and to further investigate the mechanism of action of 
evobrutinib. This study requires a complete set of samples to be obtained for the data to be 
evaluable. Complete sets of samples will be obtained from participants (N = 75) from selected sites 
which can provide appropriate samples. A larger number of participants may be sampled to 
account for participant drop-outs or the collection of incomplete sets of samples. 
Samples (predose) will be collected as noted on the SoA. One sample will be collected at Screening 
for assay performance verification. 
Samples may be analyzed by the analytical laboratory selected by the Sponsor using an 
appropriately validated bioanalytical method. 
8.8.3 
OLE Blood Biomarker PD Substudy – Biomarkers of Disease 
Activity, Progression and Response to Drug  
OLE - Blood samples will be collected from a subset of participants to evaluate the effect of 
extended evobrutinib treatment on biomarkers associated with disease progression (e.g., NfL), 
disease activity, drug-related outcomes (e.g., immune cell frequencies [TBNK assay] and Ig 
levels), candidate disease biomarkers (e.g., cytokines), and/or treatment responses. Samples will 
be obtained from participants (N = ~750; ~50% anticipated to be treated with evobrutinib and 
~50% with teriflunomide throughout the DBE at selected sites and participants will be selected in 
a blinded fashion. Due to the limited stability windows of the TBNK and Ig assays, the samples 
analyses will be performed before the study is unblinded. However, study team members will 
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remain blinded to any results and not view the data until the study is unblinded. Assays involving 
biomarkers of disease will only be performed after the study is unblinded.  
Participation in the OLE Blood Biomarker Substudy for biomarker research is optional. 
Participants who do not wish to participate in the biomarker research portion (i.e., blood sample 
collection) of the study may still participate in the MRI substudy.  
The following samples for biomarker research will be collected from a subset of participants. 
Collection times are specified in the SoA: 
• Blood samples will be tested for biomarkers of disease to evaluate disease activity or treatment 
response. (e.g., NfL). 
• Blood samples will be tested for immune cell frequencies (e.g., T cells, B cells and NK cells). 
• Blood samples will be tested for Ig levels (IgM, IgA, IgG, and IgE). 
• In addition, participants' samples may be repurposed to evaluate drug-related outcomes, 
treatment responses, role of EBV in MS, and/or for future research, as specified in the ICF. 
Samples (predose) will be collected as noted on the SoA (see Section 1.3).  
Samples will be analyzed by an analytical laboratory selected by the Sponsor using an 
appropriately validated bioanalytical method. 
For details describing the MRI substudy, please refer to Section 8.1.2  
8.8.4 
Gene Expression  
DBTP and DBE 
Blood samples for gene expression analysis will be collected, except from participants in countries 
where collection of samples is not allowed, predose at time points noted in the SoA from all 
participants enrolled in the DBTP. These samples should be obtained after the assessment of vital 
signs in all participants (where allowed by local regulations). The actual date and time of each 
sample will be recorded. Samples may be analyzed by an analytical laboratory selected by the 
Sponsor using an appropriately validated bioanalytical method. The purpose of this analysis is to 
test whether potential differences in expression of specific genes may be linked to PK, safety 
endpoints, drug response, and treatment efficacy. 
OLE  
For participants enrolled in the OLE, blood samples for gene expression analysis will not be 
collected. 
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8.9 
Health Resource Utilization  
Health resource utilization data, associated with medical encounters, will be collected by the 
Treating Investigator and study-site personnel for all participants throughout the study. Protocol-
mandated procedures, tests, and encounters are excluded.  
The data collected may be used to conduct exploratory economic analyses and will include: 
number of unplanned doctor/home/emergency visits, number of hospitalizations, paid assistance, 
and number of missed work days. 
8.10 
Immunogenicity Assessments  
Not applicable. 
9 
Statistical Considerations  
9.1 
Statistical Hypotheses  
9.1.1 
Statistical Hypotheses Related to Primary Objective  
The primary endpoint, ARR based on up to 156 weeks of follow-up and qualified relapse events 
from participants enrolled in the present study, will be assessed for superiority via a 1-sided test 
of the null hypothesis H0: rRR ≥ 1, where rRR denotes qualified relapse rate ratio comparing 
evobrutinib to teriflunomide. The alternative hypothesis is H1: rRR < 1. The rRR effect measure 
will be estimated from a NB model for qualified relapse count that adjusts for covariates based on 
stratification factors.  
9.1.2 
Statistical Hypotheses Related to Secondary Objectives  
There are 6 efficacy secondary endpoints and 2 HRQoL secondary endpoints:  
• time to first occurrence of 12-week CDP based on up to 156 weeks of follow-up (pooled) 
• time to first occurrence of 24-week CDP based on up to 156 weeks of follow-up (pooled) 
• time to first occurrence of 24-week CDI based on up to 156 weeks of follow-up (pooled) 
• CFB in PROMIS PF score over 96 weeks (pooled) 
• CFB in PROMIS Fatigue score over 96 weeks (pooled) 
• total number of T1 Gd+ lesions based on all available MRI scans  
• number of new or enlarging T2 lesions on the last available MRI scan relative to the baseline 
MRI scan  
• NfL concentration level at Week 12. 
The secondary endpoint, time to 12-week CDP (pooled), will be assessed for superiority via a 1-
sided stratified logrank test of the null hypothesis H0: Se(t) ≤ Sc(t), where Se(t) denotes the survival 
function for time to 12-week CDP in the experimental (evobrutinib) group, Sc(t) denotes the 
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survival function for time to 12-week CDP in the control (teriflunomide) group, and the variable t 
denotes time since randomization. The alternative hypothesis is H1: Se(t) > Sc(t). Strata in the 
logrank test will be based on randomization strata and study ID. The secondary endpoint time to 
24-week CDP (pooled) will be analyzed similarly, with a similar null hypothesis tested. 
The secondary endpoint, time to 24-week CDI (pooled), will be assessed for superiority via a 1-
sided stratified logrank test of the null hypothesis H0: Se(t) ≥ Sc(t), evaluated for the participants 
with baseline EDSS ≥ 2.0, where Se(t) denotes the survival function for time to 24-week CDI in 
the experimental (evobrutinib) group, Sc(t) denotes the survival function for time to 24-week CDI 
in the control (teriflunomide) group, and the variable t denotes time since randomization. The 
alternative hypothesis is H1: Se(t) < Sc(t). Strata in the logrank test will be based on randomization 
strata and study ID. 
The secondary endpoint, CFB in PROMIS PF score over 96 weeks (pooled), will be assessed for 
superiority via a 1-sided test of the null hypothesis H0: ΔPF ≤ 0, where ΔPF denotes difference in 
average PROMIS PF score CFB least-squares means, comparing evobrutinib to teriflunomide, 
with average taken over Weeks 72, 84, and 96, based on pooled data (higher score corresponds to 
improved physical function). The alternative hypothesis is H1: ΔPF > 0. Covariates in the model 
used to model CFB will be based on randomization strata and study ID. The secondary endpoint 
CFB in PROMIS Fatigue score over 96 weeks (pooled) will be analyzed similarly, based on the 
null hypothesis H0: ΔFatigue ≥ 0 (higher score corresponds to more fatigue), with the exception that 
the average will be taken over Weeks 48, 60, 72, 84, and 96. 
The secondary endpoint, total number of T1 Gd+ lesions based on all available MRI scans, from 
participants enrolled in the present study, will be assessed for superiority via a 1-sided test of the 
null hypothesis H0: lRR ≥ 1, where lRR denotes lesion rate ratio comparing evobrutinib to 
teriflunomide. The alternative hypothesis is H1: lRR < 1. The lRR effect measure will be estimated 
from a NB model for total number of T1 Gd+ lesions that adjusts for covariates based on 
stratification factors, with offset based on number of available scans.  
The secondary endpoint number of active T2 lesions on the last available MRI scan relative to the 
baseline scan, will be analyzed similarly, with a similar null hypothesis tested, with the exception 
that the offset will be based on the time (in years) between the last available scan and the baseline 
scan. 
The secondary endpoint, NfL concentrations at 12 weeks, will be assessed for superiority via a 1-
sided test of the null hypothesis H0: GMe≤GMc, where GMe denotes the Geometric Mean estimate 
at 12 weeks in the experimental (evobrutinib) group, and GMc denotes the Geometric Mean 
estimate at 12 weeks in in the control (teriflunomide) group. The alternative hypothesis is 
H1: GMe>GMc.  
9.2 
Sample Size Determination  
9.2.1 
Sample Size for Primary Endpoint: ARR  
The sample size is estimated based on the primary endpoint, ARR up to 156 weeks, under the 
assumption that participants are followed for an average of 102 weeks. The ARR at 102 weeks 
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among participants receiving evobrutinib is estimated to be 0.13 (NB dispersion parameter ≈ 2.5), 
as compared with 0.23 (NB dispersion parameter ≈ 2.5) among participants receiving the control 
treatment, teriflunomide. This represents a reduction in qualified relapse rate of 43% due to 
evobrutinib relative to teriflunomide. A 1-sided test of superiority based on the qualified relapse 
rate ratio from a NB model for qualified relapse count, H0: rRR ≥ 1.0, H1: rRR < 1.0, requires an 
evaluable sample size of 359 participants per group, followed for 102 weeks, to provide 90% 
power, assuming a 1-sided significance level of 0.025 for the evobrutinib versus teriflunomide 
comparison. To account for a drop-out rate of 20% over 2 years (i.e., normal drop-out expected in 
an MS trial in the absence of the escalating crisis in Eastern Europe), the enrollment per group is 
targeted to be 449 participants, resulting in a targeted enrollment of 898 participants. 
The assumption for evobrutinib ARR is based on 48-week data from the Phase II study of 
evobrutinib in RMS, in which the highest dose, 75 mg twice daily administered under fasted 
conditions, resulted in an ARR of 0.11 (95% CI: 0.04, 0.25). Due to the wide CI, an estimate of 
0.13 is assumed for evobrutinib in Phase III study powering. The assumption of 0.23 for 
teriflunomide ARR is based on recent Phase III studies (ASCLEPIOS I and II), wherein ARR 
ranged from 0.22 to 0.25 (Hauser 2020). The assumption of 2.5 for the dispersion parameter is 
derived from point and CI estimates for ARR from active treatment groups of recent Phase III 
studies and modeling of relapse data from the Phase II study of evobrutinib. If the distribution of 
relapse count is more disperse than assumed (i.e., dispersion ≈ 3.0 in both groups), the power 
provided by an enrolled sample size of 449 participants per group will be reduced from 90% to 
87.4%. 
The PA is to be triggered when the primary endpoint (ARR) in the present study (i.e., 
MS200527_0080), the primary endpoint in the second Phase III study (i.e., MS200527_0082), and 
the important secondary endpoint (12-week CDP pooled) are adequately powered. The power 
associated with the ARR endpoint depends on the information collected, defined as the reciprocal 
of the variance of the qualified relapse ratio estimate (evobrutinib versus teriflunomide), as in a 
group sequential design. The information for the qualified relapse rate ratio based on a negative 
binomial model (as per Appendix 5 of the ASCLEPIOS I/II protocol, available as Supplementary 
Material to Hauser 2020) is given by: 
Equation 9.2.1: Information I = [1/n {1/(λ1 T) + 1/(λ2 T) + 2 γ}]-1 
where n = evaluable sample size per group, T is the common follow-up time, λ1 is ARR for 
evobrutinib, λ2 is ARR for teriflunomide, and γ is the dispersion parameter (γ > 0). The 
assumptions for this study are n = 359, T = 1.97 years (i.e., average follow-up time of 102 weeks), 
λ1 = 0.13, λ2 = 0.23, and γ = 2.5. When the study has accrued Information I=32.3, the test of the 
qualified relapse rate ratio, comparing evobrutinib to teriflunomide at the 1-sided 0.025 alpha 
level, is powered at 90%.  
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9.2.2 
Sample Size for Secondary Endpoint: 12-week CDP  
A total of 149 events (defined as 12-week CDP) from the pooled studies is required to provide 
71.5% power to detect hazard ratio = 0.66 at the 1-sided significance level of 0.025-0.0252 = 
0.024375 (see Section 9.4.4.3). It is expected that these events will be achieved by following the 
1796 participants for up to 156 weeks, assuming a logrank test, 2-year CDP rate in the 
teriflunomide group of 15% (i.e., teriflunomide hazard rate of 0.0813), and 2-year drop-out rate of 
20%. 
The treatment effect of HR = 0.66 is justified by the assumption that evobrutinib has an impact on 
time to 12-week CDP similar to that of anti-CD20 therapies, and thus the HR reported in 
Hauser 2020, comparing ofatumumab to teriflunomide, applies to the treatment effect of 
evobrutinib relative to teriflunomide. The 2-year CDP rate in the teriflunomide group is also based 
on results reported in Hauser 2020. 
When the pooled studies have accrued 149 12-week CDP events, the test of the hazard ratio, 
comparing evobrutinib to teriflunomide at the 1-sided 0.024375 alpha level, is powered at 71.5%. 
The trial-wise and family-wise type-1 error will be preserved at the 0.025 1-sided level in the 
presence of multiple testing due to multiple endpoints (primary and secondary), as described in 
Section 9.4.4.3.  
Sample size and power calculations for the ARR and 12-week CDP endpoints were performed 
using the East v6.5 package and via simulation in R v.6.3.  
9.2.3 
Sample Size Considerations due to the Currently Escalating 
Crisis in Eastern Europe  
Initial enrollment was closed on 01 October 2021 with 1041 participants enrolled in 
Study MS200527_0080 and 1053 participants enrolled in Study MS200527_0082. These 
enrollment figures exceeded the original planned enrollment of 930 participants per study.  
The currently escalating crisis in Eastern Europe poses a challenge to the successful conduct of the 
MS200527_0080 and MS200527_0082 studies due to the large representation of this region in the 
initial enrollment. In the worst case scenario, all data from participants in the region affected by 
the crisis (Ukraine, Russian Federation, and Belarus) will be unable to be queried for cleaning 
purposes and will be considered unreliable. In that scenario, only 645 participants from 
MS200527_0080 and 487 participants from MS200527_0082 will be included in the PA, reducing 
ARR power from 90% to 77.1% and 65.1%, respectively.  
The study design introduced in Protocol Version 4.0 (i.e., variable treatment duration) decreased 
the required participants per study from 930 to 898. To ensure preservation of 90% power for the 
ARR per study, such that up to 898 participants per study have data sufficiently robust for the PA, 
enrollment will be re-opened. Up to 253 participants for MS200527_0080 and up to 
411 participants for MS200527_0082 will be recruited due to the impact on data quality of 
participants in the above mentioned regions. Participants that are in screening at the time when 
sufficient participant numbers have already been reached will still be allowed to be enrolled in the 
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study. As eligibility criteria are identical between initial and reopened enrollment periods, the 
newly enrolled participants are not expected to significantly impact key baseline and disease 
characteristics of the overall study population. 
Based on simulations that take a more precise approach to modeling dropout, the ARR for each 
study will be powered at 90% for a sample size of 887-909. Thus, under the worst-case scenario, 
the number of participants recruited to Studies MS200527 0080 and 0082 in the second phase of 
enrollment is expected to be 242 to 264 and 400 to 422, respectively. 
Throughout the currently escalating crisis in Eastern Europe, the Sponsor will assess the reliability 
and usability of efficacy and safety data from the affected regions, to determine what fraction, if 
any, of the participants’ data from these countries can robustly contribute to the study objectives 
evaluation and be accepted by Health Authorities. This will determine the extent of additional 
participants to be recruited in each study (i.e., up to 253 participants for Study MS200527_0080 
and up to 411 participants for MS200527_0082). Under the intermediate scenario where data from 
participants randomized in the crisis region are either included fully or censored due to 
unreliability, the final enrollment will be in the range of 1,041 to 1,294 participants for Study 
MS200527_0080 and 1,053 to 1,464 participants for Study MS200527_0082, where the lower 
limit of the range is the actual enrollment at the time of Protocol Version 4.0, and the upper limit 
is the expected enrollment under the worst-case scenario. The intermediate scenario assumes that 
the second phase of enrollment will be halted short of worst-case, based on an evaluation of 
information accrual within data assessed to be reliable. The decision to stop additional recruitment 
prior to reaching the pre-defined cap will be based solely on this assessment, in consultation with 
the study IDMC and Steering Committees. The Sponsor will work closely with the IDMC to 
safeguard the study integrity and the ability to reliably deliver on study objectives. 
9.2.4 
Sample Size of PK/PD Substudy  
Assuming within-participant coefficient of variation (CV) of 22.06% for AUCinf, 23% for AUCall, 
and 39.2% for Cmax, 20 evobrutinib treated participants are required to detect a difference of 
approximately 24% for AUC, and 42% for Cmax, at 80% power, using a 2-sided t-test with 
alpha = 5%. After accounting for 20% drop-out rate, the required sample size for the PK substudy 
is at least 50 participants. To align with the required sample size for the PD substudy, 
75 participants will be selected in a blinded fashion from participating sites. 
Assuming a positive correlation between % BTKO and % B cell activation inhibition at a given 
time point, 30 evobrutinib-treated participants are required to detect a Pearson correlation of 0.45 
at 80% power, using a 1-sided t test with alpha = 5%. Assuming a 19% drop-out (or missing 
sample) rate during the 24-week period over which PD assessments are made, the planned sample 
size for the PD substudy is 75 participants, selected in a blinded fashion from participating sites. 
The assumption on correlation is based on Phase I data in healthy volunteers exposed to one of 3 
evobrutinib regimens (25 mg once daily, 75 mg once daily, or 200 mg once daily), wherein a 
correlation of 0.689 between % BTKO and % B cell activation inhibition was observed at Day 7 
trough (MS200527_0017). 
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9.3 
Populations for Analyses  
The analysis sets for the primary analysis of the DBTP are specified below. The final decision to 
exclude participants from any analysis population will be made during a blinded data review 
meeting prior to database lock for the PA and unblinding. 
Analysis Set 
Description 
Screening (SCR)  
All participants, who provided informed consent, regardless of the participant’s 
randomization and study intervention status in the study. 
Full Analysis Set (FAS) 
All participants who were randomized to study intervention. Participants will be 
analyzed per the intervention group to which they were randomized (i.e., intention-to-
treat principle). This analysis set will be used for sensitivity analyses of efficacy. 
Modified FAS (mFAS) 
All participants in FAS except those participants from Ukraine, Russian Federation, 
and Belarus lacking data robustness. This analysis set will be specified in the IAP prior 
to unblinding and will be used for the PA of efficacy.  
Safety (SAF) 
All participants, who were administered any dose of any study intervention. 
Participants will be analyzed per the actual study intervention they received. This 
analysis set will be used for sensitivity analyses of safety. 
Modified SAF (mSAF) 
All participants in SAF except those participants from Ukraine, Russian Federation, 
and Belarus lacking data robustness. This analysis set will be specified in the IAP prior 
to unblinding and will be used for the PA of safety. 
PK 
All participants who receive at least 1 dose of evobrutinib and have at least 
1 quantifiable evobrutinib plasma concentration at a scheduled PK time point postdose 
without any important deviations or events that may impact the quality of the data or 
alter the evaluation of PK. Participants who receive active control will not be included. 
PD 
All participants who receive at least 1 dose of evobrutinib or active control, have a 
predose assessment, and at least one postdose assessment, without deviations or 
important events affecting PD, and who provide evaluable PD data. Participants will be 
analyzed per the actual study intervention they received. 
Analysis sets for the DBE Period are specified below. 
Analysis Set 
Description 
FAS for DBE 
All participants who enter the DBE period. Participants will be analyzed per the 
intervention group to which they are randomized. 
SAF for DBE 
All participants who enter the DBE period. Participants will be analyzed per the actual 
study intervention they received. 
Analysis sets for the OLE Period are specified below. 
Analysis Set 
Description 
FAS for OLE 
All participants who were administered any dose of any study intervention during the 
OLE period. Analyses will consider participants as treated. 
SAF for OLE 
Same as FAS for OLE 
The following subgroups of the mFAS will be considered for efficacy analyses at PA: 
• Sex, age, region, severity of disease, ethnic origin, prior treatment history (including but not 
limited to type, number, and duration of prior treatments as well as reason for switch), EDSS, 
membership in initial or second recruitment cohort. 
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9.4 
Statistical Analyses  
This section provides a description of the statistical methods to be used to analyze efficacy, safety, 
and other endpoints for the PA. Prior to locking the database, a detailed IAP will be finalized. 
Analyses of DBE and OLE endpoints will be described in separate IAPs. 
Unless otherwise specified, for the PA, the mFAS will be used for all efficacy analyses, PRO 
analyses, and reporting of demographic and Baseline characteristics and the mSAF will be used 
for all safety data reporting. 
For the PA, secondary objectives based on disability progression, disability improvement, and 
patient reported symptoms and functional status will be evaluated based on pooled data from the 
present study and the second Phase III study (i.e., MS200527_0082). 
The PA will be performed on all data until the PA trigger date. 
9.4.1 
Efficacy Analyses  
Endpoint 
Statistical Analysis Methods 
Primary 
ARR up to 156 weeks 
Primary analysis based on NB model of qualified relapse count over 156 
weeks, with terms for intervention group and randomization strata; test 
based on adjusted relapse rate ratio (evobrutinib versus comparator) 
from the model. Estimation of treatment effect (and 95% 2-sided CI) 
based on adjusted relapse rate ratio from NB model. In the PA of ARR, 
missing data assumed to be missing at random, with missing data status 
noninformative for qualified relapse. 
Secondary efficacy and HRQoL  
Time to first occurrence of 12-week 
CDP, Time to first occurrence of 
24-week CDP  
Analyzed for participants pooled from both Phase III studies. Primary 
analysis based on stratified logrank test of distribution of time to CDP 
with strata defined by randomization strata and study ID. Estimation of 
treatment effect (and 95% 2-sided CI) based on hazard ratio from 
stratified Cox model of CDP hazard rate, with terms for intervention 
group, and strata defined by randomization strata and study ID. 
Cumulative distribution function for time to CDP will be estimated via 
Kaplan-Meier method by intervention group. In the PA of time to CDP, 
censoring assumed to be noninformative for CDP. 
Time to first occurrence of 24-week 
CDI  
Analyzed for participants pooled from both Phase III studies who have 
baseline EDSS ≥ 2.0. Primary analysis based on stratified logrank test of 
distribution of time to CDI with strata defined by randomization strata and 
study ID. Estimation of treatment effect (and 95% 2-sided CI) based on 
hazard ratio from stratified Cox model of CDI hazard rate, with terms for 
intervention group, and strata defined by randomization strata and study 
ID. Cumulative distribution function for time to CDI will be estimated via 
Kaplan-Meier method by intervention group. In the PA of time to CDI, 
censoring assumed to be noninformative for CDI. 
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Endpoint 
Statistical Analysis Methods 
CFB in PROMIS PF score over 96 
weeks, CFB in PROMIS Fatigue score 
over 96 weeks 
Analyzed for participants pooled from both Phase III studies. Primary 
analysis based on MMRM where score CFB is modeled, with terms for 
intervention group, visit, intervention group by visit interaction, Baseline 
score, randomization strata, and study ID. Test and treatment effect 
estimator (with 95% 2-sided CI) based on difference (evobrutinib versus 
comparator) in average least-squares means of CFB from the model. 
Average is taken over Weeks 72, 84, 96 for PROMIS PF. Average is 
taken over Weeks 48, 60, 72, 84, 96 for PROMIS Fatigue. Cumulative 
distribution function for average CFB will be estimated by intervention 
group. In the PA of CFB, missing data assumed to be MAR, with missing 
data status noninformative for CFB. 
Total number of T1 Gd+ lesions based 
on all available MRI scans; Number of 
new or enlarging T2 lesions on the last 
available MRI scan relative to the 
baseline MRI scan 
Primary analysis based on NB model of total lesion count, with terms for 
intervention group, Baseline lesion activity, and randomization strata. For 
T1 Gd+ lesions, offset is log number of total available scans. For 
new/enlarging T2 lesions, offset is log of the time between baseline scan 
and last available scan in years. Test and treatment effect estimator (with 
95% 2-sided CI) based on adjusted lesion rate ratio (evobrutinib versus 
comparator) from model. In the PA of lesion rate, missing data assumed 
to be MAR, with missing data status noninformative for lesion count. 
Week 12 NfL concentration 
Primary analysis based on MMRM where the log(NfL concentration) will 
be modeled, with terms for intervention group, visit, intervention group by 
visit interaction, Baseline concentration and randomization strata. Test 
and treatment effect estimator (with 95% 2-sided CI) based on difference 
(evobrutinib versus comparator) in least-squares means of Week 12 from 
the model. In the PA, missing data assumed to be MAR, with missing 
data status noninformative for NfL concentrations. 
Tertiary/Exploratory 
ARR at 48 weeks, ARR at 96 weeks 
Analysis follows that of ARR up to 156 weeks, with only follow-up and 
events up to 48 weeks, or up to 96 weeks, considered. 
Time to first qualified relapse  
Stratified logrank test of distribution of time to event with strata defined 
by randomization strata. Estimation of treatment effect (and 95% 2-sided 
CI) based on hazard ratio from stratified Cox model of event hazard rate. 
Cumulative distribution function will be estimated via Kaplan-Meier 
method by intervention group. Censoring assumed to be noninformative 
for qualified relapse. 
Time to 12-week confirmed disability 
based on composite score; Time to 
≥ 20% increase (confirmed at 12 
weeks) in T25-FW; Time to ≥ 20% 
increase (confirmed at 12 weeks) in 
9-HPT. Time to first occurrence of 12 
week confirmed PF deterioration  
Analyzed for participants pooled from both Phase III studies. Primary 
analysis based on stratified logrank test of distribution of time to event 
with strata defined by randomization strata and study ID. Estimation of 
treatment effect (and 95% 2-sided CI) based on hazard ratio from 
stratified Cox model of 12-week CDP hazard rate, with terms for 
intervention group, and strata defined by randomization strata and study 
ID. Cumulative distribution function will be estimated via Kaplan-Meier 
method by intervention group. Censoring assumed to be noninformative 
for event of interest. 
NfL concentration at Weeks 24, 48, 
and 72 
Analysis follows that of NfL concentration at Week 12 
Relapse-free status at Week 96; 
NEDA-3 at Week 48 or Week 96; NEP 
at Week 48 or Week 96; NEPAD at 
Week 48 or Week 96; T1 Gd+ lesion 
free status at Week 96; new or 
enlarging T2 lesion free status at 
Week 96; CUA lesion free status at 
Week 96 
Proportions within intervention groups compared using CMH χ2 test 
stratified by randomization strata. 
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Endpoint 
Statistical Analysis Methods 
12-week (or 24-week) confirmed 
EDSS progression free status at Week 
96 
Analyzed for participants pooled from both Phase III studies. Proportions 
within intervention groups compared using CMH χ2 test stratified by 
randomization strata and study ID. 
Time to PIRA, Time to PIRMA 
The statistical analysis methods for these exploratory endpoints will be 
specified in the IAP. 
Total number of new T1 hypo-intense 
lesions based on all available MRI 
scans; Total number of CUA lesions 
based on all available MRI scans 
NB model of total lesion count, with terms for intervention group, 
Baseline lesion activity, and randomization strata. Offset is log number of 
total available scans. Estimation of treatment effect (and 95% 2-sided CI) 
based on adjusted lesion rate ratio from NB model. Missing data 
assumed to be MAR, with missing data status noninformative for lesion 
count. 
Change in volume of T1 Gd+ lesions 
from Baseline to Week 96; Change in 
volume of T2 lesions from Baseline to 
Week 96 
MMRM analysis where CFB in cube-rooted volume is modeled, with 
terms for intervention group, visit, intervention group by visit interaction, 
randomization strata, and Baseline value of cube-rooted volume. 
Estimation of treatment effect (and 95% 2-sided CI) based on adjusted 
difference in least-squares means from the model. Missing data 
assumed to be MAR, with missing data status noninformative for CFB. 
Change in normalized T1 intensity 
within pre-existing nonenhancing T2 
weighted lesion volume from Baseline 
to Week 96.  
Hodges-Lehman estimate (and 95% 2-sided CI) of shift in distribution of 
Week 96 normalized T1 intensity CFB between intervention groups and 
Wilcoxon rank sum test, stratified according to randomization strata and 
Baseline T2 lesion volume category (based on tertiles). 
Volume of SELs based on scans at 
Weeks 24, 48, and 96 
Hodges-Lehman estimate (and 95% 2-sided CI) of shift in distribution of 
SEL Volume (detected from BL to Week 96) between intervention groups 
and Wilcoxon rank sum test, stratified according to randomization strata 
and Baseline T2 lesion volume category (based on tertiles). 
Percentage change in BV from Week 
24 to Week 96; Percentage change in 
Thalamic volume from Week 24 to 
Week 96; Percentage change in 
cortical grey matter volume from Week 
24 to Week 96 
MMRM analysis where percentage change from Week 24 is modeled, 
with terms for intervention group, visit, intervention group by visit 
interaction, Week 24 value of volume, and randomization strata. 
Estimation of treatment effect (and 95% 2-sided CI) based on adjusted 
difference in least-squares means from the model. Missing data 
assumed to be MAR, with missing data status noninformative for 
percentage change from Week 24. 
Change in number of PRL at Weeks 
24, 48, and 96 
The statistical analysis methods for this exploratory endpoint will be 
specified in the IAP. 
Change in CBF in NAWM at Weeks 
24, 48, and 96 
The statistical analysis methods for this exploratory endpoint will be 
specified in a separate Statistical Analysis Plan. 
CFB in PROMIS PF score at 
Week 48, Week 96, and Week 144; 
CFB in PROMIS Fatigue score at 
Week 48, Week 96, and Week 144 
Analyzed for participants pooled from both Phase III studies. MMRM 
analysis of CFB at a specific timepoint uses same model as described for 
secondary PROMIS PRO endpoints, with inclusion of terms for additional 
timepoints as needed.  
CFB in SDMT score at Week 48 and 
Week 96; CFB in SF-36v2 score at 
Week 48, , Week 96, and Week 144; 
CFB in EQ-5D-5L score at Week 48, 
Week 96, and Week 144 
Analyzed for participants pooled from both Phase III studies. MMRM 
analysis where CFB is modeled, with terms for intervention group, visit, 
intervention group by visit interaction, Baseline value of endpoint, 
randomization strata, and study ID. Estimation of treatment effect (and 
95% 2-sided CI) based on adjusted difference in least-squares means 
from the model. Missing data assumed to be MAR, with missing data 
status noninformative for CFB. 
12-week and 24-week confirmed 
disability improvement status 
Analyzed for the subgroup of participants from the pooled Phase III 
studies with Baseline EDSS score ≥ 2.0. Participants without confirmed 
disability improvement counted as not improved, independent of follow-
up time. CMH test stratified according to randomization strata and study 
ID. 
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Endpoint 
Statistical Analysis Methods 
Absolute values of HRU endpoints at 
study visit up to 156 weeks, including 
but not limited to doctor/home/ 
emergency visits, hospitalizations, 
paid assistance, and missed work 
days 
Analyzed for participants pooled from both Phase III studies. Descriptive 
statistics (mean, SD, median, minimum/maximum, 25th and 75th 
percentile; 95% CI) at the various time points. 
anti-SARS-CoV-2 antibody levels 
Descriptive statistics for anti-SARS-CoV-2 titers. 
9-HPT = 9-Hole Peg Test, ARR = Annualized Relapse Rate, BV = brain volume, CBF = cerebral blood flow, 
CDP = Confirmed disability progression, CFB = change from Baseline, CMH = Cochran-Mantel-Haenszel, 
CI = confidence interval, CUA = combined unique active, EDSS = Expanded Disability Status Scale, EQ-5D-5L = 
EuroQoL 5 Dimension 5 Levels, Gd = gadolinium, HRQoL = health-related quality of life, HRU = Health Resource 
Utilization, MAR = Missing at Random, MMRM = Mixed Effect model for repeated measures, NB = negative binomial, 
NEDA = No Evidence of Disease Activity, NEPAD = No evidence of progression or active disease, 
NfL = neurofilament light chain, PIRA = Progression independent of Relapse Activity, PIRMA = Progression 
Independent of Relapse and brain MRI activities, PROMIS = Patient Reported Outcomes Measurement Information 
System, SD = standard deviation, SDMT = Symbol Digit Modalities Test, SEL = slowly expanding lesions, SF-36v2 = 
36-Item Short Form Survey Instrument Version 2, T25-FW = Timed 25-Foot Walk. 
9.4.1.1 
Efficacy Analyses Related to Primary Objective  
Per ICH E9(R1), Addendum on Estimands and Sensitivity Analysis in Clinical Trials (November 
2019), the primary estimand targeting the primary objective in this study is defined by the 
following attributes:  
• Variable (endpoint): The primary endpoint is ARR up to 156 weeks. Measurements on the 
participant-level are number of qualified relapses experienced by the participant and follow-up 
time over which those relapses occurred (potentially less than 156 weeks). 
• Treatment: The intervention of interest is evobrutinib 45 mg twice daily for up to 156 weeks 
and the alternative intervention is teriflunomide 14 mg once daily for up to 156 weeks. 
• Population: The population of participants targeted by the clinical question is defined by the 
inclusion/exclusion criteria. 
• Strategies for handling intercurrent events: In the absence of the currently escalating crisis 
in Eastern Europe, the main intercurrent event envisaged is discontinuation of assigned 
treatment. The strategy for dealing with this is Treatment Policy, which requires that the 
qualified relapse count up to 156 weeks post randomization be used, if available, regardless of 
treatment discontinuation. The Compositive Variable strategy is used to handle the intercurrent 
event of death attributable to MS or treatment. The While Alive strategy is used to handle the 
intercurrent event of death unattributable to MS or treatment. The intercurrent event of the crisis 
in Eastern Europe ("Ukraine crisis”) will be handled via the Hypothetical strategy; strategy 
details will be specified in the IAP prior to unblinding and after a careful evaluation of data 
robustness for participants from sites in the region affected by the crisis (Ukraine, Russian 
Federation, and Belarus). 
• Population-level summary: The population-level summary comparing the intervention groups 
is relapse rate ratio, based on an NB model for qualified relapse count, with terms for 
intervention group and randomization strata, with offset equal to log follow-up time (in years) 
over which the qualified relapses experienced by a participant are observed. 
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In accordance with Treatment Policy strategy, for participants discontinuing treatment, any 
qualified relapses occurring through Safety Follow-up will be included in the analysis up to 
156 weeks post randomization. For participants who have not been followed to 156 weeks post 
randomization, the missing data will be assumed to be MAR; treatment discontinuers will be 
assumed to experience relapse through 156 weeks post randomization at the same rate as treatment 
completers within the same intervention group and stratum. This is the assumption underlying the 
rate ratio estimator implemented by the NB model that uses observed relapse events and observed 
follow-up time for each participant, regardless of treatment completer/discontinuer status.  
In accordance with the Composite Variable strategy, for participants experiencing death 
attributable to MS or treatment, the death will be counted as a qualified relapse. In accordance with 
the While Alive strategy, for participants experiencing death unattributable to MS or treatment, 
the death will not be counted as a qualified relapse.  
In accordance with the Hypothetical strategy, for participants from sites in Ukraine, Russian 
Federation, and Belarus, the “Ukraine crisis” intercurrent event will lead to exclusion from the 
mFAS (i.e., hypothetical scenario in which participant was not recruited), or inclusion in the mFAS 
with censoring at the start of the crisis (i.e., hypothetical scenario in which crisis would not occur), 
or inclusion in the mFAS without censoring at the start of crisis, depending on the assessment of 
data robustness. Details of the Hypothetical strategy for handling the intercurrent event of the 
“Ukraine crisis” will be specified in the IAP prior to unblinding.  
The adjusted relapse rate ratio comparing evobrutinib to teriflunomide will be estimated from the 
NB model. The adjusted rate ratio, 95% 2-sided CI, and 1-sided p-value will be reported, together 
with adjusted ARR (and 95% CI) for each intervention group from the model, and unadjusted ARR 
(and 95% CI) for each intervention group estimated nonparametrically. The analysis of ARR will 
be based on data from this study alone.  
Unadjusted ARR up to 156 weeks is calculated by dividing the total number of qualified relapse 
events experienced by all participants in a given group through Week 156 by the person-time (in 
years) observed for those participants through Week 156. 
The covariates defined by randomization strata are region (4 levels: North America, Western 
Europe, Eastern Europe, Rest of World) and Baseline (Day 1) EDSS (2 levels: < 4.0, ≥ 4.0). The 
NB model assumes a common dispersion parameter for all participants, independent of 
intervention group or Baseline covariates. The adjusted relapse rate ratio estimate is given by 
exponentiation of the estimate for the treatment coefficient from the NB model. In the PA, only 
observed events and observation time will be included in the analysis; there will be no imputation 
of events for participants discontinuing study early. 
Sensitivity analyses of the primary estimand for the primary endpoint are specified in 
Section 9.4.1.3. 
The IAP will further specify rates, timings, and potential roles of intercurrent events, strategies for 
handling them, and potential consequences on the analyses and results. 
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9.4.1.2 
Efficacy Analyses Related to Secondary Objectives  
The hypotheses tested in support of secondary efficacy objectives are described, and the 
inheritance of alpha graphically depicted, in Section 9.4.4.3. 
The primary estimands targeting the secondary objectives in this study share some of the attributes 
of the primary estimand in Section 9.4.1.1, such as the treatment comparison attribute, the 
population attribute, and the strategy for dealing with the intercurrent events of treatment 
discontinuation and “Ukraine crisis.” Distinctive attributes of each estimand are described below 
for each secondary endpoint. 
Time to 12-week CDP, Time to 24-week CDP 
For the secondary efficacy endpoint, time to 12-week CDP (CDP based on EDSS), the Treatment 
Policy strategy requires that all EDSS data, up to 156 weeks post randomization, will be used if 
available, regardless of treatment discontinuation. In accordance with Treatment Policy strategy, 
for participants discontinuing treatment, all EDSS data through Safety Follow-up will be included 
in the analysis up to 156 weeks post randomization. The population-level summary comparing the 
intervention groups is 12-week CDP hazard ratio, based on a stratified Cox model for 12-week 
CDP hazard rate, with terms for intervention group, strata defined by randomization strata and 
study ID, and where the data are pooled from the mFAS of the present study and the FAS of the 
second Phase III study.  
Participants who did not experience 12-week CDP by 156 weeks post randomization, by time of 
PA trigger, by time of early study discontinuation, or before being lost to follow-up, will be 
censored at the date of the last EDSS assessment during the 156 weeks post randomization. 
Censoring will be assumed to be noninformative for 12-week CDP, conditional on intervention 
group, randomization stratum, and study ID. This is the assumption underlying the hazard ratio 
estimator implemented by the stratified Cox model that uses observed follow-up time for each 
participant, regardless of treatment completer/discontinuer status, where participants are censored 
for 12-week CDP at the latest EDSS assessment.  
In accordance with the Composite Variable strategy, for participants experiencing death 
attributable to MS or treatment, the death will be counted as 12-week CDP. In accordance with the 
While Alive strategy, for participants experiencing death unattributable to MS or treatment, the 
death will not be counted as 12-week CDP. Details of the Hypothetical strategy for handling the 
intercurrent event of the “Ukraine crisis” will be specified in the IAP prior to unblinding.  
Per Protocol Version 3, prior to the completion of enrollment, an optional IA for BSSR was 
performed based on the secondary efficacy endpoint, time to 12-week CDP, with data pooled 
across the present study and the second Phase III study (see Section 9.4.4.1). Performed in August 
2021, the outcome of this IA for BSSR was a decision to not increase sample size.  
The PA of time to 12-week CDP will report the hazard ratio comparing evobrutinib to 
teriflunomide estimated via a stratified Cox model, 95% 2-sided CI, and 1-sided p-value for the 
stratified logrank test, together with a Kaplan-Meier estimate of cumulative probability of 
experiencing 12-week CDP over time for each intervention group. Prior to pooling, the validity of 
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pooling data across the present study and the second Phase III study will be assessed by reviewing 
consistency of demographics, Baseline characteristics, ARR and 12-week CDP results. 
The secondary endpoint, time to 24-week CDP, will be analyzed in the same manner as that of the 
12-week CDP endpoint. The primary estimand attributes for the time to 24-week CDP endpoint 
are the same as the primary estimand attributes for the time to 12-week CDP endpoint. 
Time to 24-week CDI 
For the secondary efficacy endpoint, time to 24-week CDI (CDI based on EDSS), the Treatment 
Policy strategy requires that all EDSS data, up to 156 weeks post randomization, will be used if 
available, regardless of treatment discontinuation. In accordance with Treatment Policy strategy, 
for participants discontinuing treatment, all EDSS data through Safety Follow-up will be included 
in the analysis up to 156 weeks post randomization. The population-level summary comparing the 
intervention groups is 24-week CDI hazard ratio, based on a stratified Cox model for 24-week CDI 
hazard rate, with terms for intervention group, strata defined by randomization strata and study ID, 
and where the data are pooled from participants in the mFAS of the present study and the mFAS 
of the second Phase III study who have baseline EDSS ≥ 2.0.  
Participants who did not experience 24-week CDI by 156 weeks post randomization, by time of 
PA trigger, by time of early study discontinuation, or before being lost to follow-up, will be 
censored at the date of the last EDSS assessment during the 156 weeks post randomization. 
Censoring will be assumed to be noninformative for 24-week CDI, conditional on intervention 
group, randomization stratum, and study ID. This is the assumption underlying the hazard ratio 
estimator implemented by the stratified Cox model that uses observed follow-up time for each 
participant, regardless of treatment completer/discontinuer status, where participants are censored 
for 24-week CDI at the latest EDSS assessment.  
In accordance with the While Alive strategy, for participants experiencing death (any cause), 
participants will be censored at time of death. Details of the Hypothetical strategy for handling the 
intercurrent event of the “Ukraine crisis” will be specified in the IAP prior to unblinding.  
The PA of time to 24-week CDI will report the hazard ratio comparing evobrutinib to teriflunomide 
estimated via a stratified Cox model, 95% 2-sided CI, and 1-sided p-value for the stratified logrank 
test, together with a Kaplan-Meier estimate of cumulative probability of experiencing 24-week 
CDI over time for each intervention group.  
CFB in PROMIS PF score over 96 weeks, CFB in PROMIS Fatigue score over 96 weeks 
For the secondary efficacy endpoint, CFB in PROMIS PF score over 96 weeks, the Treatment 
Policy strategy requires that the CFB in PROMIS PF score over 96 weeks post randomization be 
used if available, regardless of treatment discontinuation. The population-level summary 
comparing the intervention groups is difference in average least-squares means, based on a 
MMRM for CFB, with average taken over Weeks 72, 84, and 96, where the model includes terms 
for intervention group, visit, intervention group by visit interaction, Baseline score, randomization 
strata, and study ID, and where the data are pooled from the mFAS of the present study and the 
mFAS of the second Phase III study.  
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For participants with missing PROMIS PF data, the missing data will be assumed to be MAR; 
such participants will be assumed to have the same mean PROMIS PF score CFB trajectory 
through 96 weeks as participants with available data within the same intervention group and 
stratum, and having the same Baseline score and study ID. This is the assumption underlying the 
estimator of difference of average least-squares means implemented by the MMRM that uses 
observed score CFB data from each participant, regardless of treatment completer/discontinuer 
status.  
In accordance with the While Alive strategy, for participants experiencing death, all PROMIS PF 
data up to the time of death will be used in the analysis. Details of the Hypothetical strategy for 
handling the intercurrent event of the “Ukraine crisis” will be specified in the IAP prior to 
unblinding. 
The difference (comparing evobrutinib and teriflunomide) in average least-squares mean CFB, 
95% 2-sided CI, and 1-sided p-value will be reported. For each intervention group, the average 
adjusted least-squares mean score CFB and associated 95% 2-sided CI will be reported, as will the 
estimated cumulative distribution function for average score CFB.  
The secondary endpoint, CFB in PROMIS Fatigue score over 96 weeks, will be analyzed in the 
same manner as CFB in PROMIS PF score over 96 weeks, except that the average will be taken 
over Weeks 48, 60, 72, 84, and 96. The primary estimand attributes for these 2 endpoints are the 
same. 
Total number of T1 Gd+ lesions based on all available MRI scans, Number of new or 
enlarging T2 lesions on the last available MRI scan relative to the baseline MRI scan  
For the secondary efficacy endpoint, total number of T1 Gd+ lesions based on all available MRI 
scans, the Treatment Policy strategy requires that the lesion count over all available scans post 
randomization be used, if available, regardless of treatment discontinuation. Offset will be log total 
number of available scans. The population-level summary comparing the intervention groups is 
total lesion rate ratio, based on a NB model for lesion count, with terms for intervention group, 
randomization strata, and Baseline lesion activity, with offset equal to log number of total available 
scans over which the lesions experienced by a participant are observed. 
For participants missing one or more scans, the missing data will be assumed to be MAR; such 
participants will be assumed to experience lesions through planned end of treatment (i.e., PA 
trigger or 156 weeks, whichever occurs first) at the same rate as participants with available data 
within the same intervention group and stratum, and having the same Baseline lesion activity. This 
is the assumption underlying the rate ratio estimator implemented by the NB model that uses 
observed lesion count and number of scans giving rise to that count for each participant, regardless 
of treatment completer/discontinuer status. 
In accordance with the While Alive strategy, for participants experiencing death, all T1 Gd+ lesion 
data up to the time of death will be used in the analysis. Details of the Hypothetical strategy for 
handling the intercurrent event of the “Ukraine crisis” will be specified in the IAP prior to 
unblinding. 
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The adjusted lesion rate ratio comparing evobrutinib to teriflunomide estimated from the NB 
model, 95% 2-sided CI, and 1-sided p-value will be reported, together with adjusted lesion rate for 
each intervention group and associated 95% 2-sided CI. The analysis of total number of T1 Gd+ 
lesions will be based on data from the present study only.  
The secondary endpoint, number of new or enlarging T2 lesions on the last available MRI scan 
relative to the baseline MRI scan, will be analyzed in the same manner as total number of T1 Gd+ 
lesions based on all available MRI scans, except that the offset will be log of time between the 
baseline scan and last available scan (in years). The primary estimand attributes for these two 
endpoints are the same. 
Sensitivity analyses of the primary estimands of the secondary endpoints are specified in 
Section 9.4.1.3. 
Week 12 NfL Concentration 
For the secondary efficacy endpoint, Week 12 NfL concentration, the Treatment Policy strategy 
requires that all values of NfL concentrations be used if available, regardless of treatment 
discontinuation. The population-level summary comparing the intervention groups is difference in 
least-squares means, based on a MMRM for log(NfL concentration), where the model includes 
terms for intervention group, visit, intervention group by visit interaction, Baseline concentration 
and randomization strata.  
For participants with missing NfL concentration data, the missing data will be assumed to be MAR; 
such participants will be assumed to have the same mean NfL concentration trajectory through 
planned end of treatment (i.e., PA trigger or 156 weeks, whichever occurs first) as participants 
with available data within the same intervention group and stratum, and having the same Baseline 
concentration. This is the assumption underlying the estimator of difference of least-squares means 
through Week 12 implemented by the MMRM that uses observed NfL concentration data from 
each participant, regardless of treatment completer/discontinuer status.  
In accordance with the While Alive strategy, for participants experiencing death, all NfL 
concentration data up to the time of death will be used in the analysis. Details of the Hypothetical 
strategy for handling the intercurrent event of the “Ukraine crisis” will be specified in the IAP 
prior to unblinding. 
The difference (comparing evobrutinib and teriflunomide) in least-squares mean, 95% 2-sided CI, 
and 1-sided p-value will be reported. For each intervention group, the adjusted least-squares mean 
at Week 12 and associated 95% 2-sided CI will be reported. 
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9.4.1.3 
Sensitivity Analyses  
The following sensitivity analyses for the primary endpoint ARR up to 156 weeks will be detailed 
in the IAP: 
1. Analysis to evaluate the potential influence of informative treatment discontinuation 
according to discontinuation reason. If a participant’s discontinuation is unrelated to 
treatment (i.e., unrelated to efficacy or safety issues), the participant’s relapse count will 
be multiply imputed using ARR in the comparator group, for the interval between 
discontinuation and planned end of treatment (i.e., PA trigger or 156 weeks post 
randomization, whichever occurs first). If a participant’s discontinuation is related to 
treatment, relapse count will be multiply imputed at a rate higher than ARR in comparator 
group, for the interval between discontinuation and planned end of treatment. 
2. Analysis in which participants who discontinued treatment early during the 
Treatment Period without qualified relapse in the 30 days prior to discontinuation, are 
assumed to have a qualified relapse event at the date of discontinuation. 
3. Analysis in which additional covariates are included in the NB model, such as number of 
relapses occurring within 2 years prior to study entry, Baseline presence/absence of T1 
Gd+ lesions, prior MS treatment, and age, to evaluate the potential impact of model 
misspecification. 
4. Analysis to evaluate the impact of the currently escalating crisis in Eastern Europe. All 
participants in the FAS will be included, with consideration given to including a 
time-dependent covariate indicating whether the participant is under the stress of the crisis, 
which may be associated with increased frequency of relapses. 
For the primary estimand of the secondary endpoint, time to 12-week CDP, it is important to assess 
the sensitivity of results to the assumption that censoring is noninformative for 12-week CDP, 
conditional on intervention group, study ID, and stratum. The following sensitivity analyses for 
the secondary efficacy endpoint time to 12-week CDP will be detailed in the IAP: 
1. Analysis to evaluate the potential influence of informative treatment discontinuation, 
according to discontinuation reason or occurrence of initial progression event at last 
assessment. If a participant’s discontinuation is unrelated to treatment (i.e., unrelated to 
efficacy or safety issues) and no initial progression event occurred, the participant’s time 
to CDP will be multiply imputed using hazard rate in comparator group, for the interval 
between discontinuation and planned end of treatment (i.e., PA trigger or 156 weeks post 
randomization, whichever occurs first). If a participant’s discontinuation is related to 
treatment or an initial unconfirmed progression event occurred, the participant’s time to 
CDP will be multiply imputed using hazard rate higher than that in comparator group, for 
the interval between discontinuation and planned end of treatment. 
2. Analysis in which participants who discontinued treatment early during the 
Treatment Period after having an initial progression event, but prior to 12-week 
confirmation, are assumed to have a 12-week CDP event at the date of initial progression. 
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3. Analysis with additional covariates in the stratified Cox model, such as number of relapses 
occurring within 2 years prior to study entry, Baseline presence/absence of T1 Gd+ lesions, 
prior MS treatment, and age. 
4. Analysis to evaluate the impact of the currently escalating crisis in Eastern Europe. All 
participants in the FAS will be included, with consideration given to including a time-
dependent covariate in the model. 
Sensitivity analyses for time to 24-week CDP will be similar. 
Sensitivity analyses for the secondary endpoint time to 24-week CDI will be specified in the IAP. 
For the primary estimand of the secondary endpoint, PROMIS PF CFB, it is important to assess 
the sensitivity of results to the MAR assumption that participants with missing data have the same 
mean CFB trajectory through 96 weeks or PA trigger, whichever occurs first, as participants with 
complete data, conditional on intervention group, Baseline score, study ID, and stratum. The 
following sensitivity analysis for the secondary endpoint PROMIS PF score CFB over 96 weeks 
will be detailed in the IAP: 
1. Analysis to evaluate the potential influence of informative treatment discontinuation 
according to discontinuation reason. If a participant’s discontinuation is unrelated to 
treatment (i.e., unrelated to efficacy or safety issues), the participant’s score CFB at each 
timepoint will be multiply imputed using CFB distribution at that timepoint in comparator 
group, for the interval between discontinuation and 96 weeks post randomization or PA 
trigger, whichever occurs first. If a participant’s discontinuation is related to treatment, the 
participant’s score CFB at each timepoint will be multiply imputed using a worse CFB 
distribution at that timepoint than that in comparator group, for the interval between 
discontinuation and 96 weeks post randomization or PA trigger, whichever occurs first. 
2. Analysis to evaluate the impact of the currently escalating crisis in Eastern Europe. All 
participants in the FAS will be included, with consideration given to including a time-
dependent covariate in the model. 
Sensitivity analyses for PROMIS Fatigue score CFB over 96 weeks will be similar. 
For the primary estimand of the secondary endpoint, total number of T1 Gd+ lesions based on all 
available MRI scans, it is important to assess the sensitivity of results to the MAR assumption that 
participants with missing data experience lesions until planned end of treatment at the same rate 
as participants with complete data, conditional on intervention group, Baseline lesion activity, and 
stratum. The following sensitivity analysis for the secondary efficacy endpoint total T1 Gd+ 
lesions will be detailed in the IAP: 
1. Analysis to evaluate the potential influence of informative treatment discontinuation 
according to discontinuation reason. If a participant’s discontinuation is unrelated to 
treatment (i.e., unrelated to efficacy or safety issues), the participant’s lesion count will be 
multiply imputed using rate in comparator group, for the interval between discontinuation 
and planned end of treatment (i.e., PA trigger or 156 weeks post randomization, whichever 
occurs first). If a participant’s discontinuation is related to treatment, lesion count will be 
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multiply imputed at a rate higher than that in comparator group, for the interval between 
discontinuation and planned end of treatment. 
2. Analysis to evaluate the impact of the currently escalating crisis in Eastern Europe. All 
participants in FAS will be included, with consideration given to including a time-
dependent covariate in the model. 
The following supplemental analyses for the secondary efficacy endpoint total number of T1 Gd+ 
lesions based on all available MRI scans will be detailed in the IAP: 
1. Analysis wherein lesion count at a single scan is modeled as Poisson-distributed, with a 
random effect for participant, and terms for intervention group, randomization strata, and 
Baseline lesion activity. This model will compare treatment on the basis of conditional 
adjusted lesion rate ratio, where conditioning is on the random effect. 
Sensitivity and supplemental analyses for number of new/enlarging T2 lesions on the last available 
MRI scan relative to the baseline MRI scan, except that the offset in the model will be log time 
from baseline scan to last available scan (in years), in place of log number of scans. 
Sensitivity analyses for the secondary endpoint, NfL concentration at 12 weeks, will be specified 
in the IAP. 
Further details on sensitivity analyses of ARR, 12-week CDP, and other secondary efficacy 
endpoints, which incorporate available data from participants enrolled at sites in the currently 
escalating crisis regions in Eastern Europe, will be described in the IAP. 
9.4.2 
Safety Analyses  
All safety analyses will be performed on the mSAF. 
Endpoint 
Statistical Analysis Methods 
Primary 
Not applicable. 
Secondary 
 
Adverse Events 
Descriptive statistics, AESI summaries, 3-Tier AE summaries 
Clinical Laboratory Test Values 
Descriptive statistics, shift tables, boxplots, individual participant line plots, 
Kaplan-Meier analyses of time to event, Evaluation of Drug-Induced Serious 
Hepatotoxicity (eDISH) figures 
ECG Parameters 
Descriptive statistics 
Vital Signs 
Descriptive statistics 
Immunoglobulin Levels 
Descriptive statistics 
Tertiary/Exploratory 
Not applicable 
9.4.2.1 
Adverse Events  
Adverse events will be coded using the MedDRA. All TEAEs will be summarized by intervention 
group. TEAEs are defined as AEs that occurred or worsened on or after the first dose of study 
intervention. The number and percentage of participants who experienced at least 1 TEAE will be 
summarized by SOC and preferred term. The percentage will be based on the number of 
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participants in each intervention group. TEAEs will also be summarized by relationship to 
intervention and by severity within each intervention group. Deaths, SAEs, AESIs, and AEs 
leading to study discontinuation will be tabulated and presented in data listings. Participant level 
data listings of all AEs will be presented. 
Summary and analysis of AEs will be performed based on the 3-tier approach (Crowe 2009) as 
further detailed in the IAP. Tier 1 AEs and AESIs will be predefined in the IAP. 
9.4.2.2 
Clinical Laboratory Test Values  
Clinical laboratory results (chemistry, hematology, and urinalysis) will be summarized using 
descriptive statistics for each visit by intervention group. Observed values at each visit and changes 
from Baseline to each postbaseline visit will be presented. For clinical laboratory parameters with 
associated normal ranges, number and percentage of participants having high/low/normal findings 
for worst on-treatment laboratory value will be summarized by intervention group; shift tables will 
be used to summarize changes from Baseline finding to worst on-treatment finding. For clinical 
laboratory parameters with NCI-CTCAE grades, shift tables will be used to summarize changes 
from Baseline grade to worst on-treatment grade. The distribution of selected laboratory 
parameters by time point and intervention group will be displayed via boxplots. All laboratory data 
will be provided in participant data listings. 
Analyses of liver enzyme tests will include Kaplan-Meier estimates of time to ALT or AST events, 
plots supporting evaluation of Drug-Induced Serious Hepatotoxicity (eDISH), and individual 
participant profiles. 
9.4.2.3 
Vital Signs  
Observed values at each visit and changes from Baseline to each postbaseline visit in vital signs 
(blood pressure, pulse rate, respiratory rate, and temperature) will be summarized by time point 
and intervention group using descriptive statistics. Similar summaries of descriptive statistics will 
be provided for the vital signs collected before and after the first dose of study intervention. Out-
of-range values of vital signs will be tabulated as appropriate. All vital signs will be provided in 
participant data listings. 
9.4.2.4 
Electrocardiogram Parameters  
Observed values at each visit and CFB to Week 96 in ECG parameters (e.g., PR, HR, QRS, RR, 
QT, and QTcF) will be summarized by intervention group using descriptive statistics. QTc will be 
reported based on Fridericia’s method. Percentage and counts of participants with ECG findings 
will be summarized by intervention group. Out-of-range values of ECG parameters will be 
tabulated as appropriate. All ECG data will be provided in participant data listings. 
For all ECG parameters, the results for categorical analysis will be summarized by intervention 
group and visit (or time point) in frequency tables with counts and percentages of participants. 
Categories will cover absolute values and changes from Baseline (predose Day 1): 
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HR: 
• Absolute < 50 bpm, < 40 bpm, < 30 bpm 
• Change from Baseline > 20 bpm, > 30 bpm, > 40 bpm 
PR: 
• Absolute > 200 msec and > 220 msec 
• Change from Baseline > 30 msec 
QRS: 
• Absolute > 110 msec 
QTcF: 
• Absolute > 450 msec, > 480 msec, and > 500 msec 
• Change from Baseline > 30 msec and > 60 msec 
Electrocardiogram parameters will be summarized using descriptive statistics for continuous 
variables such as QTcF intervals, and frequency counts and percentages for categorical variables. 
9.4.2.5 
Immunoglobulin Levels  
Data on Ig levels (observed values, change, and percent CFB, with Baseline defined as the Day 1 
sample) will be descriptively summarized in tabular and/or graphic format, as appropriate. 
Correlative analyses may be explored and reported separately. 
9.4.2.6 
Concomitant Medication and Procedures  
Prior and concomitant medications will each be categorized by therapeutic class and preferred term 
using WHO Drug coding dictionary. The number and percent of participants using each prior and 
concomitant medication will be summarized by therapeutic class and preferred drug name for each 
intervention group. Participants who reported more than 1 medication for a particular preferred 
term will be counted once for each preferred term and therapeutic class. 
Concomitant procedures will be categorized by SOC and preferred term using MedDRA. The 
number of and percent of participants experiencing each prior and concomitant procedure will be 
summarized by type of procedure for each intervention group. 
9.4.2.7 
Columbia-Suicide Severity Rating Scale  
Results of the C-SSRS will be listed for each visit by participant. 
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9.4.2.8 
Sensitivity Analyses  
Sensitivity analyses of important safety endpoints, which incorporate available data from 
participants enrolled at sites in the currently escalating crisis regions in Eastern Europe, will be 
described in the IAP. 
9.4.3 
Other Analyses  
9.4.3.1 
Pharmacokinetic 
Parameters, 
Pharmacodynamic 
Parameters, Biomarkers  
PK, PD, and biomarker exploratory analyses will be specified in the IAP finalized before database 
lock. Integrated analyses across studies, such as the population PK analysis and PD analyses will 
be presented separately from the main CSR. 
In general, biomarkers and PD parameters assessed at planned visits and premature early 
discontinuation from treatment will be summarized in a manner similar to safety laboratory 
parameters.  
The PK and BTK occupancy data of the current study will be used for the development of 
population PK and BTK occupancy models (possibly in combination with the corresponding data 
of earlier studies, e.g., MS200527_0019, MS200527_0017, MS200527_0086, and/or others), to 
describe the PK and BTK occupancy time profiles for the participants in the study. Population PK 
model-based exposure metrics such as Cmax and AUC (from 0 to 24 hour) at steady state will be 
derived.  
The derived PK profiles and exposure metrics will be used to develop exposure-response models 
(longitudinal or cross-sectional) for MRI, efficacy, and safety endpoints. In particular, a 
cross-sectional model of ARR as a function of steady state AUC, a longitudinal repeated time to 
event (qualified relapse) model, a longitudinal model for EDSS, cross-sectional or longitudinal 
exposure-response models for MRI lesions (T1 Gd+ lesion and new or enlarging T2 lesion count), 
and a longitudinal (if possible) exposure-response model for ALT elevations, will be developed. 
Other endpoints of interest depending on the signals that will be detected based on the 
exploratory/inferential statistical analysis of the study data may also be included in the 
exposure-response analyses. 
Full details of the planned population PK/PD modeling and other exposure-related modeling will 
be described in the study IAP. The results of the corresponding analyses will be reported separately 
from the study CSR. 
9.4.3.2 
Demographics, Baseline Characteristics, Disposition, and 
Compliance  
Participant demographics, such as age, sex, race, will be summarized by intervention group using 
descriptive statistics. Baseline disease characteristics (including MS history and MRI 
characteristics), such as Baseline EDSS, number of relapses in the 1 year and 2 years prior to 
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randomization, time (in years) since onset of MS symptoms, time (in years) since MS diagnosis, 
Baseline number of T1 Gd+ lesions, Baseline number of T2 lesions, and Baseline T2 lesion 
volume, prior MS study treatment will also be summarized. 
Disposition of participants (i.e., discontinuation from treatment by reason, discontinuation from 
study by reason) and compliance of participants to intervention will be summarized by intervention 
group using descriptive statistics. 
9.4.3.3 
Patient Reported Outcome Analyses  
The analysis of PROMIS PRO secondary endpoints is described in Section 9.4.1.2. A similar 
analysis will be performed for exploratory PRO score CFB endpoints. The exploratory endpoint, 
time to deterioration in PROMIS PF score confirmed at 12 weeks will be analyzed in a manner 
similar to that of time to 24-week CDP. 
9.4.3.4 
Health Resource Utilization  
For the exploratory endpoint HRU observed values at each visit and CFB to each postbaseline visit 
in HRU (doctor/home/emergency visits, hospitalizations, paid assistance, and missed work) will 
be summarized by time point and intervention group using descriptive statistics (mean, standard 
deviation, median, minimum/maximum, 25th and 75th percentile; 95% CI). 
9.4.3.5 
Analysis of Double-Blind Extension Period Endpoints  
Efficacy and HRQoL data collected during the DBE period will be analyzed as additional data to 
DBTP (i.e., baseline will be baseline of DBTP). Details will be provided in the IAP.  
Safety data collected during the DBE Period will be analyzed as described in Section 9.4.2. 
9.4.3.6 
Analysis of Open Label Extension Period Endpoints  
Efficacy and HRQoL data collected during the OLE Period will be summarized. Details will be 
provided in the IAP.  
Safety data collected during the OLE Period will be analyzed as described in Section 9.4.2. 
9.4.4 
Sequence of Analyses  
4 analyses are planned for the study: (1) an optional IA for BSSR based on the secondary endpoint 
12-week CDP, with data pooled across the present study and the second Phase III study, performed 
by the Sponsor, triggered when enrollment is nearing completion, (2) a PA, performed by the 
Sponsor after the PA database lock, with timing and endpoint evaluation as described in 
Section 9.4.4.2, (3) an analysis of all data from blinded periods at the end of DBE, performed by 
the Sponsor after the corresponding DBE database lock, (4) a final analysis, performed by the 
Sponsor after the final database lock, triggered when 100% of participants enrolled in the OLE 
Period complete the OLE, or discontinue prematurely from the OLE. 
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The PA of the present study (i.e., MS200527_0080) and the second Phase III study (i.e., 
MS200527_0082) will be triggered as described in Section 9.4.4.2.  
In addition, analyses will be performed at regular intervals for the purpose of safety monitoring by 
the IDMC, as described in the IDMC charter. 
9.4.4.1 
Optional Interim Analysis for Blinded Sample Size Re-
estimation  
Per Protocol Version 3, when enrollment was nearing completion, an optional IA for BSSR based 
on the secondary endpoint 12-week CDP may be performed by the Sponsor, using data pooled 
across studies. Only data relevant to 12-week CDP needed to be cleaned for the IA.  
Parametric distributions for time to 12-week CDP and time to censoring were fitted using blinded 
data pooled across studies. The resulting parameter estimates were used to estimate expected 
number of events given the originally planned sample size. If the expected number of events was 
less than the number required to power the 12-week CDP endpoint at 80%, consideration was to 
be given to increasing the sample size up to 25% so that the required number of events was 
achieved (Friede 2019). Performed in August 2021, the outcome of this IA for BSSR was a 
decision to not increase sample size. In the setting of superiority trials, an IA for BSSR has a 
minimal or non-existent effect on type-1 error inflation (Friede 2019). 
9.4.4.2 
Primary Analysis  
Based on an analysis of accumulating blinded data, the PA will be triggered for both studies 
simultaneously when all of the following conditions are met. 
• This study and the second Phase III study have individually collected ≥ 32.3 units of information 
for the primary ARR endpoint, where “Information” is defined below. At this timepoint both 
studies will provide ≥ 90% power for the detection of a 43.5% relative treatment effect on ARR 
in the primary statistical test at a 1-sided alpha level of 0.025.  
• In data pooled from the 2 studies, ≥ 149 12-week CDP events have been observed. At this 
timepoint, the combined studies have collected sufficient information to provide ≥ 71.5% power 
for the detection of 34% (hazard ratio = 0.66) relative reduction in risk of 12-week CDP in a 
logrank test at a 1-sided alpha-level of 0.025-0.0252 = 0.024375. 
• All participants have been treated for 24 weeks or discontinued prematurely. 
The default is that the PA will be triggered when all participants have been treated for 156 weeks 
or discontinued prematurely, if this occurs before the information for ARR and 12-week CDP 
event criteria are met. 
After protocol deviations are determined, and the database is locked for the PA, the drug codes 
will be broken and made available for the primary data analysis. All endpoints based on data from 
the DBTP until PA trigger date will be evaluated. This implies that the data related to 
End-of-DBTP visits occurring after the PA trigger date or any other data post PA trigger date will 
not be part of the PA. 
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Blinded review of Information for ARR 
Based on blinded data, the information associated with the ARR endpoint will be monitored to 
determine when the PA can be triggered.  
Fitting a NB model to the aggregate data (i.e., the qualified relapse data of all participants in a 
given study combined) provides an estimate of the overall ARR λ and the dispersion parameter γ. 
For an assumed rate ratio of 0.565 = 0.13/0.23, comparing evobrutinib to teriflunomide, an ARR 
estimate can be obtained for each group, denoted by λ1 for evobrutinib and λ2 for teriflunomide.  
Since the treatment allocation of the participants is unknown, but randomization was done in a 1:1 
ratio, it is assumed that the follow-up times in the 2 groups (j = 1,2, denoting evobrutinib and 
teriflunomide, respectively) are the same, i.e., T·1 = T·2 = Ttotal/2, where Ttotal is the total of the 
follow-up times at the review time. It is further assumed that the sum of the squared follow-up 
times is the same in both groups, i.e., that Σi Ti12 = Σi Ti22 = Σj Σi Tij2/2 = τtotal/2. The information 
for ARR (as per Appendix 5 of the ASCLEPIOS I/II protocol, available as Supplementary Material 
to Hauser 2020) based on blinded data is given by: 
Equation 9.4.4: Information I = [2/(λ1 Ttotal) + 2/(λ2 Ttotal) + 4 γ τtotal/Ttotal2]-1 
where λ1, λ2, and γ are the re-estimated values based on fitting a NB model to the aggregate data, 
and Ttotal and τtotal are as defined above. 
Information for ARR will be monitored in a blinded fashion throughout the study. The first 
criterion of the PA trigger is met when ≥ 32.3 units of information (Section 9.2.1) have been 
collected in the present study (i.e., MS200527_0080) and in the second evobrutinib Phase III study 
(i.e., MS200527_0082), indicating that that the ARR endpoint is powered at ≥ 90% for the 
detection of a 43.5% reduction in ARR at the 1-sided alpha level of 0.025. 
Blinded monitoring of 12-week CDP events  
Pooled CDP events will be monitored in a blinded fashion throughout the studies. The second 
criterion of the PA trigger is met when ≥ 149 pooled 12-week CDP events have been observed, 
indicating that the 12-week CDP endpoint is powered at ≥ 71.5% for the detection of a 34% 
reduction in HR at the 1-sided alpha level of 0.024375. 
9.4.4.3 
Multiplicity  
To control trial-wise and family-wise type I error at the 1-sided 0.025 level in the presence of 
multiple endpoint testing, a graphical approach to sequentially rejective multiple testing will be 
employed (Bretz 2009, Hung 2013, Bretz 2019). The 1-sided null hypotheses in the graph are as 
follows, where “Study 1” denotes the present study, and “Study 2” denotes the second Phase III 
study: 
Primary Endpoint Null Hypotheses: 
H011: rRR1 ≥ 1, where rRR1 denotes qualified relapse rate ratio comparing evobrutinib to 
teriflunomide in Study 1 
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H012: rRR2 ≥ 1, where rRR2 denotes qualified relapse rate ratio comparing evobrutinib to 
teriflunomide in Study 2 
Secondary Endpoint Null Hypotheses: 
H02: S12e(t) ≤ S12c(t), where S12e(t) denotes the survival function for time to 12-week CDP in the 
experimental (evobrutinib) group based on pooled data, S12c(t) denotes the survival function for 
time to 12-week CDP in the comparator (teriflunomide) group based on pooled data, and the 
variable t denotes time since randomization.  
H03: S24e(t) ≤ S24c(t), where S24e(t) and S24c(t) denotes the survival functions for time to 24-week 
CDP based on pooled data 
H04: S24e(t) ≥ S24c(t), where S24e(t) denotes the survival function for time to 24-week CDI in the 
experimental (evobrutinib) group based on pooled data from participants with baseline EDSS ≥ 
2.0, S24c(t) denotes the survival function for time to 24-week CDI in the comparator (teriflunomide) 
group based on pooled data from participants with baseline EDSS ≥ 2.0, and the variable t denotes 
time since randomization.  
H05: ΔPF ≤ 0, where ΔPF denotes difference in PROMIS PF score CFB over 96 weeks least-squares 
mean, comparing evobrutinib to teriflunomide, based on pooled data (higher score corresponds to 
improved physical function).  
H06: ΔFatigue ≥ 0, where ΔFatigue denotes difference in PROMIS Fatigue score CFB over 96 weeks 
least-squares mean, comparing evobrutinib to teriflunomide, based on pooled data (higher score 
corresponds to more fatigue).  
H021: lRR21 ≥ 1, where lRR21 denotes T1 Gd+ lesion rate ratio comparing evobrutinib to 
teriflunomide in Study 1 
H022: lRR22 ≥ 1, where lRR22 denotes T1 Gd+ lesion rate ratio comparing evobrutinib to 
teriflunomide in Study 2 
H031: lRR31 ≥ 1, where lRR31 denotes new or enlarging T2 lesion rate ratio comparing evobrutinib 
to teriflunomide in Study 1 
H032: lRR32 ≥ 1, where lRR32 denotes new or enlarging T2 lesion rate ratio comparing evobrutinib 
to teriflunomide in Study 2 
H041: ΔNfL1 ≥ 0, where ΔNfL1 denotes a difference in NfL Concentration at 12 weeks comparing 
evobrutinib to teriflunomide in Study 1 
H042: ΔNfL2 ≥ 0, where ΔNfL2 denotes a difference in NfL Concentration at 12 weeks comparing 
evobrutinib to teriflunomide in Study 2 
At the PA, the primary efficacy endpoint, ARR, will be tested at the 0.025 (1-sided) level in each 
study. Figure 3 shows the multiple testing procedure involving study-specific endpoints and 
pooled endpoints. 
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At the PA, the 12-week CDP pooled endpoint will be tested at the 0.025-0.0252 = 0.024375 level, 
1-sided, only if ARR is significant in both studies at the 0.025 level, 1-sided. 
If the 12-week CDP pooled endpoint is significant at the 0.024375 level, 1-sided, the subsequent 
pooled endpoints (24-week CDP, 24-week CDI, PROMIS PF CFB over 96 weeks, PROMIS 
Fatigue CFB over 96 weeks) will be tested in a hierarchical order at 0.024375 level, 1-sided. 
If the primary efficacy endpoint, ARR up to 156 weeks, is significant within a study at the 0.025 
level, 1-sided, the subsequent single-study endpoints (total number of T1 Gd+ lesions based on all 
available MRI scans, number of new/enlarging T2 lesions on the last available MRI scan relative 
to the baseline scan, Week 12 NfL concentration) will be tested in a hierarchical order at the 0.025 
level, 1-sided. 
Figure 3 
Multiplicity Graph  
 
ARR = Annualized Relapse Rate, CDI = Confirmed Disability Improvement, CDP = Confirmed Disability Progression, 
CFB = change from Baseline, Gd+ = gadolinium positive, NfL = neurofilament light chain, PROMIS = Patient Reported 
Outcomes Measurement Information System, T1 and T2 = type of Magnetic Resonance Image, Wk = Week.   
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11 
Appendices  
Appendix 1 Abbreviations  
 
9-HPT 
9 Hole Peg Test 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse Event 
AEP 
Accelerated elimination procedure 
AESI 
Adverse Event of Special Interest  
ALT 
Alanine aminotransferase  
ARR 
Annualized Relapse Rate 
AST 
Aspartate aminotransferase  
AUC 
Area under the curve 
BEA 
Blinded Extension Analysis 
BSSR 
Blinded Sample Size Re-estimation 
BTK 
Bruton’s Tyrosine Kinase 
BV 
Brain volume 
CBF 
Cerebral blood flow 
CDI 
Confirmed disability improvement 
CDP 
Confirmed disability progression 
CFB 
Change from Baseline 
CI 
Confidence interval 
CL/f 
The apparent total body clearance of study intervention following 
extravascular administration  
Cmax 
Maximum evobrutinib concentration  
CMV 
Cytomegalovirus 
CNS 
Central nervous system 
COVID 
Coronavirus disease 
CRF 
Case Report Form 
CSF 
Cerebrospinal fluid 
CSF JCV PCR Cerebrospinal fluid JC virus polymerase chain reaction 
CSR 
Clinical study report 
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C-SSRS 
Columbia-Suicide Severity Rating Scale  
CTCAE 
Common Terminology Criteria for Adverse Events 
CUA 
Combined unique active 
CYP3A 
Cytochrome P450 3A  
DBTP 
Double-blind Treatment Period 
DBE 
Double-blind extension 
DBTP 
Double-blind treatment period 
DDI 
Drug-drug interactions 
DILI 
Drug induced liver injury 
DMT 
Disease-modifying therapy 
EA 
Early antigen 
EAC 
Endpoint Adjudication Committee  
EBNA 
Epstein-Barr Nuclear Antigen 
EBV 
Epstein–Barr virus 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale 
EODBTP 
End-of-DBTP 
EODBE 
End-of-DBE 
eGFR 
Estimated glomerular filtration rate 
EQ-5D-5L 
EuroQoL 5 Dimension 5 Levels 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration  
FLAIR 
Fluid-attenuated inversion recovery 
FSH 
Follicle-stimulating hormone 
FSS 
Functional system scores 
GCP 
Good Clinical Practice 
Gd 
Gadolinium 
HAC 
Hepatology Assessment Committee 
HAV 
Hepatitis A Virus 
HBc 
Hepatitis B Core Antigen 
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HCV 
Hepatitis C virus 
HEV 
Hepatitis E Virus 
HFE 
High Iron Fe (human hemochromatosis protein) 
HIV 
Human immunodeficiency virus 
HRQoL 
Health-related quality of life 
HRU 
Health Resource Utilization 
HRT 
Hormonal replacement therapy 
IA 
Interim analysis 
IAP 
Integrated Analysis Plan 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
Ig 
Immunoglobulin 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
JCV 
John Cunningham virus 
LFT 
Liver function test 
LTBI 
Latent TB infection 
MAR 
Missing at random 
MedDRA 
Medical Dictionary of Regulatory Activities  
MRI 
Magnetic Resonance Imaging 
MMRM 
Mixed effect model for repeated measures 
MS 
Multiple sclerosis 
nT1 
Normalized T1 
NAWM 
Normal appearing white matter 
NB 
Negative binomial 
NBV 
Normalized brain volume 
NCI 
National Cancer Institute 
NEDA 
No evidence of disease activity 
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NEP 
No evidence of progression 
NEPAD 
No evidence of progression or active disease 
NfL 
Neurofilament light chain 
NK 
Natural killer 
NYHA 
New York Heart Association 
OLE 
Open-label Extension 
PA 
Primary Analysis 
PBVC 
Percent brain volume change 
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamics 
PF 
Physical function 
PIRA 
Progression Independent of Relapse Activity 
PIRMA 
Progression Independent of Relapse and Brain Magnetic Resonance 
Imaging Activities 
PK 
Pharmacokinetics 
PML 
Progressive multifocal leukoencephalopathy 
PPD 
Purified protein derivative 
PRL 
Phase rim lesions 
PRO 
Patient Reported Outcomes 
PROMIS 
Patient Reported Outcomes Measurement Information System 
QoL 
Quality of Life 
QTL 
Quality tolerance limits 
RA 
Rheumatoid arthritis 
RMS 
Relapsing multiple sclerosis 
SAE 
Serious Adverse Event 
SARS-CoV-2 
Severe acute respiratory syndrome-coronavirus-2 
SCR 
Screening 
SDMT 
Symbol Digit Modalities Test 
SEL 
Slowly expanding lesions 
SF-36v2 
36-Item Short Form Survey Instrument Version 2 
SLE 
Systemic lupus erythematosus 
SmPC 
Summary of Product Characteristics 
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SoA 
Schedule of activities 
SOC 
System Organ Class 
SPMS 
Secondary progressive multiple sclerosis 
SSC 
Study Steering Committee 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T25-FW 
Timed 25-Foot Walk  
TB 
Tuberculosis 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
USPI 
United States Prescribing Information 
USSR 
Unblinded Sample Size Re-estimation 
VCA 
Viral capsid antigen 
Vz/f 
The apparent volume of distribution during the terminal phase following 
extravascular administration 
WHO 
World Health Organization 
WOCBP 
Woman of Childbearing Potential 
 
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Appendix 2 Study Governance  
Financial Disclosure 
Investigators and Sub-Investigators 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 
• The Investigator or his/her representative will explain the nature of the study to the participant 
and answer all questions on the study. 
• Participants must be informed that their participation is voluntary. 
• Participants will be required to sign a statement of informed consent that meets the requirements 
of 21 CFR 50; local regulations; ICH guidelines; Health Insurance Portability and 
Accountability Act (HIPAA) requirements, where applicable; and the IRB/IEC or study center. 
• The medical record must 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 must also sign the ICF. 
• If the ICF is updated during their participation in the study, participants must be reconsented to 
the most current, approved version. 
• A copy of the ICF(s) must be provided to the participant. 
• The original signed and dated consent will remain at the Investigator’s site and must be safely 
archived so that it can be retrieved at any time for monitoring, auditing, and inspection purposes. 
• As this study includes optional pharmacogenetic examinations, including collection and storage 
of biological samples, participants may consent to a separate pharmacogenetic analysis, the 
process of which will need to be documented in the participant’s medical records. 
• Participants who are rescreened are required to sign a new ICF. 
• Consenting participant will enter the 4-week screening period to be evaluated for eligibility. 
Please see the SoA (see Section 1.3) for details. Participants must fulfill all entry criteria for 
participation in the study. 
• The screening period may be extended to a total period of 12 weeks after approval by the 
Medical Monitor (see Section 8). The following should be performed: 
• An Eligibility Review Form [ERF] documenting the Investigator’s assessment of each 
screened participant with regard to the protocol’s inclusion and exclusion criteria is to be 
completed by the Investigator. 
• Each participant screened must be registered in the IWRS by the Investigator or the 
Investigator’s research staff at Screening. A screen failure record must be maintained by the 
Investigator, and reasons must be captured in the IWRS. 
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• It should be stated in the medical record that the participant is participating in this clinical 
study. 
• Eligibility will be evaluated and confirmed by the study eligibility team. Sites will be 
required to submit an eligibility packet to the Medical Monitor (consisting of an eligibility 
checklist and appropriate documentation) for potential eligible participants. 
Data Protection 
• The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the identifier 
only; participant names or any identifiable information will not be transferred. 
• The Sponsor must inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure must also be explained to the 
participant and pregnant partners (if applicable), who will be required to give consent for their 
data to be used, as specified in the informed consent. 
• The participant must 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 
This clinical study will be sponsored by Merck Healthcare KGaA Darmstadt, Germany for sites 
outside of the US and Canada and EMD Serono Research & Development Institute, Inc., Billerica, 
MA, US for sites in the US and Canada. 
The study will be conducted at approximately 200 global sites anticipated from approximately 30 
countries (approximately 30 sites in the US). Sites will be a mixture of academic centers and 
outpatient clinics. 
The Coordinating Investigator listed on the title page represents all Investigators for decisions and 
discussions on this study, per ICH GCP. The Coordinating 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. 
An IDMC, HAC, EAC, and SSC will perform specific study-related activities as detailed in each 
committee’s charter (see Section 8.2.8). 
The study will appear in the following clinical studies registries: ClinicalTrials.gov and EudraCT. 
Details of structures and associated procedures will be defined in a separate Pharmacy Manual. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and the following: 
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• Consensus ethical principles derived from international guidelines, including the Declaration 
of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) 
International Ethical Guidelines 
• Applicable ICH GCP Guidelines 
• Applicable laws and regulations 
• The Investigator must submit the protocol, protocol amendments (if applicable), ICF, 
Investigator Brochure, and other relevant documents (e.g., advertisements) to an IRB/IEC and 
the IRB/IEC must review and approve them before the study is initiated. 
• Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary to 
eliminate an immediate hazard to study participants. When applicable, amendments will be 
submitted to the appropriate Health Authorities. 
• The Investigator will be responsible for the following: 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures. 
• Notifying the IRB/IEC of SAEs or other significant safety findings, as required by IRB/IEC 
procedures 
• Providing oversight of the study conduct at the site and adherence to requirements of 21 
CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
• The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site. 
Emergency Medical Support 
• The Sponsor or designee will provide Emergency Medical Support cards to participants for use 
during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any information 
about this participation that may be needed to determine the course of medical treatment for the 
participant. The information on the Emergency Medical Support card may include the process 
for emergency unblinding (if applicable). 
• The first point of contact for all emergencies will be the clinical study Investigator caring for 
the participant. Consequently, the Investigator agrees to provide his or her emergency contact 
information on the card. If the Investigator is available when an event occurs, they will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard process 
established for Investigators. 
When the Investigator is not available, the Sponsor provides the appropriate means to contact a 
Sponsor (or designee) physician. This includes provision of a 24-hour contact number at a call 
center, whereby the health care providers will be given access to the appropriate Sponsor (or 
designee) physician to assist with the medical emergency and to provide support for the potential 
unblinding of the participant concerned. 
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Clinical Study Insurance and Compensation to Participants 
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable. 
Clinical Study Report 
After study completion, the Sponsor will write a clinical study report in consultation with the 
Coordinating Investigator. 
Publication 
• The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows Merck to protect proprietary information and to provide comments.  
• The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by agreement. 
• Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
Dissemination of Clinical Study Data 
After completion of the study, a clinical study report will be written by the Sponsor in consultation 
with the Coordinating Investigator following the guidance in ICH Topic E3, and will be submitted 
in accordance with local regulations. 
Any and all scientific, commercial, and technical information disclosed by the Sponsor in this 
protocol or elsewhere should be considered the confidential and proprietary property of the 
Sponsor. The Investigator shall hold such information in confidence and shall not disclose the 
information to any third party except to such of the Investigator’s employees and staff as have 
been made aware that the information is confidential and who are bound to treat it as such and to 
whom disclosure is necessary to evaluate that information. The Investigator shall not use such 
information for any purpose other than for determining mutual interest in performing the study 
and, if the parties decide to proceed with the study, for the purpose of conducting the study. 
The Investigator understands that the information developed from this clinical study will be used 
by the Sponsor in connection with the development of the study drug and therefore may be 
disclosed as required to other clinical Investigators, to the US Food and Drug Administration, 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. 
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Data Quality Assurance 
• All participant study data will be recorded on printed or electronic CRFs or transmitted to the 
Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible for 
verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the CRF. Details for managing CRFs are in the Pharmacy Manual. 
• For PRO data (e.g., QoL and pain assessments), ePRO will be used. 
• The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF. 
• The Investigator must 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. 
• QTLs will be predefined and documented in the applicable project management database to 
help support the identification of systematic issues that could potentially impact participant 
safety and/or reliability of study results. These predefined parameters will be monitored during 
the study and important deviations from the QTL thresholds and remedial actions taken will be 
summarized in the clinical study report. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring) are in the Monitoring Plan. 
• The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once quality 
control and quality assurance procedures have been completed. PDF files of the CRFs will be 
provided to the Investigators at study completion. 
• 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. 
• Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies, or the Sponsor requires a longer retention. No records may be destroyed 
during the retention period without the Sponsor’s written approval. No records may be 
transferred to another location or party without the Sponsor’s written notification. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. 
• The Investigator must keep a paper or electronic file (medical file and original medical records) 
at the site for each study participant. The file must identify each participant, contain the 
following demographic and medical information for the participant, and should be as complete 
as possible: 
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• Participant’s full name, date of birth, sex, height, and weight 
• Medical history and concomitant diseases 
• Prior and concomitant therapies (including changes during the study) 
• Study identifier (i.e., the Sponsor’s study number) and participant’s study number. 
• Dates of entry into the study (i.e., signature date on the informed consent) and each visit to 
the site 
• Any medical examinations and clinical findings predefined in the protocol 
• All AEs 
• Date that the participant left the study, including any reason for early withdrawal from the 
study or study intervention, if applicable. 
• All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document must have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records should be performed, documented, signed, and dated by the Investigator.  
• Data recorded on printed or electronic CRFs that are transcribed from source documents must 
be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on the 
study. Also, current medical records must be available. 
• The study monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator and kept in the study file. 
• Source documents are stored at the site for the longest possible time permitted by the applicable 
regulations, and/or as per ICH GCP guidelines, whichever is longer. The Investigator ensures 
that no destruction of medical records is performed without the Sponsor’s written approval. 
• Definition of what constitutes source data is found in the eCRF guidelines. 
Study and Site Closure 
• The Sponsor reserves the right to close the study site or terminate the study at any time and for 
any reason, including but not limited to new or emerging safety information that negatively 
affects the benefit/risk assessment of the clinical study. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a site closure visit has been completed. 
• The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination. 
• Reasons for the early closure of a study site by the Sponsor or Investigator may include: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the Sponsor’s procedures, or GCP guidelines 
• Inadequate recruitment of participants by the Investigator 
• Discontinuation of further development of the Sponsor’s compound 
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• If the study is prematurely terminated or suspended, the Sponsor will promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator will promptly inform the participants 
and assure appropriate participant therapy and/or follow-up. 
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Appendix 3 Contraception  
Definitions: 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile, as specified below. 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before the first dose of study intervention, consider additional evaluation. 
A WOCBP is not: 
1. Premenarchal 
2. A premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Documentation can come from the site personnel’s review of the female’s medical 
records, medical examination, or medical history interview. 
For a female with permanent infertility due to an alternate medical cause other than the 
above, (e.g., Müllerian agenesis, androgen insensitivity), Investigator discretion applies 
to determine study entry. 
3. A postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. 
a. A high follicle-stimulating hormone (FSH) level in the postmenopausal 
range may be used to confirm a postmenopausal state in a female not using 
hormonal contraception or hormonal replacement therapy (HRT). However, 
in the absence of 12 months of amenorrhea, more than 1 FSH measurement 
is required in the postmenopausal range. 
• A female on HRT and whose menopausal status is in doubt will be required to use one of 
the 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. 
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Contraception Guidance: 
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE: 
Highly Effective Methods That Have Low User Dependency 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationa 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)a 
• 
Bilateral tubal occlusion 
• 
Vasectomized partnerb: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days. 
Highly Effective Methods That Are User Dependent  
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulationa 
o 
Oral 
o 
Intravaginal 
o 
Transdermal 
o 
Injectable 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationa 
o 
Oral 
o 
Injectable 
• 
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated 
in relation to the duration of the study. Abstinence is only acceptable as a contraceptive method for study 
purposes if it is in line with the preferred and usual lifestyle of the participant as evaluated by the Investigator. 
Barrier Methods  
• 
Male or female condom with or without spermicide 
• 
Cap, diaphragm, or sponge with spermicide 
a 
Evobrutinib has been characterized as both an inducer and a time-dependent inhibitor of CYP3A4/5 in vitro, 
an enzyme involved in the metabolism of estrogen and progestin. Although it is a low risk, it is possible that 
coadministration with evobrutinib results in increased metabolism of estrogen, progestin, and other hormones used 
for contraception, increasing the likelihood that hormonal contraception methods, marked above with a, might fail. 
However, all participants that are WOCBP are required to use a barrier method as backup (see Inclusion Criterion 6) 
in part to mitigate this potential risk. 
Teriflunomide may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should 
be given to the type or dose of contraceptives used in combination with teriflunomide (see Appendix 9 and refer to 
the locally approved product information [e.g., relevant SmPC or USPI]). There was an increase in mean 
ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, respectively) and levonorgestrel Cmax and AUC0-24 (1.33- and 
1.41-fold, respectively) following repeated doses of teriflunomide.  
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b 
If a WOCBP participant is using a highly effective method other than sexual abstinence or vasectomized 
partner, AND ALSO has a vasectomized partner, the vasectomized partner will be considered the “barrier method” 
for study purposes. 
Notes: 
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants. 
Highly effective methods are those with a failure rate of < 1% per year when used consistently and correctly. Typical 
use failure rates differ from those when used consistently and correctly. 
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action. 
Periodic abstinence (calendar, symptothermal, postovulation methods), withdrawal (coitus interruptus), spermicides 
only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for this study. Male 
condom and female condom cannot be used together (due to risk of failure with friction). 
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Appendix 4 
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting  
Definitions 
Adverse Event 
An AE is any untoward medical occurrence in a participant administered a pharmaceutical product, 
regardless of causal relationship with this treatment. Therefore, an AE can be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal product, regardless if it is considered related to the medicinal 
product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself. 
The Investigator is required to grade the severity or toxicity of each AE. 
Investigators will reference the NCI-CTCAE, version 5.0 (publication date: 27 November 2017), 
a descriptive terminology that can be used for AE reporting. 
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided. 
If the severity for an AE is not specifically graded by NCI-CTCAE, the Investigator is to use the 
general NCI-CTCAE definitions of Grade 1 through Grade 5, using his or her best medical 
judgment. 
The 5 general grades are: 
Grade 1 or Mild 
Grade 2 or Moderate 
Grade 3 or Severe  
Grade 4 or Life-threatening  
Grade 5 or Death  
Any clinical AE with severity of Grade 4 or 5 must also be reported as an SAE. However, a 
laboratory abnormality of Grade 4, such as anemia or neutropenia, is considered serious only if the 
condition meets one of the serious criteria specified below. 
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as separate event. Only, if no cause of death can be reported (e.g., sudden death, 
unexplained death), the death per se might then be reported as an SAE. 
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Investigators must also systematically assess the causal relationship of AEs to study intervention 
(including any other nonstudy interventions, radiation therapy, etc.) using the following 
definitions. Decisive factors for the assessment of causal relationship of an AE to the study 
interventions (evobrutinib and teriflunomide) include, but may not be limited to, temporal 
relationship between the AE and the study interventions, known side effects of study interventions, 
medical history, concomitant medication, course of the underlying disease, and study procedures. 
Unrelated: 
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol. A reasonable alternative explanation must be available. 
Related: 
Reasonably 
related 
to 
the 
study 
intervention. 
AE 
could 
medically 
(pharmacologically/clinically) be attributed to the study intervention under study in 
this clinical study protocol.  
Abnormal Laboratory Findings and Other Abnormal Investigational Findings 
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
study intervention discontinuation, or are considered otherwise medically important by the 
Investigator. If a laboratory abnormality fulfills these criteria, the identified medical condition 
(e.g., anemia or increased ALT) must be reported as the AE rather than the abnormal value itself. 
Serious Adverse Events 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death 
• Is life-threatening. Life-threatening refers to an event in which the participant is at risk of death 
at the time of the event, not an event that hypothetically might have caused death if it was more 
severe. 
• Requires inpatient hospitalization or prolongs an existing hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly or birth defect 
• Is otherwise considered to be medically important. Important medical events that may not result 
in death, be life-threatening, or require hospitalization may be considered as SAEs when, based 
upon appropriate medical judgment, they may jeopardize the participant or may require medical 
or surgical intervention to prevent one of the outcomes listed above. Examples of such events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs and AESIs. 
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Events that Do Not Meet the Definition of an SAE 
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., an 
overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization (i.e., 
undesirable effects of any administered treatment) must be documented and reported as SAEs. 
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions, and are not to be considered AEs. 
Worsening of the underlying disease is not routinely to be considered an AE or SAE, but is rather 
an efficacy endpoint, unless deemed to be causally related to the IMP. However, if significant 
adverse signs or symptoms occur in association with complications or a prolonging of a 
hospitalization originally due to relapse or disease progression, then these specific complications 
or hospital prolongation events should be recorded as AEs. 
Adverse Events of Special Interest 
Adverse events of special interest are liver AEs (possible drug-induced, non-infectious, 
non-alcoholic, and immune-mediated), infections (serious and opportunistic infections), lipase and 
amylase elevation, and seizure, as described in Section 6.9. 
Other Adverse Events to be Reported Following a Specialized Procedure  
The following procedures should be followed for reporting overdoses (refer to eCRF guidelines 
for further details): 
• Overdoses without an AE should be reported using the paper SAE form only, stating if the 
overdose was accidental or intentional. 
• Overdoses associated with a nonserious AE should be recorded on the AE eCRF. 
• Overdoses associated with an SAE should be recorded on the AE eCRF and the SAE reporting 
procedure outlined below should be followed. 
Recording and Follow-Up of AE and/or SAE 
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of AE 
onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given or 
other action taken, including dose modification or discontinuation of the study intervention, and 
its outcome. In addition, serious cases should be identified and the appropriate seriousness criteria 
documented.  
Specific guidance is in the CRF Completion and Monitoring Conventions provided by the Sponsor. 
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Reporting Serious Adverse Events and Adverse Events of Special Interest 
Serious Adverse Events 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately inform the Sponsor or its designee using the electronic SAE report form in the 
Electronic Data Capture (EDC) system. The site will enter into the electronic system the SAE data 
within 
24 hours 
after 
becoming 
aware 
of 
the 
event. 
It 
is 
expected 
that 
the 
investigator/sub-investigator signs off this data in the system and any relevant associated data (e.g., 
additional laboratory tests, medical records, diagnostic reports, histopathological examinations, or 
consultation with other health care professionals) will be entered as soon as it becomes available. 
Reporting of SAEs using a paper report form is required as a back-up method only for an EDC 
system failure. Names, addresses, and telephone and fax numbers will be included on the paper 
form. All information from the paper form must be transcribed into the electronic form as soon as 
the system becomes available. 
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an electronic SAE report form must be completed immediately thereafter. 
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., laboratory 
results, hospital report, autopsy report).  
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations. 
Requests for follow-up will usually be made via the study monitor, although in exceptional 
circumstances the global patient safety department may contact the Investigator directly to obtain 
further information or to discuss the event. 
Adverse Events of Special Interest 
For a non-serious 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. 
For a serious AESI, the site will complete an SAE report form, using the SAE reporting process, 
specified above. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) 
Individual Case Safety Reports will be prepared for SUSARs according to local regulatory 
requirements and Sponsor policy and forwarded to Investigators within 15 days. 
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An Investigator or sub-investigator who receives an Individual Case Safety Report describing a 
SUSAR or other specific safety information (e.g., Emerging Safety Issue Report, summary or 
listing of SAEs/SUSARs) from the Sponsor will review the safety reports and confirm completion 
of this review. This information will be filed it in the Investigator’s Site File, and the IRB/IEC will 
be notified, if appropriate, according to applicable local laws/regulations and site SOPs. 
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Appendix 5 
Clinical Laboratory Tests  
Table 5 
Protocol-Required Clinical Laboratory Assessments  
 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet count  
• 
Mean 
Corpuscular 
Volume 
(MCV) 
White Blood Cell (WBC) 
Count with Differential: 
• 
Neutrophils 
• 
Lymphocytes 
• 
Monocytes 
• 
Eosinophils 
• 
Basophils 
Reticulocytes 
Hemoglobin 
Mean corpuscular 
hemoglobin 
(MCH) 
Hematocrit 
Mean corpuscular 
hemoglobin 
concentration 
(MCHC) 
Erythrocytes 
 
LFT visits 
Aspartate aminotransferase 
γ-Glutamyl-
transferase 
Bilirubin total 
Alanine aminotransferase 
Alkaline 
phosphatase 
 
Biochemistry 
Blood Urea 
Nitrogen 
Potassium 
Aspartate 
Aminotransferase 
Bilirubin total 
 
Creatinine and 
eGFR calculation 
Sodium 
Alanine 
Aminotransferase 
Protein total 
Glucose 
Calcium 
Alkaline 
phosphatase 
Albumin 
Chloride 
Lactate 
dehydrogenase 
Lipase 
Amylase 
 
 
Magnesium 
Tocarbon dioxide 
Phosphate 
 
Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1. 
Hepatic/Autoimmune 
Panel (to be performed 
in the event of elevated 
LFTs, see Section 7.1) 
Antinuclear 
antibody 
antismooth 
muscle antibody, 
antibody to liver 
kidney 
microsomes  
Alkaline 
phosphatase, 
Albumin, ALT, 
AST, GGT and 
total bilirubin 
 
Anti-HAV IgM, HBsAg, anti-HBc IgM, 
anti-HBsAg, anti-HCV, anti-HEV IgG and IgM, 
anti-VCA IgG and IgM, anti-EA IgG, anti-EBNA 
IgG, anti-CMV IgG and IgM, EBV PCR, and 
CMV PCR 
Ferritin; 
Transferrin 
saturationb 
Fibrinogen, 
hsCRP 
Focused Genetic Testingb 
Hepatitis C 
ViRNA PCR 
 
 
Routine Urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite by dipstick 
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Laboratory 
Assessments 
Parameters 
• 
Microscopic examination (if blood or protein is abnormal) 
Reflex Testing for HBV 
DNA 
• 
Hepatitis B Virus DNA PCR 
Other Tests 
• 
QuantiFERON TB testing for high TB burden countries  
• 
Highly sensitive urine human chorionic gonadotropin (hCG) pregnancy test (as 
needed for a WOCBP). Note: Local urine testing will be standard for the protocol 
unless serum testing is required by local regulation or the IRB/IEC. 
• 
Teriflunomide levelsc 
• 
B, T, and NK cell absolute countf 
• 
Immunoglobulin (IgM, IgA, IgG, and IgE)f 
• 
Teriflunomide plasma concentration related to AEPf 
Other Screening Tests 
• 
Serology (Hepatitis C Virus antibodies, Hepatitis B Virus antibodies, HIV testingd, 
Hepatitis B Virus Surface Antigen, Hepatitis C Virus RNA PCR, QuantiFERON TB 
test) 
• 
FSH (as needed if not a WOCBP only)e 
• 
Serum pregnancy test (as needed for a WOCBP) 
• 
Ferritin and transferrin saturation 
• 
JC Virus DNA PCR to be performed if MRI has findings suggestive of progressive 
multifocal leukoencephalopathy 
• 
All study-required laboratory assessments will be performed by a central laboratory, 
except for urine dipstick (microscopic examination done centrally), urine pregnancy, 
and T-SPOT 
ALT = alanine transaminase, AST = aspartate aminotransferase, CMV = Cytomegalovirus, DNA = deoxyribonucleic 
acid, eGFR = Estimated Glomerular Filtration Rate, FSH = Follicle Stimulating Hormone, GGT = gamma-glutamyl 
transferase, HFE = High Iron Fe (human hemochromatosis protein), HIV = Human Immunodeficiency Virus, 
hsCRP = High Sensitivity C Reactive Protein, IDMC = Independent Data Monitoring Committee, IEC = Independent 
Ethics Committee, IRB = Institutional Review Board, Ig = Immunoglobulin, LFT = liver function test, OLE = Open 
Label Extension, PCR = polymerase chain reaction, TB = tuberculosis, WOCBP = Women of Childbearing Potential. 
a 
Results will not be disclosed to the sites, Sponsor, or representative, to avoid unblinding. However, the IDMC will 
have access to these data as applicable. 
b 
Focused genetic testing for variants that confer risk for liver diseases and/or drug-related liver injury, including but 
not limited to testing for variants in the HFE gene (C282Y, H63D) in the setting of abnormal ferritin/transferrin 
saturation values as defined in Exclusion Criterion 10.  
c 
During the DBTP, teriflunomide level determination might be completed for safety reasons only. Teriflunomide 
levels will be determined in all participants planning to enter the OLE. 
d HIV testing will be done at Screening centrally, unless indicated otherwise by local regulations. 
e Exam not applicable to participants in the OLE Period. 
f 
Only applicable to participants in the OLE Period. 
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Appendix 6 
Pharmacogenetics  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact study intervention absorption, distribution, metabolism, and 
excretion; mechanism of action of the study intervention; disease etiology; and/or molecular 
subtype of the disease being treated. 
• DNA samples may be used for research related to pharmacokinetics, safety endpoints, drug 
response, and treatment efficacy of evobrutinib or MS and related diseases. They may also 
be used to develop tests or assays, including diagnostic tests related to pharmacokinetics, 
safety endpoints, drug response, and treatment efficacy of evobrutinib and MS. 
Pharmacogenetic research may consist of the analysis of one or more candidate genes or the 
analysis of genetic markers throughout the genome or analysis of the entire genome (as 
appropriate). 
• The results of pharmacogenetic analyses may be reported in the CSR or in a separate study 
summary. 
• Details on processes for collection and shipment of these samples can be found in the 
Laboratory Manual. The Sponsor will store the DNA samples in a secure storage space with 
adequate measures to protect confidentiality. 
• Retention time and possible analysis of DNA sample after the study ends are specified in the 
respective ICF. 
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Appendix 7 
Guidance for Diagnosis of PML  
The safety monitoring algorithm presented in Figure 4 will be implemented in this study. 
Comprehensive neurological assessments will be performed every 12 weeks at the regular study 
visits. Additionally, telephone interviews will be conducted to assess for new or worsening 
neurological symptoms and a neurological evaluation will be conducted if clinically indicated. 
This neurological exam will include calculation of an EDSS score at the scheduled 12-week visit 
or in the event of new/worsening symptoms. This exam requires that FSS also be determined. The 
examination to calculate the FSS includes cognitive, visual, and motor assessments, as well as 
assessments of other neurological systems. These neurological systems are often affected by PML, 
and by MS as well. 
Should a non-MS etiology, such as PML, be considered as a differential etiology for any change 
in the clinical picture (neurological symptoms and/or exam), further assessments should be done. 
The evaluation of PML may include a brain MRI scan and CSF analysis per the proposed treatment 
algorithm (Figure 4). 
Action Steps if PML is suspected: 
If the clinical presentation is suggestive of PML, further investigations should include brain MRI 
evaluation as soon as possible. If MRI evaluation reveals lesions suspicious for PML a lumbar 
puncture with evaluation of the CSF for the detection of JCV DNA should be undertaken 
(performed by central laboratory). A diagnosis of PML can potentially be made by evaluating 
clinical and MRI findings plus the identification of JCV in the CSF.  
MRI Assessments 
Although there are no pathognomonic findings that differentiate PML from MS, a brain MRI scan 
that includes fluid-attenuated inversion recovery (FLAIR) and T2-weighted and T1-weighted 
sequences, with and without Gd, should be performed to assess patients with neurological changes 
suggestive of PML. 
CSF Assessment 
• The detection of JCV DNA in the CSF of a participant with clinical and MRI features suggestive 
of PML establishes the diagnosis of PML. 
• If JCV DNA is not detected in CSF and if clinical suspicion of PML remains high, a repeat 
lumbar puncture should be performed. 
• If diagnosis remains uncertain and suspicion of PML remains high, a brain biopsy may be 
considered to establish a definitive diagnosis. 
• CSF will be analyzed centrally. 
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Figure 4 
Diagnostic Algorithm for PML – Suggested Diagnostic Algorithm  
 
CSF = cerebrospinal fluid, JCV = JC virus, MRI = Magnetic Resonance Imaging, MS = multiple sclerosis, 
PML = progressive multifocal leukoencephalopathy.  
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Appendix 8 
Procedure for Accelerated Elimination of Teriflunomide  
Teriflunomide is eliminated slowly from the plasma based on the teriflunomide SmPC and 
teriflunomide USPI. Without an accelerated elimination procedure (AEP), it takes on average 
8 months to reach plasma concentrations < 0.02 mg/L, although because of individual variations 
in drug clearance it may take as long as 2 years. An AEP could be used at any time after 
discontinuation of teriflunomide. Elimination can be accelerated by either of the following 
procedures, or as per local standard of care: 
• Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three 
times a day is not well tolerated, cholestyramine 4 g three times a day can be used. 
• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.  
If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive 
unless there is a need to lower teriflunomide plasma concentration rapidly. At the end of 11 days, 
both regimens successfully accelerated teriflunomide elimination, leading to more than 98% 
decrease in teriflunomide plasma concentrations. Use of the AEP may potentially result in return 
of disease activity if the participant had been responding to treatment with teriflunomide. 
In accordance with the teriflunomide prescribing information, it is recommended to confirm a 
teriflunomide level of < 0.02 mg/L after the AEP if the AEP is being done for pregnancy-related 
considerations. All participants previously treated with teriflunomide, or with an unknown 
exposure status during the DBTP and DBE periods entering the OLE, should undergo mandatory 
AEP (all genders) upon completion of the DBE period. The Investigator should dispense 
cholestyramine or activated charcoal and to instruct participant about proper intake. The blood 
concentration of teriflunomide has to be verified upon completion of the AEP via blood sample 
collection between Day 12 to Day 30 at the central laboratory. The Investigator will remain blinded 
to the teriflunomide levels. Please refer to the study-specific central laboratory manual for detailed 
information on the teriflunomide blood level testing. If the AEP is being done for any other safety 
reason (e.g., elevated LFTs), a level can be obtained after the AEP, but is not required. 
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Appendix 9 
Teriflunomide Drug-Drug Interactions  
Teriflunomide has the potential for drug interactions and due to the blinded treatment assignment, 
these should be considered when treating participants. The following are the potential drug 
interactions as defined in the teriflunomide USPI (teriflunomide USPI). 
• DRUG INTERACTIONS 
• Effect of AUBAGIO on CYP2C8 Substrates 
• Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking AUBAGIO, exposure of 
drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may 
be increased. Monitor these patients and adjust the dose of the concomitant drug(s) 
metabolized by CYP2C8 as required. 
• Effect of AUBAGIO on Warfarin 
• Coadministration of AUBAGIO with warfarin requires close monitoring of the INR because 
AUBAGIO may decrease peak INR by approximately 25%. 
• Effect of AUBAGIO on Oral Contraceptives 
• AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. 
Consideration should be given to the type or dose of contraceptives used in combination with 
AUBAGIO. 
• Effect of AUBAGIO on CYP1A2 Substrates 
• Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO, 
exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, 
tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant 
drug(s) metabolized by CYP1A2 as required. 
• Effect of AUBAGIO on Organic Anion Transporter 3 (OAT3) Substrates 
• Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure 
of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, 
ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients 
and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required. 
• Effect of AUBAGIO on BCRP and Organic Anion Transporting Polypeptide B1 and B3 
(OATP1B1/1B3) Substrates 
• Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking 
AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates 
of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), 
especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, 
repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients 
closely for signs and symptoms of increased exposures to the drugs while patients are taking 
AUBAGIO. 
DRUG INTERACTION STUDIES 
• Teriflunomide is not metabolized by Cytochrome P450 or flavin monoamine oxidase enzymes. 
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• The potential effect of AUBAGIO on other drugs: 
• CYP2C8 substrates 
o There was an increase in mean repaglinide Cmax and AUC (1.7- and 2.4-fold, 
respectively) following repeated doses of teriflunomide and a single dose of 0.25 mg 
repaglinide, suggesting that teriflunomide is an inhibitor of CYP2C8 in vivo. The 
magnitude of interaction could be higher at the recommended repaglinide dose. 
• CYP1A2 substrates 
o Repeated doses of teriflunomide decreased mean Cmax and AUC of caffeine by 18% 
and 55%, respectively, suggesting that teriflunomide may be a weak inducer of 
CYP1A2 in vivo. 
• OAT3 substrates 
o There was an increase in mean cefaclor Cmax and AUC (1.43- and 1.54-fold, 
respectively), following repeated doses of teriflunomide, suggesting that teriflunomide 
is an inhibitor of organic anion transporter 3 (OAT3) in vivo. 
• BCRP and OATP1B1/1B3 substrates 
o There was an increase in mean rosuvastatin Cmax and AUC (2.65- and 2.51-fold, 
respectively) following repeated doses of teriflunomide, suggesting that teriflunomide 
is an inhibitor of BCRP transporter and organic anion transporting polypeptide 1B1 and 
1B3 (OATP1B1/1B3). 
• Oral contraceptives 
o There was an increase in mean ethinylestradiol Cmax and AUC0-24 (1.58- and 1.54-fold, 
respectively) and levonorgestrel Cmax and AUC0-24 (1.33- and 1.41-fold, respectively) 
following repeated doses of teriflunomide. 
• Teriflunomide did not affect the pharmacokinetics of bupropion (a CYP2B6 substrate), 
midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), omeprazole (a CYP2C19 
substrate), and metoprolol (a CYP2D6 substrate). 
• The potential effect of other drugs on AUBAGIO 
• Potent CYP and transporter inducers: Rifampin did not affect the pharmacokinetics of 
teriflunomide. 
 
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Appendix 10 
Structured Interview at Telephone Contact  
The primary purpose of this interview is to identify any new or worsening neurological symptoms 
that warrant evaluation at an unscheduled visit. Structured interviews should be performed by 
study personnel between clinic visits – see also Section 1.3 and Section 8. 
Telephone contacts between D1 and W44 are not expected to occur every 4 weeks, since 
participants are scheduled to be on site at least every 4 weeks. However, if a participant is utilizing 
the home visit option, telephone contacts should occur as indicated in the SoA. Telephone contacts 
between W44 and W156 should occur every 4 weeks if a clinic visit is not scheduled. 
If the participant is a woman of childbearing potential, please remember to confirm completion of 
home pregnancy testing and discuss results. 
Please ask the following questions and record participant’s answers during the Structured 
Interview: 
# 
Question: 
No 
Yes 
1 
Since your last visit or structured interview, have you had any new or 
worsening medical problems (such as sudden changes in your thinking, 
alterations in your behavior, visual disturbances, extremity weakness, 
limb coordination problems, or gait abnormalities) that have persisted over 
several days? 
 
 
2 
Since your last visit or structured interview, have you taken any new 
medicines or had any changes in your medicines? 
 
 
3 
Since your last visit or structured interview, have you had any notable 
medical events (e.g., new or changed signs or symptoms, procedures, 
injuries, or laboratory tests/imaging outside of the study) 
 
 
If the participant answered YES to any question, the interviewer should contact the Treating 
Investigator and review the participant’s answers. The Treating Investigator should determine if 
an unscheduled visit is required. 
Record any pertinent comments made by the participant during the interview: 
__________________________________________________________________ 
__________________________________________________________________ 
__________________________________________________________________ 
NAME:__________________________ Date:_____________________________ 
Name of individual completing the structured interview 
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Appendix 11  
Guidance on Clinically Relevant CYP Inducers, Inhibitors, 
and Substrates  
For further information and examples of clinically relevant CYP inducers, inhibitors, and 
substrates, please refer to the applicable tables from the FDA’s Drug Development and Drug 
Interactions. 
Clinically relevant inducers: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers#table3-3 
Clinically relevant inhibitors: 
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers#table3-2 
Clinically relevant sensitive substrates:  
https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-
table-substrates-inhibitors-and-inducers#table3-1 
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Appendix 12 
Protocol Amendment History  
The information for the current amendment is on the title page. 
Protocol Version 5.3-CZE (16 March 2023) 
This amendment is non-substantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is: 
• Clarification of language regarding Investigator access to MRI scans during the OLE 
period 
A high-level description of each change is summarized below, along with its rationale. 
Section # and Name 
Description of Change 
Brief Rationale 
8.1.2 Brain Magnetic 
Resonance Imaging Scans 
• 
Added clarification that the 
Investigator will have full access to 
the results of the MRI scans during 
the OLE period, starting with the first 
MRI assessment in the OLE period at 
Week 48 
Updated text to clarify that the 
Investigator will have access to the 
full MRI reports including MS 
pathology during the OLE period. 
As the EOT MRI of the DBTP is 
used as baseline for OLE period, 
this MRI will remain blinded to MS 
pathology to ensure the integrity of 
the DBTP. 
Protocol Version 5.2-GBR (18 December 2022)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to align the United Kingdom-specific protocol with 
Version 5.0 (global Protocol Version 5.0; 06 December 2022), in which the following key changes 
were implemented: 
• Introduction of an OLE period for participants completing the DBTP prior to approval of 
the long-term follow-up study in their country to enable an option for evobrutinib treatment 
continuation 
• Addition of the following exploratory endpoints: 
o Time to PIRA and time to PIRMA (to evaluate the effect of treatment on progression 
not driven by relapse events or MRI activity) 
o NEP at Weeks 48, 96 
o Level of anti-SARS-CoV-2 antibodies 
A high-level description of each change is summarized below, along with its rationale. 
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Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
• 
Changes as per the main protocol 
text 
For consistency with the main 
protocol text.  
1.2 Schema 
• 
Updated to include OLE period and 
information about transfer points to 
long-term follow-up study 
Introduction of OLE period to allow 
participants to continue evobrutinib 
treatment if separate long-term 
follow-up study is not approved in 
their country. To provide further 
clarity of transitioning into the long 
term follow-up study. 
1.3.1 Schedule of Activities – 
Double-blind Treatment Period • 
Change of study day specification for 
Week 2 PK sample in the PK 
substudy 
To clarify/correct that collection of 
the Week 2 PK sample in the PK 
substudy was specified to happen 
on Day 8. This specification was 
removed for consistency with other 
Week 2 sampling study activities 
(scheduled for Day 15). 
 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
• 
Clarification that telephone contacts 
should occur every 4 weeks through 
Week 156 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls. 
To clarify study procedures.  
 
• 
Urine pregnancy tests every 4 weeks 
from Week 108 to Week 156 were 
added 
• 
Notes for coagulation tests were 
added 
• 
Urinalysis (local) and vital signs were 
added at Week 156 
To clarify study procedures. 
 
• 
Clarification that the 
hepatic/autoimmune panel includes 
focused genetic testing (e.g., HFE) 
and that samples will only be 
collected and analyzed if elevated 
LFTs are observed 
To clarify that the 
hepatic/autoimmune panel 
performed in case of elevated LFTs 
contains a component of focused 
genetic testing. 
To clarify sample collection. 
 
• 
Removal of study intervention 
dispensation at Week 156 
To clarify study procedures. 
 
• 
Clarification that ECG is to be 
performed at Week 96 
Assessment at Week 96 was 
inadvertently omitted from previous 
protocol version (4.0); therefore, 
has been added to correct this 
inconsistency in study procedures. 
 
• 
Included detailed description of 
sample collection and use of novel 
liver function protein biomarkers 
To clarify sample collection. 
 
• 
Included information that during 
unscheduled visits for relapse, EDSS 
assessment is required.  
To clarify study procedures. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
• 
Included specification that novel liver 
function protein biomarkers were 
analyzed from serum, whereas novel 
liver function genomic biomarkers 
were analyzed from plasma  
To clarify distinction between 
samples. 
1.3.2 Schedule of Activities – 
Open-label Extension Period 
• 
Schedule of Activities for OLE period 
added 
To define study procedures to be 
conducted during the OLE period. 
2.3 Benefit/Risk Assessment 
• 
Updated number of participants in 
completed and ongoing clinical 
studies with evobrutinib 
For consistency with the most 
recent IB and DSUR. 
3 Objectives and Estimands 
• 
Addition of exploratory endpoints in 
the DBTP: NEP at Weeks 48 or 96, 
time to PIRA and PIRMA, level of 
anti-SARS-CoV-2 antibodies 
NEP at Weeks 48 or 96 added to 
exploratory endpoints to further 
evaluate the effect of treatment on 
disease activity. 
Time to PIRA and time to PIRMA 
added to exploratory endpoints to 
evaluate the effect of treatment on 
progression not driven by relapse 
events or MRI activity.  
Level of anti-SARS-CoV-2 
antibodies added to evaluate the 
impact of evobrutinib on COVID-19 
vaccinations. 
 
• 
Updated the PF deterioration 
definition to a reduction of at least 
2.7 points on PROMIS PF score 
For consistency with the most 
recent IAP (version 2) and latest 
publication as 5 points was 
provisional. 
 
• 
Addition of Objectives and Endpoints 
table for the OLE Period 
For consistency with the changes 
implemented in Section 1.2. 
4.1 Study Design 
• 
Text revised to include OLE period 
and AEP  
Introduction of OLE for participants 
completing the DBTP prior to 
approval of the long-term follow-up 
study in their country to enable an 
option for evobrutinib treatment 
continuation. 
4.2 Scientific Rationale for 
Study Design 
• 
Text revised to include rationale for 
inclusion of OLE period. 
To define the rationale for the OLE 
period. 
4.4 End of Study Definition 
• 
Included End of Study Definition to 
OLE Period 
To define treatment and study 
completion for OLE period  
5.3 Criteria for Entry into Open 
Label Extension Period 
5.3.1 Inclusion Criteria for 
Open Label Extension Period 
5.3.2 Exclusion Criteria for 
Open Label Extension Period 
• 
Added inclusion and exclusion 
criteria for entering into the OLE 
Period 
For consistency with the changes 
implemented in Section 1.2 and 
Section 4.1. 
5.4.2 Caffeine, Alcohol, and 
Tobacco 
• 
Text added to clarify alcohol 
consumption should be avoided 
during the study 
To clarify study procedures. 
6.3.2 Blinding 
• 
Clarification on blinding procedures 
for the bioanalytical laboratory  
To clarify study procedures. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
• 
Removal of Assignment Method 
Retention 
To clarify study procedures. 
6.5.3 Prohibited Medicines 
• 
Clarification for administration of 
prohibited medications (dalfampridine 
and CYP2C8 substrates) during the 
OLE Period of the study 
To specify changes in prohibited 
medications during OLE period of 
the study. 
7.1 Discontinuation of Study 
Intervention 
• 
Modification of criteria leading to 
permanent study intervention 
discontinuation after extended 
interruption beyond 30 days 
To control the duration of study 
intervention interruption to ensure 
an adequate safety monitoring as 
well as the data integrity impacted 
by the external uncontrolled 
situation (e.g., military, geopolitical 
conflicts).  
 
• 
Addition of 2 new bullet points to 
include individual ALT/AST and 
individual total bilirubin elevation as 
criteria for permanent discontinuation 
of study treatment 
To further clarify that elevated 
levels of ALT/AST and bilirubin 
may not need to occur 
simultaneously to trigger 
permanent discontinuation of study 
treatment.  
 
• 
Text added to clarify confirmation of 
ALT/AST levels elevation 
To further clarify that confirmatory 
laboratory testing will be needed 
after initial elevation of ALT/AST 
levels before interruption of study 
intervention. 
8 Study Assessments and 
Procedures 
• 
Addition of assessments in the OLE 
Period 
• 
Addition of text describing AEP 
procedure 
• 
Included information that during 
unscheduled visits for relapse, EDSS 
assessment is required 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
For consistency with changes 
implemented in the Section 1.2 and 
Section 4.1. 
To provide guidance on the AEP 
procedure required for the OLE 
period. 
To clarify study procedures. 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls. 
8.1.1 Neurological 
Assessment 
• 
Addition of details for neurological 
assessments performed in the OLE 
Period 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.1.1. Qualified Relapse 
• 
Addition of further clarification on 
qualification of relapses 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.1.4 Timed Twenty-Five 
Foot Walk 
8.1.1.5 Nine Hole Peg Test 
8.1.1.6 Symbol Digit Modalities 
Test 
• 
Added clarification that these 
assessments will be administered by 
qualified non-blinded site personnel 
during OLE period 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
Global Version ID: 78691_4679269_6096058
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Section # and Name 
Description of Change 
Brief Rationale 
8.1.2 Brain Magnetic 
Resonance Imaging Scans 
• 
Correction of Screening MRI 
instructions and clarification on the 
blinding of MRI reports to the 
Treating Investigator 
• 
Added details regarding MRI 
assessments in a respective OLE 
MRI substudy 
Correction of erroneous text. 
Updated text to clarify that the 
study-related local radiologist’s 
MRI reports should not include 
details on MS-related pathology 
findings. 
MRI assessments in OLE Period 
were introduced according to 
changes made in Section 1.2 and 
Section 4.1. 
8.1.3.1 Patient Reported 
Outcomes Measurement 
Information System 
• 
Updated the PF deterioration 
definition to a reduction of at least 2.7 
points on PROMIS PF score 
For consistency with the most 
recent IAP (version 2) and latest 
publication as 5 points was 
provisional. 
8.1.3.4 WPAI: MS v2.0 (for 
OLE period only) 
• 
Added Work Productivity and Activity 
Impairment Questionnaire for 
assessment in the OLE Period 
To characterize the associations of 
work productivity and absenteeism 
with disability, fatigue, cognition, 
and health-related quality of life. 
8.2.3 Electrocardiograms 
• 
Added clarification to reflect that no 
central ECG evaluation by central 
reader is required in the OLE period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.2.4 Clinical Safety 
Laboratory Assessments 
• 
The volume of whole blood collected 
for HBV DNA was increased to 4 mL 
To correct details of blood volume 
collection. 
8.2.8 Independent Data 
Monitoring Committee, 
Endpoint Adjudication 
Committee, and Study 
Steering Committee 
• 
Added clarification that the EAC will 
be disbanded after the DBTP has 
ended as relapses will be qualified by 
the treating investigators in the OLE 
period. 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.3.5 Pregnancy 
• 
Added clarification that participants 
who intend to become pregnant 
during the study will be discontinued 
study intervention 
To clarify study procedures. 
8.5 Pharmacokinetics 
• 
Added clarification that no blood 
samples for PK analysis will be 
collected from participants enrolled in 
the OLE. 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.6 Pharmacodynamics 
• 
Added specification for blood 
collection for measurements in  
DBTP PD Substudy 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.8 Biomarkers 
8.8.1 Biomarkers of Disease, 
Disease Activity and 
Progression, Drug-related 
Outcomes, and Treatment 
Response 
8.8.1.2 Novel Liver Function 
Biomarkers  
8.8.3 OLE Blood Biomarker 
PD Substudy – Biomarkers of 
Disease Activity, Progression 
and Response to Drug 
8.8.4 Gene Expression 
• 
Include the option to repurpose 
biomarker-of-disease-samples or 
NfL-biomarker samples for 
vaccination testing 
• 
Specification for collection of 
samples in OLE Period and OLE PD 
Substudy was added 
• 
Collection and analysis of samples 
for assessment of Novel Liver 
Function Protein Biomarkers and for 
gene expression analysis during OLE 
Period was added 
Evaluating the impact of disease-
modifying MS therapies on 
vaccinations has taken on greater 
importance during the COVID-19 
pandemic. 
To reflect assessment in OLE 
Period and to clarify that blood 
samples for gene expression will 
not be collected on OLE Period. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.2.3 Sample Size 
Considerations due to the 
Currently Escalating Crisis in 
Eastern Europe 
• 
Text was added to clarify enrollment 
numbers in the crisis region 
To clarify sample size 
considerations. 
9.3 Populations for Analyses 
• 
Added population for analysis during 
OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
9.4.1 Efficacy Analyses 
• 
Added description of analyses of 
tertiary/exploratory endpoints NEP, 
Time to PIRA, Time to PIRMA, and 
level of anti-SARS-CoV-2 antibodies 
and NfL concentrations at additional 
timepoints 
For consistency with 
tertiary/exploratory objectives in 
Section 3. 
9.4.3.5 Analysis of Open Label 
Extension Period Endpoints 
• 
Added specification of OLE 
Endpoints 
According to changes introduced in 
Section 1.2 and Section 4.1. 
9.4.4 Sequence of Analyses 
• 
Final analysis was added according 
to added OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
Appendix 5 Clinical Laboratory 
Tests 
• 
Added tests that will be only 
applicable to participants in the OLE 
Period, and indicated the tests that 
will not be applicable to those 
participants 
• 
Changes made to align with 
long-term follow-up protocol 
language 
According to changes introduced in 
Section 1.2. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
• 
Clarification added to specify 
mandatory AEP procedure for 
participants entering OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
Appendix 10 Structured 
Interview at Telephone 
Contacts 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
• 
Clarification that telephone contacts 
should occur every 4 weeks through 
Week 156 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls.  
Appendix 11 Guidance on 
Clinically Relevant CYP 
Inducers, Inhibitors, and 
Substrates 
• 
Added reference information for CYP 
inducers, inhibitors, and substrates 
Appendix added to provide 
guidance to Investigators. 
Throughout the document 
• 
Changes made to align with updated 
protocol template 
• 
Minor editorial and document 
formatting revisions 
Minor; therefore, have not been 
summarized. 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


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Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
197/262 
 
 
Protocol Version 5.1-ISR (14 December 2022)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to align the Israel-specific protocol with Version 5.0 
(global Protocol Version 5.0; 06 December 2022), in which the following key changes were 
implemented: 
• Introduction of an OLE period for participants completing the DBTP prior to approval of 
the long-term follow-up study in their country to enable an option for evobrutinib treatment 
continuation 
• Addition of the following exploratory endpoints: 
o Time to PIRA and time to PIRMA (to evaluate the effect of treatment on progression 
not driven by relapse events or MRI activity) 
o NEP at Weeks 48, 96 
o Level of anti-SARS-CoV-2 antibodies 
A high-level description of each change is summarized below, along with its rationale. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
• 
Changes as per the main protocol 
text 
For consistency with the main 
protocol text.  
1.2 Schema 
• 
Updated to include OLE period and 
information about transfer points to 
long-term follow-up study 
Introduction of OLE period to allow 
participants to continue evobrutinib 
treatment if separate long-term 
follow-up study is not approved in 
their country. To provide further 
clarity of transitioning into the long 
term follow-up study. 
1.3.1 Schedule of Activities – 
Double-blind Treatment Period • 
Change of study day specification for 
Week 2 PK sample in the PK 
substudy 
To clarify/correct that collection of 
the Week 2 PK sample in the PK 
substudy was specified to happen 
on Day 8. This specification was 
removed for consistency with other 
Week 2 sampling study activities 
(scheduled for Day 15). 
 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
• 
Clarification that telephone contacts 
should occur every 4 weeks through 
Week 156 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls. 
To clarify study procedures.  
 
• 
Urine pregnancy tests were added 
• 
Notes for coagulation tests were 
added 
To clarify study procedures. 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


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Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
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I N F O R M A T I O N 
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Section # and Name 
Description of Change 
Brief Rationale 
• 
Urinalysis (local) and vital signs were 
added at Week 156 
 
• 
Clarification that the 
hepatic/autoimmune panel includes 
focused genetic testing (e.g., HFE) 
and that samples will only be 
collected and analyzed if elevated 
LFTs are observed 
To clarify that the 
hepatic/autoimmune panel 
performed in case of elevated LFTs 
contains a component of focused 
genetic testing. 
To clarify sample collection. 
 
• 
Removal of IP dispensation at 
Week 156 
To clarify study procedures. 
 
• 
Clarification that ECG is to be 
performed at Week 96 
Assessment at Week 96 was 
inadvertently omitted from previous 
protocol version (4.0); therefore, 
has been added to correct this 
inconsistency in study procedures. 
 
• 
Included detailed description of 
sample collection and use of novel 
liver function protein biomarkers 
To clarify sample collection. 
 
• 
Included information that during 
unscheduled visits for relapse, EDSS 
assessment is required.   
To clarify study procedures. 
 
• 
Included specification that novel liver 
function protein biomarkers were 
analyzed from serum, whereas novel 
liver function genomic biomarkers 
were analyzed from plasma  
To clarify distinction between 
samples. 
1.3.2 Schedule of Activities – 
Open-label Extension Period 
• 
Schedule of Activities for OLE period 
added 
To define study procedures to be 
conducted during the OLE period 
2.3 Benefit/Risk Assessment 
• 
Updated number of participants in 
completed and ongoing clinical 
studies with evobrutinib 
For consistency with the most 
recent IB and DSUR. 
3 Objectives and Estimands 
• 
Addition of exploratory endpoints: 
NEP at Weeks 48 or 96, Time to 
PIRA and PIRMA, and level of 
anti-SARS-CoV-2 antibodies 
NEP at Weeks 48 or 96 added to 
exploratory endpoints to further 
evaluate the effect of treatment on 
disease activity. 
Time to PIRA and time to PIRMA 
added to exploratory endpoints to 
evaluate the effect of treatment on 
progression not driven by relapse 
events or MRI activity.  
Level of anti-SARS-CoV-2 
antibodies added to evaluate the 
impact of evobrutinib on COVID-19 
vaccinations. 
 
• 
Updated the PF deterioration 
definition to a reduction of at least 
2.7 points on PROMIS PF score 
For consistency with the most 
recent IAP (version 2) and latest 
publication as 5 points was 
provisional. 
 
• 
Addition of Objectives and Endpoints 
table for the OLE Period 
For consistency with the changes 
implemented in Section 1.2. 
Global Version ID: 78691_4679269_6096058
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Study Design 
• 
Text revised to include OLE period 
and AEP  
Introduction of OLE for participants 
completing the DBTP prior to 
approval of the long-term follow-up 
study in their country to enable an 
option for evobrutinib treatment 
continuation 
4.2 Scientific Rationale for 
Study Design 
• 
Text revised to include rationale for 
inclusion of OLE period. 
To define the rationale for OLE 
period. 
4.4 End of Study Definition 
• 
Included End of Study Definition to 
OLE Period 
To define treatment completion for 
OLE period  
5.3 Criteria for Entry into Open 
Label Extension Period 
5.3.1 Inclusion Criteria for 
Open Label Extension Period 
5.3.2 Exclusion Criteria for 
Open Label Extension Period 
• 
Added inclusion and exclusion 
criteria for entering into the OLE 
Period 
For consistency with the changes 
implemented in Section 1.2 and 
Section 4.1. 
5.4.2 Caffeine, Alcohol, and 
Tobacco 
• 
Text added to clarify alcohol 
consumption should be avoided 
during the study 
To clarify study procedures. 
6.3.2 Blinding 
• 
Clarification on blinding procedures 
for the bioanalytical laboratory   
To clarify study procedures. 
 
• 
Removal of Assignment Method 
Retention 
To clarify study procedures. 
6.5.3 Prohibited Medicines 
• 
Clarification for administration of 
prohibited medications (dalfampridine  
and CYP2C8 substrates) during the 
OLE Period of the study 
To specify changes in prohibited 
medications during OLE period of 
the study. 
7.1 Discontinuation of Study 
Intervention 
• 
Modification of criteria leading to 
permanent study intervention 
discontinuation after extended 
interruption beyond 30 days 
To control the duration of study 
intervention interruption to ensure 
an adequate safety monitoring as 
well as the data integrity impacted 
by the external uncontrolled 
situation (e.g., military, geopolitical 
conflicts)  
 
• 
Addition of 2 new bullet points to 
include individual ALT/AST and 
individual total bilirubin elevation as 
criteria for permanent discontinuation 
of study intervention 
To further clarify that elevated 
levels of ALT/AST and bilirubin 
may not need to occur 
simultaneously to trigger 
permanent discontinuation of study 
intervention.  
 
• 
Text added to clarify liver function 
testing criteria 
To further clarify that confirmatory 
laboratory testing will be needed 
after initial elevation of ALT/AST 
levels before interruption of study 
intervention 
8 Study Assessments and 
Procedures 
• 
Addition of assessments in the OLE 
Period 
• 
Addition of text describing AEP 
procedure 
For consistency with changes 
implemented in the Section 1.2 and 
Section 4.1. 
To provide guidance on the AEP 
procedure required for the OLE 
period. 
To clarify study procedures 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
200/262 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
• 
Included information that during 
unscheduled visits for relapse, EDSS 
assessment is required 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls 
8.1.1 Neurological 
Assessment 
• 
Addition of details for neurological 
assessments performed in the OLE 
Period 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.1.1. Qualified Relapse 
• 
Addition of further clarification on 
qualification of relapses. 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.1.4 Timed Twenty-Five 
Foot Walk 
8.1.1.5 Nine Hole Peg Test 
8.1.1.6 Symbol Digit Modalities 
Test 
• 
Added clarification that these 
assessments will be administered by 
qualified non-blinded site personnel 
during OLE period 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.2 Brain Magnetic 
Resonance Imaging Scans 
• 
Correction of Screening MRI 
instructions and clarification on the 
blinding of MRI reports to the 
Treating Investigator 
• 
Added details regarding MRI 
assessments in a respective OLE 
MRI substudy 
Correction of erroneous text. 
Updated text to clarify that the 
study-related local radiologist’s 
MRI reports should not include 
details on MS-related pathology 
findings. 
MRI assessments in OLE Period 
were introduced according to 
changes made in Section 1.2 and 
Section 4.1. 
8.1.3.1 Patient Reported 
Outcomes Measurement 
Information System 
• 
Updated the PF deterioration 
definition to a reduction of at least 2.7 
points on PROMIS PF score 
For consistency with the most 
recent IAP (version 2) and latest 
publication as 5 points was 
provisional. 
8.1.3.4 WPAI: MS v2.0 (for 
OLE period only) 
• 
Added Work Productivity and Activity 
Impairment Questionnaire for 
assessment in the OLE Period 
To characterize the associations of 
work productivity and absenteeism 
with disability, fatigue, cognition, 
and health-related quality of life. 
8.2.3 Electrocardiograms 
• 
Added clarification to reflect that no 
central ECG evaluation by central 
reader is required in the OLE period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.2.4 Clinical Safety 
Laboratory Assessments 
• 
The volume of whole blood collected 
for HBV DNA was increased to 4 mL 
To correct details of blood volume 
collection 
8.2.8 Independent Data 
Monitoring Committee, 
Endpoint Adjudication 
Committee, and Study 
Steering Committee 
• 
Added clarification that the EAC will 
be disbanded after the DBTP has 
ended as relapses will be qualified by 
the treating investigators in the OLE 
period. 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.3.5 Pregnancy 
• 
Added clarification that participants 
who intend to become pregnant 
during the study will be discontinued 
study intervention 
To clarify study procedures 
8.5 Pharmacokinetics 
• 
Added clarification that no blood 
samples for PK analysis will be 
According to changes introduced in 
Section 1.2 and Section 4.1. 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
201/262 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
collected from participants enrolled in 
the OLE. 
8.6 Pharmacodynamics 
• 
Added specification for blood 
collection for measurements in  
DBTP PD Substudy. 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.8 Biomarkers 
8.8.1 Biomarkers of Disease, 
Disease Activity and 
Progression, Drug-related 
Outcomes, and Treatment 
Response 
8.8.1.2 Novel Liver Function 
Biomarkers  
8.8.3 OLE Blood Biomarker 
PD Substudy – Biomarkers of 
Disease Activity, Progression 
and Response to Drug 
8.8.4 Gene Expression 
• 
Include the option to repurpose 
biomarker-of-disease-samples or 
NfL-biomarker samples for 
vaccination testing 
• 
Specification for collection of 
samples in OLE Period and OLE PD 
Substudy was added 
• 
Collection and analysis of samples 
for assessment of Novel Liver 
Function Protein Biomarkers and for 
gene expression analysis during OLE 
Period was added 
Evaluating the impact of disease-
modifying MS therapies on 
vaccinations has taken on greater 
importance during the COVID-19 
pandemic. 
To reflect assessment in OLE 
Period and to clarify that blood 
samples for gene expression will 
not be collected on OLE Period. 
9.2.3 Sample Size 
Considerations due to the 
Currently Escalating Crisis in 
Eastern Europe 
• 
Text was added to clarify enrollment 
numbers in the crisis region. 
To clarify sample size 
considerations. 
9.3 Populations for Analyses 
• 
Added population for analysis during 
OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
9.4.1 Efficacy Analyses 
• 
Added description of analyses of 
tertiary/exploratory endpoints NEP, 
Time to PIRA, Time to PIRMA, level 
of anti-SARS-CoV-2 antibodies, and 
NfL concentrations at additional 
timepoints 
For consistency with  
tertiary/exploratory objectives in 
Section 3 
9.4.3.5 Analysis of Open Label 
Extension Period Endpoints 
• 
Added specification of OLE 
Endpoints 
According to changes introduced in 
Section 1.2 and Section 4.1. 
9.4.4 Sequence of Analyses 
• 
Final analysis was added according 
to added OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
Appendix 5 Clinical Laboratory 
Tests 
• 
Added tests that will be only 
applicable to participants in the OLE 
Period, and indicated the tests that 
will not be applicable to those 
participants. 
• 
Changes made to align with 
long-term follow-up protocol 
language 
According to changes introduced in 
Section 1.2. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
• 
Clarification added to specify 
mandatory AEP procedure for 
participants entering OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
Appendix 10 Structured 
Interview at Telephone 
Contacts 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts. 
• 
Clarification that telephone contacts 
should occur every 4 weeks through 
Week 156 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls.  
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
202/262 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
Appendix 12 Guidance on 
Clinically Relevant CYP 
Inducers, Inhibitors, and 
Substrates 
• 
Added reference information for CYP 
inducers, inhibitors, and substrates 
Appendix added to provide 
guidance to Investigators 
Throughout the document 
• 
Changes made to align with updated 
protocol template. 
• 
Minor editorial and document 
formatting revisions.  
Minor; therefore, have not been 
summarized. 
Protocol Version 5.0 (06 December 2022)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is: 
• Introduction of an OLE period for participants completing the DBTP prior to approval of 
the long-term follow-up study in their country to enable an option for evobrutinib treatment 
continuation 
• Addition of the following exploratory endpoints: 
o Time to PIRA and time to PIRMA (to evaluate the effect of treatment on progression 
not driven by relapse events or MRI activity) 
o NEP at Weeks 48, 96 
o Level of anti-SARS-CoV-2 antibodies 
A high-level description of each change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
• 
Changes as per the main protocol 
text 
For consistency with the main 
protocol text.  
1.2 Schema 
• 
Updated to include OLE period and 
information about transfer points to 
long-term follow-up study 
Introduction of OLE period to allow 
participants to continue evobrutinib 
treatment if separate long-term 
follow-up study is not approved in 
their country. To provide further 
clarity of transitioning into the long 
term follow-up study. 
1.3.1 Schedule of Activities – 
Double-blind Treatment Period • 
Change of study day specification for 
Week 2 PK sample in the PK 
substudy 
To clarify/correct that collection of 
the Week 2 PK sample in the PK 
substudy was specified to happen 
on Day 8. This specification was 
removed for consistency with other 
Week 2 sampling study activities 
(scheduled for Day 15). 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
203/262 
 
 
Section # and Name 
Description of Change 
Brief Rationale 
 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
• 
Clarification that telephone contacts 
should occur every 4 weeks through 
Week 156 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls. 
To clarify study procedures.  
 
• 
Urine pregnancy tests were added 
• 
Notes for coagulation tests were 
added 
• 
Urinalysis (local) and vital signs were 
added at Week 156 
To clarify study procedures. 
 
• 
Clarification that the 
hepatic/autoimmune panel includes 
focused genetic testing (e.g., HFE) 
and that samples will only be 
collected and analyzed if elevated 
LFTs are observed 
To clarify that the 
hepatic/autoimmune panel 
performed in case of elevated LFTs 
contains a component of focused 
genetic testing. 
To clarify sample collection. 
 
• 
Removal of IP dispensation at 
Week 156 
To clarify study procedures. 
 
• 
Clarification that ECG is to be 
performed at Week 96 
Assessment at Week 96 was 
inadvertently omitted from previous 
protocol version (4.0); therefore, 
has been added to correct this 
inconsistency in study procedures. 
 
• 
Included detailed description of 
sample collection and use of novel 
liver function protein biomarkers 
To clarify sample collection. 
 
• 
Included information that during 
unscheduled visits for relapse, EDSS 
assessment is required.   
To clarify study procedures. 
 
• 
Included specification that novel liver 
function protein biomarkers were 
analyzed from plasma, whereas 
novel liver function genomic 
biomarkers were analyzed from 
serum  
To clarify distinction between 
samples. 
1.3.2 Schedule of Activities – 
Open-label Extension Period 
• 
Schedule of Activities for OLE period 
added 
To define study procedures to be 
conducted during the OLE period 
2.3 Benefit/Risk Assessment 
• 
Updated number of participants who 
completed clinical studies with 
evobrutinib 
For consistency with the most 
recent IB and DSUR. 
3 Objectives and Estimands 
• 
Addition of exploratory endpoints: 
NEP at Weeks 48 or 96, Time to 
PIRA and PIRMA, level of 
anti-SARS-CoV-2 antibodies 
NEP at Weeks 48 or 96 added to 
exploratory endpoints to further 
evaluate the effect of treatment on 
disease activity. 
Time to PIRA and time to PIRMA 
added to exploratory endpoints to 
evaluate the effect of treatment on 
progression not driven by relapse 
events or MRI activity.  
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Section # and Name 
Description of Change 
Brief Rationale 
Level of anti-SARS-CoV-2 
antibodies added to evaluate the 
impact of evobrutinib on COVID-19 
vaccinations. 
 
• 
Updated the PF deterioration 
definition to a reduction of at least 
2.7 points on PROMIS PF score 
For consistency with the most 
recent IAP (version 2) and latest 
publication as 5 points was 
provisional. 
 
• 
Addition of Objectives and Endpoints 
table for the OLE Period 
For consistency with the changes 
implemented in Section 1.2. 
4.1 Study Design 
• 
Text revised to include OLE period 
and AEP  
Introduction of OLE for participants 
completing the DBTP prior to 
approval of the long-term follow-up 
study in their country to enable an 
option for evobrutinib treatment 
continuation 
4.4 End of Study Definition 
• 
Included End of Study Definition to 
OLE Period 
To define treatment completion for 
OLE period  
5.3 Criteria for Entry into Open 
Label Extension Period 
5.3.1 Inclusion Criteria for 
Open Label Extension Period 
5.3.2 Exclusion Criteria for 
Open Label Extension Period 
• 
Added inclusion and exclusion 
criteria for entering into the OLE 
Period 
For consistency with the changes 
implemented in Section 1.2 and 
Section 4.1. 
5.4.2 Caffeine, Alcohol, and 
Tobacco 
• 
Text added to clarify alcohol 
consumption should be avoided 
during the study 
To clarify study procedures. 
6.3.2 Blinding 
• 
Clarification on blinding procedures 
for the bioanalytical laboratory   
To clarify study procedures. 
 
• 
Removal of Assignment Method 
Retention 
To clarify study procedures. 
6.5.3 Prohibited Medicines 
• 
Clarification for administration of 
prohibited medications 
(dalfampridine, fampridine, and 
CYP2C8 substrates) during the OLE 
Period of the study 
To specify changes in prohibited 
medications during OLE period of 
the study. 
7.1 Discontinuation of Study 
Intervention 
• 
Modification of criteria leading to 
permanent IMP discontinuation after 
extended interruption beyond 
30 days 
To control the duration of IMP 
interruption to ensure an adequate 
safety monitoring as well as the 
data integrity impacted by the 
external uncontrolled situation 
(e.g., military, geopolitical conflicts)  
 
• 
Addition of 2 new bullet points to 
include individual ALT/AST and 
individual total bilirubin elevation as 
criteria for permanent discontinuation 
of study treatment 
To further clarify that elevated 
levels of ALT/AST and bilirubin 
may not need to occur 
simultaneously to trigger 
permanent discontinuation of study 
treatment.  
 
• 
Text added to clarify confirmation of 
ALT/AST levels elevation 
To further clarify that confirmatory 
laboratory testing will be needed 
after initial elevation of ALT/AST 
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Section # and Name 
Description of Change 
Brief Rationale 
levels before interruption of study 
intervention 
8 Study Assessments and 
Procedures 
• 
Addition of assessments in the OLE 
Period 
• 
Addition of text describing AEP 
procedure 
• 
Included information that during 
unscheduled visits for relapse, EDSS 
assessment is required 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts 
For consistency with changes 
implemented in the Section 1.2 and 
Section 4.1. 
To provide guidance on the AEP 
procedure required for the OLE 
period. 
To clarify study procedures 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls 
8.1.1 Neurological 
Assessment 
• 
Addition of details for neurological 
assessments performed in the OLE 
Period 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.1.1. Qualified Relapse 
• 
Addition of further clarification on 
qualification of relapses. 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.1.4 Timed Twenty-Five 
Foot Walk 
8.1.1.5 Nine Hole Peg Test 
8.1.1.6 Symbol Digit Modalities 
Test 
• 
Added clarification that these 
assessments will be administered by 
qualified non-blinded site personnel 
during OLE period 
For consistency with changes 
implemented in Section 1.2 and 
Section 4.1. 
8.1.2 Brain Magnetic 
Resonance Imaging Scans 
• 
Correction of Screening MRI 
instructions and clarification on the 
blinding of MRI reports to the 
Treating Investigator 
• 
Added details regarding MRI 
assessments in a respective OLE 
MRI substudy 
Correction of erroneous text. 
Updated text to clarify that the 
study-related local radiologist’s 
MRI reports should not include 
details on MS-related pathology 
findings. 
MRI assessments in OLE Period 
were introduced according to 
changes made in Section 1.2 and 
Section 4.1. 
8.1.3.1 Patient Reported 
Outcomes Measurement 
Information System 
• 
Updated the PF deterioration 
definition to a reduction of at least 2.7 
points on PROMIS PF score 
For consistency with the most 
recent IAP (version 2) and latest 
publication as 5 points was 
provisional. 
8.1.3.4 WPAI: MS v2.0 (for 
OLE period only) 
• 
Added Work Productivity and Activity 
Impairment Questionnaire for 
assessment in the OLE Period 
To characterize the associations of 
work productivity and absenteeism 
with disability, fatigue, cognition, 
and health-related quality of life. 
8.2.3 Electrocardiograms 
• 
Added clarification to reflect that no 
central ECG evaluation by central 
reader is required in the OLE period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.2.4 Clinical Safety 
Laboratory Assessments 
• 
The volume of whole blood collected 
for HBV DNA was increased to 4 mL 
To correct details of blood volume 
collection 
8.2.8 Independent Data 
Monitoring Committee, 
Endpoint Adjudication 
• 
Added clarification that the EAC will 
be disbanded after the DBTP has 
ended as relapses will be qualified by 
According to changes introduced in 
Section 1.2 and Section 4.1. 
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Section # and Name 
Description of Change 
Brief Rationale 
Committee, and Study 
Steering Committee 
the treating investigators in the OLE 
period. 
8.3.5 Pregnancy 
• 
Added clarification that participants 
who intend to become pregnant 
during the study will be discontinued 
study intervention 
To clarify study procedures 
8.5 Pharmacokinetics 
• 
Added clarification that no blood 
samples for PK analysis will be 
collected from participants enrolled in 
the OLE. 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.6 Pharmacodynamics 
• 
Added specification for blood 
collection for measurements in  
DBTP PD Substudy. 
According to changes introduced in 
Section 1.2 and Section 4.1. 
8.8 Biomarkers 
8.8.1 Biomarkers of Disease, 
Disease Activity and 
Progression, Drug-related 
Outcomes, and Treatment 
Response 
8.8.1.2 Novel Liver Function 
Biomarkers  
8.8.3 OLE Blood Biomarker 
PD Substudy – Biomarkers of 
Disease Activity, Progression 
and Response to Drug 
8.8.4 Gene Expression 
• 
Include the option to repurpose 
biomarker-of-disease-samples or 
NfL-biomarker samples for 
vaccination testing 
• 
Specification for collection of 
samples in OLE Period and OLE PD 
Substudy was added 
• 
Collection and analysis of samples 
for assessment of Novel Liver 
Function Protein Biomarkers and for 
gene expression analysis during OLE 
Period was added 
Evaluating the impact of disease-
modifying MS therapies on 
vaccinations has taken on greater 
importance during the COVID-19 
pandemic. 
To reflect assessment in OLE 
Period and to clarify that blood 
samples for gene expression will 
not be collected on OLE Period. 
9.2.3 Sample Size 
Considerations due to the 
Currently Escalating Crisis in 
Eastern Europe 
• 
Text was added to clarify enrollment 
numbers in the crisis region. 
To clarify sample size 
considerations. 
9.3 Populations for Analyses 
9.4 Statistical Analyses 
• 
Added population for analysis during 
OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
9.4.1 Efficacy Analyses 
• 
Added description of analyses of 
tertiary/exploratory endpoints NEP, 
Time to PIRA, Time to PIRMA, and 
level of anti-SARS-CoV-2 antibodies 
For consistency with  
tertiary/exploratory objectives in 
Section 3 
9.4.3.5 Analysis of Open Label 
Extension Period Endpoints 
• 
Added specification of OLE 
Endpoints 
According to changes introduced in 
Section 1.2 and Section 4.1. 
9.4.4 Sequence of Analyses 
• 
Final analysis was added according 
to added OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
Appendix 5 Clinical Laboratory 
Tests 
• 
Added tests that will be only 
applicable to participants in the OLE 
Period, and indicated the tests that 
will not be applicable to those 
participants. 
• 
Changes made to align with 
long-term follow-up protocol 
language 
According to changes introduced in 
Section 1.2. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
• 
Clarification added to specify 
mandatory AEP procedure for 
participants entering OLE Period 
According to changes introduced in 
Section 1.2 and Section 4.1. 
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Section # and Name 
Description of Change 
Brief Rationale 
Appendix 10 Structured 
Interview at Telephone 
Contacts 
• 
Clarification that no telephone visits 
are to be performed in the study, but 
rather telephone contacts. 
• 
Clarification that telephone contacts 
should occur every 4 weeks through 
Week 156 
The term “telephone visit” was 
replaced with “telephone contact”, 
to clarify that a phone call is not 
replacing an on-site visit, because 
only limited topics are to be 
addressed during those calls.  
Appendix 11 Guidance on 
Clinically Relevant CYP 
Inducers, Inhibitors, and 
Substrates 
• 
Added reference information for CYP 
inducers, inhibitors, and substrates 
Appendix added to provide 
guidance to Investigators 
Throughout the document 
• 
Changes made to align with updated 
protocol template. 
• 
Minor editorial and document 
formatting revisions.  
Minor; therefore, have not been 
summarized. 
Protocol Version 4.3-GBR (25 April 2022)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to align the United Kingdom-specific protocol with 
Version 4.0 (global Protocol Version 4.0; 03 April 2022), in which required changes to the study 
design, duration, and statistical analyses were implemented as critical measures to ensure that the 
validity of the study data and the integrity of the study results are preserved despite the foreseen 
impact of the currently escalating crisis in Eastern Europe. 
A high-level description of each change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Appendix 12 Sponsor 
Signature Page 
 replaces 
 as Medical 
Responsible. 
Change in personnel 
Synopsis 
• 
Revision of treatment duration and 
corresponding update of endpoints 
as applicable. 
• 
Addition of secondary endpoints: 
Time to first occurrence of 24-week 
CDI and Week 12 NfL 
concentration. 
• 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks 
to CFB “over” 96 weeks. 
Modification of population-level 
summary from difference of 
least-squares means at 96 weeks 
to difference of average 
least-squares means, with average 
For consistency with the main protocol 
text.  
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Section # and Name 
Description of Change 
Brief Rationale 
taken over a set of timepoints 
ending with Week 96.  
• 
Modification of secondary MRI 
endpoint from “total number” of T1 
Gd+ based on assessments at 
Week 24, Week 48, and Week 96” 
to “total number of T1 Gd+ lesions 
based on all available MRI scans.” 
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline MRI 
scan.” 
• 
Inclusion of intercurrent event 
“Ukraine crisis” and strategy for 
handling. 
• 
Removal of endpoints in the OLE 
Period. 
• 
Inclusion of opportunity to enter a 
long-term follow-up study under a 
new protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
• 
Update to sample size. 
1.2 Schema 
Revision of the treatment duration 
from fixed 96 weeks to variable 
duration up to 156 weeks. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
 
Removal of OLE Period.  
Due to the extended study duration and 
the planned transition of all eligible 
study completers to the long-term 
follow-up study under a new protocol, 
the OLE Period is no longer needed. 
 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period in line with removal of the 
OLE Period. 
• 
To ensure consistency after removal 
of the OLE Period, and to ensure 
consistency in evaluation of safety 
and efficacy for all participants 
entering the long-term follow-up 
study. 
Furthermore, removal of the OLE Period 
and the mandatory AEP related to 
teriflunomide reduces the risk of 
unblinding due to the variable AEP 
duration. 
1.3 Schedule of Activities 
• 
Inclusion of regular study visits up 
to Week 156. 
• 
Section renumbered from 1.3.1 
Schedule of Activities: Screening 
and Treatment Period (All 
Participants), End of Study 
(Participants Not Entering Open 
• 
For alignment with the revised study 
duration from 96 weeks to 
156 weeks. 
• 
For consistency with the removal of 
the Schedule of Activities for the 
OLE Period. 
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Section # and Name 
Description of Change 
Brief Rationale 
Label Extension Period) to 1.3 
Schedule of Activities. 
1.3.2 Schedule of Activities - 
Optional Open Label 
Extension Period 
Removal of the Schedule of Activities 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period.  
3 Objectives and Estimands 
Revision of treatment duration and 
corresponding update of endpoints as 
applicable. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Addition of secondary endpoints: Time 
to first occurrence of 24-week CDI and 
Week 12 NfL concentration. 
CDI endpoint added to secondary 
endpoints to explore treatment effect on 
additional clinically relevant endpoint for 
disability. Week 12 NfL concentration 
added to investigate early impact of 
treatment on reducing neuronal 
damage. 
 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks to 
CFB “over” 96 weeks. Modification of 
population-level summary from 
difference of least-squares means at 
96 weeks to difference of average 
least-squares means, with average 
taken over a set of timepoints ending 
with Week 96. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
• 
Modification of secondary MRI 
endpoints from “total number” of 
T1 Gd+ lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to “total 
number of T1 Gd+ lesions based 
on all available MRI scans.”   
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline scan.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Inclusion of intercurrent event “Ukraine 
crisis” and strategy for handling. 
To reflect intercurrent event leading to 
study design change. 
 
Modification of tertiary MRI endpoint 
from “total number of CUA lesions 
based on assessments up to Week 
96” to “total number of CUA lesions 
based on all available MRI scans.” 
Modification of tertiary MRI endpoint 
from “total number of new T1 
hypo intense lesions based on 
assessments up to Week 96” to “total 
number of new T1 hypo-intense 
lesions based on all available MRI 
scans.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Removal of Objectives and Endpoints 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
Inclusion of opportunity to enter a 
long-term follow-up study under a new 
protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
A new study will allow participants who 
completed the double blind treatment 
period in the current protocol to enroll in 
a new, single-arm long-term follow-up 
study, which will also include 
participants who completed other RMS 
studies with evobrutinib. The text of the 
protocol has been amended to describe 
a transition opportunity to this long-term 
follow-up study.  
 
Revised planned number of 
participants 
For consistency with changes in Section 
9.2 
4.4 End of Study Definition 
Added clarification that treatment 
completers who enter the long-term 
follow-up study and do not require a 
Safety Follow-up Visit are also 
considered study completers. 
For consistency with the change in 
study design. 
5.3 Criteria for Entry into 
Open Label Extension Period 
Removal of separate criteria for entry 
into OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
6.3.2 Blinding 
Time point of unblinding was updated 
to after having reached the primary 
analysis trigger. 
For consistency with the increased 
study duration, updated statistical 
analyses, and removal of the OLE 
Period. 
6.5.3 Prohibited Medicines 
• 
Correction from "(including 
evobrutinib)" to "(excluding 
evobrutinib)". 
• 
Removal of prohibited medicines 
specific for the OLE Period. 
• 
Correction of typographical error. 
• 
For consistency with the removal of 
the OLE Period. 
8.1.1.3 Confirmed Disability 
Improvement 
Addition of definitions for CDI. 
For clarification. 
8.3.4 Regulatory Reporting 
Requirements for Serious 
Adverse Events 
Text on SUSAR reporting was 
updated in line with the latest protocol 
template. 
To comply with changes to the protocol 
template, which includes a clarified text 
on the SUSAR reporting process. 
8.8 Biomarkers 
Approximate blood volume planned to 
be collected during the study was 
updated. 
To reflect the increased duration 
including additional visits and 
associated sampling. 
8.8.2.1 Neurofilament Light 
Chain 
Added detailed information on NfL as 
biomarker of disease, corresponding 
to the inclusion of NfL as a new 
secondary endpoint. 
NfL has emerged as a potential 
biomarker for disease activity and 
treatment monitoring of patients with 
MS. Additional information added to 
support the inclusion of NfL as 
secondary endpoint. 
9.1.2 Statistical Hypotheses 
Related to Secondary 
Objectives 
Added description of hypotheses 
regarding secondary endpoints. Time 
to 24-Week CDI and Week 12 NfL 
concentration.  
To pre-specify hypotheses regarding all 
secondary endpoints in protocol. 
9.2.1 Sample Size for Primary 
Endpoint: ARR 
Added equation 9.2.1 for the 
information for ARR provided by a 
given sample size, followed for a 
common follow-up time.  
The target information required to 
adequately power the ARR endpoint 
should be pre-specified, as the primary 
analysis will be triggered by achieving 
the target information in both studies, 
plus target CDP events pooled.  
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Section # and Name 
Description of Change 
Brief Rationale 
9.2.2 Sample Size for 
Secondary Endpoint: 12-week 
CDP 
• 
Revised the assumption on 
treatment effect on 12-week CDP 
endpoint from HR = 0.7 to 
HR = 0.66. 
• 
Summarized the outcome of the 
optional IA for BSSR. 
• 
Evobrutinib is considered to have 
efficacy similar to that of anti-CD20 
therapies. Therefore, recent 
reporting of HR = 0.66 (Hauser et al 
2020), comparing hazard of first 
12-week CDP event between 
ofatumumab and teriflunomide, is 
used to revise the assumption of the 
12-week CDP treatment effect. 
• 
To clarify action taken previously 
(when IA for BSSR was conducted 
in August 2021) to ensure adequate 
power for 12-week CDP. 
9.2.3 Sample Size 
Considerations due to the 
Currently Escalating Crisis in 
Eastern Europe 
Added description of re-opening of 
enrollment driven by loss of data due 
to the currently escalating crisis in 
Eastern Europe. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
9.3 Population for Analyses 
• 
Inclusion of modified analysis sets 
(mFAS and mSAF) 
• 
Removal of analysis set specific for 
the OLE Period. 
• 
To address potential lack of data 
robustness for data from participants 
and sites in Ukraine, Russian 
Federation, and Belarus. 
• 
For consistency with the removal of 
the OLE Period. 
9.4.1 Efficacy Analyses 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints Time to 
24-Week CDI and Week 12 NfL 
concentration. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints and most 
exploratory endpoints in the 
protocol.  
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
To reflect intercurrent event leading 
to study design change. 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints Time-to-
24-Week CDI and Week 12 NfL 
concentration, including estimand 
framework details. 
• 
To reflect intercurrent event leading 
to study design change. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints in the protocol, 
including estimand framework 
details.  
9.4.1.3 Sensitivity Analyses 
Updated sensitivity analyses  
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.2.8 Sensitivity Analyses 
Added sensitivity analyses. 
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
9.4.4 Sequence of Analyses 
Removal of Final Analysis at the end 
of OLE. 
For consistency with removal of OLE 
Period. 
9.4.4.1 Optional Interim 
Analysis for Blinded Sample 
Size Re-estimation 
Summarized the outcome of the 
optional IA for BSSR. 
To clarify action taken previously (when 
IA for BSSR was conducted in August 
2021) to ensure adequate power for 
12-week CDP. 
9.4.4.2 Primary Analysis 
• 
Described trigger for primary 
analysis based on achieving 
sufficient information for ARR in 
each study and sufficient 12-week 
CDP events from pooled studies. 
• 
Added Equation 9.4.4 for blinded 
monitoring of information for ARR 
provided by a study. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration, where primary 
analysis is information driven. 
• 
The information should be monitored 
for each study, as the target 
information needs to be met for each 
study before the primary analysis 
can be triggered. 
9.4.4.3 Multiplicity 
Updated multiple testing strategy to 
incorporate addition of 2 secondary 
endpoints, minor change to testing 
order (CDI endpoint tested prior to 
PRO endpoints), and minor correction 
to alpha level for pooled tests. 
Multiplicity graph updated to depict the 
strategy update. 
To ensure that the multiple testing 
strategy provides a more complete 
picture of treatment effect on EDSS and 
NfL levels. Alpha level at which pooled 
tests are to be conducted was corrected 
from 0.025 to 0.024375 based on 
Bretz 2019.  
10 References  
• 
Addition of Bretz 2019.  
• 
Addition of Kuhle 2016, 
Kuhle 2017, Kuhle 2021, Disanto 
2017, Piehl 2018, Novakova 2017, 
Barro 2018. 
• 
Update of Hauser 2019 to 
Hauser 2020. 
• 
Addition in line with changes in 
Section 9.4.4.3.  
• 
Addition in line with changes in 
Section 8.8.2.1. 
• 
Full publication has become 
available. 
Appendix 4 
• 
Updated serious adverse event 
reporting requirements. 
• 
Text on SUSAR reporting was 
updated in line with the latest 
protocol template. 
To comply with changes to protocol 
template, which clarifies the SAE and 
SUSAR reporting process. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period 
To ensure consistency after removal of 
the OLE Period, to avoid potential 
unblinding due to variability in duration 
of AEP; and in evaluation of safety and 
efficacy for all participants entering the 
long-term follow-up study. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 4.2-ISR (25 April 2022)  
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This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to align the Israel-specific protocol with Version 4.0 
(global Protocol Version 4.0; 03 April 2022), in which required changes to the study design, 
duration, and statistical analyses were implemented as critical measures to ensure that the validity 
of the study data and the integrity of the study results are preserved despite the foreseen impact of 
the currently escalating crisis in Eastern Europe. 
A high-level description of each change is summarized below, along with its rationale. 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Appendix 13 Sponsor 
Signature Page 
 replaces 
 as Medical 
Responsible. 
Change in personnel 
Synopsis 
• 
Revision of treatment duration and 
corresponding update of endpoints 
as applicable. 
• 
Addition of secondary endpoints: 
Time to first occurrence of 24-week 
CDI and Week 12 NfL 
concentration. 
• 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks 
to CFB “over” 96 weeks. 
Modification of population-level 
summary from difference of 
least-squares means at 96 weeks 
to difference of average 
least-squares means, with average 
taken over a set of timepoints 
ending with Week 96.  
• 
Modification of secondary MRI 
endpoint from “total number” of T1 
Gd+ based on assessments at 
Week 24, Week 48, and Week 96” 
to “total number of T1 Gd+ lesions 
based on all available MRI scans.” 
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline MRI 
scan.” 
• 
Inclusion of intercurrent event 
“Ukraine crisis” and strategy for 
handling. 
• 
Removal of endpoints in the OLE 
Period. 
• 
Inclusion of opportunity to enter a 
long-term follow-up study under a 
For consistency with the main protocol 
text.  
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Section # and Name 
Description of Change 
Brief Rationale 
new protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
• 
Update to sample size. 
1.2 Schema 
Revision of the treatment duration 
from fixed 96 weeks to variable 
duration up to 156 weeks. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
 
Removal of OLE Period.  
Due to the extended study duration and 
the planned transition of all eligible 
study completers to the long-term 
follow-up study under a new protocol, 
the OLE Period is no longer needed. 
 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period in line with removal of the 
OLE Period. 
• 
To ensure consistency after removal 
of the OLE Period, and to ensure 
consistency in evaluation of safety 
and efficacy for all participants 
entering the long-term follow-up 
study. 
Furthermore, removal of the OLE Period 
and the mandatory AEP related to 
teriflunomide reduces the risk of 
unblinding due to the variable AEP 
duration. 
1.3 Schedule of Activities 
• 
Inclusion of regular study visits up 
to Week 156. 
• 
Section renumbered from 1.3.1 
Schedule of Activities: Screening 
and Treatment Period (All 
Participants), End of Study 
(Participants Not Entering Open 
Label Extension Period) to 1.3 
Schedule of Activities. 
• 
For alignment with the revised study 
duration from 96 weeks to 
156 weeks. 
• 
For consistency with the removal of 
the Schedule of Activities for the 
OLE Period. 
1.3.2 Schedule of Activities - 
Optional Open Label 
Extension Period 
Removal of the Schedule of Activities 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period.  
3 Objectives and Estimands 
Revision of treatment duration and 
corresponding update of endpoints as 
applicable. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Addition of secondary endpoints: Time 
to first occurrence of 24-week CDI and 
Week 12 NfL concentration. 
CDI endpoint added to secondary 
endpoints to explore treatment effect on 
additional clinically relevant endpoint for 
disability. Week 12 NfL concentration 
added to investigate early impact of 
treatment on reducing neuronal 
damage. 
 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks to 
CFB “over” 96 weeks. Modification of 
population-level summary from 
difference of least-squares means at 
96 weeks to difference of average 
least-squares means, with average 
taken over a set of timepoints ending 
with Week 96. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
• 
Modification of secondary MRI 
endpoints from “total number” of 
T1 Gd+ lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to “total 
number of T1 Gd+ lesions based 
on all available MRI scans.”   
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline scan.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Inclusion of intercurrent event “Ukraine 
crisis” and strategy for handling. 
To reflect intercurrent event leading to 
study design change. 
 
Modification of tertiary MRI endpoint 
from “total number of CUA lesions 
based on assessments up to Week 
96” to “total number of CUA lesions 
based on all available MRI scans.” 
Modification of tertiary MRI endpoint 
from “total number of new T1 
hypo intense lesions based on 
assessments up to Week 96” to “total 
number of new T1 hypo-intense 
lesions based on all available MRI 
scans.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Removal of Objectives and Endpoints 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
4.1 Overall Design 
Inclusion of opportunity to enter a 
long-term follow-up study under a new 
protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
A new study will allow participants who 
completed the double blind treatment 
period in the current protocol to enroll in 
a new, single-arm long-term follow-up 
study, which will also include 
participants who completed other RMS 
studies with evobrutinib. The text of the 
protocol has been amended to describe 
a transition opportunity to this long-term 
follow-up study.  
 
Revised planned number of 
participants 
For consistency with changes in Section 
9.2 
4.4 End of Study Definition 
Added clarification that treatment 
completers who enter the long-term 
follow-up study and do not require a 
Safety Follow-up Visit are also 
considered study completers. 
For consistency with the change in 
study design. 
5.3 Criteria for Entry into 
Open Label Extension Period 
Removal of separate criteria for entry 
into OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
6.3.2 Blinding 
Time point of unblinding was updated 
to after having reached the primary 
analysis trigger. 
For consistency with the increased 
study duration, updated statistical 
analyses, and removal of the OLE 
Period. 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5.3 Prohibited Medicines 
• 
Correction from "(including 
evobrutinib)" to "(excluding 
evobrutinib)". 
• 
Removal of prohibited medicines 
specific for the OLE Period. 
• 
Correction of typographical error. 
• 
For consistency with the removal of 
the OLE Period. 
8.1.1.3 Confirmed Disability 
Improvement 
Addition of definitions for CDI. 
For clarification. 
8.3.4 Regulatory Reporting 
Requirements for Serious 
Adverse Events 
Text on SUSAR reporting was 
updated in line with the latest protocol 
template. 
To comply with changes to the protocol 
template, which includes a clarified text 
on the SUSAR reporting process. 
8.8 Biomarkers 
Approximate blood volume planned to 
be collected during the study was 
updated. 
To reflect the increased duration 
including additional visits and 
associated sampling. 
8.8.2.1 Neurofilament Light 
Chain 
Added detailed information on NfL as 
biomarker of disease, corresponding 
to the inclusion of NfL as a new 
secondary endpoint. 
NfL has emerged as a potential 
biomarker for disease activity and 
treatment monitoring of patients with 
MS. Additional information added to 
support the inclusion of NfL as 
secondary endpoint. 
9.1.2 Statistical Hypotheses 
Related to Secondary 
Objectives 
Added description of hypotheses 
regarding secondary endpoints Time 
to 24-Week CDI and Week 12 NfL 
concentration.  
To pre-specify hypotheses regarding all 
secondary endpoints in protocol. 
9.2.1 Sample Size for Primary 
Endpoint: ARR 
Added equation 9.2.1 for the 
information for ARR provided by a 
given sample size, followed for a 
common follow-up time.  
The target information required to 
adequately power the ARR endpoint 
should be pre-specified, as the primary 
analysis will be triggered by achieving 
the target information in both studies, 
plus target CDP events pooled.  
9.2.2 Sample Size for 
Secondary Endpoint: 12-week 
CDP 
• 
Revised the assumption on 
treatment effect on 12-week CDP 
endpoint from HR = 0.7 to 
HR = 0.66. 
• 
Summarized the outcome of the 
optional IA for BSSR. 
• 
Evobrutinib is considered to have 
efficacy similar to that of anti-CD20 
therapies. Therefore, recent 
reporting of HR = 0.66 (Hauser et al 
2020), comparing hazard of first 
12-week CDP event between 
ofatumumab and teriflunomide, is 
used to revise the assumption of the 
12-week CDP treatment effect. 
• 
To clarify action taken previously 
(when IA for BSSR was conducted 
in August 2021) to ensure adequate 
power for 12-week CDP. 
9.2.3 Sample Size 
Considerations due to the 
Currently Escalating Crisis in 
Eastern Europe 
Added description of re-opening of 
enrollment driven by loss of data due 
to the currently escalating crisis in 
Eastern Europe. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
9.3 Population for Analyses 
• 
Inclusion of modified analysis sets 
(mFAS and mSAF) 
• 
Removal of analysis set specific for 
the OLE Period. 
• 
To address potential lack of data 
robustness for data from participants 
and sites in Ukraine, Russian 
Federation, and Belarus. 
• 
For consistency with the removal of 
the OLE Period. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.1 Efficacy Analyses 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints Time to 
24-Week CDI and Week 12 NfL 
concentration. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints and most 
exploratory endpoints in the 
protocol.  
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
To reflect intercurrent event leading 
to study design change. 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints Time-to-
24-Week CDI and Week 12 NfL 
concentration, including estimand 
framework details. 
• 
To reflect intercurrent event leading 
to study design change. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints in the protocol, 
including estimand framework 
details.  
9.4.1.3 Sensitivity Analyses 
Updated sensitivity analyses  
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
9.4.2.8 Sensitivity Analyses 
Added sensitivity analyses. 
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
9.4.4 Sequence of Analyses 
Removal of Final Analysis at the end 
of OLE. 
For consistency with removal of OLE 
Period. 
9.4.4.1 Optional Interim 
Analysis for Blinded Sample 
Size Re-estimation 
Summarized the outcome of the 
optional IA for BSSR. 
To clarify action taken previously (when 
IA for BSSR was conducted in August 
2021) to ensure adequate power for 
12-week CDP. 
9.4.4.2 Primary Analysis 
• 
Described trigger for primary 
analysis based on achieving 
sufficient information for ARR in 
each study and sufficient 12-week 
CDP events from pooled studies. 
• 
Added Equation 9.4.4 for blinded 
monitoring of information for ARR 
provided by a study. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration, where primary 
analysis is information driven. 
• 
The information should be monitored 
for each study, as the target 
information needs to be met for each 
study before the primary analysis 
can be triggered. 
9.4.4.3 Multiplicity 
Updated multiple testing strategy to 
incorporate addition of 2 secondary 
endpoints, minor change to testing 
order (CDI endpoint tested prior to 
PRO endpoints), and minor correction 
To ensure that the multiple testing 
strategy provides a more complete 
picture of treatment effect on EDSS and 
NfL levels. Alpha level at which pooled 
tests are to be conducted was corrected 
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Section # and Name 
Description of Change 
Brief Rationale 
to alpha level for pooled tests. 
Multiplicity graph updated to depict the 
strategy update. 
from 0.025 to 0.024375 based on 
Bretz 2019.  
10 References  
• 
Addition of Bretz 2019.  
• 
Addition of Kuhle 2016, 
Kuhle 2017, Kuhle 2021, Disanto 
2017, Piehl 2018, Novakova 2017, 
Barro 2018. 
• 
Update of Hauser 2019 to 
Hauser 2020. 
• 
Addition in line with changes in 
Section 9.4.4.3.  
• 
Addition in line with changes in 
Section 8.8.2.1. 
• 
Full publication has become 
available. 
Appendix 4 
• 
Updated serious adverse event 
reporting requirements. 
• 
Text on SUSAR reporting was 
updated in line with the latest 
protocol template. 
To comply with changes to protocol 
template, which clarifies the SAE and 
SUSAR reporting process. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period 
To ensure consistency after removal of 
the OLE Period, to avoid potential 
unblinding due to variability in duration 
of AEP; and in evaluation of safety and 
efficacy for all participants entering the 
long-term follow-up study. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 4.1-CAN (19 April 2022)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to align the Canada-specific protocol with Version 4.0 
(global Protocol Version 4.0; 03 April 2022), in which required changes to the study design, 
duration, and statistical analyses were implemented as critical measures to ensure that the validity 
of the study data and the integrity of the study results are preserved despite the foreseen impact of 
the currently escalating crisis in Eastern Europe. 
A high-level description of each change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Appendix 12 Sponsor 
Signature Page 
 replaces 
 as Medical 
Responsible. 
Change in personnel 
Synopsis 
• 
Revision of treatment duration and 
corresponding update of endpoints 
as applicable. 
• 
Addition of secondary endpoints: 
Time to first occurrence of 24-week 
For consistency with the main protocol 
text.  
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Section # and Name 
Description of Change 
Brief Rationale 
CDI and Week 12 NfL 
concentration. 
• 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks 
to CFB “over” 96 weeks. 
Modification of population-level 
summary from difference of 
least-squares means at 96 weeks 
to difference of average 
least-squares means, with average 
taken over a set of timepoints 
ending with Week 96.  
• 
Modification of secondary MRI 
endpoint from “total number” of T1 
Gd+ based on assessments at 
Week 24, Week 48, and Week 96” 
to “total number of T1 Gd+ lesions 
based on all available MRI scans.” 
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline MRI 
scan.” 
• 
Inclusion of intercurrent event 
“Ukraine crisis” and strategy for 
handling. 
• 
Removal of endpoints in the OLE 
Period. 
• 
Inclusion of opportunity to enter a 
long-term follow-up study under a 
new protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
• 
Update to sample size. 
1.2 Schema 
Revision of the treatment duration 
from fixed 96 weeks to variable 
duration up to 156 weeks. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
 
Removal of OLE Period.  
Due to the extended study duration and 
the planned transition of all eligible 
study completers to the long-term 
follow-up study under a new protocol, 
the OLE Period is no longer needed. 
 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period in line with removal of the 
OLE Period. 
• 
To ensure consistency after removal 
of the OLE Period, and to ensure 
consistency in evaluation of safety 
and efficacy for all participants 
entering the long-term follow-up 
study. 
Furthermore, removal of the OLE Period 
and the mandatory AEP related to 
teriflunomide reduces the risk of 
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Section # and Name 
Description of Change 
Brief Rationale 
unblinding due to the variable AEP 
duration. 
1.3 Schedule of Activities 
• 
Inclusion of regular study visits up 
to Week 156. 
• 
Section renumbered from 1.3.1 
Schedule of Activities: Screening 
and Treatment Period (All 
Participants), End of Study 
(Participants Not Entering Open 
Label Extension Period) to 1.3 
Schedule of Activities. 
• 
For alignment with the revised study 
duration from 96 weeks to 
156 weeks. 
• 
For consistency with the removal of 
the Schedule of Activities for the 
OLE Period. 
1.3.2 Schedule of Activities - 
Optional Open Label 
Extension Period 
Removal of the Schedule of Activities 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period.  
3 Objectives and Estimands 
Revision of treatment duration and 
corresponding update of endpoints as 
applicable. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Addition of secondary endpoints: Time 
to first occurrence of 24-week CDI and 
Week 12 NfL concentration. 
CDI endpoint added to secondary 
endpoints to explore treatment effect on 
additional clinically relevant endpoint for 
disability. Week 12 NfL concentration 
added to investigate early impact of 
treatment on reducing neuronal 
damage. 
 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks to 
CFB “over” 96 weeks. Modification of 
population-level summary from 
difference of least-squares means at 
96 weeks to difference of average 
least-squares means, with average 
taken over a set of timepoints ending 
with Week 96. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
• 
Modification of secondary MRI 
endpoints from “total number” of 
T1 Gd+ lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to “total 
number of T1 Gd+ lesions based 
on all available MRI scans.”   
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline scan.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Inclusion of intercurrent event “Ukraine 
crisis” and strategy for handling. 
To reflect intercurrent event leading to 
study design change. 
 
Modification of tertiary MRI endpoint 
from “total number of CUA lesions 
based on assessments up to Week 
96” to “total number of CUA lesions 
based on all available MRI scans.” 
Modification of tertiary MRI endpoint 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
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Section # and Name 
Description of Change 
Brief Rationale 
from “total number of new T1 
hypo intense lesions based on 
assessments up to Week 96” to “total 
number of new T1 hypo-intense 
lesions based on all available MRI 
scans.” 
 
Removal of Objectives and Endpoints 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
4.1 Overall Design 
Inclusion of opportunity to enter a 
long-term follow-up study under a new 
protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
A new study will allow participants who 
completed the double blind treatment 
period in the current protocol to enroll in 
a new, single-arm long-term follow-up 
study, which will also include 
participants who completed other RMS 
studies with evobrutinib. The text of the 
protocol has been amended to describe 
a transition opportunity to this long-term 
follow-up study.  
 
Revised planned number of 
participants 
For consistency with changes in Section 
9.2 
4.4 End of Study Definition 
Added clarification that treatment 
completers who enter the long-term 
follow-up study and do not require a 
Safety Follow-up Visit are also 
considered study completers. 
For consistency with the change in 
study design. 
5.3 Criteria for Entry into 
Open Label Extension Period 
Removal of separate criteria for entry 
into OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
6.3.2 Blinding 
Time point of unblinding was updated 
to after having reached the primary 
analysis trigger. 
For consistency with the increased 
study duration, updated statistical 
analyses, and removal of the OLE 
Period. 
6.5.3 Prohibited Medicines 
• 
Correction from "(including 
evobrutinib)" to "(excluding 
evobrutinib)". 
• 
Removal of prohibited medicines 
specific for the OLE Period. 
• 
Correction of typographical error. 
• 
For consistency with the removal of 
the OLE Period. 
8.1.1.3 Confirmed Disability 
Improvement 
Addition of definitions for CDI. 
For clarification. 
8.3.4 Regulatory Reporting 
Requirements for Serious 
Adverse Events 
Text on SUSAR reporting was 
updated in line with the latest protocol 
template. 
To comply with changes to the protocol 
template, which includes a clarified text 
on the SUSAR reporting process. 
8.8 Biomarkers 
Approximate blood volume planned to 
be collected during the study was 
updated. 
To reflect the increased duration 
including additional visits and 
associated sampling. 
8.8.2.1 Neurofilament Light 
Chain 
Added detailed information on NfL as 
biomarker of disease, corresponding 
to the inclusion of NfL as a new 
secondary endpoint. 
NfL has emerged as a potential 
biomarker for disease activity and 
treatment monitoring of patients with 
MS. Additional information added to 
support the inclusion of NfL as 
secondary endpoint. 
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Section # and Name 
Description of Change 
Brief Rationale 
9 Statistical Considerations 
Revision of treatment duration and 
corresponding update of endpoints as 
applicable. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
9.1.2 Statistical Hypotheses 
Related to Secondary 
Objectives 
Added description of hypotheses 
regarding secondary endpoints Time 
to 24-Week CDI and Week 12 NfL 
concentration.  
To pre-specify hypotheses regarding all 
secondary endpoints in protocol. 
9.2.1 Sample Size for Primary 
Endpoint: ARR 
Added equation 9.2.1 for the 
information for ARR provided by a 
given sample size, followed for a 
common follow-up time.  
The target information required to 
adequately power the ARR endpoint 
should be pre-specified, as the primary 
analysis will be triggered by achieving 
the target information in both studies, 
plus target CDP events pooled.  
9.2.2 Sample Size for 
Secondary Endpoint: 12-week 
CDP 
• 
Revised the assumption on 
treatment effect on 12-week CDP 
endpoint from HR = 0.7 to 
HR = 0.66. 
• 
Summarized the outcome of the 
optional IA for BSSR. 
• 
Evobrutinib is considered to have 
efficacy similar to that of anti-CD20 
therapies. Therefore, recent 
reporting of HR = 0.66 (Hauser et al 
2020), comparing hazard of first 
12-week CDP event between 
ofatumumab and teriflunomide, is 
used to revise the assumption of the 
12-week CDP treatment effect. 
• 
To clarify action taken previously 
(when IA for BSSR was conducted 
in August 2021) to ensure adequate 
power for 12-week CDP. 
9.2.3 Sample Size 
Considerations due to the 
Currently Escalating Crisis in 
Eastern Europe 
Added description for re-opening of 
enrollment driven by loss of data due 
to the currently escalating crisis in 
Eastern Europe. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
9.3 Population for Analyses 
• 
Inclusion of modified analysis sets 
(mFAS and mSAF) 
• 
Removal of analysis set specific for 
the OLE Period. 
• 
To address potential lack of data 
robustness for data from participants 
and sites in Ukraine, Russian 
Federation, and Belarus. 
• 
For consistency with the removal of 
the OLE Period. 
9.4.1 Efficacy Analyses 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints for Time to 
24-Week CDI and Week 12 NfL 
concentration. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints and most 
exploratory endpoints in the 
protocol.  
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
To reflect intercurrent event leading 
to study design change. 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
To reflect intercurrent event leading 
to study design change. 
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Section # and Name 
Description of Change 
Brief Rationale 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints for Time-to-
24-Week CDI and Week 12 NfL 
concentration, including estimand 
framework details. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints in the protocol, 
including estimand framework 
details.  
9.4.1.3 Sensitivity Analyses 
Updated sensitivity analyses.  
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
9.4.2.8 Sensitivity Analyses 
Added sensitivity analyses. 
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
9.4.4 Sequence of Analyses 
Removal of Final Analysis at the end 
of OLE. 
For consistency with removal of OLE 
Period. 
9.4.4.1 Optional Interim 
Analysis for Blinded Sample 
Size Re-estimation 
Summarized the outcome of the 
optional IA for BSSR. 
To clarify action taken previously (when 
IA for BSSR was conducted in August 
2021) to ensure adequate power for 
12-week CDP. 
9.4.4.2 Primary Analysis 
• 
Described trigger for primary 
analysis based on achieving 
sufficient information for ARR in 
each study and sufficient 12-week 
CDP events from pooled studies. 
• 
Added Equation 9.4.4 for blinded 
monitoring of information for ARR 
provided by a study. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration, where primary 
analysis is information driven. 
• 
The information should be monitored 
for each study, as the target 
information needs to be met for each 
study before the primary analysis 
can be triggered. 
9.4.4.3 Multiplicity 
Updated multiple testing strategy to 
incorporate addition of 2 secondary 
endpoints, minor change to testing 
order (CDI endpoint tested prior to 
PRO endpoints), and minor correction 
to alpha level for pooled tests. 
Multiplicity graph updated to depict the 
strategy update. 
To ensure that the multiple testing 
strategy provides a more complete 
picture of treatment effect on EDSS and 
NfL levels. Alpha level at which pooled 
tests are to be conducted was corrected 
from 0.025 to 0.024375 based on 
Bretz 2019.  
10 References  
• 
Addition of Bretz 2019.  
• 
Addition of Kuhle 2016, Kuhle 
2017, Kuhle 2021, Disanto 2017, 
Piehl 2018, Novakova 2017, Barro 
2018. 
• 
Update of Hauser 2019 to 
Hauser 2020. 
• 
Addition in line with changes in 
Section 9.4.4.3.  
• 
Addition in line with changes in 
Section 8.8.2.1. 
• 
Full publication has become 
available. 
Appendix 4 
• 
Updated serious adverse event 
reporting requirements. 
• 
Text on SUSAR reporting was 
updated in line with the latest 
protocol template. 
To comply with changes to protocol 
template, which clarifies the SAE and 
SUSAR reporting process. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period 
To ensure consistency after removal of 
the OLE Period, to avoid potential 
unblinding due to variability in duration 
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Section # and Name 
Description of Change 
Brief Rationale 
of AEP; and in evaluation of safety and 
efficacy for all participants entering the 
long-term follow-up study. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 4.0 (03 April 2022)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is the implementation of required changes to the study 
design, duration, and statistical analyses as critical measures to ensure that the validity of the study 
data and the integrity of the study results are preserved despite the foreseen impact of the currently 
escalating crisis in Eastern Europe.  
A high-level description of each change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Appendix 12 Sponsor 
Signature Page 
 replaces 
 as Medical 
Responsible. 
Change in personnel 
Synopsis 
• 
Revision of treatment duration and 
corresponding update of endpoints 
as applicable. 
• 
Addition of secondary endpoints: 
Time to first occurrence of 24-week 
CDI and Week 12 NfL 
concentration. 
• 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks 
to CFB “over” 96 weeks. 
Modification of population-level 
summary from difference of 
least-squares means at 96 weeks 
to difference of average 
least-squares means, with average 
taken over a set of timepoints 
ending with Week 96.  
• 
Modification of secondary MRI 
endpoint from “total number” of T1 
Gd+ based on assessments at 
Week 24, Week 48, and Week 96” 
to “total number of T1 Gd+ lesions 
based on all available MRI scans.” 
• 
Modification of secondary MRI 
endpoint from “total number of new 
For consistency with the main protocol 
text.  
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Section # and Name 
Description of Change 
Brief Rationale 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline MRI 
scan.” 
• 
Inclusion of intercurrent event 
“Ukraine crisis” and strategy for 
handling. 
• 
Removal of endpoints in the OLE 
Period. 
• 
Inclusion of opportunity to enter a 
long-term follow-up study under a 
new protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
1.2 Schema 
Revision of the treatment duration 
from fixed 96 weeks to variable 
duration up to 156 weeks. 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
 
Removal of OLE Period  
Due to the extended study duration and 
the planned transition of all eligible 
study completers to the long-term 
follow-up study under a new protocol, 
the OLE Period is no longer needed. 
 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period in line with removal of the 
OLE Period. 
• 
To ensure consistency after removal 
of the OLE Period, and to ensure 
consistency in evaluation of safety 
and efficacy for all participants 
entering the long-term follow-up 
study. 
Furthermore, removal of the OLE Period 
and the mandatory AEP related to 
teriflunomide reduces the risk of 
unblinding due to the variable AEP 
duration. 
1.3 Schedule of Activities 
• 
Inclusion of regular study visits up 
to Week 156. 
• 
Section renumbered from 1.3.1 
Schedule of Activities: Screening 
and Treatment Period (All 
Participants), End of Study 
(Participants Not Entering Open 
Label Extension Period) to 1.3 
Schedule of Activities. 
• 
For alignment with the revised study 
duration from 96 weeks to 
156 weeks. 
• 
For consistency with the removal of 
the Schedule of Activities for the 
OLE Period. 
1.3.2 Schedule of Activities - 
Optional Open Label 
Extension Period 
Removal of the Schedule of Activities 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period.  
3 Objectives and Estimands 
Revision of treatment duration and 
corresponding update of endpoints as 
applicable. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Addition of secondary endpoints: Time 
to first occurrence of 24-week CDI and 
Week 12 NfL concentration. 
CDI endpoint added to secondary 
endpoints to explore treatment effect on 
additional clinically relevant endpoint for 
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Section # and Name 
Description of Change 
Brief Rationale 
disability. Week 12 NfL concentration 
added to investigate early impact of 
treatment on reducing neuronal 
damage. 
 
Modification of secondary PROMIS 
endpoints from CFB “at” 96 weeks to 
CFB “over” 96 weeks. Modification of 
population-level summary from 
difference of least-squares means at 
96 weeks to difference of average 
least-squares means, with average 
taken over a set of timepoints ending 
with Week 96. 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
• 
Modification of secondary MRI 
endpoints from “total number” of 
T1 Gd+ lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to “total 
number of T1 Gd+ lesions based 
on all available MRI scans.”   
• 
Modification of secondary MRI 
endpoint from “total number of new 
or enlarging T2 lesions based on 
assessments at Week 24, 
Week 48, and Week 96” to 
“number of new or enlarging T2 
lesions on the last available MRI 
scan relative to the baseline scan.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Inclusion of intercurrent event “Ukraine 
crisis” and strategy for handling 
To reflect intercurrent event leading to 
study design change. 
 
Modification of tertiary MRI endpoint 
from “total number of CUA lesions 
based on assessments up to Week 
96” to “total number of CUA lesions 
based on all available MRI scans.” 
Modification of tertiary MRI endpoint 
from “total number of new T1 
hypo intense lesions based on 
assessments up to Week 96” to “total 
number of new T1 hypo-intense 
lesions based on all available MRI 
scans.” 
For consistency with the study design 
change from fixed treatment duration to 
variable treatment duration. 
 
Removal of Objectives and Endpoints 
for the OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
4.1 Overall Design 
Inclusion of opportunity to enter a 
long-term follow-up study under a new 
protocol for participants after 
completion of evobrutinib treatment 
under the current protocol. 
A new study will allow participants who 
completed the double-blind treatment 
period in the current protocol to enroll in 
a new, single-arm long-term follow-up 
study, which will also include 
participants who completed other RMS 
studies with evobrutinib. The text of the 
protocol has been amended to describe 
a transition opportunity to this long-term 
follow-up study.  
4.4 End of Study Definition 
Added clarification that treatment 
completers who enter the long-term 
For consistency with the change in 
study design. 
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Section # and Name 
Description of Change 
Brief Rationale 
follow-up study and do not require a 
Safety Follow-up Visit are also 
considered study completers. 
5.3 Criteria for Entry into 
Open Label Extension Period 
Removal of separate criteria for entry 
into OLE Period. 
For consistency with the changes in 
study design, including the removal of 
the OLE Period. 
6.3.2 Blinding 
Time point of unblinding was updated 
to after having reached the primary 
analysis trigger. 
For consistency with the increased 
study duration, updated statistical 
analyses, and removal of the OLE 
Period. 
6.5.3 Prohibited Medicines 
• 
Correction from "(including 
evobrutinib)" to "(excluding 
evobrutinib)". 
• 
Removal of prohibited medicines 
specific for the OLE Period. 
• 
Correction of typographical error. 
• 
For consistency with the removal of 
the OLE Period. 
8.1.1.3 Confirmed Disability 
Improvement 
Addition of definitions for CDI. 
For clarification. 
8.3.4 Regulatory Reporting 
Requirements for Serious 
Adverse Events 
Text on SUSAR reporting was 
updated in line with the latest protocol 
template. 
To comply with changes to the protocol 
template, which includes a clarified text 
on the SUSAR reporting process. 
8.8 Biomarkers 
Approximate blood volume planned to 
be collected during the study was 
updated. 
To reflect the increased duration 
including additional visits and 
associated sampling. 
8.8.2.1 Neurofilament Light 
Chain 
Added detailed information on NfL as 
biomarker of disease, corresponding 
to the inclusion of NfL as a new 
secondary endpoint. 
NfL has emerged as a potential 
biomarker for disease activity and 
treatment monitoring of patients with 
MS. Additional information added to 
support the inclusion of NfL as 
secondary endpoint. 
9.1.2 Statistical Hypotheses 
Related to Secondary 
Objectives 
Added description of hypotheses 
regarding secondary endpoints Time 
to 24-Week CDI and Week 12 NfL 
concentration  
To pre-specify hypotheses regarding all 
secondary endpoints in protocol. 
9.2.1 Sample Size for Primary 
Endpoint: ARR 
Added equation 9.2.1 for the 
information for ARR provided by a 
given sample size, followed for a 
common follow-up time.  
The target information required to 
adequately power the ARR endpoint 
should be pre-specified, as the primary 
analysis will be triggered by achieving 
the target information in both studies, 
plus target CDP events pooled.  
9.2.2 Sample Size for 
Secondary Endpoint: 12-week 
CDP 
• 
Revised the assumption on 
treatment effect on 12-week CDP 
endpoint from HR = 0.7 to 
HR = 0.66. 
• 
Summarized the outcome of the 
optional IA for BSSR. 
• 
Evobrutinib is considered to have 
efficacy similar to that of anti-CD20 
therapies. Therefore, recent 
reporting of HR = 0.66 (Hauser et al 
2020), comparing hazard of first 
12-week CDP event between 
ofatumumab and teriflunomide, is 
used to revise the assumption of the 
12-week CDP treatment effect. 
• 
To clarify action taken previously 
(when IA for BSSR was conducted 
in August 2021) to ensure adequate 
power for 12-week CDP. 
9.2.3 Sample Size 
Considerations due to the 
Added description of re-opening of 
enrollment driven by loss of data due 
To ensure primary and important 
secondary endpoints are adequately 
powered despite loss of data from 
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Section # and Name 
Description of Change 
Brief Rationale 
Currently Escalating Crisis in 
Eastern Europe 
to the currently escalating crisis in 
Eastern Europe. 
participants at sites in Ukraine, Russian 
Federation, and Belarus. 
9.3 Population for Analyses 
• 
Inclusion of modified analysis sets 
(mFAS and mSAF) 
• 
Removal of analysis set specific for 
the OLE Period. 
• 
To address potential lack of data 
robustness for data from participants 
and sites in Ukraine, Russian 
Federation, and Belarus. 
• 
For consistency with the removal of 
the OLE Period. 
9.4.1 Efficacy Analyses 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints Time to 
24-Week CDI and Week 12 NfL 
concentration. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints and most 
exploratory endpoints in the 
protocol.  
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
• 
Updated ARR endpoint to indicate 
“up to 156 weeks”. 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration. 
• 
To reflect intercurrent event leading 
to study design change. 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
• 
Updated intercurrent event 
strategy to include “Ukraine crisis” 
as intercurrent event. 
• 
Modification of secondary PROMIS 
and MRI endpoints. 
• 
Added description of analyses of 
secondary endpoints Time-to-
24-Week CDI and Week 12 NfL 
concentration, including estimand 
framework details. 
• 
To reflect intercurrent event leading 
to study design change. 
• 
For consistency with the secondary 
PROMIS and MRI objective in 
Section 3. 
• 
To pre-specify analyses of all 
secondary endpoints in the protocol, 
including estimand framework 
details.  
9.4.1.3 Sensitivity Analyses 
Updated sensitivity analyses  
For consistency with change to study 
from fixed to variable treatment duration 
and to evaluate the impact of the 
currently escalating crisis in Eastern 
Europe. 
9.4.4 Sequence of Analyses 
Removal of Final Analysis at the end 
of OLE. 
For consistency with removal of OLE 
Period. 
9.4.4.1 Optional Interim 
Analysis for Blinded Sample 
Size Re-estimation 
Summarized the outcome of the 
optional IA for BSSR. 
To clarify action taken previously (when 
IA for BSSR was conducted in August 
2021) to ensure adequate power for 
12-week CDP. 
9.4.4.2 Primary Analysis 
• 
Described trigger for primary 
analysis based on achieving 
sufficient information for ARR in 
each study and sufficient 12-week 
CDP events from pooled studies. 
• 
Added Equation 9.4.4 for blinded 
monitoring of information for ARR 
provided by a study. 
• 
For consistency with change to 
study from fixed to variable 
treatment duration, where primary 
analysis is information driven. 
• 
The information should be monitored 
for each study, as the target 
information needs to be met for each 
study before the primary analysis 
can be triggered. 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.4.3 Multiplicity 
Updated multiple testing strategy to 
incorporate addition of 2 secondary 
endpoints, minor change to testing 
order (CDI endpoint tested prior to 
PRO endpoints), and minor correction 
to alpha level for pooled tests. 
Multiplicity graph updated to depict the 
strategy update. 
To ensure that the multiple testing 
strategy provides a more complete 
picture of treatment effect on EDSS and 
NfL levels. Alpha level at which pooled 
tests are to be conducted was corrected 
from 0.025 to 0.02475 based on 
Bretz 2019.  
10 References  
• 
Addition of Bretz 2019.  
• 
Addition of Kuhle 2016, Kuhle 
2017, Disanto 2017, Piehl 2018, 
Novakova 2017, Barro 2018. 
• 
Update of Hauser 2019 to 
Hauser 2020. 
• 
Addition in line with changes in 
Section 9.4.4.3.  
• 
Addition in line with changes in 
Section 8.8.2.1. 
• 
Full publication has become 
available. 
Appendix 4 
Text on SUSAR reporting was 
updated in line with the latest protocol 
template. 
To comply with changes to protocol 
template, which clarifies the SUSAR 
reporting process. 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
Removal of the mandatory AEP for 
male participants prior to entry into the 
OLE Period 
To ensure consistency after removal of 
the OLE Period, to avoid potential 
unblinding due to variability in duration 
of AEP; and in evaluation of safety and 
efficacy for all participants entering the 
long-term follow-up study. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document 
formatting revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 3.3-GBR (11 June 2021)  
The primary purpose of this amendment is to add clarification based on the latest MHRA guideline 
in the United Kingdom on concomitant use of COVID-19 vaccines (MHRA Managing Clinical 
Trials During COVID-19; last updated 16 March 2021). A high-level description of each change 
is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
2.3 Benefit/Risk Assessment 
Added information that efficacy rate of 
approved COVID-19 vaccines under the 
study interventions treatments are 
unknown. 
To comply with MHRA regulatory 
requirements 
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
Added information that the examples of 
intercurrent events to be further specified 
in the IAP include COVID-19 infection 
and COVID-19 vaccination. 
To include information that 
appropriate analyses will be 
conducted to track potential 
COVID-19 infection/vaccines 
impact on endpoints. 
9.4.1.3 Sensitivity Analyses 
Added information to clarify that 
appropriate analyses will be conducted 
to track impact of potential COVID-19 
infection/COVID-19 vaccination. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor; therefore, have not been 
summarized. 
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Section # and Name 
Description of Change 
Brief Rationale 
Minor editorial and document formatting 
revisions. 
Protocol Version 3.2-ISR (07 June 2021)  
Overall Rationale for the Amendment 
The primary purpose of this amendment is to revise that genetic samples will not be tested for sites 
in Israel, with the exception of testing for variants in the High Iron Fe (human hemochromatosis 
protein) (HFE) gene. A high-level description of each change is summarized below, along with its 
rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
Added a note to clarify that the items 
(gene expression, pharmacogenetics, 
and/or novel liver function genomic 
biomarkers) are not collected/applicable 
to sites in Israel. 
Due to regulatory requirements in 
Israel. 
1.3.1 Schedule of Activities: 
Screening and Treatment Period 
(All Participants), End of Study 
(Participants Not Entering Open 
Label Extension Period) 
1.3.2 Schedule of Activities: 
Optional Open Label Extension 
Period 
3 Objectives and Estimands: 
Table 2 Tertiary/Exploratory 
Objectives and Endpoint 
Table 3 Objectives and 
Endpoints for the Open Label 
Extension Period 
4.2 Scientific Rationale for Study 
Design 
8.7 Pharmacogenetics 
8.8 Biomarkers 
8.8.3 Novel Liver Function 
Protein Biomarkers and Novel 
Liver Function Genomic 
Biomarkers 
8.8.4 Gene Expression 
Appendix 2 Study Governance 
Appendix 6 Pharmacogenetics, 
Use/Analysis of DNA 
1.3.1 Schedule of Activities: 
Screening and Treatment Period 
(All Participants), End of Study 
(Participants Not Entering Open 
Label Extension Period) 
Added a note to clarify that the genetic 
testing in Israel is restricted to testing for 
variants in HFE gene. 
Due to regulatory requirements in 
Israel. 
1.3.2 Schedule of Activities: 
Optional Open Label Extension 
Period 
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Section # and Name 
Description of Change 
Brief Rationale 
4.2 Scientific Rationale for Study 
Design 
7.1 Discontinuation of Study 
Intervention 
8.8 Biomarkers 
8.8.4 Gene Expression 
Appendix 5 Clinical Laboratory 
Tests 
Appendix 11 Country-specific 
Requirements 
Included Appendix 11 to clarify that 
genetic samples will not be tested for 
sites in Israel, with the exception of 
testing for variants in the HFE gene. 
Due to regulatory requirements in 
Israel. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document formatting 
revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 3.1-CAN (26 May 2021)  
Overall Rationale for the Amendment 
The purpose of this amendment is to align the Canada-specific protocol with Version 3.0 (global 
protocol amendment; 19 May 2021), in which changes and clarifications were made to remove the 
interim analysis (IA) for unblinded sample size re-estimation (USSR) and include an optional IA 
for blinded sample size re-estimation (BSSR). A high-level description of each change is 
summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
 
 replaces 
 as Medical Monitor. 
Change in personnel. 
1.1 Synopsis 
 
- Updated this section to reflect the 
inclusion of an optional IA for BSSR 
which are detailed below. 
- Included clarification that enrollment in 
the Open Label Extension (OLE) can 
comprise participants who are still under 
study treatment when an event-driven 
primary analysis (PA) is triggered. 
For consistency and clarification. 
1.2 Study Schema 
Updated the footnote to remove details 
of treatment period for participants 
entering the OLE period. 
To be aligned with the inclusion of 
an optional IA for BSSR. 
4.1 Overall Design 
- Included clarification that enrollment in 
the OLE can comprise participants who 
are still under study treatment when an 
event-driven PA is triggered. 
- Included an optional IA for BSSR and 
the information that the number of 
participants to be enrolled may be 
Due to unexpectedly rapid 
enrollment, the trigger for the IA for 
USSR is projected to occur months 
after the completion of enrollment, 
considered too late to implement 
changes following outcome of IA 
from an operational perspective. 
The optional IA for BSSR, triggered 
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Global Version ID: 78691_4679269_6105942
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MS200527_0080 
 
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Section # and Name 
Description of Change 
Brief Rationale 
increased 
to 
approximately 
1162 randomized participants. 
- Removed the IA for USSR triggered 
when approximately 35% to 45% of 
planned 12-week CDP events have been 
observed. 
- Included clarification that enrollment in 
the OLE will be offered to participants who 
have their blinded Treatment Period 
interrupted due to PA trigger as they will 
be considered as study completers. 
prior to completion of enrollment, 
does not have this disadvantage. 
5.3.1 Inclusion Criteria for Open 
Label Extension Period 
5.3.2 Exclusion Criteria for Open 
Label Extension Period 
- Included clarification that inclusion in the 
OLE can comprise participants who are 
still under study treatment when an 
event-driven PA is triggered. 
- Included clarification that exclusion in 
the OLE can happen for participants who 
had discontinued blinded treatment prior 
to the PA trigger (in the case of an event-
driven PA). 
For clarification. 
6.3.2 Blinding 
Minor update to consider current 
changes related to PA trigger. 
For consistency. 
7.1 Discontinuation of Study 
Intervention 
Criteria for Temporary Discontinuation of 
Study Intervention: 
Amylase and lipase retest criteria 
amended to include the fasting state. 
For clarification. 
8 Study Assessments and 
Procedures 
Included the information that T-SPOT 
test will be conducted at the local 
laboratories after positive QuantiFERON 
test. 
To correct error as the requirement 
was included in Protocol Version 
2.0. 
8 Study Assessments and 
Procedures 
Sentence was rephrased to clarify that 
reported relapse will be adjudicated by 
the Endpoint Adjudication Committee. 
For clarification. 
8 Study Assessments and 
Procedures 
Removed coagulation. 
To correct error as the requirement 
was removed in Protocol Version 
2.0. 
8 Study Assessments and 
Procedures 
Included clarification that enrollment in 
the OLE will be offered to participants 
who have their blinded Treatment Period 
interrupted due to PA trigger as they will 
be considered as study completers. 
For clarification. 
8 Study Assessments and 
Procedures 
8.2.3 Electrocardiograms 
9.4.2.4 Electrocardiogram 
Parameters 
Sections were rephrased to consider 
central ECG reading. 
To avoid variability in interpretation 
of ECGs by non-cardiologists and 
in reports obtained from the locally 
sourced ECG machines. 
8.2.8 Independent Data 
Monitoring Committee, Endpoint 
Adjudication Committee, and 
Study Steering Committee 
Removed the information that IDMC will 
review unblinded interim data. 
Due to the removal of the IA for 
USSR, the role played by the IDMC 
in making the sample size increase 
recommendation is no longer 
required. 
9.2 Sample Size Determination 
Removed the IA for USSR and included 
an optional IA for BSSR and the 
information that a minimal or 
Rationale same as for change to 
Section 4.1. 
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Section # and Name 
Description of Change 
Brief Rationale 
non-existent effect on type-1 error 
inflation is expected. 
9.4.1 Efficacy Analyses 
Clarified that Time to 24-week confirmed 
disability progression (CDP) will be 
analyzed in the same manner as the 
Time to 12-week CDP. 
Due to removing the IA for USSR, 
there is no need to control type-1 
error in the 12-week CDP analysis 
using the Cui, Hung, Wang 
method. Thus, 12-week CDP and 
24-week CDP will be analyzed in 
the same manner. 
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
Updated the treatment duration to 
consider the participants who have their 
blinded Treatment Period interrupted due 
to PA trigger. 
To be aligned with the inclusion of 
an optional IA for BSSR. 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
- Removed the IA for USSR and included 
an optional IA for BSSR with details 
regarding methodology. 
- Changed the statistical test for the 
secondary endpoint Time to 12-week 
CDP from Cui, Hung, Wang to stratified 
logrank and clarified that Time to 
24-week CDP will be analyzed in the 
same manner. 
Rationale same as for change to 
Section 9.4.1. 
9.4.4 Sequence of Analyses 
- Removed the IA for USSR and included 
an optional IA for BSSR. 
- Clarified how the PA is triggered if the 
sample size is increased. 
Rationale for replacing IA for USSR 
with optional IA for BSSR same as 
that for change to Section 4.1.   
Clarification. 
9.4.4.1 Optional Interim Analysis 
for Blinded Sample Size 
Re-estimation 
Removed the IA for USSR and included 
an optional IA for BSSR with details 
regarding methodology. 
Rationale same as for change to 
Section 4.1. 
9.4.4.2 Primary Analysis 
- Clarified how the PA is triggered if the 
sample size is increased. 
- Clarified that the PA is based on data 
from the blinded Treatment Period. 
Clarification. 
9.4.4.3 Multiplicity 
Removed the multiplicity approach for 
controlling family wise type I error at the 
1 sided 0.025 level in the presence of 
USSR based on pooled 12-week CDP. 
 
Rationale same as for change to 
Section 9.4.1. 
10 References 
Removed Cui, Hung, Wang reference 
that is no longer applicable and included 
new reference applicable to BSSR 
(Friede et al., 2019). 
Rationale same as for change to 
Section 4.1 and Section 9.4.1. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document formatting 
revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 3.0 (19 May 2021)  
Overall Rationale for the Amendment 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942


Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
234/262 
 
 
The primary purpose of this amendment is to remove the interim analysis (IA) for unblinded 
sample size re-estimation (USSR) and include an optional IA for blinded sample size re-estimation 
(BSSR). A high-level description of each change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
 
 replaces 
as Medical Monitor. 
Change in personnel. 
1.1 Synopsis 
 
- Updated this section to reflect the 
inclusion of an optional IA for BSSR 
which are detailed below. 
- Included clarification that enrollment in 
the Open Label Extension (OLE) can 
comprise participants who are still under 
study treatment when an event-driven 
primary analysis (PA) is triggered. 
For consistency and clarification. 
1.2 Study Schema 
Updated the footnote to remove details 
of treatment period for participants 
entering the OLE period. 
To be aligned with the inclusion of 
an optional IA for BSSR. 
4.1 Overall Design 
- Included clarification that enrollment in 
the OLE can comprise participants who 
are still under study treatment when an 
event-driven PA is triggered. 
- Included an optional IA for BSSR and 
the information that the number of 
participants to be enrolled may be 
increased 
to 
approximately 
1162 randomized participants. 
- Removed the IA for USSR triggered 
when approximately 35% to 45% of 
planned 12-week CDP events have been 
observed. 
- Included clarification that enrollment in 
the OLE will be offered to participants who 
have their blinded Treatment Period 
interrupted due to PA trigger as they will 
be considered as study completers. 
Due to unexpectedly rapid 
enrollment, the trigger for the IA for 
USSR is projected to occur months 
after the completion of enrollment, 
considered too late to implement 
changes following outcome of IA 
from an operational perspective. 
The optional IA for BSSR, triggered 
prior to completion of enrollment, 
does not have this disadvantage. 
5.3.1 Inclusion Criteria for Open 
Label Extension Period 
5.3.2 Exclusion Criteria for Open 
Label Extension Period 
- Included clarification that inclusion in the 
OLE can comprise participants who are 
still under study treatment when an 
event-driven PA is triggered. 
- Included clarification that exclusion in 
the OLE can happen for participants who 
had discontinued blinded treatment prior 
to the PA trigger (in the case of an event-
driven PA). 
For clarification. 
6.3.2 Blinding 
Minor update to consider current 
changes related to PA trigger. 
For consistency. 
7.1 Discontinuation of Study 
Intervention 
Criteria for Temporary Discontinuation of 
Study Intervention: 
Amylase and lipase retest criteria 
amended to include the fasting state. 
For clarification. 
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Global Version ID: 78691_4679269_6105942
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Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
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Section # and Name 
Description of Change 
Brief Rationale 
8 Study Assessments and 
Procedures 
Included the information that T-SPOT 
test will be conducted at the local 
laboratories after positive QuantiFERON 
test. 
To correct error as the requirement 
was included in Protocol Version 
2.0. 
8 Study Assessments and 
Procedures 
Sentence was rephrased to clarify that 
reported relapse will be adjudicated by 
the Endpoint Adjudication Committee. 
For clarification. 
8 Study Assessments and 
Procedures 
Removed coagulation. 
To correct error as the requirement 
was removed in Protocol Version 
2.0. 
8 Study Assessments and 
Procedures 
Included clarification that enrollment in 
the OLE will be offered to participants 
who have their blinded Treatment Period 
interrupted due to PA trigger as they will 
be considered as study completers. 
For clarification. 
8 Study Assessments and 
Procedures 
8.2.3 Electrocardiograms 
9.4.2.4 Electrocardiogram 
Parameters 
Sections were rephrased to consider 
central ECG reading. 
To avoid variability in interpretation 
of ECGs by non-cardiologists and 
in reports obtained from the locally 
sourced ECG machines. 
8.2.8 Independent Data 
Monitoring Committee, Endpoint 
Adjudication Committee, and 
Study Steering Committee 
Removed the information that IDMC will 
review unblinded interim data. 
Due to the removal of the IA for 
USSR, the role played by the IDMC 
in making the sample size increase 
recommendation is no longer 
required. 
9.2 Sample Size Determination 
Removed the IA for USSR and included 
an optional IA for BSSR and the 
information that a minimal or 
non-existent effect on type-1 error 
inflation is expected. 
Rationale same as for change to 
Section 4.1. 
9.4.1 Efficacy Analyses 
Clarified that Time to 24-week confirmed 
disability progression (CDP) will be 
analyzed in the same manner as the 
Time to 12-week CDP. 
Due to removing the IA for USSR, 
there is no need to control type-1 
error in the 12-week CDP analysis 
using the Cui, Hung, Wang 
method. Thus, 12-week CDP and 
24-week CDP will be analyzed in 
the same manner. 
9.4.1.1 Efficacy Analyses 
Related to Primary Objective 
Updated the treatment duration to 
consider the participants who have their 
blinded Treatment Period interrupted due 
to PA trigger. 
To be aligned with the inclusion of 
an optional IA for BSSR. 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
- Removed the IA for USSR and included 
an optional IA for BSSR with details 
regarding methodology. 
- Changed the statistical test for the 
secondary endpoint Time to 12-week 
CDP from Cui, Hung, Wang to stratified 
logrank and clarified that Time to 24-
week CDP will be analyzed in the same 
manner. 
Rationale same as for change to 
Section 9.4.1. 
9.4.4 Sequence of Analyses 
- Removed the IA for USSR and included 
an optional IA for BSSR. 
- Clarified how the PA is triggered if the 
sample size is increased. 
Rationale for replacing IA for USSR 
with optional IA for BSSR same as 
that for change to Section 4.1.   
Clarification. 
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Global Version ID: 78691_4679269_6105942


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MS200527_0080 
 
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Section # and Name 
Description of Change 
Brief Rationale 
9.4.4.1 Optional Interim Analysis 
for Blinded Sample Size 
Re-estimation 
Removed the IA for USSR and included 
an optional IA for BSSR with details 
regarding methodology. 
Rationale same as for change to 
Section 4.1. 
9.4.4.2 Primary Analysis 
- Clarified how the PA is triggered if the 
sample size is increased. 
- Clarified that the PA is based on data 
from the blinded Treatment Period. 
Clarification. 
9.4.4.3 Multiplicity 
Removed the multiplicity approach for 
controlling family wise type I error at the 
1 sided 0.025 level in the presence of 
USSR based on pooled 12-week CDP. 
 
Rationale same as for change to 
Section 9.4.1. 
10 References 
Removed Cui, Hung, Wang reference 
that is no longer applicable and included 
new refence applicable to BSSR (Friede 
et al., 2019). 
Rationale same as for change to 
Section 4.1 and Section 9.4.1. 
Throughout the document 
Changes made to align with updated 
protocol template. 
Minor editorial and document formatting 
revisions. 
Minor; therefore, have not been 
summarized. 
Protocol Version 2.1-CAN (04 December 2020)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The purpose of this amendment is to align the Canada-specific protocol with Version 2.0 (global 
protocol amendment; 27 November 2020), in which changes and clarifications were made based 
on feedback from early enrolling investigational sites, and newly available data from studies of 
other agents in multiple sclerosis, and to clarify COVID mitigation procedures. A high-level 
description of each change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Appendix 12 Sponsor Signature 
Page 
 replaces 
 
 as Medical Responsible 
 replaces 
 
 as Medical Monitor 
Change in personnel 
1.1 Synopsis, Study Intervention 
Groups and Duration 
1.2 Schema 
4.1 Overall Design 
Additional text included, and minor 
rewording, to clarify the follow-up window 
for ‘confirmation’ of disability progression 
as measured by the EDSS 
For additional clarification 
1.1 Synopsis 
1.2 Schema 
With approval from the Medical Monitor, 
the Screening period may be extended 
to 12 weeks maximum (increased from 
8 weeks maximum). See Section 8 Study 
Assessments and Procedures 
To allow sufficient time for repeat 
laboratory results and other 
unanticipated events prior to 
randomization 
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Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
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Section # and Name 
Description of Change 
Brief Rationale 
4.1 Overall Design 
5.5 Screen Failures 
Appendix 2 Study Governance 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
1.3 Schedule of Activities 
Added that female participants may 
undergo AEP at the Investigator’s 
discretion, and that the same AEP 
process should be followed as for male 
participants 
To clarify the process in the event 
of a female participant undergoing 
AEP 
1.3 Schedule of Activities 
(Main Study) 
‘F/D’ changed to SFU (Safety Follow-up) 
F/D visit window changed from ± 3 days 
to + 3 days 
Added note that visit window for Week 4 
is ± 2 days 
To clarify that this is a safety visit 
SFU visit must be ≥ 28 days after 
last study intervention 
Clarification 
1.3 Schedule of Activities 
(Main Study and OLE) 
Telephone 
Visit:  
Simplified 
notes 
and 
referred 
to 
Structured Interview 
Clarified individual visits 
Clarification/simplification of 
protocol. Structured interview put 
into place. 
Telephone Visit not required when 
participants attend clinic 
1.3 Schedule of Activities 
(Main Study) 
QuantiFERON testing removed from 
W48 and W96 visits 
 
 
Separate row added for TB testing for 
high TB burden countries 
TB testing is only required at 
Screening if the participant resides 
in a country that has a high TB 
burden 
Separated testing in high TB 
burden countries to avoid 
confusion. Clarified that the assay 
used to confirm eligibility should be 
used for monitoring during the 
study 
1.3 Schedule of Activities 
Efficacy 
(Main Study and OLE) 
Added note that neurological evaluation 
EDSS, T25-FW, 9-HPT, and SDMT 
should preferably be done after the PRO 
assessments 
EDSS evaluation: added note that this 
can be done by phone, if available, if the 
participant is unable to attend scheduled 
visit 
To clarify that these should 
preferably be completed before 
other assessments, but PROs are 
done first 
Mitigation in light of the COVID-19 
pandemic, if the participant is 
unable to attend scheduled visit. 
(Lechner-Scott 2003) 
1.3 Schedule of Activities 
PRO Assessments 
(Main Study) 
SF-36 v2 assessment added at 
Week 108 
Assessment required at Week 108 
for participants for whom this is 
also D1 of the OLE 
1.3 Schedule of Activities 
PRO Assessments 
(Main Study and OLE) 
PROs: Removed reference to the use of 
a tablet 
For flexibility in method of 
collection 
1.3 Schedule of Activities 
Safety Assessments 
C-SSRS: Removed reference to the use 
of a tablet 
For flexibility in method of 
collection 
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MS200527_0080 
 
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Section # and Name 
Description of Change 
Brief Rationale 
(Main Study and OLE) 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
Coagulation test will be done at 
Screening, W96, OLE D1 and W144 only 
No exposure-related abnormalities 
in PT or PTT have been identified 
in prior studies of evobrutinib. 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
Text amended to indicate that urinalysis 
will be assessed locally and microscopy 
will be submitted for central evaluation 
only if indicated 
Clarification 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study) 
Noted that a second ECG will be 
collected postdose on Day 1, and that 
additional ECGs can be done at the 
Investigator’s discretion 
To clarify that there are 2 ECGs on 
Day 1 and to allow additional ECGs 
if required 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
Removed notes regarding telephone 
visits from ‘AE, SAE & AESI Review‘ and 
‘Concomitant Medication and 
Procedures Review’ rows 
Clarification/simplification of 
protocol. Structured interview put 
into place 
1.3 Schedule of Activities 
Study Intervention 
(Main Study) 
Added dispensing of study intervention 
at Week 4 
Requested by the study team 
1.3 Schedule of Activities 
Study Intervention 
(Main Study and OLE) 
Text amended to state when study 
intervention should be administered on 
site: PK sampling days (Main Study) and 
biomarker sample collection days (OLE) 
Removed detail about self-administration 
at home 
To clarify when study intervention 
should be administered in the clinic 
 
 
To avoid confusion; detail is in 
Section 6.1 
1.3 Schedule of Activities 
Study Intervention 
(Main Study and OLE) 
Compliance: Clarified that participant 
should complete the Participant diary. 
Note added that the diary should be 
reviewed during on-site visits 
Clarification 
1.3 Schedule of Activities 
Biomarkers 
(Main study and OLE) 
8.8.3 Novel Liver Function 
Protein Biomarkers and Novel 
Liver Function Genomic 
Biomarkers 
Removed requirement for novel liver 
function protein and genomic biomarkers 
to be collected prior to first daily dose 
Dosing time is not relevant to 
sample collection time 
1.3 Schedule of Activities 
(OLE) 
Note ‘d’: Added ‘unless they are 
undergoing AEP’ 
The last visit in the main study will 
not be the first visit in the OLE for 
female participants undergoing 
AEP 
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Global Version ID: 78691_4679269_6105942


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MS200527_0080 
 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
(OLE) 
Informed consent: Removed reference to 
‘male’ and added reference to notes on 
AEP 
 
Added text so that consent to the OLE 
Period can be given before Day 1 
To clarify that the consent 
procedure for participants 
undergoing AEP also applies to 
females 
Clarification 
1.3 Schedule of Activities 
(OLE) 
Blinded Teriflunomide Levels: note 
amended to refer to all participants 
undergoing AEP rather than male 
participants only 
Sample moved from D1 to AEP period 
Teriflunomide should also be 
measured for females undergoing 
AEP 
 
To correct error 
1.3 Schedule of Activities 
(OLE) 
Medical history was removed from the 
OLE 
Medical history is collected at 
Screening; any changes thereafter 
are recorded as AEs 
1.3 Schedule of Activities 
(OLE) 
Added text to state that a serum 
pregnancy test is only required on Day 1 
of the OLE if the last monthly urine 
pregnancy test was ≥ 1 month ago 
A urine pregnancy test is sufficient 
at this visit unless there has been a 
gap of ≥1 month since the last test 
1.3 Schedule of Activities 
(OLE) 
‘QuantiFERON testing’ replaced with ‘TB 
testing’ in high TB burden countries and 
notes aligned with Main Study SoA 
TB test removed from Week 108 
TB testing is only required in the 
OLE if the participant resides in a 
country that has a high TB burden 
Test at Week 108 is unnecessary 
1.3 Schedule of Activities 
Study Intervention 
(OLE) 
Study Intervention(s) Administration: 
Dosing will only occur on site at visits 
when biomarkers are collected 
Dosing does not need to be on site 
for all visits 
1.3 Schedule of Activities 
Safety Assessments 
(OLE) 
Added reference to Section 7.1 in the 
notes section of the OLE Biochemistry 
and Hematology assessments. 
To clarify that the criteria for 
discontinuation of study 
intervention apply in the OLE 
2.3 Benefit/Risk Assessment 
 
Added text to address potential risk and 
mitigation to decrease risk of severe 
acute respiratory syndrome coronavirus 
2 (SARS CoV-2) infection 
To address new risks associated 
with the emergence of the COVID-
19 pandemic 
3 Objectives and Endpoints 
1.1 Synopsis 
Header changed to ‘Objectives and 
Estimands’, and Table 1 changed to a 
2-column format with estimand details 
added 
To comply with change to protocol 
template which clarifies estimand 
strategy 
3 Objectives and Estimands: 
Table 
2 
Tertiary/Exploratory 
Objectives and Endpoints 
9.4.1 Efficacy Analyses 
Two more endpoints added for the 
evaluation of the efficacy of evobrutinib 
relative to that of teriflunomide on MRI 
parameters 
Previously missing 
3 Objectives and Estimands 
Table 
2 
Tertiary/Exploratory 
Objectives and Endpoints 
9.4.1 Efficacy Analyses 
 ‘New T1 Gd+ lesions’ changed to ‘T1 
Gd+ lesions’ 
Changes to wording of endpoints 
measured to evaluate the effect on 
composite parameters to use the term 
‘confirmed worsening’ rather than CDP in 
relation to the 9-HPT score and T25-FW 
times 
To align with the correct definition 
for NEDA 
Clarification 
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MS200527_0080 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Clarification that progression or 
worsening should be confirmed 
3 Objectives and Estimands: 
Table 2 Tertiary/Exploratory 
Objectives and Endpoints 
Tmax removed from list of PK parameters 
for evaluation 
Tmax is not needed for any analyses 
and will not be calculated 
3 Objectives and Estimands 
Table 
3 
Objectives 
and 
Endpoints for the Open Label 
Extension Period 
1.1 Synopsis 
Objectives and endpoints added for 
biomarkers collected during the OLE 
Previously missing 
4.2 Scientific Rationale for Study 
Design 
Rationale for biomarkers added 
Previously missing 
4.4 End of Study Definition 
Expanded definition of study completer 
Clarification 
5 Study Population; 
Appendix 2 Study Governance, 
Informed Consent Process 
Removed reference to ‘legal 
representative’ throughout document 
Regulatory authority request (to 
clarify that legal representative will 
not be allowed in the study) 
5.1 Inclusion Criteria 
Inclusion 5: Added text to clarify 
definition of neurologically stable 
Clarification 
5.2 Exclusion Criteria 
Exclusion 6: Wording changed from 
‘within 4 weeks of Screening’ to ‘within 
4 weeks before or during Screening’ 
Clarification in the event of 
extension of the Screening period 
5.2 Exclusion Criteria 
Exclusion 7: ‘QuantiFERON testing’ 
replaced with ‘TB testing’ in high TB 
burden countries. Text added to allow 
use of an alternative test to the assay 
used at Screening per protocol 
Separated testing in high TB 
burden countries to avoid 
confusion. To clarify when an 
orthogonal Interferon Gamma 
Release Assay should be used to 
assess TB status, and that for 
monitoring, the assay used to 
confirm eligibility should be used 
for monitoring during the study 
5.2 Exclusion Criteria 
Exclusion 8: Amended to include 
reevaluation of false positive 
QuantiFERON results 
Removed text stating that individuals 
should be excluded if T-SPOT.TB is not 
available 
False positive results were not 
addressed in the original protocol 
 
To enable sites to do another 
QuantiFERON if a local 
T-SPOT.TB is not available 
5.2 Exclusion Criteria 
Exclusion 10: reworded to exclude 
participants with highly elevated ferritin 
levels independent of transferrin 
saturation 
Revised after review of current 
guidelines for evaluation of 
hemochromatosis and expert 
consultation. 
5.2 Exclusion Criteria 
Exclusion 14: Amended language 
regarding suicidal behavior and C-SSRS 
scores 
To ensure exclusion of individuals 
considered a significant suicide risk 
and to clarify a time period for the 
assessment 
5.2 Exclusion Criteria 
Exclusion 22: amended time frame for 
discontinuation of treatment with beta-
interferons or glatiramer acetate prior to 
randomization to 1 day 
This does not need to be 
discontinued as early as 4 weeks 
before randomization 
5.2 Exclusion Criteria 
Exclusion 23: Removed reference to 
lymphocyte count as this is in a separate 
criterion 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
Exclusion 24: Added that reason for 
switch to teriflunomide must not have 
been because of efficacy or safety 
related considerations 
Clarification regarding study 
population, changes made to 
ensure teriflunomide is an 
appropriate therapeutic option for 
individuals entering the study 
5.2 Exclusion Criteria 
Exclusion 25: 
Amended wording and timing regarding 
use of lymphocyte trafficking blockers 
Added use of S1P inhibitors as an 
exclusion 
Reflects recently published clinical 
trials in RMS indicating that the 
revised exclusion periods are safe 
and appropriate 
5.2 Exclusion Criteria 
Exclusion 26: Time frame for use of IV Ig 
or plasmapheresis prior to randomization 
changed from 12 to 8 weeks 
Reflects recently published clinical 
trials in RMS indicating that the 
revised exclusion periods are safe 
and appropriate 
5.2 Exclusion Criteria 
Exclusion 27: ofatumumab added to list 
of exclusionary treatments 
Clarification. Ofatumumab is a 
B-cell depleting therapy; added to 
avoid confusion as it is now an 
approved agent in some countries 
5.2 Exclusion Criteria 
Exclusion 28: amended to provide 
timings and clarification of 
immunosuppressive medications  
Reflects recently published clinical 
trials in RMS indicating that the 
revised exclusion periods are safe 
and appropriate. Provides more 
complete guidance to sites 
regarding prior treatments. 
5.2 Exclusion Criteria 
Exclusion 30: Removed this exclusion 
criterion (treatment with medical 
marijuana) 
Removed given the complex nature 
of marijuana regulation in different 
countries and lack of anticipated 
impact on patient safety. 
5.2 Exclusion Criteria 
Exclusion 31: Changed the time for 
stopping fish oil supplements from 
4 weeks prior to randomization to just 
prior to randomization (first dose) 
Given size and durability of effects 
of fish oil supplements on 
coagulation, a 4 week period off 
fish oil supplements is not required. 
5.2 Exclusion Criteria 
6.5.3 Prohibited Medicines 
Exclusion 32:  
Removed text “Diabetes medications 
such as tolbutamide, and pioglitazone, 
repaglinide and rosiglitazone or other 
CYP2C8 substrates are also 
exclusionary” and replaced with 
“CYP2C8 substrates with a narrow 
therapeutic index must also be stopped 
at least 1 day prior to randomization” 
Added clarification that CYP2B6 
substrates with a narrow therapeutic 
index, as well as substrates of P-gp, 
BCRP, OCT1, MATE1 and/or MATE2K 
should be used with caution. 
 
To correct an error 
 
 
 
 
 
 
 
Clarification on medicines to be 
used with caution. 
5.2 Exclusion Criteria 
 
 
 
 
Exclusion 34: Amended to permit 
inclusion of participants with HBV DNA 
detectable at levels below 20 IU/mL 
 
 
Clarified level of detectable HBV DNA for 
study intervention discontinuation 
In prior studies of evobrutinib, 
evobrutinib was given to individuals 
with HBV DNA < 20 IU/mL, and 
HBV reactivation was not 
observed.  
To align with change to Exclusion 
Criterion 34 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1 Discontinuation of Study 
Intervention 
5.3.2 Exclusion Criteria for Open 
Label Extension Period 
Exclusion 6: Gamma glutamyl 
transferase removed from list of 
abnormal blood tests requiring 
discontinuation 
Correction aligns OLE exclusion 
criterion with main study stopping 
rules. GGT was included 
unintentionally. 
5.4.1 Meals and Dietary 
Restrictions 
Red wine removed from restrictions 
No clinically relevant interaction 
between red wine and either study 
medication is anticipated. Red wine 
was not prohibited from prior 
studies of evobrutinib and no 
interactions were observed 
6.1 Study Intervention(s) 
Administration 
Dosing Instructions amended 
 
Packaging and Labeling information 
expanded 
To align with elsewhere in the 
protocol 
Clarification 
6,2 Study Intervention(s) 
Preparation, Handling, Storage, 
and Accountability 
Details of storage conditions for 
teriflunomide and its placebo were 
replaced with a reference to the 
teriflunomide product label. 
Clarification 
6.3.2 Blinding 
Clarified the wording regarding the 
assignment of a Treating Investigator 
Designee 
Moved the Treating Investigator text 
before the Examining Investigator text 
Added bullet to state that the Treating 
Investigator (or designee) and the 
Examining Investigator (or designee) 
cannot perform the same tests 
Clarification 
 
 
Logical flow 
 
For additional clarity 
6.4 Study Intervention 
Compliance 
8 Study Assessments and 
Procedures 
Clarified that food intake only needs to 
be recorded in the Participant diary 
around the time of dosing on the day 
prior to PK sampling and the day of PK 
sampling, and around the time of the last 
dose prior to evobrutinib concentration 
assessment sampling 
Clarification 
6.4 Study Intervention 
Compliance 
Added text to indicate that participants 
only need to bring in study intervention at 
study visits ‘during which IMP is 
dispensed’ 
To relieve burden on participants 
6.5 Concomitant Therapy 
6.5.3 Prohibited Medicines 
“During the OLE, initiation of therapy with 
dalfampridine (Ampyra®) is allowed, if 
indicated by the Treating Investigator”: 
text moved from Section 6.5 
Concomitant Therapy to Section 6.5.3 
Prohibited Medicines  
Incorrect location 
6.5.1 Rescue Medicine 
Text added to allow use of 
methylprednisolone as an oral 
formulation 
Text added to allow use of an approved 
equivalent of Acthar gel 
To provide flexibility (particularly in 
light of the Covid-19 pandemic) 
To allow use of an approved 
equivalent of Acthar gel 
6.5.2 Permitted Medicines 
Amended restrictions on use of 
marijuana 
To align with removal of marijuana 
exclusion criterion 
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Section # and Name 
Description of Change 
Brief Rationale 
6.5.3 Prohibited Medicines 
Ofatumumab added to list of medicines 
prohibited during the study 
 
 
Added azathioprine and methotrexate as 
examples of prohibited 
immunosuppressive treatments 
Live-attenuated vaccines added to list of 
medicines prohibited during the study 
Systemic corticosteroids (oral, injected, 
IV) added to list of medicines prohibited 
during the study (topical, intranasal, or 
inhaled corticosteroids are permitted) 
Ofatumumab is a B-cell depleting 
therapy; added to avoid confusion 
as it is now an approved agent in 
some countries 
To align with the updated exclusion 
criterion #28 
 
Omitted in error 
 
Omitted in error 
6.5.4 Other Interventions 
Resveratrol > 500 mg/day added to list of 
herbal and nutritional supplements that 
must be stopped at least 1 week prior to 
randomization 
Resveratrol supplements of 
> 500 mg/day may result in 
clinically significant inhibition of 
CYP3A 
6.9 Management of Adverse 
Events of Interest 
Liver adverse events: 
Level of increase clarified for 
transaminases and bilirubin elevations to 
be considered AESIs 
Amylase and Lipase Elevations: 
CTCAE Grade ≥3 elevation changed to 
> 2 × ULN for AESI classification 
Clarification 
 
 
 
To clarify a discrepancy between 
CTCAE Version 4.03 and 
Version 5.0 
7.1 Discontinuation of Study 
Intervention 
Added template mandatory text 
regarding permanent discontinuation (at 
start of section) 
Added text to indicate that the criteria for 
discontinuation of study intervention 
apply during both the main study and the 
OLE Period 
Added local standard of care option for 
accelerated elimination of teriflunomide 
Previously missing 
 
 
Clarification 
 
 
 
To allow investigators to manage 
participants in accordance with 
local standard of care 
7.1 Discontinuation of Study 
Intervention, Criteria for 
Permanent Discontinuation of 
Study Intervention 
 
Text added to clarify that the lab criteria 
should be confirmed before study 
intervention is discontinued 
For pregnancy reasons: changed the 
requirement that AEP ‘must’ be 
performed to ‘should’ be performed, and 
teriflunomide level < 0.02 mg/L ‘has to’ 
be reached to ‘should’ be reached 
Added text that a protocol deviation 
should be documented if prohibited 
medication is used 
Clarification 
 
 
This is a decision for the 
Investigator and the participant; it is 
not absolutely mandatory 
 
 
Clarification 
7.1 Discontinuation of Study 
Intervention 
8 Study Assessments and 
Procedures 
Appendix 5 Clinical Laboratory 
Tests 
Erythrocyte sedimentation rate removed 
from list of hepatic assessments 
ESR via on-site/local laboratory 
was included in error as hsCRP is 
already collected and processed 
via central laboratory 
7.1 Discontinuation of Study 
Intervention 
Criteria for Temporary Discontinuation of 
Study Intervention: 
To clarify a discrepancy between 
CTCAE Version 4.03 and 
Version 5.0 
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Section # and Name 
Description of Change 
Brief Rationale 
Amylase retest criteria amended and 
simplified to allow reinitiation of study 
intervention if value decreases to 
≤2 × ULN upon retest 
Lipase retest criteria amended and 
simplified to allow reinitiation of study 
intervention if value decreases to 
≤2 × ULN upon retest 
7.1 Discontinuation of Study 
Intervention 
Criteria for Temporary Discontinuation of 
Study Intervention: 
Serum creatinine criteria changed to “For 
any increase in serum creatinine > 1.5 × 
ULN but ≤ 3 × ULN…” 
Criteria did not cover an exact 
3 × ULN and required clarification 
7.1 Discontinuation of Study 
Intervention 
8.3.5 Pregnancy 
Changed requirement for AEP in 
pregnant participant from ‘must’ to 
‘should’ be performed 
To align with the AEP 
8 Study Assessments and 
Procedures  
Date of last menstrual period will not be 
collected. 
Not required 
8 Study Assessments and 
Procedures  
Additional criteria added for extending 
the Screening Period, and permitted 
extension increased to a maximum of 
12 weeks  
Instructions added for repeating ferritin 
or transferrin saturation tests 
To provide guidance for retesting of 
ferritin or transferring saturation 
tests and allow sufficient time for 
repeat laboratory results and other 
unanticipated events prior to 
randomization 
8 Study Assessments and 
Procedures 
Telephone Visit: Replaced bulleted list of 
discussion items with a reference to the 
Structured Interview in Appendix 10 
Clarification/simplification of 
protocol. Structured interview put 
into place. 
8.1.1 Neurological Assessment 
Added text to clarify the assignment of a 
Qualified Examining Designee 
Clarification 
8.1.1.1 Qualified Relapse 
Added that if neurological signs and 
symptoms are identified that are 
consistent with relapse, the participant 
should be evaluated on site 
Clarification; relapse cannot be 
confirmed over the phone 
8.1.1.6 Symbol Digit Modalities 
Test 
Text added to clarify that two different 
SDMT forms will be used, administered 
at alternating visits. 
Clarification 
8.1.2 Brain Magnetic Resonance 
Imaging Scans 
Amended text to state that images will be 
assessed (not assessed and reported) 
Added that the Treating Investigator can 
have access to the Screening (baseline) 
MRI scan in order to evaluate eligibility 
To correct an error 
 
Access to the Screening (baseline) 
MRI scan is needed to evaluate 
eligibility 
8.1.2 Brain Magnetic Resonance 
Imaging Scans 
1.3 Schedule of Activities (Main 
Study) 
Changed ‘Screening/Baseline MRI’ to 
‘Screening (Baseline) MRI’ 
To clarify that the MRI done at 
screening is the baseline MRI, 
rather than suggesting that an MRI 
might be done at the baseline visit. 
8.1.3 Patient Reported 
Outcomes 
1.3 Schedule of Activities 
Added text to allow an alternative 
method of PRO data collection 
Removed reference to the use of a tablet 
for PRO assessments 
To allow an alternative method of 
collection in the event that a tablet 
cannot be used 
8.2.2 Vital Signs 
Text added to indicate that temperature 
should be measured at the same 
location throughout the study 
To avoid variation in results if 
different methods were used 
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Section # and Name 
Description of Change 
Brief Rationale 
8.2.3 Electrocardiograms 
Text amended to indicate that QTcF will 
be automatically calculated in the eCRF; 
it is not obtained from the ECG 
Clarification 
8.2.7 Columbia-Suicide Severity 
Rating Scale 
1.3 Schedule of Activities (Main 
Study and OLE) 
Text added to state that the C-SSRS 
may be administered by an assigned 
designee of the Treating Investigator 
To clarify that the C-SSRS may be 
delegated per Section 6.3.2 
8.3.5 Pregnancy 
Amended all text regarding collection 
and reporting of pregnancy information 
Added that information on pregnant 
partners only needs to be collected in the 
Main Study 
Text updated in accordance with 
new protocol template 
Once a male participant switches 
to evobrutinib in the OLE, it is not 
necessary to collect information on 
pregnancies in their partners 
8.4 Treatment of Overdose 
Definition of overdose amended to: 
“…within a 24-hour time period – [minus] 
6 hours…” 
To prevent erroneous reports of 
overdose 
8.5 Pharmacokinetics 
Tmax removed from list of PK parameters 
for evaluation 
Revisions to definitions of PK 
parameters 
Tmax is not needed for any analyses 
and will not be calculated 
Correction 
9.1.2 Statistical Hypotheses 
Related to Secondary 
Objectives 
Change to null hypothesis for the 
secondary endpoint CFB in PROMIS 
Fatigue score at 96 weeks 
Correction 
9.4.1 Efficacy Analyses 
Secondary efficacy endpoints: 
Time to 12-week CDP 
Time to 24-week CDP 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
Statistical Analysis Methods: Cox model 
made consistent with Logrank test which 
has strata defined by randomization 
strata and study ID 
Correction 
9.4.1 Efficacy Analyses 
Tertiary/Exploratory endpoints 
Statistical Analysis Methods:  
Correction to test regarding stratified Cox 
model strata 
Minor edits to text 
 
Correction 
 
Clarification of statistical methods 
9.4.1 Efficacy Analyses 
Tertiary/Exploratory endpoints 
‘Change in normalized T1 intensity…’ 
endpoint moved to a new row 
New text for statistical method for the 
‘Volume of SELs…’ endpoint 
Correction of statistical method 
based on information from 
NeuroRx indicating one 
postbaseline value per participant 
9.4.4.3 Multiplicity 
Secondary Endpoint Null Hypotheses for 
H05: ‘ΔFatigue ≤ 0’ changed to ‘ΔFatigue ≥ 0’, 
and ‘higher score corresponds to 
reduced fatigure’ changed to ‘higher 
score corresponds to more fatigure’ 
Correction 
10 References 
Additional references added 
In line with changes to text 
Appendix 2 Study Governance 
Study and Site Closure: Text added to 
indicate that new or emerging safety 
information that negatively affects the 
benefit/risk assessment of the clinical 
study may be a reason for closing study 
sites or terminating the study 
Health Authority Request 
Appendix 3 Contraception 
Added missing footnote label ‘a’ 
Label was missing in footnotes 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
Added footnote ‘b’ to indicate that if a 
WOCBP is using a highly effective 
method other than sexual abstinence or 
vasectomized partner, AND ALSO has a 
vasectomized partner, the vasectomized 
partner will be considered the “barrier 
method” for study purposes 
Appendix 4 Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-
up, and Reporting 
Events Not to Be Considered as 
AEs/SAEs: 
Text added to state that worsening of the 
underlying disease is not routinely 
considered an AE or SAE 
Text on reporting of AESIs was updated 
in line with the latest protocol template 
Alignment with template wording 
 
 
 
 
For clarification and so that EDC 
can be used 
Appendix 5 Clinical Laboratory 
Tests 
Moved some assessments listed in 
‘Other screening tests’ into new row 
‘Other tests’ 
JCV DNA PCR added to list of ‘Other 
screening tests’ 
Estradiol removed from list of ‘Other 
screening tests’ 
 
βhCG removed from routine urinalysis 
 
Teriflunomide footnote amended to 
include all participants undergoing AEP 
Clarification; not all tests listed 
were Screening only 
 
To include missing information 
 
Estradiol not used to determine 
postmenopausal status in this 
study 
This is a serum test; now listed 
under other tests 
To include females undergoing 
AEP 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
Text added to allow accelerated 
elimination of teriflunomide in 
accordance with standard of care 
Text added to note that it is only required 
to confirm a level of < 0.02 mg/L after the 
AEP if the AEP is being done for 
pregnancy-related considerations 
To allow accelerated elimination of 
teriflunomide in accordance with 
local guidance 
For clarification 
Appendix 10 Structured 
Interview at Telephone Visit 
New appendix added: ‘Structured 
Interview at Telephone Visit’ 
Clarification/simplification of 
protocol. Structured interview put 
into place to identify any new or 
worsening neurological symptoms 
that warrant evaluation at an 
unscheduled visit  
Throughout the document 
Changes made to align with updated 
protocol template 
Minor editorial and document formatting 
revisions 
Minor; therefore, have not been 
summarized 
Protocol Version 2.0 (27 November 2020)  
This amendment is substantial based on the criteria in Article 10(a) of Directive 2001/20/EC of 
the European Parliament and the Council of the European Union. 
Overall Rationale for the Amendment 
The primary purpose of this amendment is to make changes and clarifications based on feedback 
from early enrolling investigational sites, and newly available data from studies of other agents in 
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multiple sclerosis, and to clarify COVID mitigation procedures. A high-level description of each 
change is summarized below, along with its rationale. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
Appendix 12 Sponsor Signature 
Page 
 replaces 
 
 as Medical Responsible 
 replaces 
 
 as Medical Monitor 
Change in personnel 
1.1 Synopsis, Study Intervention 
Groups and Duration 
1.2 Schema 
4.1 Overall Design 
Additional text included, and minor 
rewording, to clarify the follow-up window 
for ‘confirmation’ of disability progression 
as measured by the EDSS 
For additional clarification 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
5.5 Screen Failures 
Appendix 2 Study Governance 
With approval from the Medical Monitor, 
the Screening period may be extended 
to 12 weeks maximum (increased from 
8 weeks maximum). See Section 8 Study 
Assessments and Procedures 
To allow sufficient time for repeat 
laboratory results and other 
unanticipated events prior to 
randomization 
1.1 Synopsis 
1.2 Schema 
4.1 Overall Design 
1.3 Schedule of Activities 
Added that female participants may 
undergo AEP at the Investigator’s 
discretion, and that the same AEP 
process should be followed as for male 
participants 
To clarify the process in the event 
of a female participant undergoing 
AEP 
1.3 Schedule of Activities 
(Main Study) 
‘F/D’ changed to SFU (Safety Follow-up) 
F/D visit window changed from ± 3 days 
to + 3 days 
Added note that visit window for Week 4 
is ± 2 days 
To clarify that this is a safety visit 
SFU visit must be ≥ 28 days after 
last study intervention 
Clarification 
1.3 Schedule of Activities 
(Main Study and OLE) 
Telephone 
Visit:  
Simplified 
notes 
and 
referred 
to 
Structured Interview 
Clarified individual visits 
Clarification/simplification of 
protocol. Structured interview put 
into place. 
Telephone Visit not required when 
participants attend clinic 
1.3 Schedule of Activities 
(Main Study) 
QuantiFERON testing removed from 
W48 and W96 visits 
 
 
Separate row added for TB testing for 
high TB burden countries 
TB testing is only required at 
Screening if the participant resides 
in a country that has a high TB 
burden 
Separated testing in high TB 
burden countries to avoid 
confusion. Clarified that the assay 
used to confirm eligibility should be 
used for monitoring during the 
study 
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Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
Efficacy 
(Main Study and OLE) 
Added note that neurological evaluation 
EDSS, T25-FW, 9-HPT, and SDMT 
should preferably be done after the PRO 
assessments 
EDSS evaluation: added note that this 
can be done by phone, if available, if the 
participant is unable to attend scheduled 
visit 
To clarify that these should 
preferably be completed before 
other assessments, but PROs are 
done first 
Mitigation in light of the COVID-19 
pandemic, if the participant is 
unable to attend scheduled visit. 
(Lechner-Scott 2003) 
1.3 Schedule of Activities 
PRO Assessments 
(Main Study) 
SF-36 v2 assessment added at 
Week 108 
Assessment required at Week 108 
for participants for whom this is 
also D1 of the OLE 
1.3 Schedule of Activities 
PRO Assessments 
(Main Study and OLE) 
PROs: Removed reference to the use of 
a tablet 
For flexibility in method of 
collection 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
C-SSRS: Removed reference to the use 
of a tablet 
For flexibility in method of 
collection 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
Coagulation test will be done at 
Screening, W96, OLE D1 and W144 only 
No exposure-related abnormalities 
in PT or PTT have been identified 
in prior studies of evobrutinib. 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
Text amended to indicate that urinalysis 
will be assessed locally and microscopy 
will be submitted for central evaluation 
only if indicated 
Clarification 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study) 
Noted that a second ECG will be 
collected postdose on Day 1, and that 
additional ECGs can be done at the 
Investigator’s discretion 
To clarify that there are 2 ECGs on 
Day 1 and to allow additional ECGs 
if required 
1.3 Schedule of Activities 
Safety Assessments 
(Main Study and OLE) 
Removed notes regarding telephone 
visits from ‘AE, SAE & AESI Review‘ and 
‘Concomitant Medication and 
Procedures Review’ rows 
Clarification/simplification of 
protocol. Structured interview put 
into place 
1.3 Schedule of Activities 
Study Intervention 
(Main Study) 
Added dispensing of study intervention 
at Week 4 
Requested by the study team 
1.3 Schedule of Activities 
Study Intervention 
(Main Study and OLE) 
Text amended to state when study 
intervention should be administered on 
site: PK sampling days (Main Study) and 
biomarker sample collection days (OLE) 
To clarify when study intervention 
should be administered in the clinic 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Removed detail about self-administration 
at home 
To avoid confusion; detail is in 
Section 6.1 
1.3 Schedule of Activities 
Study Intervention 
(Main Study and OLE) 
Compliance: Clarified that participant 
should complete the Participant diary. 
Note added that the diary should be 
reviewed during on-site visits 
Clarification 
1.3 Schedule of Activities 
Biomarkers 
(Main study and OLE) 
8.8.3 Novel Liver Function 
Protein Biomarkers and Novel 
Liver Function Genomic 
Biomarkers 
Removed requirement for novel liver 
function protein and genomic biomarkers 
to be collected prior to first daily dose 
Dosing time is not relevant to 
sample collection time 
1.3 Schedule of Activities 
(OLE) 
Note ‘d’: Added ‘unless they are 
undergoing AEP’ 
The last visit in the main study will 
not be the first visit in the OLE for 
female participants undergoing 
AEP 
1.3 Schedule of Activities 
(OLE) 
Informed consent: Removed reference to 
‘male’ and added reference to notes on 
AEP 
 
Added text so that consent to the OLE 
Period can be given before Day 1 
To clarify that the consent 
procedure for participants 
undergoing AEP also applies to 
females 
Clarification 
1.3 Schedule of Activities 
(OLE) 
Blinded Teriflunomide Levels: note 
amended to refer to all participants 
undergoing AEP rather than male 
participants only 
Sample moved from D1 to AEP period 
Teriflunomide should also be 
measured for females undergoing 
AEP 
 
To correct error 
1.3 Schedule of Activities 
(OLE) 
Medical history was removed from the 
OLE 
Medical history is collected at 
Screening; any changes thereafter 
are recorded as AEs 
1.3 Schedule of Activities 
(OLE) 
Added text to state that a serum 
pregnancy test is only required on Day 1 
of the OLE if the last monthly urine 
pregnancy test was ≥ 1 month ago 
A urine pregnancy test is sufficient 
at this visit unless there has been a 
gap of ≥1 month since the last test 
1.3 Schedule of Activities 
(OLE) 
‘QuantiFERON testing’ replaced with ‘TB 
testing’ in high TB burden countries and 
notes aligned with Main Study SoA 
TB test removed from Week 108 
TB testing is only required in the 
OLE if the participant resides in a 
country that has a high TB burden 
Test at Week 108 is unnecessary 
1.3 Schedule of Activities 
Study Intervention 
(OLE) 
Study Intervention(s) Administration: 
Dosing will only occur on site at visits 
when biomarkers are collected 
Dosing does not need to be on site 
for all visits 
1.3 Schedule of Activities 
Safety Assessments 
(OLE) 
Added reference to Section 7.1 in the 
notes section of the OLE Biochemistry 
and Hematology assessments. 
To clarify that the criteria for 
discontinuation of study 
intervention apply in the OLE 
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Section # and Name 
Description of Change 
Brief Rationale 
2.3 Benefit/Risk Assessment 
Added text to address potential risk and 
mitigation to decrease risk of severe 
acute respiratory syndrome coronavirus 
2 (SARS CoV-2) infection 
To address new risks associated 
with the emergence of the COVID-
19 pandemic 
3 Objectives and Endpoints 
1.1 Synopsis 
Header changed to ‘Objectives and 
Estimands’, and Table 1 changed to a 
2-column format with estimand details 
added 
To comply with change to protocol 
template which clarifies estimand 
strategy 
3 Objectives and Estimands: 
Table 
2 
Tertiary/Exploratory 
Objectives and Endpoints 
9.4.1 Efficacy Analyses 
Two more endpoints added for the 
evaluation of the efficacy of evobrutinib 
relative to that of teriflunomide on MRI 
parameters 
Previously missing 
3 Objectives and Estimands 
Table 
2 
Tertiary/Exploratory 
Objectives and Endpoints 
9.4.1 Efficacy Analyses 
 ‘New T1 Gd+ lesions’ changed to ‘T1 
Gd+ lesions’ 
Changes to wording of endpoints 
measured to evaluate the effect on 
composite parameters to use the term 
‘confirmed worsening’ rather than CDP in 
relation to the 9-HPT score and T25-FW 
times 
Clarification that progression or 
worsening should be confirmed 
To align with the correct definition 
for NEDA 
Clarification 
3 Objectives and Estimands: 
Table 2 Tertiary/Exploratory 
Objectives and Endpoints 
Tmax removed from list of PK parameters 
for evaluation 
Tmax is not needed for any analyses 
and will not be calculated 
3 Objectives and Estimands 
Table 
3 
Objectives 
and 
Endpoints for the Open Label 
Extension Period 
1.1 Synopsis 
Objectives and endpoints added for 
biomarkers collected during the OLE 
Previously missing 
4.2 Scientific Rationale for Study 
Design 
Rationale for biomarkers added 
Previously missing 
4.4 End of Study Definition 
 
Expanded definition of study completer 
Clarification 
5 Study Population; 
Appendix 2 Study Governance, 
Informed Consent Process 
Removed reference to ‘legal 
representative’ throughout document 
Regulatory authority request (to 
clarify that legal representative will 
not be allowed in the study) 
5.1 Inclusion Criteria 
Inclusion 5: Added text to clarify 
definition of neurologically stable 
Clarification 
5.2 Exclusion Criteria 
Exclusion 6: Wording changed from 
‘within 4 weeks of Screening’ to ‘within 
4 weeks before or during Screening’ 
Clarification in the event of 
extension of the Screening period 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
Exclusion 7: ‘QuantiFERON testing’ 
replaced with ‘TB testing’ in high TB 
burden countries. Text added to allow 
use of an alternative test to the assay 
used at Screening per protocol 
Separated testing in high TB 
burden countries to avoid 
confusion. To clarify when an 
orthogonal Interferon Gamma 
Release Assay should be used to 
assess TB status, and that for 
monitoring, the assay used to 
confirm eligibility should be used 
for monitoring during the study 
5.2 Exclusion Criteria 
Exclusion 8: Amended to include 
reevaluation of false positive 
QuantiFERON results 
Removed text stating that individuals 
should be excluded if T-SPOT.TB is not 
available 
False positive results were not 
addressed in the original protocol 
 
To enable sites to do another 
QuantiFERON if a local 
T-SPOT.TB is not available 
5.2 Exclusion Criteria 
Exclusion 10: reworded to exclude 
participants with highly elevated ferritin 
levels independent of transferrin 
saturation 
Revised after review of current 
guidelines for evaluation of 
hemochromatosis and expert 
consultation. 
5.2 Exclusion Criteria 
Exclusion 14: Amended language 
regarding suicidal behavior and C-SSRS 
scores 
To ensure exclusion of individuals 
considered a significant suicide risk 
and to clarify a time period for the 
assessment 
5.2 Exclusion Criteria 
Exclusion 22: amended time frame for 
discontinuation of treatment with beta-
interferons or glatiramer acetate prior to 
randomization to 1 day 
This does not need to be 
discontinued as early as 4 weeks 
before randomization 
5.2 Exclusion Criteria 
Exclusion 23: Removed reference to 
lymphocyte count as this is in a separate 
criterion 
Clarification 
5.2 Exclusion Criteria 
Exclusion 24: Added that reason for 
switch to teriflunomide must not have 
been because of efficacy or safety 
related considerations 
Clarification regarding study 
population, changes made to 
ensure teriflunomide is an 
appropriate therapeutic option for 
individuals entering the study 
5.2 Exclusion Criteria 
Exclusion 25: 
Amended wording and timing regarding 
use of lymphocyte trafficking blockers 
Added use of S1P inhibitors as an 
exclusion 
Reflects recently published clinical 
trials in RMS indicating that the 
revised exclusion periods are safe 
and appropriate 
5.2 Exclusion Criteria 
Exclusion 26: Time frame for use of IV Ig 
or plasmapheresis prior to randomization 
changed from 12 to 8 weeks 
Reflects recently published clinical 
trials in RMS indicating that the 
revised exclusion periods are safe 
and appropriate 
5.2 Exclusion Criteria 
Exclusion 27: ofatumumab added to list 
of exclusionary treatments 
Clarification. Ofatumumab is a 
B-cell depleting therapy; added to 
avoid confusion as it is now an 
approved agent in some countries 
5.2 Exclusion Criteria 
Exclusion 28: amended to provide 
timings and clarification of 
immunosuppressive medications  
Reflects recently published clinical 
trials in RMS indicating that the 
revised exclusion periods are safe 
and appropriate. Provides more 
complete guidance to sites 
regarding prior treatments. 
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Section # and Name 
Description of Change 
Brief Rationale 
5.2 Exclusion Criteria 
Exclusion 30: Removed this exclusion 
criterion (treatment with medical 
marijuana) 
Removed given the complex nature 
of marijuana regulation in different 
countries and lack of anticipated 
impact on patient safety. 
5.2 Exclusion Criteria 
Exclusion 31: Changed the time for 
stopping fish oil supplements from 
4 weeks prior to randomization to just 
prior to randomization (first dose) 
Given size and durability of effects 
of fish oil supplements on 
coagulation, a 4 week period off 
fish oil supplements is not required. 
5.2 Exclusion Criteria 
6.5.3 Prohibited Medicines 
Exclusion 32:  
Removed text “Diabetes medications 
such as tolbutamide, and pioglitazone, 
repaglinide and rosiglitazone or other 
CYP2C8 substrates are also 
exclusionary” and replaced with 
“CYP2C8 substrates with a narrow 
therapeutic index must also be stopped 
at least 1 day prior to randomization” 
Added clarification that CYP2B6 
substrates with a narrow therapeutic 
index, as well as substrates of P-gp, 
BCRP, OCT1, MATE1 and/or MATE2K 
should be used with caution. 
 
To correct an error 
 
 
 
 
 
 
 
Clarification on medicines to be 
used with caution. 
5.2 Exclusion Criteria 
 
 
 
 
7.1 Discontinuation of Study 
Intervention 
Exclusion 34: Amended to permit 
inclusion of participants with HBV DNA 
detectable at levels below 20 IU/mL 
 
 
Clarified level of detectable HBV DNA for 
study intervention discontinuation 
In prior studies of evobrutinib, 
evobrutinib was given to individuals 
with HBV DNA < 20 IU/mL, and 
HBV reactivation was not 
observed.  
To align with change to Exclusion 
Criterion 34 
5.3.2 Exclusion Criteria for Open 
Label Extension Period 
Exclusion 6: Gamma glutamyl 
transferase removed from list of 
abnormal blood tests requiring 
discontinuation 
Correction aligns OLE exclusion 
criterion with main study stopping 
rules. GGT was included 
unintentionally. 
5.4.1 Meals and Dietary 
Restrictions 
Red wine removed from restrictions 
No clinically relevant interaction 
between red wine and either study 
medication is anticipated. Red wine 
was not prohibited from prior 
studies of evobrutinib and no 
interactions were observed 
6.1 Study Intervention(s) 
Administration 
Dosing Instructions amended 
 
Packaging and Labeling information 
expanded 
To align with elsewhere in the 
protocol 
Clarification 
6.2 Study Intervention(s) 
Preparation, Handling, Storage, 
and Accountability 
Details of storage conditions for 
teriflunomide and its placebo were 
replaced with a reference to the 
teriflunomide product label. 
Clarification 
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Section # and Name 
Description of Change 
Brief Rationale 
6.3.2 Blinding 
Clarified the wording regarding the 
assignment of a Treating Investigator 
Designee 
Moved the Treating Investigator text 
before the Examining Investigator text 
Added bullet to state that the Treating 
Investigator (or designee) and the 
Examining Investigator (or designee) 
cannot perform the same tests 
Clarification 
 
 
Logical flow 
 
For additional clarity 
6.4 
Study 
Intervention 
Compliance 
8 Study Assessments and 
Procedures 
Clarified that food intake only needs to 
be recorded in the Participant diary 
around the time of dosing on the day 
prior to PK sampling and the day of PK 
sampling, and around the time of the last 
dose prior to evobrutinib concentration 
assessment sampling 
Clarification 
6.4 Study Intervention 
Compliance 
Added text to indicate that participants 
only need to bring in study intervention at 
study visits ‘during which IMP is 
dispensed’ 
To relieve burden on participants 
6.5 Concomitant Therapy 
6.5.3 Prohibited Medicines 
“During the OLE, initiation of therapy with 
dalfampridine (Ampyra®) is allowed, if 
indicated by the Treating Investigator”: 
text moved from Section 6.5 
Concomitant Therapy to Section 6.5.3 
Prohibited Medicines  
Incorrect location 
6.5.1 Rescue Medicine 
Text added to allow use of 
methylprednisolone as an oral 
formulation 
Text added to allow use of an approved 
equivalent of Acthar gel 
To provide flexibility (particularly in 
light of the Covid-19 pandemic) 
To allow use of an approved 
equivalent of Acthar gel 
6.5.2 Permitted Medicines 
Amended restrictions on use of 
marijuana 
To align with removal of marijuana 
exclusion criterion 
6.5.3 Prohibited Medicines 
Ofatumumab added to list of medicines 
prohibited during the study 
 
 
Added azathioprine and methotrexate as 
examples of prohibited 
immunosuppressive treatments 
Live-attenuated vaccines added to list of 
medicines prohibited during the study 
Systemic corticosteroids (oral, injected, 
IV) added to list of medicines prohibited 
during the study (topical, intranasal, or 
inhaled corticosteroids are permitted) 
Ofatumumab is a B-cell depleting 
therapy; added to avoid confusion 
as it is now an approved agent in 
some countries 
To align with the updated exclusion 
criterion #28 
 
Omitted in error 
 
Omitted in error 
6.5.4 Other Interventions 
Resveratrol > 500 mg/day added to list of 
herbal and nutritional supplements that 
must be stopped at least 1 week prior to 
randomization 
Resveratrol supplements of 
> 500 mg/day may result in 
clinically significant inhibition of 
CYP3A 
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Section # and Name 
Description of Change 
Brief Rationale 
6.9 Management of Adverse 
Events of Interest 
Liver adverse events: 
Level of increase clarified for 
transaminases and bilirubin elevations to 
be considered AESIs 
Amylase and Lipase Elevations: 
CTCAE Grade ≥3 elevation changed to 
> 2 × ULN for AESI classification 
Clarification 
 
 
 
To clarify a discrepancy between 
CTCAE Version 4.03 and 
Version 5.0 
7.1 Discontinuation of Study 
Intervention 
Added template mandatory text 
regarding permanent discontinuation (at 
start of section) 
Added text to indicate that the criteria for 
discontinuation of study intervention 
apply during both the main study and the 
OLE Period 
Added local standard of care option for 
accelerated elimination of teriflunomide 
Previously missing 
 
 
Clarification 
 
 
 
To allow investigators to manage 
participants in accordance with 
local standard of care 
7.1 Discontinuation of Study 
Intervention, Criteria for 
Permanent Discontinuation of 
Study Intervention 
Text added to clarify that the lab criteria 
should be confirmed before study 
intervention is discontinued 
For pregnancy reasons: changed the 
requirement that AEP ‘must’ be 
performed to ‘should’ be performed, and 
teriflunomide level < 0.02 mg/L ‘has to’ 
be reached to ‘should’ be reached 
Added text that a protocol deviation 
should be documented if prohibited 
medication is used 
Clarification 
 
 
This is a decision for the 
Investigator and the participant; it is 
not absolutely mandatory 
 
 
Clarification 
7.1 Discontinuation of Study 
Intervention 
8 
Study 
Assessments 
and 
Procedures 
Appendix 5 Clinical Laboratory 
Tests 
Erythrocyte sedimentation rate removed 
from list of hepatic assessments 
ESR via on-site/local laboratory 
was included in error as hsCRP is 
already collected and processed 
via central laboratory 
7.1 Discontinuation of Study 
Intervention 
Criteria for Temporary Discontinuation of 
Study Intervention: 
Amylase retest criteria amended and 
simplified to allow reinitiation of study 
intervention if value decreases to 
≤2 × ULN upon retest 
Lipase retest criteria amended and 
simplified to allow reinitiation of study 
intervention if value decreases to 
≤2 × ULN upon retest 
To clarify a discrepancy between 
CTCAE Version 4.03 and 
Version 5.0 
7.1 Discontinuation of Study 
Intervention 
Criteria for Temporary Discontinuation of 
Study Intervention: 
Serum creatinine criteria changed to “For 
any increase in serum creatinine > 1.5 × 
ULN but ≤ 3 × ULN…” 
Criteria did not cover an exact 
3 × ULN and required clarification 
7.1 Discontinuation of Study 
Intervention 
8.3.5 Pregnancy 
Changed requirement for AEP in 
pregnant participant from ‘must’ to 
‘should’ be performed 
To align with the AEP 
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Section # and Name 
Description of Change 
Brief Rationale 
8 Study Assessments and 
Procedures 
Date of last menstrual period will not be 
collected. 
Not required 
8 Study Assessments and 
Procedures 
Additional criteria added for extending 
the Screening Period, and permitted 
extension increased to a maximum of 
12 weeks  
Instructions added for repeating ferritin 
or transferrin saturation tests 
To provide guidance for retesting of 
ferritin or transferring saturation 
tests and allow sufficient time for 
repeat laboratory results and other 
unanticipated events prior to 
randomization 
8 Study Assessments and 
Procedures 
Telephone Visit: Replaced bulleted list of 
discussion items with a reference to the 
Structured Interview in Appendix 10 
Clarification/simplification of 
protocol. Structured interview put 
into place. 
8.1.1 Neurological Assessment 
Added text to clarify the assignment of a 
Qualified Examining Designee 
Clarification 
8.1.1.1 Qualified Relapse 
Added that if neurological signs and 
symptoms are identified that are 
consistent with relapse, the participant 
should be evaluated on site 
Clarification; relapse cannot be 
confirmed over the phone 
8.1.1.6 Symbol Digit Modalities 
Test 
Text added to clarify that two different 
SDMT forms will be used, administered 
at alternating visits. 
Clarification 
8.1.2 Brain Magnetic Resonance 
Imaging Scans 
Amended text to state that images will be 
assessed (not assessed and reported) 
Added that the Treating Investigator can 
have access to the Screening (baseline) 
MRI scan in order to evaluate eligibility 
To correct an error 
 
Access to the Screening (baseline) 
MRI scan is needed to evaluate 
eligibility 
8.1.2 Brain Magnetic Resonance 
Imaging Scans 
1.3 Schedule of Activities (Main 
Study) 
Changed ‘Screening/Baseline MRI’ to 
‘Screening (Baseline) MRI’ 
To clarify that the MRI done at 
screening is the baseline MRI, 
rather than suggesting that an MRI 
might be done at the baseline visit. 
8.1.3 
Patient 
Reported 
Outcomes 
1.3 Schedule of Activities 
Added text to allow an alternative 
method of PRO data collection 
Removed reference to the use of a tablet 
for PRO assessments 
To allow an alternative method of 
collection in the event that a tablet 
cannot be used 
8.2.2 Vital Signs 
Text added to indicate that temperature 
should be measured at the same 
location throughout the study 
To avoid variation in results if 
different methods were used 
8.2.3 Electrocardiograms 
Text amended to indicate that QTcF will 
be automatically calculated in the eCRF; 
it is not obtained from the ECG 
Clarification 
8.2.7 Columbia-Suicide Severity 
Rating Scale 
1.3 Schedule of Activities (Main 
Study and OLE) 
Text added to state that the C-SSRS 
may be administered by an assigned 
designee of the Treating Investigator 
To clarify that the C-SSRS may be 
delegated per Section 6.3.2 
8.3.5 Pregnancy 
Amended all text regarding collection 
and reporting of pregnancy information 
Added that information on pregnant 
partners only needs to be collected in the 
Main Study 
Text updated in accordance with 
new protocol template 
Once a male participant switches 
to evobrutinib in the OLE, it is not 
necessary to collect information on 
pregnancies in their partners 
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Section # and Name 
Description of Change 
Brief Rationale 
8.4 Treatment of Overdose 
Definition of overdose amended to: 
“…within a 24-hour time period – [minus] 
6 hours…” 
To prevent erroneous reports of 
overdose 
8.5 Pharmacokinetics 
Tmax removed from list of PK parameters 
for evaluation 
Revisions to definitions of PK 
parameters 
Tmax is not needed for any analyses 
and will not be calculated 
Correction 
9.1.2 Statistical Hypotheses 
Related to Secondary 
Objectives 
Change to null hypothesis for the 
secondary endpoint CFB in PROMIS 
Fatigue score at 96 weeks 
Correction 
9.4.1 Efficacy Analyses 
Secondary efficacy endpoints: 
Time to 12-week CDP 
Time to 24-week CDP 
9.4.1.2 Efficacy Analyses 
Related to Secondary 
Objectives 
Statistical Analysis Methods: Cox model 
made consistent with Logrank test which 
has strata defined by randomization 
strata and study ID 
Correction 
9.4.1 Efficacy Analyses 
Tertiary/Exploratory endpoints 
Statistical Analysis Methods:  
Correction to test regarding stratified Cox 
model strata 
Minor edits to text 
 
Correction 
 
Clarification of statistical methods 
9.4.1 Efficacy Analyses 
Tertiary/Exploratory endpoints 
‘Change in normalized T1 intensity…’ 
endpoint moved to a new row 
New text for statistical method for the 
‘Volume of SELs…’ endpoint 
Correction of statistical method 
based on information from 
NeuroRx indicating one 
postbaseline value per participant 
9.4.4.3 Multiplicity 
Secondary Endpoint Null Hypotheses for 
H05: ‘ΔFatigue ≤ 0’ changed to ‘ΔFatigue ≥ 0’, 
and ‘higher score corresponds to 
reduced fatigure’ changed to ‘higher 
score corresponds to more fatigure’ 
Correction 
10 References 
Additional references added 
In line with changes to text 
Appendix 2 Study Governance 
Study and Site Closure: Text added to 
indicate that new or emerging safety 
information that negatively affects the 
benefit/risk assessment of the clinical 
study may be a reason for closing study 
sites or terminating the study 
Health Authority Request 
Appendix 3 Contraception 
Added missing footnote label ‘a’ 
Added footnote ‘b’ to indicate that if a 
WOCBP is using a highly effective 
method other than sexual abstinence or 
vasectomized partner, AND ALSO has a 
vasectomized partner, the vasectomized 
partner will be considered the “barrier 
method” for study purposes 
Label was missing in footnotes 
Clarification 
Appendix 4 Adverse Events: 
Definitions and Procedures for 
Recording, Evaluating, Follow-
up, and Reporting 
Events Not to Be Considered as 
AEs/SAEs: 
Text added to state that worsening of the 
underlying disease is not routinely 
considered an AE or SAE 
Alignment with template wording 
 
 
 
 
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Section # and Name 
Description of Change 
Brief Rationale 
Text on reporting of AESIs was updated 
in line with the latest protocol template 
For clarification and so that EDC 
can be used 
Appendix 5 Clinical Laboratory 
Tests 
Moved some assessments listed in 
‘Other screening tests’ into new row 
‘Other tests’ 
JCV DNA PCR added to list of ‘Other 
screening tests’ 
Estradiol removed from list of ‘Other 
screening tests’ 
 
βhCG removed from routine urinalysis 
 
Teriflunomide footnote amended to 
include all participants undergoing AEP 
Clarification; not all tests listed 
were Screening only 
 
To include missing information 
 
Estradiol not used to determine 
postmenopausal status in this 
study 
This is a serum test; now listed 
under other tests 
To include females undergoing 
AEP 
Appendix 8 Procedure for 
Accelerated Elimination of 
Teriflunomide 
Text added to allow accelerated 
elimination of teriflunomide in 
accordance with standard of care 
Text added to note that it is only required 
to confirm a level of < 0.02 mg/L after the 
AEP if the AEP is being done for 
pregnancy-related considerations 
To allow accelerated elimination of 
teriflunomide in accordance with 
local guidance 
For clarification 
Appendix 10 Structured 
Interview at Telephone Visit 
New appendix added: ‘Structured 
Interview at Telephone Visit’ 
Clarification/simplification of 
protocol. Structured interview put 
into place to identify any new or 
worsening neurological symptoms 
that warrant evaluation at an 
unscheduled visit  
Throughout the document 
Changes made to align with updated 
protocol template 
Minor editorial and document formatting 
revisions 
Minor; therefore, have not been 
summarized 
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Protocol Version 1.3-BEL (12 August 2020)  
Overall Rationale for the Amendment 
This local amendment updates the Medical Responsible and clarifies that CYP2B6 substrates with 
a narrow therapeutic index, as well as substrates of P-gp, BCRP, OCT1, MATE1 and/or MATE2K 
medicines should be used with caution. 
 
Section # and Name 
Description of Change 
Brief Rationale 
Title page;  
Appendix 11 
Updated with new Medical Responsible 
Change in personnel  
5.2; 
6.5.3 
Added clarification that CYP2B6 substrates 
with a narrow therapeutic index, as well as 
substrates of P-gp, BCRP, OCT1, MATE1 
and/or MATE2K should be used with 
caution. 
Clarification on medicines to be used 
with caution. 
Protocol Version 1.2-DEU (04 August 2020)  
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
This local amendment updates the Medical Responsible, deletes language referring to the 
participant’s legal representative and updates the benefit/risk assessment to account for the 
Caronavirus disease 2019 (COVID-19) pandemic. 
Section # and Name 
Description of Change 
Brief Rationale 
Title page;  
Appendix 11 Sponsor 
Signature Page 
Updated with new Medical Responsible 
Change in personnel  
2.3 Benefit/Risk 
Assessment 
Added text to address potential risk and 
mitigation to decrease risk of severe 
acute respiratory syndrome coronavirus 2 
(SARS-CoV-2) infection  
To address new risks associated with the 
emergence of the COVID-19 pandemic 
5.0 Study Population; 
Appendix 2 Study 
Governance 
Deleted reference to participant’s legal 
representative 
Removal of template language not 
applicable for the trial 
Protocol Version 1.1-CAN (03 July 2020)  
This amendment is nonsubstantial based on the criteria in Article 10(a) of Directive 2001/20/EC 
of the European Parliament and the Council of the European Union because it neither significantly 
impacts the safety or physical/mental integrity of participants nor the scientific value of the study. 
Overall Rationale for the Amendment 
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This local amendment has been created to align the Clinical Study Protocol with the Canadian 
Product Monograph for Aubagio® (teriflunomide). 
Section # and Name 
Description of Change 
Brief Rationale 
5.4.2 Caffeine, Alcohol 
and Tobacco 
Section has been rephrased  
Alignment with the Canadian Product 
Monograph for teriflunomide 
 
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Appendix 13 
Sponsor Signature Page  
 
Study Title: 
A Phase III, Multicenter, Randomized, Parallel Group, 
Double Blind, Double Dummy, Active Controlled Study 
of Evobrutinib Compared with Teriflunomide, in 
Participants with Relapsing Multiple Sclerosis to Evaluate 
Efficacy and Safety. 
Regulatory Agency Identifying 
Numbers: 
EudraCT: 2019-004972-20 
US IND: 129428 
Clinical Study Protocol Version: 
Version 6.0/26 April 2023 
I approve the design of the clinical study: 
_________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
  
 
Institution: 
Ares Trading SA, an affiliate of Merck Serono GmbH  
Address: 
Route de Crassier 1, 1262 Eysins, Switzerland 
Telephone number: 
 
Fax number: 
Not Applicable 
E-mail address: 
 
 
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Appendix 14 
Coordinating Investigator Signature Page  
 
Study Title: 
A Phase III, Multicenter, Randomized, Parallel Group, 
Double Blind, Double Dummy, Active Controlled Study 
of Evobrutinib Compared with Teriflunomide, in 
Participants with Relapsing Multiple Sclerosis to Evaluate 
Efficacy and Safety. 
Regulatory Agency Identifying 
Numbers: 
EudraCT: 2019-004972-20 
US IND: 129428 
Clinical Study Protocol Version: 
Version 6.0/26 April 2023 
Site Number: 
 
I approve the design of the clinical study, am responsible for the conduct of the study at this site, 
and understand and will conduct it per the clinical study protocol, any approved protocol 
amendments, International Council on Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws. 
_________ 
Signature 
Date of Signature 
 
Name, academic degree: 
  
Function/Title: 
 
Institution: 
 
Address: 
 
 
Telephone number: 
 
Fax number: 
Not Applicable 
E-mail address: 
 
 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942
PPD
PPD
PPD
PPD
PPD
PPD
PPD


Evobrutinib 
Phase III Study of Evobrutinib in RMS 
MS200527_0080 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
262/262 
 
 
Appendix 15 
Principal Investigator Signature Page  
 
Study Title: 
A Phase III, Multicenter, Randomized, Parallel Group, 
Double-Blind, Double-Dummy, Active Controlled Study 
of Evobrutinib Compared with Teriflunomide, in 
Participants with Relapsing Multiple Sclerosis to Evaluate 
Efficacy and Safety. 
Regulatory Agency Identifying 
Numbers: 
EudraCT: 2019-004972-20 
US IND: 129428 
Clinical Study Protocol Version: 
Version 6.0/26 April 2023 
Site Number: 
 
I am responsible for the conduct of the study at this site, and understand and will conduct it per the 
clinical study protocol, any approved protocol amendments, International Council on 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws. 
I also understand that Health Authorities may require the Sponsors of clinical studies to obtain and 
supply details about ownership interests in the Sponsor or Investigational Medicinal Product and 
any other financial ties with the Sponsor. The Sponsor will use any such information solely for 
complying with the regulatory requirements. Therefore, I agree to supply the Sponsor with any 
necessary information regarding ownership interest and financial ties including those of my spouse 
and dependent children, and to provide updates as necessary to meet Health Authority 
requirements. 
____________________________________ 
____________________________ 
Signature 
Date of Signature 
 
Name, academic degree: 
 
Function/Title: 
 
Institution: 
 
Address: 
 
Telephone number: 
 
Fax number: 
 
E-mail address: 
 
 
Global Version ID: 78691_4679269_6096058
Global Version ID: 78691_4679269_6105942

SAP_001.pdf: 
E v o br uti ni b  
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I nte gr ate d A n al ysis Pl a n  
Cli nic al St u d y  Pr ot oc ol 
I de ntific ati o n N o. 
M S 2 0 0 5 2 7 _ 0 0 8 0
 
Title  
A P hase III, M ultice nter, Ra n d o mize d, Parallel Gr o u p, D o u ble 
Bli n d, D o u ble D u m m y, Acti ve C o ntr olle d St u d y of E v o br uti ni b 
C o m pare d wit h Terifl u n o mi de, i n Partici pa nts wit h Rela psi n g 
M ulti ple Scler osis t o E val uate Efficac y a n d Safet y  
St u d y P h ase  
III 
I n vesti gati o n al Me dici n al 
Pr o d uct(s)  
E v o br uti ni b ( M 2 9 5 1)  
Cli nic al St u d y  Pr ot oc ol 
Versi o n  
Versi o n 6 . 0 dated 2 6 ( 0 0 8 0
I nte gr ate d A n al ysis Pl a n 
A ut h or  
C o or di n ati n g A ut h or  
 
, M er c k 
 
F u n cti o n  
A ut h or( s) / D at a A n al y st( s)  
, 
 
 
, 
 
 
 
 
 
I nte gr ate d A n al ysis Pl a n 
D ate a n d Versi o n  
2 0  N o ve m ber 2 0 2 3 / V ersi o n 8 . 0 
I nte gr ate d A n al ysis Pl a n 
Re vie wers  
Merc k/ E M D -Ser o n o Re vie wers:  
F u n cti o n  
N a m e  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.  
It is i nte n de d f or restricte d use o nl y a n d ma y n ot –  i n f ull or part –  be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K g a A, Dar msta dt, Ger ma n y or its affiliate.  
C o p yri g ht © 2 0 2 3  b y M erc k K g a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.  
A p pr o v al  P a ge   
 
I nte gr ate d A n al ysis Pl a n: M S 2 0 0 5 2 7 _ 0 0 8 0
A P hase III, M ultice nter, Ra n d o mize d, Parallel Gr o u p, D o u ble Bli n d, D o u ble D u m m y, Acti ve 
C o ntr olle d St u d y of E v o br uti ni b C o m pare d wit h Terifl u n o mi de, i n Partici pa nts wit h Rela psi n g 
M ulti ple Scler osis t o E val uate Efficac y a n d Safet y.  
A p pr o val of t he IA P b y Merc k D ata A nal ysis Res p o nsi ble is d oc u me nte d wit hi n t he E D M S via 
e Si g nat ur e. Wit h t he a p pr o val wit hi n E D M S, t he Merc k res p o nsi ble f or eac h of t he a nal ysis als o 
ta kes res p o nsi bilit y t hat all re vie wers’ c o m me nts are a d dresse d a d e q uatel y. 
B y usi n g e Si g n at ure, t he si g nat ur e will a p pear at t he e n d of t he d oc u me nt.  
 
 
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1  
T a ble of C o nte nts   
A p pr o val Pa ge  
2  
1  
Ta ble of C o nte nts  ..................................................................................3  
2  
List of A b bre viati o ns a n d Defi niti o n of Ter ms  ..................................1 1  
3  
M o dificati o n Hist or y  ..........................................................................1 6  
4  
P ur p ose of t he I nte grate d A nal ysis Pla n  .............................................1 9  
5  
O bjecti ves a n d Esti ma n ds  ...................................................................2 0  
6  
O ver vie w of Pla n ne d A nal yses  ...........................................................2 5  
6. 1  
O pti o nal I nteri m A nal ysis f or Bli n de d Sa m ple Size Re -esti mati o n  ...2 6  
6. 2  
Pri mar y A n al ysis  ................................................................................2 6  
6. 3  
D B E A n al ysis  .....................................................................................2 7  
6. 4  
Fi nal A nal ysis  .....................................................................................2 7  
7  
C ha n ges t o t he Pla n ne d A nal ys es i n t he Cli nical St u d y Pr ot o c ol  ......2 7  
8  
A nal ysis Sets a n d S u b gr o u ps  ..............................................................2 8  
8. 1  
Defi niti o n of A nal ysis Sets  .................................................................2 8  
8. 2  
S u b gr o u p D efi nit i o n a n d Para meterizati o n ........................................3 1  
9  
Ge neral S pecificati o ns f or Data A n al ys es  ..........................................3 3  
9. 1  
St u d y i nter ve nti o n  ...............................................................................3 3  
9. 2  
Pr ese ntati o n of c o nti n u o us a n d q ualitati ve varia bl es  ..........................3 3  
9. 3  
Data Ha n dli n g After C ut off Date  .......................................................3 5  
9. 4  
Defi niti o n of Bas eli ne a n d C ha n ge fr o m Baseli ne  .............................3 5  
9. 5  
St u d y Da y  ...........................................................................................3 6  
9. 6  
Defi niti o n of D urati o n a n d ‘ti me si nce’ Varia bles  .............................3 6  
9. 7  
C o n versi o n Fact ors  .............................................................................3 6  
9. 8  
Ti me Wi n d o w  .....................................................................................3 6  
9. 9  
Re peate d a n d U nsc he d ul e d Meas ure me nts  ........................................3 7  
9. 1 0  
Defi niti o n of O n -treat me nt Peri o d ......................................................3 7  
9. 1 1  
Defi niti o n of 4 8  wee ks P ost  Ra n d o mizati o n Peri o d  ...........................3 7  
9. 1 2  
Defi niti o n of 9 6  wee ks P ost  Ra n d o mizati o n Peri o d  ...........................3 7  
9. 1 3  
Defi niti o n of 1 5 6  wee ks P ost  Ra n d o mizati o n Peri o d  .........................3 7  
9. 1 4  
I m p utati o n of Missi n g Data ................................................................3 7  
9. 1 5  
Sc ori n g of H R Q O L Dat a  ....................................................................3 9  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
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I N F O R M A T I O N 
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9. 1 6  
C o ntr ol of M ulti plicit y  ........................................................................3 9  
9. 1 7  
S oft ware  ..............................................................................................4 1  
9. 1 8  
U n bli n di n g  ..........................................................................................4 1  
9. 1 9  
Ter mi n ol o g y C o n ve nti o ns  ..................................................................4 1  
1 0  
St u d y Partici pa nts  ...............................................................................4 1  
1 0. 1  
D is p ositi o n of Partici pa nts a n d Disc o nti n uati o ns ...............................4 1  
1 0. 2  
Pr ot oc ol De viati o ns / E xcl usi o n fr o m A nal ysis P o p ulati o ns  ..............4 5  
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De viati o ns ............................................................4 5  
1 0. 2. 2  
Reas o ns Lea di n g t o t he E x cl usi o n fr o m a n A nal ysis P o p ulati o n  .......4 6  
1 1  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .............................4 6  
1 1. 1  
De m o gra p hics  .....................................................................................4 6  
1 1. 2  
Me dical Hist or y  ..................................................................................4 7  
1 1. 3  
Ot her Baseli ne C haracteristics  ............................................................4 7  
1 1. 3. 1  
Disease Hist or y  ...................................................................................4 7  
1 1. 3. 2  
Baseli ne Lesi o n Meas ures, Ne ur ol o gical Assess m e nts, P R Os a n d 
Nf L C o nce ntr ati o n  ..............................................................................4 8  
1 1. 3. 3  
Hist or y of D M T  ..................................................................................4 9  
1 1. 3. 4  
Ot her Scree ni n g C haract eristics  .........................................................5 0  
1 1. 3. 5  
Baseli ne S u bsta nce Use C haracteristics  .............................................5 0  
1 2  
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures  .............................5 1  
1 2. 1  
Pre vi o us or C o nc o mita nt Me dicati o ns  ................................................5 1  
1 2. 2  
Pri or or C o nc urre nt Pr oce d ures  ..........................................................5 2  
1 2. 3  
C O VI D -1 9 V acci n ati o ns  ....................................................................5 2  
1 3  
St u d y Treat me nt: C o m plia nce a n d E x p os ure  .....................................5 2  
1 3. 1  
E x p os ure Calc ulati o n  ..........................................................................5 3  
1 3. 2  
C o m plia nce Calc ulati o n  ......................................................................5 4  
1 4  
Efficac y A nal yses  ...............................................................................5 5  
1 4. 1  
Pri mar y Esti ma n d: A n n ualize d Rela pse Rate u p t o 1 5 6 Wee ks  .........5 5  
1 4. 1. 1  
Pri mar y O bj ecti ve: Deri vati o n a n d A nal ysis of A R R u p t o 1 5 6 
Wee ks  .................................................................................................5 5  
1 4. 1. 2  
Se nsiti vit y A nal ys es of A R R  ..............................................................5 9  
1 4. 1. 3  
S u b gr o u p A n al ys es of A R R  ................................................................6 2  
1 4. 2  
Sec o n dar y Esti ma n ds  ..........................................................................6 2  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
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1 4. 2. 1  
Ti me t o C o nfir me d Disa bilit y Pr o gressi o n  .........................................6 2  
1 4. 2. 1. 1  
Ti me t o 1 2 -wee k C D P  ........................................................................6 3  
1 4. 2. 1. 2  
Ti me t o 2 4 -wee k C D P  ........................................................................6 5  
1 4. 2. 1. 3  
Se nsiti vit y A nal ys es: Ti me t o C o nfir me d Disa bilit y Pr o gressi o n  ......6 5  
1 4. 2. 2  
Ti me t o 2 4 -Wee k C o nfir me d Disa bilit y I m pr o ve me nt ......................6 8  
1 4. 2. 3  
P R O MI S Sc ores  ..................................................................................7 0  
1 4. 2. 3. 1  
P R O MI S P F Sc ore C F B o ver 9 6  Wee ks  ............................................7 0  
1 4. 2. 3. 2  
P R O MI S Fati g ue Sc ore C F B o ver 9 6  Wee ks  .....................................7 3  
1 4. 2. 3. 3  
Se nsiti vit y A nal ys es: P R O MI S Sc ore C F B  ........................................7 3  
1 4. 2. 4  
M RI Lesi o n Meas ures  .........................................................................7 5  
1 4. 2. 4. 1  
T otal N u m ber of T 1 G d + lesi o ns Base d o n All A v aila ble M RI 
Sca ns  ...................................................................................................7 5  
1 4. 2. 4. 2  
N u m ber of ne w or e nl ar gi n g T 2 lesi o ns o n t he Last A vaila ble 
M RI Sca n Rel ati ve t o t he Baseli ne M RI Sca n ....................................7 7  
1 4. 2. 4. 3  
Se nsiti vit y / S u p ple me ntar y A nal yses: M RI Lesi o n Meas ures  ..........7 8  
1 4. 2. 5  
Ne ur ofila me nt Li g ht C ha i n C o nce ntrati o n at Wee k 1 2  ......................8 0  
1 4. 2. 5. 1  
Se nsiti vit y A nal ys es: Ne ur ofila me nt Li g ht C hai n C o nce ntrati o n  ......8 2  
1 4. 2. 6  
S u b gr o u p A n al ys es f or S ec o n dar y Esti ma n ds  ....................................8 3  
1 4. 3  
Tertiar y/ E x pl orat or y E n d p oi nts  ..........................................................8 3  
1 4. 3. 1  
A R R at W ee ks 4 8 a n d 9 6  ....................................................................8 4  
1 4. 3. 2  
Ti me t o First Q ualifie d R ela pse o ver 1 5 6  Wee ks  ...............................8 4  
1 4. 3. 3  
Q ualif yi n g Rel a pse -free Stat us at Wee k 9 6  ........................................8 4  
1 4. 3. 4  
1 2 -wee k ( 2 4 -w ee k) C o nfir me d E D S S Pr o gressi o n -Free Stat us at 
Wee k  9 6  ..............................................................................................8 4  
1 4. 3. 5  
2 4 -wee k C o nfir m e d Disa bil it y I m pr o ve me nt Stat us at Wee k 9 6  .......8 5  
1 4. 3. 6  
Lesi o n -Free Stat us at Wee k  9 6  ...........................................................8 6  
1 4. 3. 7  
T otal N u m ber of Lesi o ns Base d o n All A vaila ble M RI Sca ns  ...........8 6  
1 4. 3. 8  
C ha n ge i n V ol u me of Lesi o ns fr o m Baseli ne t o W ee k  9 6  .................8 6  
1 4. 3. 9  
Perce nta ge C ha n ge i n Brai n V ol u me fr o m Wee k 2 4 t o Wee k  9 6  ......8 7  
1 4. 3. 1 0  
C ha n ge i n N or malize d T 1 I nte nsit y wit hi n Pre -E xisti n g 
N o n -E n ha nci n g T 2 Wei g hte d Lesi o n V ol u me fr o m Baseli ne t o 
Wee k  9 6  ..............................................................................................8 8  
1 4. 3. 1 1  
V ol u me of S E Ls Bas e d o n Sca ns at Wee ks 2 4, 4 8, a n d 9 6  ................8 8  
1 4. 3. 1 2  
C ha n ge i n N u m ber of P h ase Ri m Lesi o ns at Wee ks 2 4, 4 8 a n d 9 6  ...8 9  
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C ha n ge i n Cere bral Bl o o d Fl o w i n N or mal -A p peari n g W hite 
Matter at W ee ks 2 4, 4 8 a n d 9 6  ...........................................................8 9  
1 4. 3. 1 4  
Ti me t o ≥ 2 0 % I n crease ( C o nfir me d at 1 2  Wee ks) i n T 2 5 -F W ( 9 -
H P T) u p t o 1 5 6  Wee ks  .......................................................................8 9  
1 4. 3. 1 5  
N E D A -3 at W ee k  4 8, W ee k  9 6  ..........................................................9 0  
1 4. 3. 1 6  
Ti me t o 1 2 -wee k C o nfir me d Disa bilit y Base d o n C o m p osite Sc ore  ..9 1  
1 4. 3. 1 7  
N E P at W ee k  4 8, Wee k  9 6  .................................................................9 2  
1 4. 3. 1 8  
N E P A D at W ee k  4 8, Wee k  9 6  ...........................................................9 2  
1 4. 3. 1 9  
C F B i n S D M T sc ore at Wee k  4 8 a n d Wee k  9 6  ..................................9 3  
1 4. 3. 2 0  
PI R A u p t o Wee k  1 5 6  .........................................................................9 4  
1 4. 3. 2 1  
PI R M A u p t o Wee k  1 5 6  .....................................................................9 5  
1 5  
Safet y A nal yses  ..................................................................................9 6  
1 5. 1  
A Es  .....................................................................................................9 7  
1 5. 1. 1  
All A Es  ...............................................................................................9 7  
1 5. 1. 1. 1  
3 Tier A p pr oac h  ..................................................................................9 8  
1 5. 1. 1. 2  
O ver vie w of T E A Es  ...........................................................................9 9  
1 5. 1. 1. 3  
Ta b ulati o n of A Es b y S O C a n d P T ...................................................1 0 0  
1 5. 1. 1. 4  
Se nsiti vit y A nal ys es of A Es  .............................................................1 0 1  
1 5. 2  
Deat hs, Ot her Seri o us A Es, a n d Ot her Si g nifica nt A Es  ...................1 0 2  
1 5. 2. 1  
Deat hs  ...............................................................................................1 0 2  
1 5. 2. 2  
Seri o us A Es  ......................................................................................1 0 2  
1 5. 2. 3  
T E A Es of S pecial I nt erest  ................................................................1 0 2  
1 5. 2. 4  
Ot her Si g nifica nt T E A Es  ..................................................................1 0 3  
1 5. 3  
Cli nical La b orat or y E val uati o n  .........................................................1 0 4  
1 5. 4  
Vital Si g ns  ........................................................................................1 1 1  
1 5. 5  
1 2 -Lea d E C G  ....................................................................................1 1 1  
1 5. 6  
P h ysical E x a mi nati o n  .......................................................................1 1 2  
1 5. 7  
Pre g n a nc y T est  ..................................................................................1 1 3  
1 5. 8  
Safet y/ P har mac o d y n a mic E n d p oi nts: I m m u n o gl o b uli n le vels  .........1 1 3  
1 5. 9  
Uri nal ysis Micr osc o pic E val uati o n  ...................................................1 1 3  
1 5. 1 0  
C -S S R S  .............................................................................................1 1 3  
1 5. 1 1  
H B V D N A  ........................................................................................1 1 4  
1 5. 1 2  
L ocal La b orat or y Res ults  ..................................................................1 1 5  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
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1 5. 1 3  
A nti -S A R S -C o V -2 A nti b o dies Le vels  .............................................1 1 5  
1 5. 1 4  
F oc use d Ge netic T esti n g  ...................................................................1 2 0  
1 6  
A nal ys es of Ot her E n d p oi nts  ............................................................1 2 0  
1 6. 1  
P K  .....................................................................................................1 2 0  
1 6. 1. 1  
Ge neral S pecificati o ns f or P K C o nce ntrati o n a n d P K Para meter 
Data  ...................................................................................................1 2 0  
1 6. 1. 2  
Esti mati o n of P K Para meters  ............................................................1 2 2  
1 6. 1. 3  
Prese ntati o n of P K Para meter Data  ..................................................1 2 6  
1 6. 2  
P D  .....................................................................................................1 2 6  
1 6. 2. 1  
B T K O cc u pa n c y at Baseli ne a n d Wee ks  2, 4, 8, 1 2 a n d 2 4  .............1 2 6  
1 6. 2. 2  
Nf L C o nce ntr ati o n at Baseli ne a n d Wee ks 2 4, 4 8, 7 2, 9 6, a n d 1 2 0  .1 2 7  
1 6. 2. 3  
Ot her P D E n d p oi nt A nal ys es at Baseli ne a n d Wee ks 2, 4, 8, 1 2 
a n d 2 4  ................................................................................................1 2 7  
1 6. 3  
P o p ulati o n P K M o deli n g a n d E x p os ure -Res p o nse A nal ys es  ...........1 2 7  
1 6. 4  
P R O –  E x pl orat or y E n d p oi nts  ..........................................................1 2 8  
1 6. 4. 1  
C ha n ge fr o m Baseli ne i n P R O MI S Sc ore at Wee k  4 8, Wee k  9 6 
a n d Wee k 1 4 4  ...................................................................................1 2 8  
1 6. 4. 2  
C ha n ge fr o m Baseli ne i n S F -3 6 v 2 sc ore at Wee k  4 8, Wee k  9 6 a n d 
Wee k 1 4 4  ..........................................................................................1 2 9  
1 6. 4. 3  
C ha n ge fr o m Baseli ne i n E Q  5 D -5 L V A S a n d I n de x at Wee k  4 8, 
Wee k  9 6 a n d Wee k 1 4 4  ....................................................................1 2 9  
1 6. 4. 4  
Ti me t o First Occ urre n ce of 1 2 -wee k C o nfir me d P F Deteri orati o n 
C o m pare d t o Bas eli ne u p t o 1 5 6  Wee ks  ...........................................1 3 0  
1 6. 4. 5  
Ti me t o First Occ urre n ce of 2 4 -wee k C o nfir me d P F I m pr o ve m e nt 
C o m pare d t o Bas eli ne u p t o 1 5 6  Wee ks  ...........................................1 3 0  
1 6. 4. 6  
Ti me t o First Occ urre n ce of 1 2 -wee k C o nfir me d Fati g ue 
Deteri or ati o n C o m pare d t o Baseli ne u p t o 1 5 6  Wee ks  ....................1 3 1  
1 6. 4. 7  
Ti me t o First Occ urre n ce of 2 4 -wee k C o nfir me d Fati g ue 
I m pr o v e me nt C o m pare d t o Baseli ne u p t o 1 5 6 Wee ks  ....................1 3 1  
1 6. 4. 8  
P R O MI S Fati g ue Sc ore C F B o ver 9 6  Wee ks I n d e pe n de nt of 
Rela pse Acti vit y  ................................................................................1 3 2  
1 6. 4. 9  
P R O MI S Res p o nse u p t o Wee k  1 5 6  .................................................1 3 2  
1 6. 5  
H R U  ..................................................................................................1 3 3  
1 7  
Refere n ces  .........................................................................................1 3 4  
1 8  
A p pe n dices  .......................................................................................1 3 6  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 /1 5 9  
 
 
 
1 8. 1  
P R O MI S Sc ores  ................................................................................1 3 6  
1 8. 2  
3 6 -It e m S h ort F or m S ur ve y ( S F-3 6) Sc ori n g I nstr ucti o ns  ...............1 3 7  
1 8. 3  
E Q -5 D -5 L  .........................................................................................1 4 4  
1 8. 4  
A nal ysis Visit Wi n d o ws  ...................................................................1 4 5  
1 8. 5  
Tier 1 A Es a n d A E SIs  .......................................................................1 5 0  
1 8 . 6 
La b orat or y Para meters t o be S u m marize d i n t he T L Fs  ....................1 5 1  
1 8. 7  
Ha n dli n g of la b orat or y res ults wit h m o difiers  ..................................1 5 5  
1 8. 8  
M ulti plicit y Gra p h  ............................................................................1 5 7  
1 8. 9  
Statistical Met h o d ol o g y  ....................................................................1 5 8  
1 8. 1 0  
S A P f or I D M C/ S M C  ........................................................................1 5 9  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 /1 5 9  
 
 
 
T a ble of I n -Te xt T a bles   
Ta ble 1  
O bjecti ves a n d Esti ma n ds f or t he D B T P:  ...........................................2 1  
Ta ble 2  
O bjecti ves a n d E n d p oi nts f or t he D B T P:  ...........................................2 3  
Ta ble 3  
A nal ysis Sets  .......................................................................................2 9  
Ta ble 4  
Use of A nal ysis Sets  ...........................................................................3 0  
Ta ble 5  
St u d y I nter v e nti o ns a n d Re gi me ns  .....................................................3 3  
Ta ble 6  
Dis p ositi o n  ..........................................................................................4 1  
Ta ble 7  
D osa ge a n d a d mi nistrati o n  .................................................................5 3  
Ta ble 8  
Data Ha n dli n g f or Efficac y A nal ysis  ..................................................5 5  
Ta ble 9  
Details of Ste ps t o be A p plie d W he n t he Pri mar y M o del Fails t o 
C o n ver ge  .............................................................................................5 7  
Ta ble 1 0  
Data Ha n dli n g f or Safet y A nal ysis  .....................................................9 7  
Ta ble 1 1  
Tier 1 A Es  ...........................................................................................9 8  
Ta ble 1 2  
S u m mar y Ta bl es of T E A Es  ................................................................9 9  
Ta ble 1 3  
T E A E Ta bles  ....................................................................................1 0 0  
Ta ble 1 4  
E AI R of T E A E T a bles  ......................................................................1 0 1  
Ta ble 1 5  
T E A E Ta bles t o be pr o d uce d  ............................................................1 0 3  
Ta ble 1 6  
La b orat or y Para meters  ......................................................................1 0 6  
Ta ble 1 7  
Vital Si g ns Cate g ories  ......................................................................1 1 1  
Ta ble 1 8  
P K Sa m pli n g Ti me Wi n d o ws –  Mai n St u d y  ....................................1 2 1  
Ta ble 1 9  
P K Sa m pli n g Ti me Wi n d o ws –  S u bst u d y  ........................................1 2 2  
Ta ble 2 0  
S F -3 6 –  A b bre vi ate d Ite m C o nte nt f or t he S F -3 6 v 2 Healt h 
D o mai n Scales  ..................................................................................1 3 7  
Ta ble 2 1  
S F -3 6 –  Rec o di n g  .............................................................................1 3 8  
Ta ble 2 2  
S F -3 6 –  Val ues us e d i n Tra nsf or mi n g S F -3 6 v 2 Healt h S ur ve y 
Healt h D o mai n Scale T ot al Ra w Sc ores o n t he 0 -1 0 0 Scale  ............1 3 9  
Ta ble 2 3  
S F -3 6 –  1 9 9 8 Ge n eral U S P o p ulati o n Mea ns a n d Sta n dar d 
De viati o ns use d t o Calc ulate N or malize d Healt h D o mai n Sc ores  ...1 4 0  
Ta ble 2 4  
S F -3 6 –  Fact or Sc ore C oefficie nts use d t o Calc ul ate P C S a n d 
M C S Sc ores f or t he S F -3 6 v 2  ............................................................1 4 1  
Ta ble 2 5  
S F -3 6 –  N u merical E x a m ple –  Ra w Data  .........................................1 4 1  
Ta ble 2 6  
S F -3 6 –  N u merical E x a m ple –  D o mai n Sc ores  ................................1 4 3  
Ta ble 2 7  
E Q -5 D -5 L –  E x a m ple  .......................................................................1 4 4  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 /1 5 9  
 
 
 
Ta ble 2 8  
A nal ysis visit wi n d o ws f or Ne ur ol o gical E val uati o n E D S S, T 2 5 -
F W, 9 -H P T, S D M T, C -S S R S, P R O MI S, E Q -5 D -5 L a n d H R U 
t hr o u g h Wee k 1 5 6  .............................................................................1 4 5  
Ta ble 2 9  
A nal ysis visit wi n d o ws f or Vital Si g ns a n d Wei g ht t hr o u g h 
Wee k  1 5 6  ..........................................................................................1 4 5  
Ta ble 3 0  
A nal ysis visit wi n d o ws f or M R I t hr o u g h Wee k 1 5 6  ........................1 4 6  
Ta ble 3 1  
A nal ysis visit wi n d o ws f or S F -3 6 v 2 t hr o u g h Wee k  1 5 6  ..................1 4 6  
Ta ble 3 2  
A nal ysis visit wi n d o ws f or 1 2 -lea d E C G t hr o u g h Wee k 1 5 6  ...........1 4 6  
Ta ble 3 3  
A nal ysis visit wi n d o ws f or Bi oc he mistr y (e x ce pt tests n ote d as 
S u p ple me nt L F Ts) a n d He mat ol o g y t hr o u g h Wee k  1 5 6  ..................1 4 6  
Ta ble 3 4  
A nal ysis visit wi n d o ws f or Bi oc he mistr y tests n ot e d as 
S u p ple me nt L F Ts t hr o u g h Wee k  1 5 6  ...............................................1 4 7  
Ta ble 3 5  
A nal ysis visit wi n d o ws f or Uri nal ysis t hr o u g h Wee k  1 5 6  ...............1 4 8  
Ta ble 3 6  
A nal ysis visit wi n d o ws f or Bi o mar kers (i ncl u di n g Nf L a n d I g 
le vels) t hr o u g h Wee k 1 5 6  .................................................................1 4 8  
Ta ble 3 7  
A nal ysis visit wi n d o ws f or P D/ Bi o mar kers meas ure d as part of 
t he P D s u bst u d y ( B T K O, cell ular f u ncti o n a n d c yt o ki nes) t hr o u g h 
Wee k  1 5 6  ..........................................................................................1 4 8  
Ta ble 3 8  
A nal ysis visit wi n d o ws f or H B V D N A t hr o u g h W ee k  1 5 6  .............1 4 9  
Ta ble 3 9  
La b orat or y Para meters t o be S u m marize d i n t he T L Fs  ....................1 5 1  
 
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 /1 5 9  
 
 
 
2  
List of A b bre vi ati o ns a n d Defi niti o n of Ter ms   
9 -H P T  
9 -h ole p e g test  
A d a M  
anal ysis d ata m o del  
A E  
ad verse eve nt  
A E P  
accelerat e d eli mi nati o n p r oce d ure 
A E SI  
ad verse eve nt of sp ecial interest  
A L T  
ala ni ne a mi n otra nsferas e 
A R R  
an n ualize d rela pse rate  
A S T  
as partate a mi n otra nsferas e 
A T C  
anat o mical thera pe utic cl ass 
BI D  
twice per da y  
B L Q  
b el o w t he li mit of q ua ntificati o n  
B MI  
b o d y m ass in de x  
B O A  
b i ostatistics o ut p uts asse m bl y 
B S S R  
b li n de d sa m ple siz e re-esti mati o n 
B T K  
Br ut o n’s tyr osi ne k i nas e 
B U N  
b l o o d urea nitr o ge n 
B V  
b rai n v ol u me  
c C D P 
c o nfir me d disa bilit y as a c o m p osite sc ore  
C DI  
c o nfir me d disa bilit y i m pr o ve me nt  
C DI S C  
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m  
C D P  
c o nfir me d disa bilit y pr o gressi o n  
C F B  
c ha n ge fr o m Baseli ne 
cI P D  
cli nicall y i m p orta nt pr ot o c ol de viati o n  
C M H  
C oc hra n -Ma nt el -Hae nszel  
C O VI D -1 9  
C or o na vir us disease of 2 0 1 9  
C P  
c o n diti o nal p o wer  
C R  
c o p y-refere nce 
(e) C R F 
(electr o ni c) case re p ort f or m 
C S R  
cli nical st u d y re p ort  
C -S S R S  
C ol u m bia -s uici de se verit y rati n g s cale 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 /1 5 9  
 
 
 
C U A  
c o m bi ne d u ni q ue acti ve  
C V %  
c oeffi cie nt of variati o n  
D B E  
d o u ble -bli n d e xte nsi o n  
D B P  
diast olic bl o o d press ure  
D B T P  
d o u ble -bli n d treat me nt p eri o d 
D M T  
disease m o dif yi n g t h era p y  
D R M  
data re vie w meeti n g  
E A C  
e n d p oi nt a dj u dicati o n c o m mittee  
E AI R  
e x p os ure a dj uste d i nci de nce rat e  
E C G  
electr ocar di o gra m  
e-DI S H  
e val uati o n of dr u g-i n d u ce d seri o us he p at ot o xicit y 
E D M S  
electr o nic d o c u me nt ma na ge me nt s yste m  
E D S S  
e x pa n de d disa bilit y st at us scale  
E E A  
E ur o pea n E c o n o mic Area  
E Q -5 D -5 L  
E ur o Q o L 5 di me nsi o n 5 le vels  
E u dra C T  
E ur o pea n U ni o n Dr u g Re g ul ati n g A ut h orities Cli nical Trials  
F A S  
f ull a nal ysis set 
G d  
ga d oli ni u m  
G G T  
ga m ma -gl uta m yl tra nsferase  
G L M M  
ge n eralize d li near mi x e d m o del  
H B V  
he patitis B vir us  
H R  
hazar d rati o  
H R Q O L  
healt h relate d q u alit y of life  
H R U  
healt h res o ur ce utilizati o n  
I A 
i nteri m a nal ysis 
I A P 
i nte grate d a n al ysis pla n 
I C E 
i nterc urre nt e ve nt 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D A C 
i n de pe n de nt data a nal ysis ce nter 
I D M C 
i n de pe n de nt data m o nit ori n g c o m mittee  
I g 
i m m u n o gl o b uli n 
I P D 
i m p orta nt pr ot oc ol de viati o n 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 /1 5 9  
 
 
 
I Q R 
i nter q uartile ra n ge 
I T T 
i nte nt-t o-treat 
I W R S 
i nteracti ve w e b res p o ns e s yste m 
K M  
Ka pla n -Mei er  
L F T  
li ver f u ncti o n tests 
L L R  
l o wer li mit of re p orti n g 
M & S  
m o delli n g a n d si m ulati o n 
M A R  
missi n g at ra n d o m  
M CI D  
mi ni mal cli nicall y i m p ort a nt differe nce  
M C S  
me ntal c o m p o ne nt s u m mar y  
Mea n  
arit h metic mea n  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
m F A S  
m o difie d f ull a nal ysis set  
MI  
m ulti ple i m p utati o n  
M M R M  
mi x e d effect m o del f or re peate d meas ures  
M N  
Mietti ne n & N ur mi ne n  
M RI  
ma g n etic res o n a nce i ma gi n g  
M S  
m ulti ple scler osis  
n  
n u m ber o f n o n -missi n g o bser vati o ns  
N B  
ne gati ve bi n o mial  
N CI -C T C A E  
Nati o nal Ca ncer I nstit ute –  C o m m o n Ter mi n ol o g y Criteria f or A d verse 
E ve nts  
N E D A  
n o e vi de nce of disease acti vit y  
N E P  
n o e vi de nce of pr o gressi o n  
N E P A D  
n o e vi de nce of pr o gressi o n or acti ve dise ase  
Nf L  
ne ur ofila me nt li g ht c hai n  
n T 1  
n or malize d T 1  
P A  
pri mar y a nal ysis  
P B V C  
perce nt brai n v ol u me c h a n ge  
P C R  
p ol y merase c h ai n reacti o n 
P C S  
p h ysical c o m p o ne nt s u m mar y  
P D  
p har mac o d y n a mics  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 /1 5 9  
 
 
 
P D B T K O   
P D  Br ut o n’s t yr osi ne ki n ase  occ u p a nc y  
P De v  
pr ot oc ol de viati o n  
P D M P  
pr ot oc ol de viati o ns ma na ge m e nt pla n  
P F  
p h ysical f u ncti o n  
P H  
pr o p orti o nal -hazar ds  
PI R A  
pr o gressi o n i n de pe n d e nt of  rela pse acti vit y 
PI R M A  
pr o gressi o n i n de pe n d e nt of rela pse a n d brai n M RI acti vities  
P K  
p har mac o ki netics  
P K S U B  
P K s u bst u d y  
P R O  
patie nt re p orte d o ut c o me  
P R O MI S  
patie nt re p orte d o ut c o mes meas ure me nt i nf or m ati o n s yste m  
P T  
preferre d t er m  
Q 1  
first q uartile, 2 5 t h perce ntile  
Q 3  
t hir d q uartile, 7 5 t h perce ntile  
Q o L  
q ualit y of life  
R M S  
rela psi n g m ulti ple scler osis 
R O W  
rest of w orl d 
r R R 
rela pse rate rati o 
R R M S  
rela psi n g-re mitti n g m ulti ple scler osis 
S A E  
seri o us a d vers e e v e nt 
S A F  
safet y a n al ysis set 
S A P  
statistical a nal ysis pla n 
S A S  
statistical a nal ysis s yste m 
S B P  
s yst olic bl o o d press ur e 
S C R  
scree ni n g a nal ysis set 
S D  
sta n dar d de viati o n 
S D G  
sta n dar dize d dr u g gr o u pi n g 
S D M T  
s y m b ol di git m o dalities test 
S D T M  
st u d y data ta b ul ati o n m o del 
S E L  
sl o wl y e x pa n di n g lesi o n 
S F -3 6 v 2  
me dical o utc o mes st u d y 3 6 ite m s h ort f or m healt h s ur ve y  
SI  
S yste m I nter n ati o nal  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 /1 5 9  
 
 
 
S M C  
safet y m o nit ori n g c o m mittee 
S M Q  
sta n dar dize d Me d D R A q uer y 
S O C  
s yste m or ga n class 
S P M S  
sec o n dar y pr o gressi ve m ulti ple scler osis 
S T E R M  
st u d y ter mi nati o n 
T 1 G d +  
T 1 wei g ht e d ga d oli ni u m -e n ha nci n g  
T 2 5 -F W  
ti me d 2 5-f o ot wal k 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T L F  
ta bles, listi n gs, a n d fi g ures 
T T E R M  
treat me nt ter mi nati o n 
V A S  
vis ual a nal o g s cale  
W H O -D D  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 6 /1 5 9  
 
 
 
3  
M o dific ati o n Hist or y   
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n 
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
1. 0  
2 0 J a n u ar y 2 0 2 1  
 
I niti al V er si o n 
 
2. 0  
0 4 A u g u st 2 0 2 2  
 
 
U p d at e s r e g ar di n g Pr ot o c ol V er si o n s 2 a n d 3 : 
N e w e x pl or at or y e n d p oi nt s ( P R L a n d C B F [ S e cti o n s 5 
a n d 1 4. 3])  
R e m o v e d t h e I A f or u n bli n d e d s a m pl e si z e r e -e sti m ati o n 
a n d i n cl u d e o pti o n al I A f or B S S R wit h d et ail s r e g ar di n g 
m et h o d ol o g y [ S e cti o n s 6, 9. 1 3 a n d 1 4]  
U p d at e s r e g ar di n g Pr ot o c ol V er si o n 4 : 
R e vi si o n of t h e tr e at m e nt d ur ati o n fr o m fi x e d 9 6 w e e k s 
t o v ari a bl e d ur ati o n u p t o 1 5 6 w e e k s, a n d r e m o v al of 
O L E  p eri o d (t hr o u g h o ut t h e d o c u m e nt).  
R e vi s e d hi er ar c h y of s e c o n d ar y e n d p oi nt s i n t h e pri m ar y 
a n al y si s (ti m e t o fir st o c c urr e n c e of C DI a n d W e e k  1 2 
Nf L c o n c e ntr ati o n n e w s e c o n d ar y e n d p oi nt s [ S e cti o n  5 
a n d S e cti o n  1 4. 2], a n d n e w str at e g y t o c o ntr ol t h e T y p e I 
err or at st u d y a n d p o oli n g l e v el [ S e cti o n  9. 1 3]).  
M o difi c ati o n of s e c o n d ar y P R O MI S e n d p oi nt s fr o m C F B 
“ at 9 6  w e e k s t o C F B “ o v er 9 6  w e e k s” a n d m o difi c ati o n of 
p o p ul ati o n l e v el -s u m m ar y t o diff er e n c e of a v er a g e 
l e a st-s q u ar e s m e a n s, wit h a v er a g e t a k e n o v er a s et of 
ti m e p oi nt s e n di n g wit h W e e k  9 6 [ S e cti o n  5 a n d 
S e cti o n  1 4. 2. 3].  
M o difi c ati o n of s e c o n d ar y M RI e n d p oi nt s t o a c c o u nt f or 
all a v ail a bl e M RI s c a n s [ S e cti o n  5 a n d S e cti o n  1 4. 2. 4].  
I n cl u si o n of i nt er c urr e nt e v e nt “ U kr ai n e cri si s” a n d 
str at e g y f or h a n dli n g i n all pri m ar y a n d s e c o n d ar y 
e n d p o i nt s. 
S u m m ari z e t h e o ut c o m e of t h e o pti o n al I A f or B S S R a n d 
i nf or m ati o n f or A R R pr o vi d e d t o a d e q u at el y p o w er t h e 
e n d p oi nt wit h c orr e s p o n di n g tri g g er f or P A [ S e cti o n  6].  
I n cl u si o n of m o difi e d a n al y si s s et s ( m F A S a n d m S A F) 
[S e cti o n  8].  
P o p ul ati o n P K/ P D m o d eli n g s e cti o n r e vi s e d t o s p e cif y 
t h at all a n al y s e s will b e d e s cri b e d i n a p h ar m a c o m etri c 
m o d eli n g a n al y si s pl a n a n d r e p ort e d s e p ar at el y 
[S e cti o n  1 6. 3].  
U p d at e s r e g ar di n g dr aft Pr ot o c ol V er si o n 5 : 
A d diti o n of e x pl or at or y e n d p oi nt s ti m e t o PI R A, ti m e t o 
P I R M A, N E P at W e e k 4 8 or 9 6 a n d l e v el of 
a nti -S A R S -C o V -2 a nti b o di e s [ S e cti o n s  1 4. 3 a n d 1 5. 1 3].  
A d d e d d et ail s t o s e n siti vit y a n d s u p pl e m e nt ar y 
a n al y s e s f or pri m ar y a n d s e c o n d ar y effi c a c y 
e n d p oi nt s a s w ell a s s af et y e n d p oi nt s  
[S e cti o n s  1 4. 1. 2, 1 4. 2, 1 5. 1. 1. 4,  A p p e n di x  1 8. 9].  
A d diti o n of e x pl or at or y e n d p oi nt s  ti m e t o c o nfir m e d 
P R O MI S P F i m pr o v e m e nt [ S e cti o n  1 6. 4. 5] a n d C F B i n 
P R O MI S F ati g u e s c or e i n d e p e n d e nt of r el a p s e a cti vit y 
[ S e cti o n 1 6. 4. 6].  
A d diti o n of L T F a n al y s e s [ S e cti o n  1 5. 3].  
T hr o u g h o ut t h e d o c u m e nt : 
U p d at e s f or c o n si st e n c y a n d cl arifi c ati o n.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 7 /1 5 9  
 
 
 
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n 
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
3. 0  
1 6  F e br u ar y  2 0 2 3  
 
U p d at e s r e g ar di n g Pr ot o c ol V er si o n  5 : 
O L E tr e at m e nt p eri o d a d d e d b a c k (r e m o v e d f oll o wi n g 
Pr ot o c ol V er si o n  # 4) [ S e cti o n s  5 a n d  6].  
U p d at e s r e g ar di n g F D A f e e d b a c k o n I A P V er si o n 2. 0 : 
C h a n g e i n d efi niti o n of p arti ci p a nt s  at ri s k f or ti m e t o 
e v e nt a n al y s e s, all p arti ci p a nt s fr o m m F A S ar e n o w 
i n cl u d e d [ S e cti o n s 1 4. 2. 1, 1 4. 2. 2, 1 4. 3. 4, 1 4. 3. 5, 
1 4. 3. 1 4] . 
R e m o v al of t h e A E  s e n siti vit y a n al y si s e v al u ati n g t h e 
p ot e nti al i m p a ct of C O VI D -1 9  r el at e d I C E s 
[ S e cti o n 1 5. 1. 1. 4] . 
C h a n g e i n t h e d eri v ati o n of C O VI D -1 9 v a c ci n e r el at e d  
A E s [ S e cti o n  1 5. 2. 4] . 
Ot h er u p d at e s : 
A d d e d S e cti o n 9. 1 1  t o d efi n e t h e a n al y si s st u d y d a y f or 
W e e k  4 8 e n d p oi nt s.  
U p d at e d D M D t o b e D M T [ S e cti o n 1 1. 3. 3 a n d t hr o u g h o ut 
d o c u m e nt] . 
Ali g n e d S 1/ S 2 I g G a nti b o di e s t o S A R S -C o V -2 a n al y si s 
wit h t h e 0 0 8 6 st u d y a n al y si s  a n d a d d e d a d diti o n al 
s u m m ari e s  [ S e cti o n 1 5. 1 3] . 
U p d at e d t h e d e s cri pti o n f or c e n s ori n g d u e t o t h e I C E of 
' U kr ai n e cris i s' t o diff er e nti at e b et w e e n c e n s ori n g f or 
m F A S  a n d e x cl u si o n fr o m m F A S [ S e cti o n s  8. 1 a n d 1 4].  
U p d at e d s e n siti vit y a n al y si s 1 t o a p pl y a r a n g e of d elt a 
v al u e s [ S e cti o n s  1 4. 1. 2, 1 4. 2. 1. 3, 1 4. 2. 2, 1 4. 2. 3. 3 a n d 
1 4. 2. 4. 3].  
C h a n g e d E AI R t o b e pr e s e nt e d i n 1 0 0 p arti ci p a nt y e ar s, 
fr o m 1 0 0 0 p arti ci p a nt y e ar s [S e cti o n  1 5. 1. 1. 3].  
A d d e d m e di a n li n e pl ot s f or i m m u n o gl o b uli n p ar a m et er s 
[ S e cti o n 1 5. 8]. 
A d d e d a n al y s e s u p t o W e e k  1 2 0 f or Nf L c o n c e ntr ati o n 
[ S e cti o n 1 6. 2. 2]. 
U p d at e d a b br e vi ati o n s et c t o f oll o w t h e l at e st Gl o b al 
St yl e G ui d e [t hr o u g h o ut t h e d o c u m e nt].  
4. 0  
1 3  J ul y  2 0 2 3  
 
U p d at e s r e g ar di n g Pr ot o c ol V er si o n 6:  
U p d at e d P A tri g g er d e s cri pti o n [ S e cti o n s  6. 2  a n d 7 ] 
A d d e d D B E a n al y si s [ S e cti o n s 6. 0 a n d  6. 3]  
U p d at e d t h e d efi niti o n of o n -tr e at m e nt p eri o d t o c o n si d er 
o nl y t h e D B T P [ S e cti o n  9. 1 0]  
T h e o v er vi e w t a bl e s u m m ari zi n g t h e r e s ult s of t h e 
m ulti -st a g e t e sti n g pr o c e d ur e w a s u p d at e d t o i n cl u d e 
e sti m at e s [ S e cti o n 9. 1 6]  
R e m o v e d r ef er e n c e t o l o n g -t er m f oll o w-u p st u d y a n d 
a d d e d D B E [ S e cti o n  1 0. 1]  
U p d at e d d efi niti o n of a tr e at m e nt c o m pl et er f or t h e P A 
[S e cti o n  1 0. 1]  
U p d at e t o Ti er 1  A E s d efi niti o n, to r efl e ct t h e r e c e nt 
u p d at e t o t h e ri s k pr ofil e of e v o br uti ni b (i. e. i m p ort a nt 
i d e ntifi e d ri s k of dr u g-i n d u c e d li v er i nj ur y) [ S e cti o n 
1 5. 1. 1. 1] .  
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 8 /1 5 9  
 
 
 
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n 
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
Crit eri a f or t e m p or ar y tr e at m e nt di s c o nti n u ati o n a n d 
r e c h all e n g e w a s u p d at e d [ S e cti o n 1 5. 3] 
R e pl a c e d “P A tri g g er ” wit h “P A c ut off ” [ T hr o u g h o ut] 
U p d at e s d u e t o F D A f e e d b a c k:  
A d d e d a d diti o n al s e n s iti vit y a n al y si s t o c e n s or d at a at 
t h e ori gi n all y pr oj e ct e d d at e of t h e P A tri g g er, f or A R R 
a n d 1 2 -w e e k C D P e n d p oi nt s [ S e cti o n s 1 4. 1. 2 a n d 
1 4. 2. 1. 3]  
Ot h er u p d at e s:  
C orr e ct e d t h e P D B T K O a n al y si s s et t o i n cl u d e o nl y 
p arti ci p a nt s w h o r e c ei v e d at l e a st 1 d o s e of e v o br uti ni b 
[ S e cti o n 8. 1]  
D at a h a n dli n g aft er c ut off w a s u p d at e d t o f oll o w t h e 
c urr e nt S D T M pr o c e s s [ S e cti o n 9. 3]  
St u d y d a y d efi niti o n w a s cl arifi e d, d eri v e d fr o m st art of 
st u d y i nt er v e nti o n [ S e cti o n  9. 5]  
U p d at e d e x p o s ur e a n d c o m pli a n c e c al c ul ati o n s t o u s e 
d o s e ( m g) i n st e a d of n u m b er of t a bl et s. [ S e cti o n  1 3]  
U p d at e d d e s cri pti v e st ati sti c s f or M RI l e si o n m e a s ur e s t o 
b e b y ti m e p oi nt o nl y [ S e cti o n s  1 4. 2. 4. 1 a n d 1 4. 2. 4. 2]  
A d d e d r e p e at s of c o m p o sit e e n d p oi nt s o n all r el a p s e s 
[ S e cti o n s 1 4. 3. 1 5, 1 4. 3. 1 8, 1 4. 3. 2 0, 1 4. 3. 2 1 a n d 1 6. 4. 8]  
A d d e d d et ail s f or I C E h a n dli n g i n e x pl or at or y e n d p oi nt 
s e cti o n s [ S e cti o n s  1 4. 3 a n d 1 6. 4]  
R e m o v e d 1 2 -w e e k C DI st at u s at W e e k  9 6 [ S e cti o n s 
1 4. 3. 5, 5 a n d 7]  
A d d e d a n al y si s t o e v al u at e cli ni c all y m e a ni n gf ul 
i m pr o v e m e nt i n S D M T [ S e cti o n 1 4. 3. 1 9]  
PI R A u p t o W e e k 1 5 6 w a s u p d at e d t o f o c u s o n q u alifi e d 
r el a p s e s, i n st e a d of i n v e sti g at or r e p ort e d r el a p s e s 
[ S e cti o n 1 4. 3. 3 0] 
R e p e at l a b s u m m ar y b y vi sit o n o nl y c e ntr al l a b d at a a n d 
u p d at e d p ar a gr a p h o n b o x pl ot s f or l a b or at or y 
p ar a m et er s [ S e cti o n  1 5. 3]  
D e s cri pti o n of pr e s e nt ati o n of s u m m ar y st ati sti c s of P K 
p ar a m et er d at a a d d e d [ S e cti o n 9. 2]  
A  fl a g will b e a d d e d f or c o n c o mit a nt a d mi ni str ati o n of 
pr ot o n p u m p i n hi bit or s , H 2 bl o c k ers , a n d a nt a ci ds  
[S e cti o n 1 6. 1. 1]  
A d diti o n al d et ail s r e g ar di n g h a n dli n g of d u pli c at e P K 
s a m pl e s i n cl u d e d [ S e cti o n 1 6. 1. 1]  
Vi sit wi n d o w i nf or m ati o n a d d e d f or P K c oll e cti o n s 
[S e cti o n 1 6. 1. 1]  
E sti m ati o n of P K p ar a m et er s f or e v o br uti ni b a n d 
M S C 2 7 2 9 9 0 9 A fr o m D a y 1 a n d W e e k 4 of P K s u b st u d y 
a d d e d [ S e cti o n 1 6. 1. 2]  
D e s cri pti o n of t h e pr e s e nt ati o n of P K p ar a m et er s  i n 
o ut p ut s  a d d e d [ S e cti o n 1 6. 1. 3]  
T hr o u g h o ut t h e d o c u m e nt:  
U p d at e s f or c o n si st e n c y a n d cl arifi c ati o n. 
5. 0  
2 8 S e pt e m b er 
2 0 2 3  
 
8. 1 - U p d at e t o d efi niti o n of f ull y o p er ati o n al st at u s f or 
sit e s i n U kr ai n e  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 9 /1 5 9  
 
 
 
U ni q u e  
I d e ntifi er f or 
V er si o n  
D at e of  
I A P V er si o n 
A ut h or  
C h a n g e s fr o m t h e Pr e vi o u s V er si o n  
6. 0  
3 1  O ct o b er 2 0 2 3  
 
U p d at e d t h e s o ur c e of b a s eli n e E D S S t o b e t h e v e n d or 
d at a, n ot t h e e C R F [ S e cti o n 8. 2 a n d t hr o u g h o ut] 
A d d e d b a s eli n e t a bl e s o n s u b s et of s u bj e ct s wit h 
b a s eli n e E D S S ≥2 [ S e cti o n 1 1. 1 a n d 1 1. 3. 1]  
A d d e d S e cti o n 1 5. 1 4 o n F o c u s e d G e n eti c T e sti n g  
A d d e d st e p s i n c a s e t h e pri m ar y m o d el f ail s t o c o n v er g e 
[S e cti o n 1 4. 1. 1]  
T ot al C ar b o n Di o xi d e  w or st o n -tr e at m e nt dir e cti o n w a s 
c orr e ct e d [ S e cti o n 1 8. 6]  
T hr o u g h o ut t h e d o c u m e nt:  
U p d at e s f or c o n si st e n c y a n d cl arifi c ati o n.  
7. 0  
 8 N o v e m b er 2 0 2 3  
 
A ct u ali z e d d at e of P A tri g g er 0 2 O ct o b er 2 0 2 3 ( M o n d a y) 
fr o m 0 1 O ct o b er 2 0 2 3 ( S u n d a y) [ S e cti o n 7] 
A d d e d r a c e a n d et h ni cit y i n s u b gr o u p s  [ S e cti o n 8. 2] 
Cl arifi e d st e p s i n c a s e t h e pri m ar y m o d el f ail s t o 
c o n v er g e [ S e cti o n 1 4. 1. 1]  
C orr e ct e d i n c o n si st e n c y [ S e cti o n 1 4. 2. 5]  
8. 0  
2 0 N o v e m b er 2 0 2 3  
 
U p d at e d t h e d efi niti o n of F A S a n d m F A S [ S e cti o n 8. 1 ] 
U p d at e d F A S a s pri m ar y a n al y si s p o p ul ati o n t hr o u g h o ut 
t h e effi c a c y s e cti o n [ S e cti o n 1 4 ] 
C h a n g e d I T T s e n siti vit y a n al y si s t o m F A S s e n siti vit y 
a n al y si s  t hr o u g h o ut t h e effi c a c y s e cti o n [ S e cti o n 14 ]  
 
T h e u p d at e s  li st e d a b o v e w er e m a d e i n a c c or d a n c e wit h 
t h e F D A r e q u e st fr o m 1 3/ 1 5 N o ve m b er  2 0 2 3 t o c o n d u ct 
t h e pri m ar y a n al y si s i n all r a n d o mi z e d p arti ci p a nt s  (i. e. 
t h e i nt e nti o n t o tr e at p o p ul ati o n), a n d t h at pr e-s p e cifi e d 
s e n siti vit y a n al y s e s b e c o n d u ct e d i n ot h er d efi n e d 
a n al y si s p o p ul ati o n s t o e v al u at e t h e i m p a ct of t h e st at e d 
c o n c er n s ( e. g., U kr ai n e C o nfli ct, pr ot o c ol vi ol ati o n s, 
et c.).  
4  
P ur p ose of t he I nte gr ate d A n al ysis Pl a n  
T he p ur p ose of t his  I A P is t o d oc u me nt tec h nical a n d det aile d s pecificati o ns f or t he pri mar y  
a nal ysis of dat a c ollecte d f or pr ot o c ol s M S 2 0 0 5 2 7 _ 0 0 8 0  a n d 
. Res ults of t he 
a nal ys es descri be d i n t his I A P will b e i ncl u de d eit her i n t he C S R  or se parate re p orts. A d diti o nall y, 
t he pla n ne d a nal yses i de ntifie d i n t his I A P ma y  be i ncl u de d i n re g ulat or y s u b missi o ns or f ut ure 
ma n uscri pts. A n y p os t-h oc, or u n pla n ne d a nal ys es perf or me d t o pr o vi de res ults f or i ncl usi o n i n 
t he CS R b ut n ot i de ntifie d i n t his pr os pecti ve I A P will be clearl y i de ntifie d i n t he C S R.  
T h is I A P is base d u p o n Secti o n  9  ( Statistical C o nsi derati o ns ) of t he st u d y pr ot oc ol s a n d pr ot oc ol 
a me n d me nts a n d is pre p are d i n c o m plia nce wit h I C H E 9. It d escri b es a n al yses pla n ne d i n t he 
pr ot oc ol s a n d pr ot oc ol s a me n d me nts . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 0 /1 5 9  
 
 
 
5  
O bjecti ves a n d Esti m a n ds   
Pri mar y a n d s ec o n dar y o bjecti ves a n d esti ma n ds f or t he D B T P  are s u m marize d i n  Ta ble 1 . 
Tertiar y/e x pl orat or y o bje cti ves a n d e n d p oi nts f or t he D B T P are s u m marize d i n Ta ble 2 . 
O bjecti ves a n d e n d p oi nts f or t he D B E  a n d t he O L E peri o d s will be s pecifie d i n se parate I A P s. T he 
D B E I A P will be  fi n alize d bef ore t h e pri mar y a nal ysis data b ase l oc k. 
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 1 /1 5 9  
 
 
 
T a ble 1  
O bjecti ve s a n d Esti m a n ds  f or t he D B T P :   
O bj e cti v e s  
E sti m a n d Attri b ut e s  
I A P s e cti o n  
Pri m ar y  
 
 
T o d e m o n str at e 
s u p eri or effi c a c y wit h 
e v o br uti ni b c o m p ar e d 
t o t erifl u n o mi d e i n 
t er m s of A R R 
E n d p oi nt:  A R R b a s e d o n q u alifi e d r el a p s e s u p t o 1 5 6 w e e k s  i n 
p arti ci p a nt s wit h R M S  
P o p ul ati o n:   
P ati e nt s wit h R M S a s d efi n e d b y i n cl u si o n/ e x cl u si o n 
crit eri a  
Tr e at m e nt:   
E v o br uti ni b v s. terifl u n o mi d e  
I nt er c urr e nt E v e nt Str at e g y: 
•  
Tr e at m e nt di s c o nti n u ati o n: tr e at m e nt p oli c y  
•  
D e at h attri b ut a bl e t o M S or tr e at m e nt: c o m p o sit e v ari a bl e  
•  
D e at h u n attri b ut a bl e t o M S or tr e at m e nt: w hil e ali v e  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  r R R a n d CI ([ N B m o d el), wit h t e st of 
tr e at m e nt eff e ct b a s e d o n t e st of r R R 
1 4. 1. 1  
S e c o n d ar y  
 
 
T o d e m o n str at e t h e 
effi c a c y of e v o br uti ni b 
r el ati v e t o t h at of 
t erifl u n o mi d e o n 
di s a bilit y pr o gr e s si o n  
E n d p oi nt s:  
•  
Ti m e t o fir st o c c urr e n c e of 1 2 -w e e k C D P a s m e a s ur e d b y t h e 
E D S S u p t o 1 5 6  w e e k s  
•  
Ti m e t o fir st o c c urr e n c e of 2 4 -w e e k C D P a s m e a s ur e d b y t h e 
E D S S u p t o 1 5 6  w e e k s  
P o p ul ati o n:  
s e e Pri m ar y  
Tr e at m e nt:  
E v o br uti ni b v s. t erifl u n o mi d e 
I nt er c urr e nt E v e nt Str at e g y: 
•  
Tr e at m e nt di s c o n ti n u ati o n: tr e at m e nt p oli c y 
•  
D e at h attri b ut a bl e t o M S or tr e at m e nt: c o m p o sit e v ari a bl e  
•  
D e at h u n attri b ut a bl e t o M S or tr e at m e nt: w hil e ali v e  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  h a z ar d r ati o a n d CI b a s e d o n a C o x m o d el 
f or pr o gr e s si o n h a z ard, wit h t e st of tr e at m e nt eff e ct b a s e d o n l o gr a n k t e st  
1 4. 2. 1  
T o d e m o n str at e t h e 
effi c a c y of e v o br uti ni b 
r el ati v e t o t h at of 
t erifl u n o mi d e o n 
di s a bilit y i m pr o v e m e nt  
E n d p oi nt s:  
•  
Ti m e t o fir st o c c urr e n c e of 2 4 -w e e k C DI a s m e a s ur e d b y t h e 
E D S S u p t o 1 5 6  w e e k s  
P o p ul ati o n:  
P ati e nt s wit h R M S a s d efi n e d b y i n cl u si o n/ e x cl u si o n 
crit eri a a n d w h o h a v e b a s eli n e  E D S S ≥ 2. 0  
Tr e at m e nt:  
E v o br uti ni b v s. terifl u n o mi d e  
I nt er c urr e nt E v e nt Str at e g y: 
•  
Tr e at m e nt di s c o nti n u ati o n: tr e at m e nt p oli c y  
•  
D e at h ( a n y c a u s e): w hil e ali v e  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  h a z ar d r ati o a n d CI b a s e d o n a C o x m o d el, 
wit h t e st of tr e at m e nt eff e ct b a s e d o n l o gr a n k t e st  
1 4. 2. 2  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 2 /1 5 9  
 
 
 
O bj e cti v e s  
E sti m a n d Attri b ut e s  
I A P s e cti o n  
T o d e m o n str at e t h e 
effi c a c y of e v o br uti ni b 
r el ati v e t o t h at of 
t erifl u n o mi d e o n 
p ati e nt r e p ort e d 
s y m pt o m s a n d 
f u n cti o n al st at u s 
E n d p oi nt s:   
•  
C F B i n P R O MI S P F s c or e o v er 9 6  w e e k s  
•  
C F B i n P R O MI S F ati g u e s c or e o v er 9 6  w e e k s  
P o p ul ati o n:  
s e e Pri m ar y  
Tr e at m e nt:  
E v o br uti ni b v s. t erifl u n o mi d e 
I nt er c urr e nt E v e nt Str at e g y: 
•  
Tr e at m e nt di s c o nti n u ati o n: tr e at m e nt p oli c y  
•  
D e at h  ( a n y c a u s e): w hil e ali v e  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  diff er e n c e of a v er a g e l e a st-s q u ar e s m e a n s 
of s c or e C F B ( a v er a g e o v er w e e k s 7 2, 8 4 a n d 9 6 f or P R O MI S P F a n d 
a v er a g e o v er w e e k s 4 8, 6 0, 7 2, 8 4 a n d 9 6 f or P R O MI S F ati g u e)  a n d CI 
b a s e d o n a M M R M, wit h t e st of tr e at m e nt eff e ct b a s e d o n diff er e n c e of 
a v er a g e l e a st-s q u ar e s m e a n s  
1 4. 2. 3  
T o d e m o n str at e t h e 
effi c a c y of e v o br uti ni b 
r el ati v e t o t h at of 
t erifl u n o mi d e o n M RI 
l e si o n p ar a m et er s 
E n d p oi nt s:   
•  
T ot al n u m b er of T 1 G d + l e si o n s b a s e d o n all a v ail a bl e  M RI 
s c a n s  
•  
N u m b er of n e w or e nl ar gi n g T 2 l e si o n s o n t h e l a st a v ail a bl e M RI 
s c a n r el ati v e t o t h e b a s eli n e  M RI s c a n  
P o p ul ati o n:  
s e e Pri m ar y  
Tr e at m e nt:  
E v o br uti ni b v s. t erifl u n o mi d e 
I nt er c urr e nt E v e nt Str at e g y: 
•  
Tr e at m e nt di s c o nti n u ati o n: tr e at m e nt p o li c y 
•  
D e at h  ( a n y c a u s e): w hil e ali v e  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  l e si o n r at e r ati o a n d CI b a s ed  o n a N B 
m o d el, wit h t e st of tr e at m e nt eff e ct b a s e d o n t e st of l e si o n r at e r ati o  
1 4. 2. 4  
T o d e m o n str at e t h e 
effi c a c y of e v o br uti ni b 
r el ati v e t o t h at of 
t erifl u n o mi d e b y 
e v al u ati n g r e s p o n s e  
o n Nf L c o n c e ntr ati o n 
i n s er u m 
E n d p oi nt s:   
•  
Nf L c o n c e ntr ati o n at 1 2  w e e k s  
P o p ul ati o n:  
s e e Pri m ar y  
Tr e at m e nt:  
E v o br uti ni b v s. terifl u n o mi d e  
I nt er c urr e nt E v e nt Str at e g y: 
•  
Tr e at m e nt di s c o nti n u ati o n: tr e at m e nt p oli c y  
•  
D e at h ( a n y c a u s e): w hil e ali v e  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  r ati o of g e o m etri c m e a n s at 1 2  w e e k s a n d 
CI b a s e d o n a M M R M, wit h t e st of tr e at m e nt eff e ct b a s e d o n diff er e n c e of 
l e a st-s q u ar e s  m e a n s  
1 4. 2. 5  
T o c h ar a ct eri z e t h e 
s af et y a n d t ol er a bilit y 
of e v o b r uti ni b. 
 
S af et y a s a s s e s s e d b y t h e n at ur e, s e v erit y, a n d o c c urr e n c e of A E s a n d 
A E SI s; vit al si g n s; E C G s; a b s ol ut e c o n c e ntr ati o n s a n d C F B  i n I g l e v el s; 
a n d cli ni c al l a b or at or y s af et y p ar a m et er s u p t o t h e e n d of t h e S af et y 
F oll o w -u p p eri o d  
P o p ul ati o n:  
s e e Pri m ar y  
Tr e at m e nt:  
E v o br uti ni b v s. terifl u n o mi d e  
I nt er c urr e nt E v e nt Str at e g y:  
•  
U kr ai n e cri si s: h y p ot h eti c al  
P o p ul ati o n -L e v el S u m m ar y:  n ot a p pli c a bl e  
1 5  
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 3 /1 5 9  
 
 
 
T a ble 2  
O bjecti ves a n d E n d p oi nts  f or t he D B T P :   
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P 
s e cti o n  
T erti ar y/ E x pl or at or y  
 
 
T o e v al u at e t h e eff e ct of 
e v o br uti ni b c o m p ar e d t o 
t erifl u n o mi d e o n cli ni c al 
p ar a m et er s  
•  A R R b a s e d o n q u alifi e d r el a p s e s at W e e k s  4 8  a n d 9 6  
•  Ti m e t o fir st q u alifi e d r el a p s e o v er  1 5 6 w e e k s  
•  Q u alif yi n g r el a p s e -fr e e st at u s at W e e k  9 6  
•  1 2 -w e e k c o nfir m e d E D S S pr o gr e s si o n fr e e st at u s at W e e k  9 6  
•  2 4 -w e e k c o nfir m e d E D S S pr o gr e s si o n fr e e st at u s at W e e k  9 6  
•  2 4 -w e e k c o nfir m e d di s a bilit y i m pr o v e m e nt st at u s at  W e e k  9 6  
1 4. 3  
T o e v al u at e t h e effi c a c y of 
e v o br uti ni b r el ati v e t o t h at of 
t erifl u n o mi d e o n M RI p ar a m et er s 
•  T 1 G d + l e si o n fr e e st at u s at W e e k  9 6  b a s e d o n a s s e s s m e nt s 
u p t o W e e k  9 6  
•  C h a n g e i n v ol u m e of T 1 G d + l e si o n s fr o m B a s eli n e t o 
W e e k  9 6  b a s e d o n a s s e s s m e nt s u p t o W e e k  9 6  
•  N e w or e nl ar gi n g T 2 l e si o n fr e e st at u s at W e e k  9 6  b a s e d o n 
a s s e s s m e nt s u p t o W e e k  9 6  
•  C h a n g e i n v ol u m e of T 2 l e si o n s fr o m B a s eli n e t o W e e k  9 6  
b a s e d o n a s s e s s m e nt s  u p t o W e e k  9 6  
•  C U A l e si o n fr e e st at u s at W e e k  9 6  b a s e d o n a s s e s s m e nt s u p 
t o W e e k  9 6   
•  T ot al n u m b er of C U A l e si o n s b a s e d o n all a v ail a bl e M RI 
s c a n s   
•  T ot al n u m b er of n e w T 1 h y p o -i nt e n s e l e si o n s b a s e d o n all 
a v ail a bl e M RI s c a n s  
•  P er c e nt a g e c h a n g e B V fr o m W e e k 2 4 t o W e e k  9 6  b a s e d o n 
a s s e s s m e nt s u p t o W e e k  9 6  
•  P er c e nt a g e c h a n g e i n t h al a mi c v ol u m e fr o m W e e k 2 4 t o 
W e e k  9 6  b a s e d o n a s s e s s m e nt s u p t o W e e k  9 6  
•  P er c e nt a g e c h a n g e i n c orti c al gr e y m att er v ol u m e fr o m W e e k 
2 4 t o W e e k  9 6  b a s e d o n a s s e s s m e nt s u p t o W e e k  9 6  
•  C h a n g e i n n or m ali z e d T 1 i nt e n sit y wit hi n pr e -e xi sti n g 
n o n e n h a n ci n g T 2 w ei g ht e d l e si o n v ol u m e fr o m B a s eli n e t o 
W e e k  9 6  b a s e d o n a s s e s s m e nt s u p t o W e e k  9 6  
•  V ol u m e of S E L s b a s e d o n s c a n s at W e e k s  2 4, 4 8 a n d 9 6  
•  C h a n g e i n n u m b er of P R L  at W e e k s  2 4, 4 8 a n d 9 6  
•  C h a n g e i n C er e br al B l o o d F l o w i n n or m al-a p p e ari n g w hit e 
m att er at W e e k s  2 4, 4 8 a n d 9 6  
1 4. 3  
T o e v al u at e t h e eff e ct of 
e v o br uti ni b c o m p ar e d t o 
t erifl u n o mi d e o n f u n cti o n al 
p ar a m et er s  
•  Ti m e t o ≥ 2 0 % i n cr e a s e ( c o nfir m e d at 1 2  w e e k s) i n T 2 5 -F W 
u p t o 1 5 6  w e e k s  
•  Ti m e t o ≥ 2 0 % i n cr e a s e ( c o nfir m e d at 1 2 w e e k s) i n 9 -H P T u p 
t o 1 5 6  w e e k s  
1 4. 3. 1 4  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 4 /1 5 9  
 
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P 
s e cti o n  
T o e v al u at e t h e eff e ct of 
e v o br uti ni b c o m p ar e d t o 
t erifl u n o mi d e o n c o m p o sit e 
p ar a m et er s  
•  N E D A -3  at W e e k  4 8 , W e e k  9 6 d efi n e d b y:  
o  
Q u alif yi n g r el a p s e -fr e e st at u s 
o  
T 1 G d + l e si o n s fr e e st at u s a n d n e w or e nl ar gi n g 
T 2  l e si o n fr e e st at u s 
o  
1 2 -w e e k c o nfir m e d E D S S pr o gr e s si o n fr e e st at u s  
•  Ti m e t o fir st o c c urr e n c e of 1 2 -w e e k C D P  u p t o 1 5 6  w e e k s 
b a s e d o n a c o m p o sit e s c or e d efi n e d b y:  
o  
1 2 -w e e k c o nfir m e d E D S S pr o gr e s si o n ( at l e a st 
0. 5 - or  1. 0 - p oi nt c h a n g e, d e p e n di n g o n t h e b a s eli n e  
E D S S) or;  
o  
1 2 -w e e k c o nfir m e d w or s e ni n g  ( ≥ 2 0 %) i n T 2 5 -F W v er s u s 
B a s eli n e or;  
o  
1 2 -w e e k c o nfir m e d w or s e ni n g  ( ≥ 2 0 %) i n 9 -H P T v er s u s 
B a s eli n e.  
•  
N E P at W e e k 4 8 , W e e k  9 6  a s d efi n e d b y:  
o  
N o 1 2 -w e e k C D P o n E D S S  
o  
N o 1 2 -w e e k c o nfir m e d w or s e ni n g ( ≥ 2 0 %) i n 9 -H P T 
s c or e  
o  
N o 1 2 -w e e k c o nfir m e d w or s e ni n g ( ≥ 2 0 %) i n T 2 5 -F W 
ti m e 
•  
N E P A D at W e e k  4 8 , W e e k  9 6  a s d efi n e d b y:  
o  
N o pr ot o c ol -d efi n e d r el a p s e s o n tr e at m e nt  
o  
N o 1 2 -w e e k C D P  o n E D S S  
o  
N o 1 2 -w e e k c o nfir m e d w or s e ni n g  ( ≥ 2 0 %) i n 9-H P T 
s c or e  
o  
N o 1 2 -w e e k c o nfir m e d w or s e ni n g  ( ≥ 2 0 %) i n T 2 5-F W 
ti m e 
o  
N o n e w or e nl ar gi n g T 2 l e si o n s a n d n o T 1 G d + l e si o n s 
o n M RI  
1 4. 3  
T o e v al u at e t h e effi c a c y of 
e v o br uti ni b r el ati v e t o t h at of 
t erifl u n o mi d e o n pr o gr e s si o n 
i n d e p e n d e nt of r el a p s e a cti vit y 
•  Ti m e t o PI R A, w h er e di s a bilit y pr o gr e s si o n i s d efi n e d f or e a c h 
of 2 e n d p oi nt s a s f oll o w s : 
o  
1 2 -w e e k C D P o n E D S S  
o  
1 2 -w e e k c o nfir m e d w or s e ni n g a s a c o m p o sit e of 
3  e n d p oi nt s ( E D S S, 9 -H P T, T 2 5 -F W)  
1 4. 3. 2 0  
T o e v al u at e t h e effi c a c y of 
e v o br uti ni b r el ati v e t o t h at of 
t erifl u n o mi d e o n pr o gr e s si o n 
i n d e p e n d e nt of r el a p s e a n d br ai n 
M RI a cti vit y  
•  Ti m e t o PI R M A , w h er e di s a bilit y pr o gr e s si o n i s d efi n e d f or 
e a c h of 2 e n d p oi nt s a s f oll o w s:  
o  
1 2 -w e e k C D P o n E D S S  
o  
1 2 -w e e k c o nfir m e d w or s e ni n g a s a c o m p o sit e of t h e 
3  e n d p oi nt s ( E D S S, 9 -H P T, T 2 5 -F W)  
1 4. 3. 2 1  
T o e v al u at e t h e effi c a c y of 
e v o br uti ni b r el ati v e t o t h at of 
t erifl u n o mi d e o n c o g niti v e 
f u n cti o n 
•  C h a n g e fr o m b a s eli n e  S D M T s c or e at W e e k  4 8 , W e e k  9 6  
1 4. 3. 1 9  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 5 /1 5 9  
 
 
 
O bj e cti v e s  
E n d p oi nt s ( O ut c o m e M e a s ur e s)  
I A P 
s e cti o n  
T o e v al u at e t h e effi c a c y of 
e v o br uti ni b r el ati v e t o t h at of 
t erifl u n o mi d e o n p ati e nt r e p ort e d 
s y m pt o m s a n d f u n cti o n al st at u s  
•  C h a n g e fr o m b a s eli n e  i n P R O MI S P F s c or e at W e e k 4 8 , 
W e e k  9 6 , a n d  W e e k 1 4 4   
•  C h a n g e fr o m b a s eli n e  i n P R O MI S f ati g u e s c or e at W e e k 4 8 , 
W e e k  9 6 , a n d  W e e k  1 4 4  
•  Ti m e t o fir st o c c urr e n c e of 1 2 -w e e k c o nfir m e d P F 
d et eri or ati o n c o m p ar e d t o b a s eli n e ( d e cr e a s e of at l e a st 
2. 7  p oi nt s o n P R O MI S P F s c or e) u p t o 1 5 6  w e e k s  
•  C h a n g e fr o m b a s eli n e  i n P ati e nt R e p ort e d O ut c o m e s c or e s at 
W e e k  4 8 , W e e k  9 6  a n d W e e k  1 4 4 : 
o  
S F -3 6 v 2  
o  
E Q -5 D -5 L  
1 6. 4  
T o e v al u at e t h e eff e ct of 
e v o br uti ni b o n H R U r el ati v e t o 
t h at of t erifl u n o mi d e o v er 
9 6  w e e k s  
A b s ol ut e v al u e s of H R U, i n cl u di n g b ut n ot li mit e d t o 
d o ct or/ h o m e/ e m er g e n c y vi sit s, h o s pit ali z ati o n s, p ai d a s si st a n c e, 
a n d mi s s e d w or k  
1 6. 5  
T o c h ar a ct eri z e t h e P K pr ofil e of 
e v o br uti ni b i n p arti ci p a nt s wit h 
M S a n d t o d e s cri b e t h e 
e x p o s ur e -r e s p o n s e r el ati o n s hi p 
b et w e e n e v o br uti ni b a n d effi c a c y 
e n d p oi nt s a n d s af et y e n d p oi nt s  
P K p ar a m et er s: C L/ F, V z/f, C m a x, a n d A U C aft er a si n gl e d o s e 
( D a y 1 d at a), a n d at st e a d y st at e ( W e e k s 2, 4, 8, 1 2, 2 4, 4 8, 7 2, 
a n d 9 6 d at a)  
1 6. 1 , 1 6. 3  
T o d e s cri b e t h e e x p o s ur e -
r e s p o n s e r el ati o n s hi p b et w e e n 
e v o br uti ni b a n d  P D  bi o m ar k er s  
P D bi o m ar k er e n d p oi nt s at B a s eli n e / S cr e e ni n g, W e e k s  2,  4, 8, 
1 2, a n d 2 4  
1 6. 2 , 1 6. 3  
T o a s s e s s r el ati o n s hi p b et w e e n 
c a n di d at e di s e a s e bi o m ar k er a n d 
di s e a s e a cti vit y or tr e at m e nt 
r e s p o n s e 
•  L e v el of bi o m ar k er s of di s e a s e wit h di s e a s e a cti vit y/tr e at m e nt 
r e s p o n s e at B a s eli n e, W e e k s  1 2 , 2 4, 4 8, 7 2, 9 6; a n d u p o n 
r el a p s e/ di s e a s e pr o gr e s si o n ( u n s c h e d ul e d) 
•  Nf L c o n c e ntr ati o n at W e e k s  2 4, 4 8, 7 2, a n d 9 6  
1 6. 2  
T o m e a s ur e t h e a nti b o d y l e v el s 
t o S A R S-C o V -2 v a c ci n e 
a d mi ni st er e d i n p arti ci p a nt s  
L e v el of a nti -S A R S -C o V -2 a nti b o di e s t o v a c ci n e s pr e - a n d 
p o s t-v a c ci n ati o n  i n a s u b s et of p arti ci p a nt s w h o h a v e r e c ei v e d 
a nti -C O VI D  v a c ci n ati o n s  d uri n g t h e st u d y  
1 5. 1 3  
T o e v al u at e t h e r el ati o n s hi p of 
t h e n o v el bi o m ar k er s of li v er 
f u n cti o n e. g.  pr ot ei n, mi R N A, et c.  
c o m p ar e d t o st a n d ar d cli ni c al 
c h e mi str y e n d p oi nt s ( A L T)  
L e v el s of n o v el bi o m ar k er s of h e p ati c  f u n cti o n c o m p ar e d t o A L T 
at B a s eli n e, a n d o n tr e at m e nt  
N A  –  
a n al y s e s 
will b e 
c o n d u ct e d 
p o s t-P A 
a n d b e 
d e s cri b e d 
i n a 
s e p ar at e 
IA P  
T o a s s e s s t h e eff e ct of 
e v o br uti ni b o n g e n e e x pr e s si o n 
i n w h ol e bl o o d 
G e n e e x pr e s si o n at B a s eli n e, W e e k s  1 2, 2 4, 4 8, a n d 9 6  
1 6. 2. 3  
6  
O ver vie w of Pl a n ne d A n al yses   
4  a nal ys es perf or me d b y t he S p o ns or  are pla n ne d f or t he st u d ies: ( 1) a n o pti o nal I A f or B S S R 
base d o n t he sec o n d ar y e n d p oi nt 1 2 -wee k C D P, wit h data p o ole d acr oss st u dies 0 0 8 0 a n d 
, 
tri g gere d w he n e nr oll me nt is neari n g c o m pleti o n , ( 2) a P A wit h ti mi n g a n d e n d p oi nt e val uati o n as 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 6 /1 5 9  
 
 
 
de scri be d i n Secti o n 6. 2 , ( 3) a n a n al ysis of all d ata fr o m bli n de d p eri o ds at t he e n d of t he D B E  
Peri o d , perf or me d after t he c orres p o n di n g D B E d ata base l oc k, a n d ( 4) a fi nal a nal ysis, tri g gere d 
w he n 1 0 0 % of partici pa nts e nr olle d i n t h e O L E Peri o d c o m plete, or disc o nti n ue pre mat urel y fr o m 
t he O L E Peri o d .  
Details of t he I D M C a nal yses will be descri be d i n t he I D M C S A P ( See A p pe n di x  1 8. 1 0 ) a n d t he 
I D M C C harter a n d relate d d oc u me ntati o n. 
6. 1  
O pti o n al 
I nteri m 
A n al ysis f or Bli n de d S a m ple Size 
Re-
esti m ati o n   
Per P r ot oc ol Versi o n  3, w he n e nr oll me nt was  n eari n g c o m pleti o n, a n o pti o nal I A f or B S S R base d 
o n t he sec o n d ar y e n d p oi nt 1 2 -wee k C D P was  perf or me d b y t he S p o ns or, usi n g  bli n de d  d ata p o ole d 
acr oss st u dies. O nl y data rele va nt t o 1 2 -wee k C D P were  clea n e d f or t he I A.  
Para metric distri b uti o ns f or ti me t o 1 2 -wee k C D P a n d ti me t o ce ns ori n g were fitte d usi n g bli n de d 
data p o ole d acr oss st u dies. T he res ulti n g para m eter esti mates were  use d t o esti mate e x pecte d 
n u m ber of e ve nts gi ve n t he ori gi nall y pl a n ne d sa m ple siz e. If t he e x pecte d n u m ber of e ve nts was  
less t ha n t he n u m ber re q uire d t o p o w er t he 1 2-wee k C D P e n d p oi nt at 8 0 %, c o nsi derati o n was t o  
be gi v e n t o i ncreasi n g t he sa m ple siz e u p t o  2 5 % s o t hat t he re q uire d n u m ber of e v e nts was  
ac hie ve d (Frie de 2 0 1 9 ).  
Perf or me d i n A u g ust 2 0 2 1, t he o utc o me of t his I A f or B S S R was a decisi o n t o n ot i ncrease sa m ple 
siz e. I n t he s etti n g of s u peri orit y trials, a n I A f or B S S R has a mi ni mal or n o n-e xiste nt effect o n 
t y pe-1 err or i nflati o n ( Fri e de 2 0 1 9 ). T he a nal ysis datasets re q uire d f or t he i nteri m a nal ysis of 1 2 -
wee k C D P were s pecifi e d i n t he sa me wa y as t he a n al ysis datasets re q uir e d f or t he pri mar y a n al ysis 
of 1 2  wee k C D P ( Secti o n  1 4. 2. 1. 1 ).  
Pri or t o t he I A, a detaile d B S S R S A P was  pr o vi de d.  
6. 2  
Pri m ar y A n al ysis   
Per pr ot oc ol, t he Pri mar y A nal ysis will be tri g gere d f or b ot h st u dies si m ulta ne o usl y w he n all of 
t he f oll o wi n g c o n diti o ns are met, bas e d o n a n a nal ysis of acc u m ulati n g bli n de d data: 
•  T he 2  P hase 3 st u dies ha ve i n di vi d uall y c ollecte d ≥ 3 2. 3 u nits of i nf or mati o n f or t he pri mar y 
A R R e n d p oi nt, w here “I n f or mati o n” is defi ne d i n Pr ot oc ol Secti o n  9. 2. 1 , E q uati o n 9. 2. 1. At 
t his ti me p oi nt b ot h st u dies will pr o vi de ≥ 9 0 % p o wer f or t he d etecti o n of a 4 3. 5 % relati ve 
treat me nt effect o n A R R i n t he pri mar y statistical test at a 1 -si de d al p h a-le vel of 0. 0 2 5.  
•  I n d ata p o ole d fr o m t he 2 st u dies, ≥ 1 4 9  1 2 -wee k C D P e ve nts ha ve bee n o bser ve d. At t his 
ti me p oi nt, t he c o m bi ne d st u dies ha ve c ollecte d s ufficie nt i nf or mati o n t o pr o vi de ≥ 7 1.5 % 
p o wer f or t he detecti o n of 3 4 % ( hazar d rati o = 0. 6 6) relati ve re d ucti o n i n ris k of  1 2 -wee k 
C D P i n a l o g -ra n k test at a 1 -si de d al p ha-le vel of 0. 0 2 5-0. 0 2 5 2 = 0. 0 2 4 3 7 5.  
•  All partici pa nts ha ve b ee n treate d f or 2 4 wee ks or disc o nti n ue d pre mat urel y.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 7 /1 5 9  
 
 
 
After pr ot oc ol d e viati o ns are det er mi ne d, a n d t he data base is l oc ke d f or t h e P A, t he dr u g c o de s 
will be br o ke n a n d ma de a vaila ble f or t he pri mar y data a nal ysis. All e n d p oi nts base d o n data fr o m 
t he D B T P  (see Secti o n 9. 1 0 ) will be e val uate d.  
6. 3  
D B E  A n al ysis   
T he D B E a nal ysis will occ ur at t he e n d of t he  D B E  peri o d , w he n t he pr ot oc ol de viati o ns are 
deter mi ne d, a n d t he d ata base is l oc ke d f or t he D B E peri o d.  
6. 4  
Fi n al A n al ysis    
T he fi nal a nal ysis will occ ur o nl y w h e n 1 0 0 % of partici pa nts  e nr olle d i n t he O L E  c o m plete t he 
O L E , or disc o nti n ue  pre mat urel y  fr o m t he O L E, t he pr ot oc ol de viati o ns are deter mi ne d, a n d t he 
data base is l oc k e d f or t he fi nal a nal ysis.  
7  
C h a n ges t o t he Pl a n ne d 
A n al yses i n t he 
Cli nic al St u d y 
Pr ot oc ol   
•  Pri mar y A n al ysis:  
I n li g ht of a n e wl y i de ntifie d dr u g i n d u ce d li ver i nj ur y , it a p p ears esse ntial t o bala nce t his wit h t he 
nee d t o ha ve t h e statistical p o wer t o better el uci date t he be nefit -ris k assess me nt. T he c urre nt re vie w 
of bli n de d e ve nt rates f or 1 2 -wee k C D P s h o we d t hat 1 4 9  e ve nts  (t he mi ni m u m n u m ber re q uire d 
b y t he pr ot oc ol)  acr oss t he t w o st u dies were reac he d o n 0 1 J u ne 2 0 2 3. T o i ncreas e t he p o wer t o 
7 5 -8 0 % f or t h e ke y disa bilit y e n d p oi nt, 1 2 -wee k C D P, t he P A tri g ger wa s s hifte d to 0 2  Oct o ber 
2 0 2 3. T his decisi o n wa s ma de wit h o ut u n bli n di n g a n y d ata of t he t w o P h ase  3  st u dies a n d w as 
c o m m u nicate d t o t he F D A i n Ma y 2 0 2 3.   
•  A nal ysis sets a n d s u b gr o u p s 
I n t h e pr ot oc ol, it w as defi ne d t hat t he m F A S w o ul d be use d f or t he P A of efficac y. In acc or da n ce 
wit h t he F D A re q u est fr o m 1 3/ 1 5 N o v e m ber  2 0 2 3 t o c o n d u ct t he pri mar y a n al ysis i n all 
ra n d o mize d partici pa nts, it was deci de d t hat F A S defi ne d as all ra n d o mize d partici pa nts  will be 
use d f or t he P A of efficac y a n d m F A S will be use d f or se nsiti v it y a n al yses of pri mar y a n d 
sec o n dar y effic ac y e n d p oi nts . I n that  c o nte xt, t he defi niti o n of m F A S was re vise d t o e x cl u de 
p artici pa nts wit h certai n cI P Ds relate d t o eli gi bilit y vi olati o ns, ra n d o mizati o n i n err or or fail ure t o 
recei v e st u d y i nt er ve nti o n, per I C H E 9. I n a d diti o n, t he m F A S e x cl u des partici pa nts fr o m sites 
lac ki n g data r o b ust ness t hr o u g h o ut t he st u d y, re gar dless of t heir c o u ntr y. T his was a c ha n ge fr o m 
t he defi niti o n i n t he Pr ot oc ol , w hic h state d t hat o nl y partici pa nts fr o m U krai ne, R ussia n 
Fe de rati o n, a n d Belar us lac ki n g data r o b ust ness were t o  be e x cl u de d.  T he m S A F a nal ysis set will 
n ot be defi ne d as n o s afet y d ata r o b ust n ess iss ues ha ve bee n i de ntifi e d t hat w o ul d warra nt 
e x cl usi o n of a S A F partici pa nt fr o m t he pri mar y a nal ysis of safet y.  
T he P D B T K O a nal ysis s et has bee n d efi ne d f or all a nal ys es relat e d t o B T K O data.  
Et h nic ori gi n is liste d as a s u b gr o u p i n t he Pr ot oc ol b ut will n ot be i ncl u de d as a s u b gr o u p i n t he 
I A P. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 8 /1 5 9  
 
 
 
•  C D P deri vati o n  
C D P will be deri ve d base d o n E D S S sc ores o nl y. Assess me nt w het her t he i ncreas e i n E D S S sc ore 
is n ot attri b uta ble t o a n ot her eti ol o g y will be disre gar de d i n t he C D P deri vati o n beca us e t his 
i nf or mati o n is n ot c ollecte d i n t he e C R F. 
•  C DI a nal ysis  
As Ti me t o 1 2 -wee k C DI is n ot a rele va nt e n d p oi nt a n d n ot i ncl u de d i n t he pr ot oc ol, t he 
e x pl orat or y e n d p oi nt “ 1 2 -wee k c o nfir me d disa bilit y i m pr o ve me nt stat us at Wee k  9 6 ” will n ot be 
a nal yze d as part of t h e P A.  
•  M RI distri b uti o n a nal ysis  
T he s u p ple me ntar y a n al ysis m o del f or M RI lesi o n meas ures is descri be d as P oiss o n -distri b ute d  i n 
t he pr ot oc ol. D ue t o t h e lar ge s a m ple siz e, ne gati v e bi n o mial  m o del li n g is m ore a p pr o priate, a n d 
t he m o delli n g details are descri be d  i n Secti o n  1 4. 2. 4. 3 . 
•  A Es se verit y  
T he se verit y a n d gra di n g criteria were  re m o v e d f or t he A E s of s pecial i nterest: o p p ort u nistic 
i nfecti o ns, b y t h e Safet y Tea m. T his is reflecte d i n a n u p date d file, refer t o A p p e n di x  1 8. 5 . 
8  
A n al ysis Sets a n d S u b gr o u ps   
8. 1  
Defi niti o n of A n al ysis Sets   
T he a nal ysis sets are s pecifie d i n Ta ble 3  bel o w . T he fi nal decisi o n t o ex cl u de partici pa nts fr o m 
a n y a nal ysis set will be ma de d uri n g a bli n de d data re vie w meeti n g pri or t o data base l oc k a n d 
u n bli n di n g.  E x cl usi o n fr o m P K set will be perf or me d after u n bli n di n g p os t-data base l oc k as o nl y 
partici pa nts w h o recei ve d at least o ne d o se of e v o br uti ni b are c o nsi dere d. 
De pe n di n g o n t he e n d p oi nts, t he a nal ysis set will be defi ne d at st u d y le vel (i.e. f or eac h 0 0 8 0 a n d 
 se parat el y) a n d/or at t he p o ole d le vel.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
2 9 /1 5 9  
 
 
 
T a ble 3  
A n al ysis Sets   
A n al y si s S et  
D e s cri pti o n  
S cr e e ni n g ( S C R)  
All p arti ci p a nt s w h o pr o vi d e d i nf or m e d c o n s e nt, r e g ar dl e s s of t h e p arti ci p a nt’ s 
r a n d o mi z ati o n a n d st u d y i nt er v e nti o n st at u s i n t h e st u d y. 
F ull A n al y si s S et ( F A S)  
All p arti ci p a nt s w h o w er e r a n d o mi z e d t o st u d y i nt er v e nti o n. P arti ci p a nt s will b e 
a n al y z e d p er t h e i nt er v e nti o n gr o u p t o w hi c h t h e y w er e r a n d o mi z e d (i. e. i nt e nti o n -
t o-tr e at pri n ci pl e). 
T hi s a n al y si s s et will b e u s e d f or t h e pri m ar y a n al y si s of effi c a c y.  
M o difi e d F A S ( m F A S)  
P er I C H E 9, all p arti ci p a nt s i n F A S e x c e pt p arti ci p a nt s  
•  
wit h eli gi bilit y vi ol ati o n s  
•  
w h o ar e s cr e e n f ail ur e s r a n d o mi z e d i n err or  
•  
w h o di d n ot r e c ei v e st u d y i nt er v e nti o n  
•  
fr o m sit e s l a c ki n g d at a r o b u st n e s s (i. e. i n a bilit y t o v erif y d at a s o ur c e) 
t hr o u g h o ut t h e c o ur s e of t h e st u d y 
T hi s a n al y si s s et will b e u s e d f or s e n siti vit y a n al y s e s of pri m ar y a n d s e c o n d ar y 
effi c a c y e n d p oi nt s.  
S af et y ( S A F)  
All p arti ci p a nt s w h o r e c ei v e d at l e a st o n e d o s e of st u d y i nt er v e nti o n. P arti ci p a nt s 
will b e a n al y z e d p er t h e a ct u al st u d y i nt er v e nti o n t h e y r e c ei v e d. T hi s a n al y si s s et 
will b e u s e d f or all  a n al y s e s of s af et y.  
M o difi e d S af et y 
( m S A F) 
N ot d efi n e d. W hil e t h e pr ot o c ol all o w s f or t h e d efi niti o n of m S A F , no s af et y d at a 
r o b u st n e s s i s s u e s h a v e b e e n i d e ntifi e d t h at w o ul d w arr a nt e x cl u si o n of a S A F 
p arti ci p a nt fr o m t h e pri m ar y a n al y si s of s af et y.   
P K  
All p arti ci p a nt s w h o h a v e r e c ei v ed  at l e a st 1 d o s e of e v o br uti ni b a n d h a v e at l e a st 
1  q u a ntifi a bl e e v o br uti ni b  a n d/ or m et a b olit e  pl a s m a c o n c e ntr ati o n at a s c h e d ul e d 
P K ti m e p oi nt p o st d o s e wit h o ut a n y i m p ort a nt d e vi ati o n s or e v e nt s t h at m a y i m p a ct 
t h e q u alit y of t h e d at a or alt er t h e e v al u ati o n of P K. P arti ci p a nt s w h o r e c ei v e a cti v e 
c o ntr ol will n ot b e i n cl u d e d.  P arti ci p a nt s will b e  a n al y z e d p er t h e a ct u al st u d y 
i nt er v e nti o n t h e y r e c ei v e d. 
P D  
All p arti ci p a nt s w h o h a v e r e c ei v ed  at l e a st 1 d o s e of e v o br uti ni b or a cti v e c o ntr ol, 
h a v e a pr e d o s e a s s e s s m e nt, a n d at l e a st o n e p o st d o s e a s s e s s m e nt, wit h o ut 
d e vi ati o n s or i m p ort a nt e v e nt s aff e cti n g P D, a n d w h o pr o vi d e e v al u a bl e P D d at a. 
P arti ci p a nt s will b e a n al y z e d p er t h e a ct u al st u d y i nt er v e nti o n t h e y r e c ei v e d.  T hi s 
a n al y si s s et i s o nl y a p pli c a bl e f or t h e M S 2 0 0 5 2 7 _ 0 0 8 0 st u d y.  
P D B T K O  
All p arti ci p a nt s w h o h a v e r e c ei v e d at l e a st 1 d o s e of e v obr uti ni b , h a v e a pr e d o s e 
a s s e s s m e nt,  a n d h a v e at l e a st 1 m e a s ur e d B T K o c c u p a n c y v al u e at a s c h e d ul e d 
P D ti m e p oi nt p o st b a s eli n e  wit h o ut d e vi ati o n or i m p ort a nt e v e nt s aff e cti n g P D, a n d 
w h o pr o vi d e e v al u a bl e P D d at a. T hi s a n al y si s s et i s o nl y a p pli c a bl e f or  t h e 
M S 2 0 0 5 2 7 _ 0 0 8 0 st u d y.  
P K S U B  
A s u b s et of p arti ci p a nt s fr o m t h e P K a n al y si s s et w h o ar e e nr oll e d at sit e s s el e ct e d 
f or t h e P K s u b st u d y. T hi s a n al y si s s et i s o nl y a p pli c a bl e f or t h e M S 2 0 0 5 2 7 _ 0 0 8 0 
st u d y.  
It is a ntici pat e d t hat a s u bset of sites i n U krai ne, R ussia n Fe derati o n a n d Belar us  will n ot re mai n 
f ull y o perati o nal p ost start of U krai ne crisis. F or partici pa nts  fr o m t hese sites (c o nsi deri n g site at 
ti me of ra n d o mizati o n a n d ne w site i n case of tra nsfer)), t he I C E “ U krai ne  crisis” will be h a n dled 
via t he H y p ot hetical str ate g y, w herei n data p ost st art of crisis will be ce ns ore d  i n t he a n al ysis of 
effic ac y (s ee Secti o n  1 4 ).   
“ F ull y o perati o nal” is d efi ne d wit h t he f oll o wi n g criteria: 1. Sites o pe n f or  p artici pa nt o nsite visits,  
2. Sites wit h  n o iss ues wit h st u d y i nter ve nti o n dis pe nsati o n/res u p pl y, 3. Sites wit h n o iss ues wit h 
c ollecti n g/ pr o cessi n g  bi ol o gical s a m ples  eit her ce ntrall y or l ocall y. If t h ere is a si n gle m o nt h after 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 0 /1 5 9  
 
 
 
t he start of t he crisis d uri n g w hi c h a site’s stat us is n ot f ull y o perati o nal, t he n data fr o m p artici pa nts 
at t hat site will be ass u me d t o lac k r o b ust ness starti n g wit h t he d ate at w hic h t he site l ost f ull y 
o perati o nal stat us.  
A site is c o nsi dere d t o la c k data r o b ust ness t hr o u g h o ut t he st u d y if s o urce d ata verificati o n ca n n ot 
be perf or me d. Partici pa nts fr o m s uc h sites are e x cl u de d fr o m t he m F A S.  
Sites wit h l ac k of data r o b ust ness t hr o u g h o ut t he st u d y (i.e. e x cl u de d fr o m m F A S) a n d n ot 
c o nti n u o usl y o p erati o nal  p ost start of t he crisis  (i.e. ce ns ore d i n pri mar y effi cac y a n al ys es)  will be 
i de ntifie d bef ore D B L a n d u n bli n di n g b y c o n d ucti n g a bli nde d l o n git u di nal a nal ysi s of site 
o perati o nal stat us . T h e list of t he c orres p o n di n g sit es will be i ncl u de d i n a n IA P A p pe n di x pri or t o 
D B L.  
P Ds  lea di n g t o e x cl usi o n fr o m t h e m F A S  a n al ysis set will b e e n c o de d as cI P Ds i n t he d ata bas e.  
See Secti o n  1 0. 2  f or det ails. 
F or t h e P D B T K O a nal ysis set, a ssa y de viati o n f or B T K O data will be i de ntifie d i n t he ra w data 
recei v e d fr o m t he v e n d ors. 
Act u al Tre at me nt Assi g n me nt  
A partici pa nt  w h o recei ve d 2 differe nt t y pes of st u d y i nter ve nti o n re gi me n o ver t he c o urse of st u d y 
i nter ve nti o n s h o ul d be ta b ulate d acc or di n g t o t he st u d y i nter ve nti o n re gi me n recei ve d m ost 
fre q ue ntl y ( base d o n n u m ber of kits recei ve d). If t here is a “tie”, t hen  e v o br uti ni b will be c h ose n.  
T he f oll o wi n g T a ble 4  s u m marizes t he use of t he a nal ysis sets i n t he differe nt a nal ys es.  
T a ble 4  
Use of A n al ysis Sets   
 
A n al y si s S et  
A n al y s e s  
F ull 
A n al y si s 
S et  
m o difi e d 
F A S 
( m F A S) 
S af et y  
 
P K  
P D  
P D B T K O  
 
P K S U B  
B a s eli n e C h ar a ct eri sti c s*  
✓ 
 
 
 
 
 
 
Pr e vi o u s a n d C o n c o mit a nt T h er a pi e s  
 
 
✓ 
 
 
 
 
C o m pli a n c e a n d E x p o s ur e  
 
 
✓ 
 
 
 
 
Effi c a c y: Pri m ar y  
✓ 
✓ 
 
 
 
 
 
Effi c a c y: S e c o n d ar y  
✓ 
✓ 
 
 
 
 
 
Effi c a c y: T erti ar y/ E x pl or at or y  
✓ 
 
 
 
 
 
 
S af et y a n d T ol er a bilit y  
 
 
✓ 
 
 
 
 
P h ar m a c o ki n eti c s  
 
 
 
✓ 
 
 
✓ 
P h ar m a c o d y n a mi c s  
 
 
 
 
✓ 
✓ 
 
Bi o m ar k er s  
 
 
 
 
✓ 
 
 
P R O  
✓ 
 
 
 
 
 
 
* Pr e s e nt e d o n b ot h F A S/ m F A S a s w ell a s S A F if t h er e i s a diff er e n c e i n t h e a n al y si s s et s gr e at er or e q u al t o  1 0 % . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 1 /1 5 9  
 
 
 
8. 2  
S u b gr o u p Defi niti o n a n d P ar a meteriz ati o n   
S u b gr o u p a nal yses will be p erf or me d o n t he pri mar y esti ma n d A R R a n d o n t he s ec o n dar y 
esti ma n ds ti me t o 1 2 -wee k  C D P , ti me t o 2 4-wee k C D P  a n d ti me t o 2 4 -wee k C DI as d efi ne d bel o w.  
All s u b gr o u p a n al yses will be e x pl orat or y, n o a dj ust me nt f or m ulti plicit y will be perf or me d.  
F or t he defi niti o n of s u b gr o u p le vel, data as d oc u me nte d i n t he e C R F or ve n d or data  will be ta ke n.  
T he cate g or y “ missi n g” will n ot be i ncl u de d i n a n y s u b gr o u p a nal ysis.  
T he f oll o wi n g s u b gr o u ps will be defi ne d  a n d re -gr o u pi n g det er mi ne d at ti me of a nal ysis i n t he 
e ve nt of t o o fe w partici p a nts i n s o me le vels : 
•  Baseli ne  E D S S ( ve n d or data ): 
o  E D S S < 4. 0 (refe re n ce le vel) 
o  E D S S ≥ 4. 0  
•  Re gi o n ( e C R F) : 
o  N ort h A meric a  
o  Wester n E ur o pe (refere n ce le vel)  
o  Easter n E ur o p e  
o  R O W  
•  Se x : 
o  Male (refere nce le vel)  
o  Fe male  
•  A ge : 
o  A ge < 4 0 years (refere n ce le vel)  
o  A ge ≥ 4 0 years  
•  Race:  
o  W hite  (refere nce le vel),  
o  Blac k or Afri ca n A merica n,  
o  Asia n,  
o  A merica n I n dia n or Alas ka Nati ve,  
o  Nati ve Ha w aiia n or Ot her Pacific Isla n d er  
Partici pa nts wit h m ulti ple races, race not c ollecte d at site, or ‘ Ot her’ will n ot be i ncl u de d i n t he 
s u b gr o u p a n al ysis. Cate g ories wit h 5 partici pa nts  or less i n o ne or b ot h treat me nt ar ms will n ot be 
i ncl u de d i n t he s u b gr o u p a nal ysis. F or t his s u b gr o u p, t he strat u m Re gi o n will n ot be i ncl u de d i n 
a n y m o d eli n g. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 2 /1 5 9  
 
 
 
•  Et h nicit y:  
o  His pa nic or Lati n o ,  
o  N ot His pa nic or Lati n o  (refere nce le vel) 
F or t his s u b gr o u p, t he str at u m Re gi o n will n ot be i ncl u de d i n a n y m o deli n g.  
•  N u m ber of rela pses i n pre vi o us 2  years  b ef ore Scree ni n g : 
o  ≤ 2  (refere n ce le v el) 
o  > 2  
•  Prese nce of T 1 G d + l esi o ns wit hi n 6  m o nt hs  pri or t o ra n d o mizati o n : 
o  0 (refere n ce le v el)  
o  ≥ 1  
•  A n y D M T  b ef ore st u d y e ntr y : 
o  Yes (refere nce le vel)  
o  N o  
•  T 2 lesi o n n u m ber at Baseli ne : 
o  ≥ 9 (refere n ce le v el)  
o  < 9  
•  T 2 lesi o n v ol u me at Bas eli ne : 
o  ≤ me dia n (refere nce l e vel)  
o  > me dia n  
•  Ti me ( years) si nce i nitial M S dia g n osis date ( d eri ve d base d o n i nf or m e d c o nse nt date):  
o  ≤ 3 (refere n ce le v el) 
o  > 3 - ≤ 1 0  
o  > 1 0  
•  Nf L c o nce ntrati o n  at Bas eli ne : 
o  ≤ me dia n (refere nce l e vel)  
o  > me dia n  
•  Me m bers hi p i n i nitial or sec o n d r ecr uit me nt c o h ort : 
o  I nitial c o h ort (refere nce l e vel) 
o  Sec o n d c o h ort  
T here were 2  recr uit me nt c o h orts d uri n g st u d y c o n d uct. T he first c o h ort was recr uite d J ul y 2 0 2 0 –  
Oct o ber 2 0 2 1. T he sec o n d c o h ort was recr uite d starti n g i n J ul y 2 0 2 2. T his s u b gr o u p a n al ysis will 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 3 /1 5 9  
 
 
 
be defi ne d i f t he n u m ber of partici pa nts recr uite d  i n t he sec o n d recr uit ment c o h ort  re prese nts at 
least 1 0 % of t he F A S  partici pa nts.  
9  
Ge ner al S pecific ati o ns f or D at a A n al yses   
T his secti o n descri bes a n y ge n eral s p ecificati o ns n ot i ncl u de d i n s u bse q ue nt secti o ns.  
9. 1  
St u d y i nter ve nti o n   
St u d y i nter ve nti o ns  i n t he d o u ble bli n d, d o u ble d u m m y p eri o d are defi ned as i n dicate d i n  Ta ble 5 : 
T a ble 5  
St u d y I nter ve nti o ns  a n d Re gi me ns   
 
R e gi m e n a  
St u d y I nt er v e nti o n Pr e s e nt ati o n  
1  
E v o br uti ni b 4 5  m g BI D  
E v o br uti ni b  
2  
T erifl u n o mi d e 1 4 m g Q D  
T erifl u n o mi d e  
a  T h e st u d y will h a v e a d o u bl e d u m m y d e si g n.  
9. 2  
Prese nt ati o n of c o nti n u o us a n d q u alit ati ve v ari a bles   
C o nti n u o us varia bles will be s u m marize d usi n g t he f oll o wi n g d escri pti ve st atistics:  
•  n u m ber a n d perce nt a ge of partici pa nts wit h n o n -missi n g val ues  
•  n u m ber a n d perce nt a ge of partici pa nts wit h missi n g val u es  
•  mea n, S D  
•  me dia n, 2 5 t h Perce ntile - 7 5 t h Perce ntile  ( Q 1-Q 3)  
•  mi ni m u m, a n d ma xi m u m  
T he n u m ber of di gits f or n o n -deri ve d a n d deri ve d data, prese nt e d i n o ut p uts or a vaila ble i n A Da M 
datasets, is s pecifie d i n t he  B O A d oc u m e nt.  F or efficac y e n d p oi nts fr o m S ecti o n  1 4 , me dia n a n d 
S D will be prese nte d wit h 1 m ore di git c o m pare d t o t he ori gi nal dat a, w hereas mea n, mi n, ma x, 
Q 1 -Q 3 will be pres e nte d wit h t he sa me n u m ber of di gits as t he ori gi nal data.  
F or b ot h c o nti n u o us a n d q ualitati ve varia bles, p erce nta ges s u c h as 0 % or 1 0 0 % s h o ul d be re p orte d 
wit h t he sa me f or mat use d f or t he c ol u m n, t o get her wit h t he c o u nt of o bser vati o ns. F or e x a m ple, 
if t he c o u nt of o bser vati o ns is zer o, t he n dis pla y ‘ 0 (  0. 0)’; if t he c o u nt of o bser vati o ns is 1 0 0 % 
t he n dis pla y ‘ x x ( 1 0 0. 0)’. 
Q ualitati ve vari a bles will be s u m marize d b y c o u nts a n d perce nta ges. T h e “ Missi n g” cate g or y 
s h o ul d al wa ys b e dis pla ye d at Bas eli ne  –  e ve n w he n t here are n o missi n g d ata at Baseli ne . At 
ti me p oi nts ot her tha n Baseli ne , t he “ Missi n g” cat e g or y s h o ul d o nl y be dis pla ye d w he n t here are 
missi n g data.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 4 /1 5 9  
 
 
 
U nless ot her wise state d, t he calc ulati o n of pr o p orti o ns will be base d o n t he n u m ber of partici p a nts 
i n t he a nal ysis set of i nterest. T heref ore,  c o u nts of missi n g o bs er vati o ns will be i ncl u de d i n t he 
de n o mi nat or a n d prese nt e d as a se p arat e cat e g or y.  
T he t otal of missi n g a n d n o n -missi n g o bser vati o ns at eac h ti me p oi nt will reflect t he p o p ulati o n 
still i n t he st u d y at t hat ti me. F or e x a m ple, if a partici pa nt is still i n the st u d y at t he ti me p oi nt b ut 
wit h missi n g data, t hat p artici pa nt s h o ul d be c o u nte d i n t he n u m ber of missi n g o bser vati o ns. 
Visits will be prese nte d i n b y -visit descri pti ve s u m maries if t here are at least 1 0 partici pa nts still 
i n t he st u d y at t hat ti me p oi nt. 
Prese nt ati o n of P K C o n ce ntr ati o n D at a  
P har mac o ki netic c o nce ntrati o n data will be descri pti vel y s u m marize d usi n g: n u m ber of n, m ea n, 
S D, C V %, mi ni m u m, me dia n, a n d ma xi m u m.  
Descri pti ve statistics will o nl y be calc ul ate d f or n  >  2 i n w hic h a meas ure m e nt of  B L Q re prese nts 
a vali d meas ure me nt a n d will be ta ke n as zer o f or s u m mar y statistics. I n n  ≤ 2, o nl y n, mi ni m u m , 
a n d m a x i m u m will be prese nte d i n s u m mar y ta bles . 
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o urce d ata a n d r o u n de d f or re p orti n g p ur p oses o nl y. P K c o nce ntr ati o ns will be 
carri e d o ver wit h f ull precisi o n as pr o vi de d i n t he s o urce data wi t h o ut a n y r o u n di n g a p plie d t o 
C DI S C S D T M P C a n d A Da M P C d o mai ns.  
T he f oll o wi n g c o n v e nti o ns 
will be a p plie d 
w he n re p orti n g des cri pti ve statistics of P K 
c o nce ntr ati o n data:  
n:  
 
 
 
 
 
 
0 deci mal place  
mea n , m i ni m u m, m e dia n, m a x i m u m:  
 
3 si g nifica nt di gits  
S D:  
 
 
 
 
 
 
4 si g nifica nt di gits  
C V %:   
 
 
 
 
 
1 deci mal place  
Prese nt ati o n of P K P ar a meter D at a  
P K para meter d ata will be descri pti vel y s u m marize d usi n g: n, mea n, S D, C V %, mi ni m u m, me dia n, 
ma xi m u m, ge o metric me a n, t he ge o metri c c oefficie nt of variati o n a n d t he 9 5 %  c o nfi de nce i nter val 
f or t he ge o metric me a n.  F or P K p ara met ers relate d t o ti me (e. g. t ma x ), o nl y n, m i ni m u m, m e dia n, 
a n d m a x i m u m ma y b e re p orte d.  
Descri pti ve statistics will o nl y be calc ulate d f or a P K para meter w he n n  >  2. I n  case n ≤ 2,  
i n di vi d ual data  will be prese nte d ( mi n i m u m, ma xi m u m) i n s u m mar y ta bles. 
P K para m eters rea d directl y fr o m t he meas ure m e nts (i.e. C ma x ) will be re p orte d wit h t h e sa m e 
precisi o n as t he s o urce data. All ot her P K para meters will be re p orte d t o 3  si g nifica nt fi g ures. 
Descri pti v e statistics of P K para m eter d ata will be calc ulate d usi n g f ull precisi o n a n d r o u n de d f or 
re p orti n g p ur p oses o nl y. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 5 /1 5 9  
 
 
 
P K para meters will be pr o vi de d wit h f ull precisi o n, wit h o ut a n y r o u n di n g a p plie d t o C DI S C S D T M 
P P a n d A Da M P P d o mai ns.  
T he f oll o wi n g c o n v e nti o ns will be a p plie d w he n re p orti n g des cri pti ve statistics of P K para meter 
data:  
n  
0 deci mal place  
mea n,  
mi ni m u m,  
me dia n, 
ma xi m u m, 
ge o metric 
mea n, 
9 5 % CI:  
3 si g nifica nt di gits  
S D:  
4 si g nifica nt di gits  
C V %, ge o metric C V %:  
1 deci mal place  
9. 3  
D at a  H a n dli n g A fter C ut off  D ate   
F or t he P A, t he tri g ger date will be use d as  t he c ut off date.  
Data o btai ne d after t h e c ut off d ate will n ot b e dis pla ye d i n a n y listi n gs or use d f or s u m mar y 
statistics, i.e. la b orat or y val ues of sa m ples ta ke n after data c ut off, A Es wit h o nset date after data 
c ut off, etc. will n ot be i ncl u de d i n a n y a n al ysis or listi n g.  
T he c ut off date will be a p plie d a t t he S D T M le vel (refer t o S D T M C u t-off d ate i m ple me nt ati o n 
r ules _ B T Ki( M 2 9 5 1)-C o m p o u n d _v 3 . 0. d ocx). 
9. 4  
Defi niti o n of B aseli ne  a n d C h a n ge fr o m B aseli ne   
Defi niti o n of B aseli ne  
U nless ot her wise s pecifie d, baseli ne  is defi ne d as t he last n o n-missi n g val ue o n t he da y of or pri or 
t o first a d mi nistrati o n of st u d y i nter ve nti o n i n t he D B T P . Of n ote, ti me of first d osi n g 
a d mi nistrati o n a n d assess me nt of baseli ne  ( b ot h d o ne o n t he sa m e B aseli n e da y) will n ot be use d 
i n t he deter mi nati o n of b aseli ne  val ue, e x ce pt f or E C Gs.  
If b ot h ce ntr al a n d l oc al la bs are c ollecte d, t he bas eli ne  will be deri ve d bas e d o nl y o n t h e ce ntral 
la b c ollecte d data. O nl y ce ntral rea d E C Gs dat a will be use d t o deri ve baseli ne  as well as 
s u bse q ue nt visits. 
Defi niti o n of C F B  
C F B a n d p erce nt C F B at a gi v e n p ost  Bas eli ne  V isit will be c o m p ute d as f oll o ws:  
•  C F B = visit val ue –  b aseli ne  val ue  
•  Perce nt C F B = 1 0 0 * ( visit val ue –  baseli ne  val ue) / baseli ne  val ue  
At t he Bas eli ne  V isit, t he C F B will be e q u al t o zer o a n d t he perce nt C F B will be missi n g.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 6 /1 5 9  
 
 
 
9. 5  
St u d y D a y   
Da y  1 is t he d a y of start of st u d y i nt er ve nti o n, t he d a y bef ore is Da y  -1 ( n o Da y  0 is defi n e d). St u d y 
da y is defi ne d relati ve t o Da y  1 . 
9. 6  
Defi niti o n of D ur ati o n  a n d ‘ti me si nce’ V ari a bles   
D urati o n i n da ys will be calc ulate d as t he differe n ce bet wee n start a n d st o p dates pl us 1 (e .g . A E 
d urati o n ( da ys) = A E e n d date - A E start date + 1).  
T he ti me si nce a n e ve nt ( e. g. ti me si nce first dia g n osis) will be calc ulate d as refere nce date mi n us 
date of e v e nt.  
9. 7  
C o n versi o n F act ors   
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert da ys i nt o m o nt hs or years:  
1 wee k = 7 d a ys, 1 m o nt h = 3 0. 4 3 7 5 da ys, 1 year = 3 6 5. 2 5 da ys.  
T he f oll o wi n g c o n versi o n fact ors will be use d t o c o n vert s u bsta nce u nits:  
1  oz = 3 0  m L ; 2 0  ci gar ettes = 1  pac k  
9. 8  
Ti me  W i n d o w  
Assess me nts ma y be m a de at ti mes ot her t ha n t he n o mi nal ti mes of pla n ne d visits, d ue t o 
partici pa nt  sc he d uli n g iss ues, u nsc he d ule d visits f or ne ur ol o gi cal w orse ni n g or rela pse assess me nt, 
or earl y tr eat me nt ter mi n ati o n visits.  
F or b y -visit a nal yses of effi cac y a n d s afet y (e x ce pt c o a g ulati o n), eac h meas ure me nt will be 
assi g ned a n a n al ysis visit n u m ber acc or di n g t o t he pres pecifie d ti me 
wi n d o w , u p t o 
W ee k 1 5 6  V isit. All visit wi n d o wi n g will be d o n e base d u p o n st u d y da y, a n d a n y assess me nts 
c o m plete d o n t h e sa me d a y as st u d y i nter ve nti o n start will be c o nsi dere d f or baseli ne , e x ce pt i n 
t he case of Da y 1 E C Gs, w hic h re q uire a deter mi nati o n of pre d ose a n d p os t-d ose.  T he a nal ysis 
visit will t he n be use d f or missi n g data i m p utati o ns, a nal ysis vari a ble deri vati o ns, statistical 
calc ulati o ns a n d prese ntati o ns.  
All Safet y  F oll o w -u p  V isit data will be prese nte d u n der t he Safet y  F oll o w -u p  V isit, re gar dless of 
w het her t he p artici pa nt is a n earl y tr eat me nt disc o nti n uer or a treat me nt c o m pleter.  
F or b y -visit s u m mar y of t he c oa g ul ati o n safet y e n d p oi nts, visit wi n d o wi n g will n ot be perf or me d 
as t his data o nl y bei n g c ollecte d at S cree ni n g a n d E n d of D B T P V isits. Assess me nts will be 
prese nte d b y n o mi nal visit (as c ollecte d i n t he dat a base) .  
F or partici pa nt  data l isti n gs b y ti me p oi nt, t he n o mi nal visit as well as t he a nal ysis visit will be 
dis pla ye d.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 7 /1 5 9  
 
 
 
F or t he calc ulati o n of a nal ysis visit usi n g t he ti me wi n d o ws, 1 m o nt h is e x presse d as 3 0  d a ys.  
As t he sc h e d ule of assess me nts is differe nt f or eac h visit, s pecific t i me wi n d o ws m ust be use d f or 
eac h e n d p oi nt. T he y are defi ne d i n A p pe n di x  1 8. 4 . 
If t h ere are m ulti ple assess me nts wit hi n a sa me visit wi n d o w, t he n t he o ne cl osest to t he tar get da y 
will be use d. If 2  assess me nts ha ve t h e sa me differe n ce wit h tar get da y, t he earlier o n e will be 
use d.  
9. 9  
Re pe ate d a n d U nsc he d ule d Me as ure me nts   
Re peate d a n d u ns c he d ul e d meas ure me nts are i ncl u de d i n t he listi n gs. Data c ollecte d at b ot h 
u nsc he d ule d a n d s c he d ul e d visits will be use d f or s hift ta bles. F or s u m mar y statistics, fi g ures, or 
i nfere ntial a nal ysis, dat a are re-all ocate d t o a n a nal ysis visit usi n g ti me wi n d o w calc ulati o ns 
(Secti o n  9. 8 ). 
9. 1 0  
Defi niti o n of O n -tre at me nt P eri o d  
F or t h e P A, o n -treat me nt val ues are res ults of ass ess me nts d o ne fr o m t h e first st u d y i nter ve nti o n 
a d mi nistrati o n o n 
Da y 1 u ntil en d  of  t he D B T P  (c o m pleti o n, earl y ter mi nati o n  i ncl u di n g 
Safet y  F oll o w -u p , or t he c ut off dat e, w hic h e ver is earliest ). Val ues re p orte d i n t he D B E or O L E 
peri o d s are n ot d efi ne d as o n -treat me nt f or t h e P A . 
9. 1 1  
Defi niti o n of 4 8  w ee ks P ost  R a n d o miz ati o n Peri o d   
T he 4 8  wee ks p ost  ra n d o mizati o n peri o d used i n efficac y a nal ysis is defi ne d fr o m t he da y of 
ra n d o mizati o n u n til Da y 3 4 4, w hic h c orres p o n ds t o t he st u d y d a y of Wee k  4 8  Visit + 7 da ys visit 
wi n d o w defi ne d i n t he pr ot oc ol.  
9. 1 2  
Defi niti o n of 9 6  w ee ks P os t R a n d o miz ati o n Peri o d   
T he 9 6  wee ks p ost  ra n d o mizati o n peri o d use d i n efficac y a nal ysis is defi ne d fr o m t he da y of 
ra n d o mizati o n u n til Da y 6 8 0 , w hic h c orres p o n ds t o t he st u d y d a y of Wee k 9 6  V isit + 7  da ys visit 
wi n d o w defi ne d i n t he pr ot oc ol.  
9. 1 3  
Defi niti o n of 1 5 6  wee ks P os t R a n d o miz ati o n Peri o d   
T he 1 5 6  wee ks p ost  ra n d o mizati o n peri o d use d i n efficac y a n al ysis f or earl y tr eat me nt 
disc o nti n uers is defi ne d fr o m t he da y of ra n d o mizati o n u n til Da y  1 1 0 0, w hic h c orres p o n ds t o t he 
st u d y da y of Wee k 1 5 6  V isit + 7 da ys visit wi n d o w defi ne d i n t he pr ot o c ol. 
9. 1 4  
I m p ut ati o n of M issi n g D at a   
Prese nt ati o n of missi n g d at a  
F or efficac y a n al ysis, met h o ds of missi n g data ha n dli n g are detaile d i n Secti o n  1 4 . 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 8 /1 5 9  
 
 
 
I n all partici pa nt  data listi n gs, partial dat es, w hic h are n ot t o be i m p ute d acc or di n g t o t his I A P, will 
be prese nte d usi n g t he f or mat “ _ _ _ _ _ Y Y Y Y” . W he n prese nte d, i m p ute d dates will be fla g ge d (i .e. 
D f or da y, M f or m o nt h).  
Missi n g  statistics, e.g . w he n t he y ca n n ot be calc ulate d, s h o ul d be prese nte d as ‘ n d’, wit h ‘ n d’ 
sta n di n g f or ‘ n ot d o ne’. F or e x a m ple, if n = 1, t he meas ure of varia bilit y ( S D) ca n n ot be c o m p ute d 
a n d s h o ul d be pres e nte d as ‘ n d’.  
I n cas e of zer o rec or ds a vaila ble for prese ntati o n i n a gi ve n T L F, a n e m pt y o ut p ut wit h 0 
occ urre nce or a se nt e nce stati n g t hat t h ere are n o data will be pr o vi de d. F or ta bl es of A E s a n d 
Deat hs ( o ut p uts re q uire d f or E u dra C T a n d/ or cli nicaltrial. g o v), if t here is n o o bser vati o n, t he 
o ut p ut m u st c o ntai n t he first li ne ‘Partici pa nt  wit h …’ or ‘ Partici p a nt  w h o die d’ dis pla ye d wit h 0 
occ urre nce.  
If a S O C or A T C ter m is missi n g/ n ot c o de d yet, t h e n ‘ U nc o d e d S O C’ ( or ‘ U nc o de d A T C’) will be 
i n dicate d at t h e o ut p ut le vel. W he n a P T is missi n g, it will be set t o ‘ U n c o d e d P T:’ T E A E ver bati m 
te xt. 
H a n dli n g of missi n g or p arti al A E s d ates 
F or defi ni n g t he T E A E fl a g, missi n g or partial A E  dates will be i m p ute d as f oll o ws:  
•  I n cas e t he o ns et date is missi n g c o m pletel y or missi n g partiall y b ut t h e o nset m o nt h a nd year, 
or t he o nset year are e q u al t o t he start of st u d y i nt er ve nti o n, t he n t he o nset d ate will be re place d 
b y t he mi ni m u m of start of st u d y i nter ve nti o n a n d A E res ol uti o n date.  
•  I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1.  
•  I n c o m plete st o p dates will be re place d b y t he last da y of t he m o nt h (if da y is missi n g o nl y), if 
n ot res ulti n g i n a date later t ha n t he date of partici pa nt 's deat h or t he c ut off date . I n t he latter 
case t he d ate of d eat h , or c ut off date, will be use d t o i m p ute t he i nc o m plete st o p date.  
•  I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d.  
•  S pecial cases : A Es ma y b e s plit i nt o m ulti ple rec or ds if t he t o xicit y Gra de  a n d/ or t he seri o us ness 
c ha n ges (see Secti o n  1 5. 1  f or m ore details). T he e n d date of t he pre vi o us rec or d a n d t he start 
date of t he ne w rec or d are e x pecte d t o be t he sa me. I n t he e ve nt t hat t he m o nt h a n d year are 
in dee d t he sa me, b ut t he da y is missi n g, it will be i m p ute d b y 1 5. I n case t he i m p ute d start date 
of t he ne w rec or d is after t he e n d date of t his sa me rec or d, n o i m p utati o n will be perf or me d.  
I m p ute d d ates will o nl y b e use d f or d efi ni n g t he T E A E fla g f or t he o n -treat me nt peri o d.  
H a n dli n g of p arti all y missi n g M S d ate s 
F or ti me si nc e M S first attac k, M S dia g n osis  or d ate of c o n versi o n fr o m R R M S , a missi n g o nset 
da y/ m o nt h will be re pl ace d b y 1 f or t he d urati o n deri vati o n.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
3 9 /1 5 9  
 
 
 
9. 1 5  
Sc ori n g of H R Q O L D at a   
U nless ot her wise s p ecifie d, 
H R Q O L q u esti o n naires 
will be s c ore d usi n g t heir p u blis he d 
a d mi nistrati o n a n d sc ori n g ma n ual. F or ite ms wit h missi n g res p o nses, t he res p o nse will be 
m a na ge d as p er t he sc ori n g ma n u al. See A p pe n di ces 1 8. 1 , 1 8. 2  a n d 1 8. 3  f or details. 
9. 1 6  
C o ntr ol of M ulti plicit y   
As detaile d i n Secti o n  9. 4. 4. 3 of t he cli nical st u d y pr ot oc ol.  
T o c o ntr ol trial-wise a n d fa mil y -wise t y p e I err or at t he 1 -si de d 0. 0 2 5 le vel i n t he prese n ce of 
m ulti ple e n d p oi nt testi n g, a gra p hical a p pr oac h t o se q ue ntiall y rejecti ve m ulti ple testi n g will be 
e m pl o ye d ( Bretz  2 0 0 9 , H u n g  2 0 1 3 , Bretz 2 0 1 9 ).  
T he 1 -si de d n ull h y p ot heses i n t he gra p h are as f oll o ws, w here “ St u d y 1 ” de n otes st u d y 0 0 8 0, a n d 
“ St u d y 2” st u d y 
: 
Pri mar y E n d p oi nt N ull H y p ot heses:  
H 0 1 1: r R R1 ≥ 1, w here r R R 1 de n otes q ualifie d rela pse rate rati o c o m p ari n g e v o br uti ni b t o 
terifl u n o mi de i n St u d y 1  
H 0 1 2: r R R2 ≥ 1, w here r R R 2 de n otes q ualifie d rela pse rate rati o c o m p ari n g e v o br uti ni b t o 
terifl u n o mi de i n St u d y 2  
Sec o n dar y E n d p oi nt N ull H y p ot hes es:  
H 0 2: S1 2e(t) ≤ S 1 2 c(t), w here S1 2e(t) de n otes t he s ur vi val f u ncti o n f or ti me t o 1 2-wee k C D P i n t he 
e x peri me ntal (e v o br uti ni b) gr o u p bas e d o n p o ole d data, S 1 2c(t) de n otes t he s ur vi val f u ncti o n f or 
ti me t o 1 2-wee k C D P i n t he c o m parat or (terifl u n o mi de) gr o u p bas e d o n p o ole d da ta, a n d t he 
varia ble t de n otes ti me si nce ra n d o mizati o n.  
H 0 3: S2 4e(t) ≤ S 2 4c(t), w here S2 4e(t) a n d S2 4c(t) de n otes t he s ur vi val f u ncti o ns f or ti me t o 2 4-wee k 
C D P base d o n p o ole d dat a  
H 0 4: S2 4e(t) ≥ S 2 4c(t), w here S2 4e(t) de n otes t he s ur vi val f u ncti o n f or ti me t o 2 4-wee k C DI i n t he 
e x peri me ntal (e v o br uti ni b) gr o u p bas e d o n p o ole d data  fr o m p artici pa nts wit h baseli ne  E D S S ≥ 
2. 0 , S2 4c(t) de n otes t he s ur vi val f u ncti o n f or ti me t o 2 4-wee k C DI i n t he c o m p arat or (terifl u n o mi de) 
gr o u p bas e d o n p o ole d data  fr o m partici pa nts wit h baseli ne  E D S S ≥ 2. 0 , a n d t he varia ble t de n otes 
ti me si nce ra n d o mizati o n.  
H 0 5: ΔP F  ≤ 0, w here Δ P F  de n otes differe nce i n P R O MI S P h ysic al F u ncti o n sc ore C F B o ver  
9 6  wee ks least -s q uares mea n, c o m pari n g e v o br uti ni b t o terifl u n o mi de, base d o n p o ole d data 
( hi g her sc ore c orres p o n ds t o i m pr o ve d p h ysical f u ncti o n).  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 0 /1 5 9  
 
 
 
H 0 6: ΔFati g ue  ≥ 0, w here Δ Fati g ue  de n otes differe n ce i n P R O MI S Fati g u e sc ore C F B o ver  9 6  wee ks 
least-s q uares mea n, c o m pari n g e v o br uti ni b t o terifl u n o mi de, base d o n p o ole d data ( hi g her sc o re 
c orres p o n ds t o m or e fati g ue).  
H 0 2 1: l R R2 1 ≥ 1, w here  l R R2 1 de n otes T 1 G d + lesi o n rate rati o c o m pari n g e v o br uti ni b t o 
terifl u n o mi de i n St u d y 1  
H 0 2 2: l R R2 2 ≥ 1, w here l R R2 2 de n otes T 1 G d + lesi o n rate rati o c o m pari n g e v o br uti ni b t o 
terifl u n o mi de i n St u d y  2  
H 0 3 1: l R R3 1 ≥ 1, w here l R R3 1 de n otes ne w or e nl ar gi n g T 2 lesi o n rat e rati o c o m pari n g e v o br uti ni b 
t o terifl u n o mi de i n St u d y 1  
H 0 3 2: l R R3 2 ≥ 1, w here l R R3 2 de n otes ne w or e nl ar gi n g T 2 lesi o n rat e rati o c o m pari n g e v o br uti ni b 
t o terifl u n o mi de i n St u d y 2  
H 0 4 1: ΔNf L 1  ≥ 0, w here Δ Nf L 1  de n otes a differe nce i n Nf L  C o nce ntrati o ns at 1 2  wee ks c o m pari n g 
e v o br uti ni b t o terifl u n o mi de i n St u d y 1  
H 0 4 2: ΔNf L 2  ≥ 0, w here Δ Nf L 2  de n otes a differe nce i n Nf L  C o nce ntrati o ns at 1 2  wee ks c o m pari n g 
e v o br uti ni b t o terifl u n o mi de i n St u d y  2  
At t he P A, t he pri mar y efficac y e n d p oi nt, A R R, will be teste d at t he 0. 0 2 5  ( 1-si de d) le vel i n eac h 
st u d y. A p pe n di x  1 8. 8  s h o ws t he m ulti ple testi n g pr oce d ure i n v ol vi n g st u d y-s pecific e n d p oi nts a n d 
p o ole d e n d p oi nts.  
At t he P A, t he 1 2 -wee k C D P p o ole d e n d p oi nt will be teste d at t he 0. 0 2 5 -0. 0 2 5 2 = 0. 0 2 4 3 7 5  le vel, 
1 -si de d, o nl y if A R R is si g nifica nt i n b ot h st u dies at t he 0. 0 2 5 le vel, 1-si de d. 
If t he 1 2-wee k C D P p o ole d e n d p oi nt is si g nifica nt at t he 0. 0 2 4 3 7 5  le vel, 1-si de d, t he s u bse q ue nt 
p o ole d e n d p oi nts ( 2 4 -wee k C D P, 2 4 -wee k C DI, P R O MI S P F C F B o ver 9 6  wee ks , P R O MI S 
Fati g ue C F B o ver  9 6  wee ks ) will be teste d i n a hi erarc hical or der at 0.0 2 4 3 7 5  le vel, 1-si de d. 
If t he pri mar y efficac y e n d p oi nt, A R R  u p t o 1 5 6 wee ks,  is si g nifica nt wit hi n a st u d y at t he 0. 0 2 5 
le vel, 1 -si de d, t he s u bse q ue nt si n gle-st u d y e n d p oi nts (t otal n u m ber of  T 1 G d + lesi o ns base d o n all 
a vaila ble M RI sca ns, n u m ber of ne w/e nlar gi n g T 2 lesi o ns o n t he last a vaila ble M RI sca n rel ati ve 
t o t he baseli ne  sca n, Wee k  1 2  Nf L c o n ce ntrati o n) will be teste d i n a hierarc hical or der at t he 0. 0 2 5 
le vel, 1-si de d. 
A n o ver vie w  ta ble s u m marizi n g t he res ults of t h e m ulti-sta ge testi n g pr oce d ure will be pr o vi de d . 
T his ta ble  will i ncl u de t he esti mates a n d p -val ues f or eac h c o m paris o n of t he ev o br uti ni b 
i nter ve nti o n gr o u p t o t he terifl u n o mi de i nter ve nti o n gr o u p, f or t he h y p ot hesis fa mil y 
c orres p o n di n g t o t he pri mar y e n d p oi nt , a n d f or t he h y p ot hesis fa milies c orres p o n di n g t o eac h of 
t he sec o n dar y e n d p oi nts . T he critical val ue use d t o assess eac h p-val ue f or si g nifica n ce will be 
re p orte d i n f o ot n otes, wit h a n a n n otati o n of t he p -val ue i n dicati n g si g nifica nce, ill ustrati n g t he 
p oi nt i n t he pr oce d ure at w hic h t he h y p ot h esis testi n g halte d. T his o ver vi e w ta ble will be pr o vi de d  
i n a d diti o n t o ta bles t hat s u m mariz e t he a nal ysis of eac h e n d p oi nt  se paratel y. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 1 /1 5 9  
 
 
 
9. 1 7  
S oft w are   
All statistical a nal yses will be perf or me d usi n g S A S ®  ( Statistical A nal ysis S yste m, S A S-I nstit ute, 
Car y, N ort h Car oli na 
Wi n d o ws Versi o n 9. 4 or hi g her). Gra p hics will  b e pre p are d wit h S A S 
Versi o n 9. 4, or hi g her.  
T he c o m p uter pr o gra m P h oe ni x ® Wi n N o nli n ® Versi o n 8. 3 , or hi g her ( Certara, L. P., Pri ncet o n, 
Ne w J erse y, U S A) will be use d  t o re vie w P K data f or p ossi ble e x cl usi o n a n d f or para meter 
esti mati o n i n t he P K s u bst u d y .  
9. 1 8  
U n bli n di n g   
Details re gar di n g t he u n bli n di n g pr ocess are a vaila ble i n t he latest versi o n of u n bli n di n g pla ns f or 
eac h st u d y. 
9. 1 9  
Ter mi n ol o g y  C o n ve nti o n s  
Ge nerall y, t he ter m ‘ partici pa nt’ will be use d i nstea d of ‘s u bject’ or ‘ patie nt’. H o we v er, i n t a bles 
a n d listi n gs t he ter m ‘s u bject’ will be use d t o matc h C DI S C re q uir e me nts, e x ce pt f or i n -te xt ta bles 
w here ‘ partici pa n t’ will be use d t o matc h t he C S R a n d pr ot oc ol te m plates.  
Si milarl y, t h e ter m ‘st u d y i nter ve nti o n’ will be use d i n t his d oc u me nt i nstea d of ‘treat me nt’ t o 
matc h pr ot oc ol a n d C S R te m plates, h o we ver, ta bl es a n d listi n gs will use ‘treat me nt’ f or bre vit y 
reas ons. 
E x ce pti o ns fr o m t his r ule 
are 
c o m m o nl y 
use d ter ms li ke 
“ o n -treat me nt”, 
“treat me nt-e mer ge nt”, “treat me nt p olic y”, “s u bjec t-years”, “ b y -s u bject”, or na mes of e C R F pa ges 
li ke “ Treat me nt Ter mi nati o n” pa ge. 
1 0  
St u d y P artici p a nt s  
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g partici pa nt  dis p ositi o n a n d 
st u d y treat me nt/st u d y dis c o nti n uati o ns. A d diti o nall y , pr oce d ures f or re p orti n g pr ot o c ol de viati o ns 
are pr o vi d e d.  
1 0. 1  
Dis p ositi o n of P artici p a nts a n d Disc o nti n u ati o ns   
A ta ble o n scree ne d partici pa nt s descri bi n g t he n u m ber a n d perce nt of p artici pa nt s i n eac h of t h e 
f oll o wi n g dis p ositi o n cate g ories will be pr o d uce d b y st u d y i nter ve nti o n gr o u p  as i n dicate d i n Ta ble 
6 , f or eac h st u d y a n d o n p o ole d data: 
T a ble 6  
Dis p ositi o n   
•  
T ot al n u m b er of s cr e e n e d p arti ci p a nt s, i. e. p arti ci p a nt s t h at g a v e i nf or m e d c o n s e nt ( o v er all s u m m ar y 
o nl y)  
•  
N u m b er of p arti ci p a nt s w h o di s c o nti n u e d pri or t o r a n d o mi z ati o n a n d r e a s o n ( o v er all s u m m ar y o nl y) 
•  
N u m b er of r a n d o mi z e d p arti ci p a nt s  
•  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di d n ot st art tr e at m e nt a n d r e a s o n s  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 2 /1 5 9  
 
 
 
•  
N u m b er of D B T P tr e at m e nt o n g oi n g p arti ci p a nt s, i. e. p arti ci p a nt s w h o n eit h er p er m a n e ntl y di s c o nti n u e d 
tr e at m e nt d uri n g D B T P n or c o m pl et e d D B T P b ef or e  t h e d at a c ut off * 
•  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o c o m pl et e d D B T P **  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o c o m pl et e d D B T P  a n d e nt er e d D o u bl e Bli n d E xt e n si o n  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o c o m pl et e d D B T P  a n d e nt er e d O p e n L a b el E xt e n si o n  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o c o m pl et e d D B T P  pl u s s af et y f oll o w-u p  p eri o d a c c or di n g t o 
pr ot o c ol  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di s c o nti n u e d fr o m st u d y aft er c o m pl eti o n of D B T P  d uri n g 
s af et y f oll o w-u p  a n d r e a s o n   
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di s c o nti n u e d fr o m st u d y aft er c o m pl eti o n of D B T P  
d uri n g s af et y f oll o w-u p  d u e t o C O VI D -1 9  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di s c o nti n u e d fr o m st u d y aft er c o m pl eti o n of D B T P  
d uri n g s af et y f oll o w-u p  d u e t o t h e U kr ai n e cri si s  
•  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o p er m a n e ntl y di s c o nti n u e d tr e at m e nt d uri n g D B T P  a n d r e a s o n  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o p er m a n e ntl y di s c o nti n u e d tr e at m e nt d u e t o C O VI D -1 9  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o p e r m a n e ntl y di s c o nti n u e d tr e at m e nt d u e t o t h e U kr ai n e 
cri si s.  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o c o m pl et e d s af et y f oll o w-u p  p eri o d  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di s c o nti n u e d fr o m st u d y d uri n g s af et y f oll o w-u p  a n d r e a s o n  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di s c o nti n u e d fr o m st u d y d uri n g s af et y f oll o w-u p  d u e 
t o C O VI D -1 9  
o  
N u m b er of r a n d o mi z e d p arti ci p a nt s w h o di s c o nti n u e d fr o m st u d y d uri n g s af et y f oll o w-u p  d u e 
t o t h e U kr ai n e cri si s. 
* N o E n d of T r e at m e nt e C R F p a g e c o m pl et e d  
** A p arti ci p a nt i s c o n si d er e d t o h a v e c o m pl et e d t h e D B T P if h e/ s h e c o m pl et e d t h e E n d  of  T r e at m e nt V i sit a n d w a s 
a s si g n e d  t h e st at u s ‘ C o m pl et e d’.  
Reas o n f or recei vi n g n o st u d y i nter ve nti o n f or ra n d o mize d partici pa nts is retrie ve d fr o m t he 
S T E R M e C R F pa ge. T he reas o n ‘ di d n ot meet eli gi bilit y criteria’ will a p pl y t o  all partici pa nts f or 
w h o m reas o n i n S T E R M is e ntere d as ‘ Ot her’ wit h s pecificati o n be gi n ni n g wit h ‘ra n d o mize d i n 
err or’.  
Partici pa nt s’ i nf or mati o n o n i nf or me d c o nse nt, Scree ni n g  a n d ra n d o mizati o n will be liste d. 
Partici pa nt s disc o nti n ue d fr o m st u d y i nter ve nti o n or st u d y will be liste d wit h t heir reas o n f or 
wit h dra wal (fr o m st u d y i nter ve nti o n or st u d y).  
Partici pa nts wit h st u d y p artici pati o n i m pacte d b y C O VI D -1 9  will be liste d wit h a descri pti o n of 
t he differe nt e v e nts a n d i m pacts. T his c o ul d i ncl u de A Es (relate d t o C O VI D -1 9  or t o C O VI D -1 9  
vacci nes) , pr ot o c ol de viati o ns, st u d y i nter ve nti o n disc o nti n uati o n or st u d y disc o nti n uati o n, deat h, 
me dical hist or y, c o n c o mita nt me dicati o ns or pr oce d ures  (i n cl u di n g C O VI D -1 9  vacci nati o ns) . 
Partici pa nts i m pacte d b y C O VI D -1 9  d o n ot c orres p o n d necessaril y t o t he partici pa nts e x perie nci n g 
t he I C Es of ‘C O VI D -1 9  i nfecti o n’ a n d ‘C O VI D -1 9  vacci n ati o n’ defi ne d  i n efficac y a nal yses (s ee 
S ecti o n 1 4 ). De pe n di n g o n t he Me d D R A versi o n a vaila ble at t he ti me of a nal ysis, a p plica ble 
a d vice fr o m I C H M 1 P oi nts t o C o nsi der W or ki n g Gr o u p a n d Me d D R A Mai nte na nce a n d S u p p ort 
Ser vices Or ga niz ati o n  C o m m u nicati o n o n C or o na vir us or m ore rece nt official g ui da nce will be 
a p plie d t o c o di n g a n d re p orti n g C or o na vir us c o nce pts.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 3 /1 5 9  
 
 
 
Partici pa nts i m pacte d b y t he U krai ne crisis  will als o be liste d wit h a descri pti o n of t he differe nt 
e ve nts a n d i m pacts  t h at t he partici pa nt e x perie nce d. T his c o ul d i ncl u de st u d y i nter ve nti o n 
disc o nti n uati o n, st u d y dis c o nti n uati o n, site tra nsfer, pr ot oc ol de viati o ns, misse d d oses a n d misse d 
visits.  I n a d diti o n, a c orres p o n di n g s u m mar y st atistics ta ble will be pr o d uce d prese nti n g t h e 
n u m ber a n d perce nta ge of partici p a nts wit h st u d y i nter ve nti o n i nterr u pti o n, site tra nsfer d u e t o t he 
U krai ne crisis as w ell as n u m ber of misse d d oses , n u m ber of p artici pa nts wit h per ma ne nt treat me nt 
disc o nti n uati o n  a n d me dia n ti me t o treat me nt disc o nti n uati o n b y c o u ntr y. O nl y e v e nts wit h ca use 
attri b ute d t o t he U krai ne crisis will be i ncl u de d. T hese are i de ntifie d b y  t h e te xt “ B C P 2 2” a d de d 
as a prefi x t o e x pla nati o ns i n e C R F free -te xt fiel ds or t he pr ot oc ol d e viatio n descri pti o n, e x plai ne d 
i n t he st u d y s pecifi c e C R F c o m pleti o n g ui deli nes a n d t he M S 2 0 0 5 2 7 -0 0 8 0. 
_ P D M P. p df 
d oc u me nt.  
Partici pa nts i m pacte d b y t h e U krai n e crisis d o n ot c orres p o n d necess aril y t o t he partici pa nts 
e x perie nci n g t h e I C E of ‘ U krai ne crisis’ defi ne d i n efficac y a n al ys es (see Secti o n  1 4 ).  
A listi n g of sites n ot c o nti n u o usl y o perati o nal d ue t o t he U krai n e crisis will be pr o d uce d, det aili n g 
t he site I D, c o u ntr y, n u m ber of ra n d o mize d partici pa nts  at t he site, dat e t h e site was d ee me d n ot 
o perati o nal a n d reas o n.  
Listi n gs f or h o me visits a n d tel e p h o ne c o ntacts will be pr o d uce d.  
A ta ble base d o n scree ne d partici pa nts , descri bi n g t he n u m ber a n d perce nt of partici pa nts i n eac h 
a nal ysis s et b y i nter ve nti o n gr o u p, will be pr o d uce d.  
T he f oll o wi n g s u m maries will be pr o vi de d:  
•  N u m ber of partici pa nts i n eac h a nal ysis set b y re gi o n, c o u ntr y a n d site 
•  N u m ber of ra n d o mize d partici pa nts  (fr o m I W R S) b y re gi o n a n d c o u ntr y 
•  N u m ber of ra n d o mize d partici pa nts (I W R S) b y ra n d o mizati o n strata  
•  Cr oss ta b ulati o n: strat u m b y I W R S vers us strat u m b y e C R F/ v e n d or data  
•  Cr oss ta b ulati o n: partici pa nts ra n d o mize d ( T erifl u n o mi de /e v o br uti ni b ) vs. treate d 
(Terifl u n o mi de/e v o br uti ni b / n o) 
•  B y -visit n u m ber a n d perce nt a ge of partici p a nts wit h o n -site vers us at h o me vers us 
tele p h o ne visits /c o ntact 
•  N u m ber of ra n d o mize d partici pa nts b y a ge cate g or y. 
Re -scree ne d p artici pa nts will be prese nte d i n a listi n g. 
Dis p ositi o n of P R O MI S Q uesti o n n aire s 
T he dis p ositi o n of t he P R O MI S q uesti o n naires ( P R O MI S P F a n d Fati g ue) will be descri be d 
se parat el y at eac h sc he d ule d visit i n ter ms of c o m pleti o n a n d c o mplia nce rates as descri be d bel o w:  
•  N u m ber a n d perce nta ge of ra n d o mize d p artici pa nts w h o ret ur ne d t he q u esti o n naire at t he 
visit as e x pecte d (c o m plia nce rate usi n g all e x pect e d q uesti o n naires i n t he d e n o mi nat or)  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 4 /1 5 9  
 
 
 
•  N u m ber a n d perce nta ge of ra n d o mize d parti ci pa nts 
wit h at least o ne e v al ua ble 
q uesti o n naire at t he visit (c o m pleti o n rate usi n g all e x pecte d q uesti o n naires i n t he 
de n o mi nat or)  
•  P o p ulati o n -le vel s u m mar y ( per q uesti o n nair e ):  
o  %  C o m pli a nc e = 1 0 0  ×
n u m b e r  of  p a rti ci p a nt s  w h o  r et u r n e d  t h e P R O  q u e sti o n n ai r e
n u m b e r  of  p a rti ci p a nt s  f o r w h o m  a  P R O  q u e sti o n n ai r e  i s e x p e ct e d   
o  %  C o m pl eti o n = 1 0 0  ×
n u m b e r  of  p a rti ci p a nt s  wit h  at  l e a st o n e  e v al u a bl e  P R O  
n u m b e r  of  p a rti ci p a nt s  f o r w h o m  a  P R O  q u e sti o n n ai r e  i s e x p e ct e d   
A q uesti o n naire is c o nsi d ere d ret ur ne d if at least o n e ite m fr o m t he q u esti o n naire is a ns w ere d. A 
q uesti o n naire is c o nsi dere d e val ua bl e if P R O MI S T -sc ores ca n be d eri ve d. 
C o m plia nce a n d c o m pleti o n rates f or eac h P R O MI S q u esti o n naire  will b e pr o vi de d at Baseli ne  
a n d s u bse q ue nt sc h e d ule d visits b y st u d y i nter v e nti o n gr o u p.  
T he reas o ns f or n o n -c o m plia nce a n d n o n -c o m pleti o n will be d escri be d at Baseli ne  a n d s u bse q ue nt 
sc he d ule d visits b y st u d y i nter ve nti o n gr o u p as f oll o ws:  
•  N u m ber a n d perce nta ge of ra n d o mize d partici p a nts wit h missi n g  q uesti o n naire at a n 
e x pecte d visit b y reas o n  f or n o n-c o m plia nce :  
o  Deat h  
o  L ost t o f oll o w-u p  
o  Wit h dra wal b y s u bject  
o  Ot her reas o n f or st u d y ter mi nati o n  
•  N u m ber a n d perce nt a ge of ra n d o mize d p artici pa nts wit h missi n g q uesti o n n aire at t he visit 
b y reas o n w hile e x pecte d –  reas o ns f or n o n -c o m pl eti o n : 
o  S u bject felt t o o ill  
o  Cli nicia n or n urse felt t he s u bject was t o o ill  
o  S u bject u na ble t o c o me t o site  
o  Site was cl ose d  
o  I n v esti gat or decisi o n 
o  S u bject di d n ot c o me f or u n k n o w n reas o ns  
o  Ot her  
o  C O VI D -1 9  relate d ( yes/ n o/ u n k n o w n) 
o  U krai ne crisis relate d ( yes/ n o/ u n k n o w n)  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 5 /1 5 9  
 
 
 
1 0. 2  
Pr ot oc ol De vi ati o ns / E xcl usi o n fr o m A n al ysis P o p ul ati o ns   
1 0. 2. 1  
I m p ort a nt Pr ot oc ol De vi ati o ns  
I P Ds are P D e vs t h at mi g ht si g nifica ntl y affect t h e c o m plete ness, acc urac y, a n d/ or relia bilit y of t he 
st u d y d ata or t hat mi g ht si g nifica ntl y affect a parti ci pa nt's ri g hts, safet y, or well-bei n g . I m p orta nt 
pr ot oc ol de viati o ns are d efi ne d i n a se parate d oc u me nt ( latest versi o n of M S 2 0 0 5 2 7-0 0 8 0. 
_  
P D M P . p df). 
All de viati o ns will be i de ntifie d 
b y eit her site 
m o nit ori n g, 
m e dical re vie w pr ocesses or 
pr o gra m mi n g a n d c o nfir me d pri or t o or at t he D R M, w hic h will occ ur bef ore t he data base l oc k . 
cI P Ds are a s u bs et of i m p orta nt pr ot oc ol d e viati o ns t hat c o ul d i m pact t he ke y o bjecti ves of t he 
st u d y. A s mall n u m ber of partici pa nts ma y be e x cl u de d fr o m t he m F A S o n t he basis of cI P Ds 
relate d t o eli gi bilit y, ra n d o mizati o n err or or fail ure t o recei ve st u d y i nter ve nti o n , per I C H E 9 (i.e. 
cI P Ds wit h P D c o des e q ual t o P D E V 0 4 till P D E V 5 0, or P D E V 7 1 or P D E V 7 3  or P D E V 7 4  as 
defi ne d i n P D M P) . Partici pa nts fr o m sites i n U krai ne, R ussia n Fe derati o n a n d Belar u s lac ki n g data 
r o b ust ness t hr o u g h o ut t he st u d y ma y b e e x cl u de d fr o m m F A S o n t he basis of assess me nt of site 
o perati o nalit y . W he n e v al uati n g m F A S e x cl usi o n pri or t o D B L a n d u n bli n di n g, sites  fr o m all 
c o u ntries will be re vie we d . 
As descri be d i n Secti o n  8. 1 , t he pr ot oc ol all o ws t he fle xi bilit y t o e x cl u de S A F partici pa nts fr o m 
m S A F, if sites wit h lac k of safet y data r o b ust ness t hr o u g h o ut t he st u d y are i de ntifie d. At t he ti me 
of fi naliz ati o n of t his IA P, n o s uc h site ha s bee n i de ntifie d.  
T he o utc o me of t he D R M will d oc u me nt t he I P Ds (i ncl u di n g cI P Ds) as well as t h e fi n alizati o n of 
t he a nal ysis p o p ulati o ns i n a me m o. I P Ds will be d oc u me nte d i n C DI S C S D T M w het her i de ntifie d 
t hr o u g h sites m o nit ori n g, me dical re vie w a n d/ or pr o gra m mi n g. 
C O VI D -1 9  relat e d P De vs will i ncl u de all P De vs i ncl u di n g t he me nti o n “C O VI D -1 9 ” at t he 
be gi n ni n g of t heir descri pti o n.  
U krai ne crisis relate d P De vs will i ncl u de all P De vs i ncl u di n g t he m e nti o n “ B C P 2 2” at t he 
be gi n ni n g of t heir descri pti o n.  
T he f oll o wi n g s u m mar y ta bles a n d listi n gs of I P Ds/ P De vs will be pr o vi de d  o n all ra n d o mize d 
partici pa nts : 
•  Ta ble pr o vi di n g fre q ue nc y f or eac h t y pe of I P D/cI P D: 
o  C O VI D -1 9  relate d I P Ds will be s u m marize d as a s e parat e cate g or y wit hi n t he ta ble. 
o  U krai ne crisis relate d I P Ds will als o be s u m mari ze d as a se parate cat e g or y wit hi n 
t he ta ble. 
•  Ta ble pr o vi di n g fre q ue nc y f or eac h t y pe of mi n or C O VI D -1 9  relate d P De v  
•  Ta ble pr o vi di n g fr e q ue nc y f or eac h t y pe of mi n or U krai ne crisis relate d P De v  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 6 /1 5 9  
 
 
 
•  Listi n g of I P Ds  
•  A s pecific listi n g f or C O VI D -1 9  relate d I P Ds/ P De vs 
•  A s pecific listi n g f or U krai ne cris is rel ate d I P Ds/ P Devs  
1 0. 2. 2  
Re as o ns 
Le a di n g t o t he 
E xcl usi o n fr o m 
a n 
A n al ysis 
P o p ul ati o n   
A fre q ue nc y ta ble per reas o n of e x cl usi o n fr o m t he F A S , m F A S, S A F,  P K , P K S U B,  P D , a n d  
P D B T K O  p o p ulati o ns as well as a listi n g  will be pr o vi de d.  
1 1  
De m o gr a p hics a n d Ot her B aseli ne  C h ar acteristics   
De m o gra p hics a n d bas eli ne  c haract eristics will be s u m marize d o n F A S . T he y will be prese nt e d b y 
i nter ve nti o n gr o u p a n d o verall , f or eac h st u d y a n d o n p o ole d data. All liste d data will be o n F A S  
wit h a n a d diti o nal c ol u m n or fla g f or p artici pa nts i n m F A S . 
1 1. 1  
De m o gr a p hics   
•  De m o gra p hic c haracteristics :  
o  Se x: male, fe male  
o  Race: W hite, Blac k or Africa n A merica n, Asia n, A merica n I n dia n or Alas ka Nati ve, Nati ve 
Ha waiia n 
or 
Ot her 
Pacific 
Isla n der, 
M ulti ple 
( C o m bi nati o ns 
i ncl u de d 
as 
s u b-s u m marizati o n), N ot c ollecte d at t his site, Ot her  
o  Et h nicit y: His pa nic or Lati n o, N ot His pa nic  or Lati n o  
o  A ge ( years) at i nf or me d c o nse nt: s u m mar y st atistics  
o  A ge ( years) at i nf or me d c o nse nt cate g ories: <  4 0 , ≥ 4 0  
•  Ge o gra p hic R e gi o n: N ort h A merica, Wester n E ur o pe, Easter n E ur o pe, R O W  
•  E E A  
S pecificati o ns f or c o m p utati o n:  
•  A ge ( years):  
•  ( date of gi ve n i nfor me d c o nse nt - date of birt h + 1) / 3 6 5. 2 5  
•  I n case of missi n g da y f or date of birt h , b ut m o nt h a n d year a vaila ble :  
•  F or t he deri vati o n of a ge, t he da y of birt h will be set t o 1 a n d t he f or m ula a b o ve will be 
use d  
•  I n case of missi n g m o nt h f or at date of bir t h, b ut year a v aila ble:  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 7 /1 5 9  
 
 
 
•  F or t he d eri vati o n of a ge, t he da y a n d t he m o nt h of birt h will be set t o 1 a n d t he f or m ula 
a b o ve will be use d  
C o u ntr y will be utilize d t o  i de ntif y t he ge o gra p hi c re gi o n a n d E E A me m b ers hi p.  
Ge o gra p hic re gi o n a n d E E A me m bers hi p f or p artici pa nts fr o m U krai ne w h o m o ve d t o a n ot her 
c o u ntr y after t he start of t he U krai ne crisis are d eri ve d base d o n t he ori gi nal  c o u ntr y t h e partici pa nts 
were ra n d o mize d t o (i.e. U krai ne) . 
De m o gra p hic s u m mar y will als o be prese nt e d b y t he s u b gr o u p ‘ me m b ers hi p i n i nitial or sec o n d 
recr uit me nt c o h orts’ (i.e. i nitial c o h ort vs. sec o n d c o h ort). 
De m o gra p hic s u m mar y will als o be prese nte d b y t he s u b set ‘E D S S ≥ 2 at baseli ne ’. 
1 1. 2  
Me dic al Hist or y   
T he me dical hist or y will be s u m marize d fr o m t he “ Me dical Hist or y  Details ” e C R F p a ge, usi n g t he 
m ost rece nt Me d D R A v ersi o n  at ti me of data base l oc k , P T as e ve nt cat e g or y a n d S O C b o d y ter m 
as B o d y S yste m cate g o r y. T he 
Me d D R A versi o n use d will be i n dicate d i n f o ot n ote. Eac h 
partici pa nt will be c o u nte d o nl y o nce wit hi n eac h P T or S O C.  
Me dical hist or y will be dis pla ye d i n ter ms of fre q ue nc y t a bles  base d u p o n F A S : or dere d b y pri mar y 
S O C a n d P T i n al p ha betical or der.  All me dical hist or y dat a will be liste d.  
1 1. 3  
Ot her B aseli ne  C h ar acteristics   
1 1. 3. 1  
Dise ase Hist or y   
I nf or mati o n o n M S baseli ne  disease c haracteristics, base d o n d ata c ollecte d o n Da y 1 pre d ose a n d 
d uri n g Scree ni n g , will be s u m marize d b y st u d y i nter ve nti o n gr o u p. Descri pti ve statistics will be 
prese nte d f or:  
•  T y pe of M S, eit her R R M S or S P M S  wit h rela pses  
o  Ti me ( years) si nce c o n versi o n fr o m R R M S t o S P M S (f or partici pa nts wit h S P M S)  
•  Ti me ( years) si nce o nset of s y m pt o ms  
•  Ti me ( years) si nce i nitial M S dia g n osis date 
•  S yste m(s) affecte d b y first attac k  
•  N u m ber of rela pse(s) i n t he last 2  years  b ef ore Scree ni n g  
•  N u m b er of rela pse(s) fr o m last year  pri or t o r a n d o mizati o n  
•  F ulfills Mc D o nal d criteria 2 0 1 7  at Scree ni n g  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 8 /1 5 9  
 
 
 
•  Prese nce of  at least 1 T 1  G d +  lesi o n wit hi n 6  m o nt hs  pri or t o ra n d o mizati o n  
Ti me ( year s) si nce e ve nt  deri vati o n is descri be d i n Secti o n  9. 6 . 
D isease hist or y s u m mar y will als o be prese nte d b y t he s u bset ‘E D S S ≥ 2 at baseli ne ’. 
1 1. 3. 2  
B aseli ne  Lesi o n Me as ures, Ne ur ol o gic al Assess me nts , P R O s 
a n d Nf L C o nce ntr ati o n   
Baseli ne  ne ur ol o gic al me as ures b ase d o n M RI a n d P R O assess me nts will be s u m marize d b y st u d y 
i nter ve nti o n gr o u p. Descri pti ve statistics will be prese nte d f or: 
•  N u m ber of T 1 G d + lesi o ns  
•  V ol u me of T 1 G d + lesi o ns  (cc) 
•  N u m ber of T 2 lesi o ns  
•  V ol u me of T 2 lesi o ns  (cc) 
•  N or maliz e d Brai n V ol u m e  (c m3) 
•  N or maliz e d C ortical Gre y Matter V ol u me  (c m3) 
•  T hala mic V ol u me  (c m3) 
•  E D S S sc ore (fr o m v e n d or data ) 
•  Sc ores f or eac h of t he 7 F u ncti o nal S yste ms ( Vis ual, Brai nste m, P yra mi dal, Cere bellar, 
Se ns or y, B o w el/ Bla d der, Cere bral) a n d sc ore f or A m b ulati o n use d t o deri ve E D S S sc ore.  
•  P R O MI S P h ysic al F u ncti o ni n g sc ore  
•  P R O MI S Fati g ue s c ore  
•  E Q -5 D -5 L I n de x a n d V A S  
•  S F -3 6 v 2 n or maliz e d sc ore f or e ac h of t h e 8 healt h d o mai n scales  
•  S F -3 6 v 2 P C S  sc ore a n d M C S  sc ore  
•  T 2 5 -F W sc ore  
•  9 -H P T sc ore  
•  S D M T sc ore  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
4 9 /1 5 9  
 
 
 
•  Nf L c o nce ntrati o n  
1 1. 3. 3  
Hist or y of D M T   
I nf or mati o n o n D M T s, as c ollecte d o n t he “ HI S T O R Y O F DI S E A S E M O DI F YI N G D R U G S 
D E T AI L S”  e C R F pa ge , will be s u m marize d b y st u d y i nter v e nti o n. Descri pti ve statistics will be 
prese nte d f or:  
•  A n y D M T b ef ore st u d y e ntr y: y es/ no  
•  Pri or D M T t y pe: 
o  A u ba gi o (terifl u n o mi de)  
o  Re bif / A v o ne x / Ple gri d y (I F N beta -1 a)  
o  Betas er o n / Betafer o n / E xta via (I F N beta -1 b)  
o  C o pa x o ne / Glat o pa ( glatira mer acetate ) 
o  Gile n ya (fi n g oli m o d) / Ma yze nt (si p o ni m o d) / Ze p osia ( oza ni m o d) / P o n v or y ( p o n esi m o d )  
o  Le mtra da (ale mt uz u ma b)  
o  Ma ve ncla d (cla dri bi ne)  
o  N o va ntr o ne ( mit o x a ntr o ne)  
o  Ocre v us ( ocreliz u ma b) / Kesi m pta ( ofat u m u ma b) / Rit u x a n ( rit u xi ma b) / U blit u xi ma b 
(B RI U M VI ) 
o  T ysa bri ( nataliz u ma b)  
o  Tecfi dera ( Di met h yl f u m arate) / V u merit y ( dir o xi mel f u marate)  
o  I n v esti gati o nal dr u g 
o  Ot her  
•  Reas o n f or disc o nti n uati o n fr o m last pri or D M T : 
o  Lac k of Effic ac y 
o  A E  
o  Ot her  
•  N u m ber of pri or treat me nts ( 1, 2, ≥ 3)  
•  Pri or treat me nt d urati o n –  c o m bi ne d (s u m of all pri or D M T ); as a c o nti n u o us varia ble a n d 
cate g oricall y:  
o  ≤ 1 m o nt h  
o  > 1 - 6 m o nt hs  
o  > 6 - 1 2  m o nt hs  
o  > 1 2 - 2 4 m o nt hs  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 0 /1 5 9  
 
 
 
o  > 2 4 - 3 6 m o nt hs  
o  > 3 6 - 4 8 m o nt hs  
o  > 4 8 –  6 0 m o nt hs  
o  > 6 0 m o nt hs  
Alt h o u g h o nl y m o nt h a n d year f or D M T  st art a n d e n d dat es are c ollecte d, d urati o n will be 
calc ulate d as d escri b e d i n Secti o n  9. 6  ( defi niti o n of d urati o n) a n d c o n v erte d i nt o m o nt hs, as 
descri be d i n Secti o n  9. 7  (c o n versi o n fact ors), after t he f oll o wi n g i m p utati o ns are perf or me d:  
Start date:  
•  Da y will be i m p ute d as 1  
•  I n case t h e m o nt h is missi n g, th e m o nt h will be i m p ute d as J a n uar y  
E n d date:  
•  If t he m o nt h a n d year are pri or t o t h e m o nt h a n d year of first st u d y i nter ve nti o n, t he n da y 
will be i m p ute d as t he last da y of t h e m o nt h  
•  If t he m o nt h a n d year are e q ual t o t he m o nt h a n d year of first st u d y i nt er ve nti o n, t he n da y 
will be i m p ute d as t he first da y of t h e m o nt h  
•  I n case t h e m o nt h is missi n g: 
o  If t h e year is pri or t o t he year of t he first st u d y i nter ve nti o n, t he m o nt h will be 
i m p ute d as Dece m b er 
o  If t he year is the sa me as t he year of t he first st u d y i nter ve nti o n, t he m o nt h will be 
i m p ute d as t he m o nt h pri or t o t he m o nt h of first st u d y i nter ve nti o n. If t he m o nt h of 
t he first st u d y i nter ve nti o n is J a n uar y, t he date i m p ute d will be 0 1 J a n uar y 
If t he start or e n d dat e is c o m pletel y missi n g, n o i m p utati o n will be perf or me d a n d t he d urati o n 
will be missi n g.  
1 1. 3. 4  
Ot her Scree ni n g C h ar acteristics   
Ot her c haracteristics li ke viral ser ol o g y, Q ua nti F E R O N ® -T B test a n d Ferriti n a n d tra nsferri n 
sat urati o n will be liste d o nl y.  
1 1. 3. 5  
B aseli ne  S u bst a nce Use C h ar acteristics   
C o n versi o n fa ct ors f or e x p os ure will be as per s pecificati o ns i n Secti o n  9. 7 . 
Nic oti ne usa ge  will be s u m marize d b y st u d y i nter ve nti o n gr o u p as f oll o ws:  
•  Nic oti ne use stat us f or eac h e x p os ure t y p e ( ne v er / c urre nt  / f or mer user) 
•  E x p os ure t y pe (ci garettes / c he wi n g t o bacc o / nic oti ne g u m / e -ci garettes a n d va p or)  
•  E x p os ure s u m mar y statistics per wee k f or eac h e x p os ure t y p e  e x ce pt ci garettes  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 1 /1 5 9  
 
 
 
Ci garettes will be s u m mariz e d b y pac k s per da y. 
Alc o h ol usa ge  will be s u m marize d b y st u d y i nter ve nti o n gr o u p as f oll o ws:  
•  Alc o h ol use stat us  f or eac h e x p os ure t y p e ( yes / n o) 
•  E x p os ure t y pe ( beer / wi ne / s pirits)  
•  E x p os ure s u m mar y statistics per wee k f or eac h e x p os ure t y p e  
Caffei ne u s a ge will be s u m marize d b y st u d y i nter ve nti o n gr o u p as f oll o ws:  
•  Caffei ne use stat us ( n o use / occasi o nal use ( n ot dail y us e) / re g ular use ( 1 -2 c u p(s)/ da y) / 
re g ular use ( > 3 c u ps/ da y)) 
All nic oti ne, alc o h ol, a n d caffei ne usa ge data will be liste d as c olle cte d o n t he rele va nt e C R F pa ges.  
1 2  
Pre vi o us or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures   
1 2. 1  
Pre vi o us or C o nc o mit a nt Me dic ati o ns   
Base d 
o n “ R E L E V A N T 
P R E VI O U S 
M E DI C A TI O N S  Details ” 
& “ C O N C O MI T A N T 
M E DI C A TI O N S  D etails ” e C R F pa ges.  
F or t h e P A, pre vi o us a n d c o nc o mita nt me di cati o ns will be s u m marize d s e p aratel y b y i nter ve nti o n 
gr o u p o n S A F  f or eac h st u d y. Data fr o m t he o n -treat me nt peri o d i n cl u di n g S afet y F oll o w -u p data 
will be i ncl u de d.   
St atistic al a n al ysis  
T he A T C -2 n d le vel a n d P T will be ta b ulate d as gi ve n fr o m t he W H O-D D c urre nt versi o n. I n cas e 
m ulti ple A T Cs are assi g n e d t o a dr u g, o nl y A T C -2 n d le vel relate d t o t he i n dicati o n will be use d f or 
re p orti n g.  
T he n u m ber a n d pr o p orti o n of partici pa nt s wit h pre vi o us or c o nc o mita nt me dicati o ns will be 
se parat el y s u m marize d b y st u d y i nter ve nti o n gr o u p a n d will be prese nte d b y desce n di n g fre q ue n c y 
of A T C 2 n d le vel ter m a n d t he n b y desce n di n g fre q ue nc y of P T i n t he e v o br uti ni b  c ol u m n. If 
m ulti ple A T Cs/ P Ts ha ve t he sa me fre q ue nc y, t he y will be s orte d al p ha beticall y. T he W H O -D D 
versi o n use d will be i n dicate d i n f o ot n ote.  
Pre vi o us or c o nc o mita nt me dicati o ns will be als o liste d.  
Pre vi o us me dic ati o ns  are me dicati o ns, ot her t ha n st u d y i nter ve nti o ns, w hi c h eit her:  
•  starte d a n d st o p pe d bef ore first a d mi nistrati o n of a n y st u d y i nter ve nti o n (terifl u n o mi de or 
e v o br uti ni b).  
•  starte d pri or t o t he first a d mi nistrati o n of st u d y i nt er ve nti o n (terifl u n o mi de or e v o br uti ni b) a n d 
are ta ke n b y p artici pa nts o n or after t he first a d mi nistrati o n of st u d y i nt er ve nti o n d uri n g t he 
treat me nt peri o d (i n cl u di n g S afet y F oll o w -u p f or earl y disc o nti n ue d partici pa nts).  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 2 /1 5 9  
 
 
 
C o nc o mit a nt me dic ati o ns  are me dicati o ns, ot her t ha n st u d y i nter ve nti o ns, w hic h eit her:  
•  starte d o n or after t he first a d mi nistrati o n of a n y st u d y i nter ve nti o n i n t he D B T P .  
•  starte d pri or t o t he first a d mi nistrati o n of st u d y i nt erve nti o n i n t he D B T P  a n d are ta ke n b y 
partici pa nts o n or aft er t he first a d mi nistrati o n of st u d y i nter ve nti o n (i ncl u di n g 
Safet y  F oll o w -u p  f or earl y disc o nti n ue d partici pa nts). 
Partial dates will be ha n dle d as f oll o ws:  
•  F or pre vi o us me dicati o ns, i n cas e t he d ate v al ues will n ot all o w a me dicati o n t o b e 
u ne q ui v ocall y all ocate d t o pre vi o us me dicati o n, t he me dicati o n will be c o nsi dere d as 
pre vi o us me dicati o n.  
•  F or c o nc o mita nt me dicati o ns, i n case t he date val ues will n ot all o w a me dicati o n t o be 
u ne q ui v ocall y all ocate d t o c o nc o mita nt me dicati o n, t he me dicati o n will be c o nsi dere d as 
c o nc o mita nt me dicati o n.  
1 2. 2  
Pri or or C o nc urre nt Pr oce d ures   
Base d o n t he “ R E L E V A N T P R E VI O U S P R O C E D U R E S  Details ” & 
“ C O N C O MI T A N T 
P R O C E D U R E S  Details ” e C R F pa ge . Pri or a n d c o nc urre nt pr oce d ures will be s u m marize d t he 
sa me wa y as m e dicati o ns (see Secti o n  1 2. 1 ). 
N u m ber of partici pa nt s wit h pri or/c o nc urre nt pr oce d ures o v erall a n d b y S O C a n d P T will be 
s u m marize d b y i nter v e nti o n gr o u p, usi n g c urre nt v ersi o n of Me d D R A dicti o nar y.  S O C ter ms will 
be s or te d al p ha b eticall y. P Ts wit hi n eac h S O C will be s orte d b y des ce n di n g fre q u e nc y of t he 
e v o br uti ni b i nter ve nti o n gr o u p, a n d t he n al p ha beticall y if m ulti ple P Ts ha ve t he sa me fre q ue n c y .  
Pri or a n d c o nc urre nt pr o ce d ures will be als o liste d.  
1 2. 3  
C O VI D -1 9  V acci n ati o ns   
C O VI D -1 9  v acci n ati o ns will be i de ntifie d acc or di n g t o t he S D Gs s u b gr o u p “ Vacci nes f or 
C O VI D -1 9 ” a n d c orres p o n di n g S D G s u bcate g ori es of t he latest versi o n of t he W H O -D D. T h e 
su m mar y ta ble will i ncl u de c o u nts f or vacci nes t hat were gi ve n pri or t o first a d mi nistrati o n of a n y 
st u d y i nter ve nti o n as w ell as c o nc o mita nt. 
Partici pa nts e x perie nci n g t he I C E “C O VI D -1 9  vacci nati o n” will be i de ntifie d as t h ose  recei vi n g a 
C O VI D -1 9  vacci nati o n c o nc o mita nt wit h st u d y i nter ve nti o n.  
1 3  
St u d y T re at me nt : C o m pli a nce a n d E x p os ure   
E x p os ure, c u m ulati ve/calc ulate d t otal d ose a n d c o m plia nce will be s u m m arize d b y i nter venti o n 
gr o u p o n S A F. Dat a fr o m t he o n -treat me nt peri o d will be a nal yze d.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 3 /1 5 9  
 
 
 
1 3. 1  
E x p os ure C alc ul ati o n   
D ose i nterr u pti o ns/c ha n ges 
will 
n ot 
be 
c o nsi dere d i n 
e x p os ure 
calc ulati o n. 
D ose 
i nterr u pti o ns/c ha n ges wit h t he ass ociate d reas o n will o nl y b e liste d. 
Details descri bi n g st u d y t hera p y d osi n g a n d a d mi nistrati o n are pr o vi de d i n  Ta ble 7 . 
T a ble 7  
D os a ge a n d a d mi nistr ati o n   
Tr e at m e nt Gr o u p  
N u m b er of T a bl et s p er d a y  
N u m b er of T a b l et s p er d a y 
4 5  m g  
1 4 m g  
E v o br uti ni b  
Pl a c e b o  
T erifl u n o mi d e  
Pl a c e b o  
E v o br uti ni b 4 5 m g t wi c e 
d ail y  
2  
0  
0  
1  
T erifl u n o mi d e 1 4 m g o n c e  
d ail y  
0  
2  
1  
0  
Treat me nt d ur ati o n i n wee ks will be calc ulat e d acc or di n g t o t he f oll o wi n g f or m ula:  
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐸𝑣𝑜𝑏𝑟𝑢𝑡𝑖𝑛𝑖𝑏 𝑜𝑟 𝑇𝑒𝑟𝑖𝑓𝑙𝑢𝑛𝑜𝑚𝑖𝑑𝑒 ( w e e ks) = 
(𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡 𝑑𝑜𝑠𝑒 − 𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠𝑡 𝑑𝑜𝑠𝑒 +  1 )
7
 
First d ose refers t o t h e first a d mi nistrati o n of acti ve st u d y i nter ve nti o n i n t h e o n -tr eat me nt peri o d. 
Last d ose refers t o t he last a d mi nistrati o n of acti ve st u d y i nter ve nti o n i n t he o n -treat me nt peri o d. 
B ot h dates of first a n d last d ose will be retrie ve d fr o m S D T M E X d o mai n  (“ E v o br uti ni b / Place b o 
A d mi nistrati o n Details” a n d “ Terifl u n o mi de  / Place b o A d mi nistrati o n Details” e C R F pa ge s). If 
t he e n d date of t he l ast d ose i n E X is missi n g f or partici pa nts w h o disc o nti n ue d treat me nt 
pre mat urel y, t he date of last d ose will be re place d b y t he e n d of treat me nt date rec or de d i n T T E R M  
e C R F pa ge or E n d  of  S t u d y dat e rec or de d i n S T E R M e C R F pa ge.  
Treat me nt d urati o n will be prese nte d b y s u m mar y statistics a n d acc or di n g t o t he f oll o wi n g 
cate g ories:  
•  ≤ 1 wee k  
•   > 1 t o 1 2  wee ks  
•   > 1 2 t o 2 4 wee ks  
•   > 2 4 t o 3 6 wee ks  
•   > 3 6 t o 4 8 wee ks  
•  > 4 8 t o 6 0 wee ks  
•  > 6 0 t o 7 2 wee ks  
•  > 7 2 t o 8 4  wee ks  
•  > 8 4 t o 9 6  wee ks  
•  > 9 6  t o 1 0 8  wee ks  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 4 /1 5 9  
 
 
 
•  > 1 0 8  t o 1 2 0  wee ks  
•  > 1 2 0 t o 1 3 2 wee ks  
•  >  1 3 2  t o 1 4 4  wee ks  
•  > 1 4 4 t o 1 5 6 wee ks  
•  > 1 5 6 wee ks  
T he e x pecte d t otal d ose ( m g) per partici pa nt  f or t h e o n -treat me nt peri o d will als o be s u m marize d 
f or t he i nter ve nti o n gr o u ps, base d o n t he act ual st u d y i nter ve nti o n t he partici pa nt  recei ves. T he 
e x pecte d t otal d ose is defi ne d acc or di n g t o t he f oll o wi n g f or m ula:  
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓𝐸𝑣𝑜 𝑏𝑟𝑢𝑡 𝑖𝑛𝑖 𝑏𝑜𝑟𝑇𝑒𝑟𝑖𝑓𝑙𝑢𝑛 𝑜𝑚 𝑖𝑑𝑒𝑑𝑎𝑡𝑒𝑜𝑓𝑙𝑎𝑠𝑡 (𝑑𝑜) = 𝑠𝑒𝑑𝑎𝑡𝑒𝑜𝑓𝑓 𝑖𝑟𝑠𝑡𝑑𝑜𝑠𝑒 (𝑑𝑎𝑦𝑠) × 𝐷𝑎𝑖𝑙𝑦 𝑑𝑜𝑠𝑒 
w here t he d ail y d os e f or eac h i nter ve nti o n  is pr o vi de d i n Ta ble 7 . 
T he c u m ulati ve act ual d ose ( m g ) per partici pa nt  f or t he o n -treat me nt peri o d will als o be 
s u m marize d f or t he acti ve i nter ve nti o n gr o u ps. T h e c u m ulati ve act ual d ose is defi ne d acc or di n g t o 
t he f oll o wi n g f or m ula: 
𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑎𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒 𝑓𝑜𝑟 𝐸𝑣𝑜𝑏𝑟𝑢𝑡𝑖𝑛𝑖𝑏 𝑜𝑟 𝑇𝑒𝑟𝑖𝑓𝑙𝑢𝑛𝑜𝑚𝑖𝑑𝑒 (𝑚𝑔)
= 𝑆𝑢𝑚 𝑜𝑓 𝑑𝑜𝑠𝑒 𝑝𝑒𝑟 𝑑𝑎𝑦 𝑓𝑜𝑟 𝐸𝑣𝑜𝑏𝑟𝑢𝑡𝑖𝑛𝑖𝑏 𝑜𝑟 𝑇𝑒𝑟𝑖𝑓𝑙𝑢𝑛𝑜𝑚𝑖𝑑𝑒 𝑟𝑒𝑐𝑜𝑟𝑑𝑠   
w here t h e d ose  per da y  is deri ve d i n t he S D T M E X d o mai n, fr o m t he n u m ber of ta blets i n geste d 
per da y, rec or de d o n t he “ E v o br uti ni b / Place b o A d mi nistrati o n Details” a n d “Terifl u n o mi de  / 
Place b o A d mi nistrati o n Details” e C R F pa ges, a n d t he d osa ge i nf or mati o n i n Ta ble 7 .   
St u d y dr u g a d mi nistrati o ns will be liste d b y i nter ve nti o n gr o u p, a n d parti ci pa nt , wit h start/e n d 
dates of a d mi nistrati o n, a n d reas o n f or d ose c h a n ge or n o d ose (if a p plica bl e).  
1 3. 2  
C o m pli a nce C alc ul ati o n   
F or t he o n -treat me nt peri o d, c o m plia nce wit h st u d y i nt er ve nti o n is defi ne d as t he c u m ulati ve act ual 
d ose d uri n g a peri o d di vi de d b y t he e x pecte d t otal d ose f or  t hat peri o d, m ulti plie d b y 1 0 0 t o yiel d 
a perce nta ge, i. e.:  
C o m pli a nc e = 1 0 0 × (  𝐶𝑢𝑚𝑢𝑙𝑎𝑡𝑖𝑣𝑒 𝑎𝑐𝑡𝑢𝑎𝑙 𝑑𝑜𝑠𝑒 (𝑚𝑔)
𝐸𝑥𝑝𝑒𝑐𝑡𝑒𝑑 𝑡𝑜𝑡𝑎𝑙 𝑑𝑜𝑠𝑒 (𝑚𝑔)
)  
C o m plia nce wit h st u d y i nter ve nti o n will be ta b ulate d b y i nter ve nti o n gr o u p fr o m first i nta ke t o 
last i nta ke d uri n g t h e  o n -treat me nt peri o d.  
C o m plia nce wit h st u d y i nter ve nti o n will als o be prese nte d i nt o cate g ories as f oll o ws:  
•  < 8 0 %  (I ns ufficie nt c o m plia nce) 
•  ≥ 8 0 % t o ≤ 1 0 0 %  
•  >  1 0 0 % t o ≤ 1 1 0 %  
•  > 1 1 0 %  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 5 /1 5 9  
 
 
 
F or eac h a n al ysis, t he  f oll o wi n g listi n gs will be pr o vi de d: 
•  listi n g of kit n u m bers wit h date of dis pe nse, dat e of ret ur n, a m o u nt dis pe nse d a n d a m o u nt 
ret ur ne d. T his listi n g will be re peate d base d o n partici pa nts w h o recei v e d acti ve treat me nt or 
place b o  t hat t he y w ere n ot ra n d o mize d t o, or recei ve d b ot h acti ve treat me nts. 
•  listi n g of start/e n d dates wit h d ose ( m g) per da y , reas o ns f or misse d/ m o difie d d ose 
•  listi n g wit h e x p os ure ti me, c u m ulati ve d ose (t otal a n d act ual), a n d c o m plia nce 
1 4  
Effic ac y A n al yses   
T his secti o n i ncl u de s s pecificati o ns f or a nal yzi n g efficac y e n d p oi nts.  
D ata ha n dli n g f or effi cac y e n d p oi nts is descri be d i n Ta ble 8  f or t he I A f or B S S R  a n d t he P A.  
T a ble 8  
D at a H a n dli n g f or Effic ac y A n al ysis   
A n al y si s  
A n al y si s 
s et s  
P eri o d c o v er e d  
Tr e at m e nt gr o u p s  
I A f or 
B S S R  
F A S  
1 2 -w e e k C D P d at a fr o m t h e tr e at m e nt 
p eri o d ( S af et y  F oll o w -u p i n cl u d e d) 
t hr o u g h d at a c ut off  f or B S S R  
N ot a p pli c a bl e ( Bli n d e d)  
P A  
F A S/ m F A S  
All d at a fr o m t h e D B T P  
( S af et y F oll o w -u p i n cl u d e d)  u ntil t h e P A 
c ut off  d at e   
E v o br uti ni b 4 5 m g t wi c e d ail y 
T erifl u n o mi d e  1 4 m g  o n c e  d ai l y 
T he sec o n d ar y o bje cti ves base d o n disa bilit y pr o gressi o n a n d disa bilit y i m pr o ve me nt, a n d p atie nt 
re p orte d s y m pt o ms a n d f u ncti o nal stat us will be e val uate d base d o n p o ole d data fr o m st u d y 
M S 2 0 0 5 2 7 _ 0 0 8 0 a n d st u d y 
. A nal ysis b ase d o n p o ol e d data will als o b e 
prese nte d f or eac h st u d y.  
T he ra n d o mizati o n strata use d i n efficac y a n al ys es are t h ose bas e d o n ve n d or data f or E D S S a n d 
e C R F f or re gi o n . 
F urt her d etails re gar di n g i m p utati o ns a n d statistical met h o ds will be i ncl u de d i n t he Statistical 
Met h o d ol o g y d oc u me nt ( A p pe n di x  1 8. 9 ). 
1 4. 1  
Pri m ar y Esti m a n d : A n n u alize d Rel a pse R ate u p t o 1 5 6  W ee ks   
T his secti o n pr o vi des detaile d i nf or mati o n relate d t o t he a nal ysis of t he pri mar y efficac y esti ma n d, 
i ncl u di n g pri mar y, s e nsiti vit y, a n d s u b gr o u p a n al yses.  
1 4. 1. 1  
Pri m ar y O bjecti ve: Deri v ati o n a n d A n al ysis of A R R u p t o 1 5 6  
Wee ks   
T his secti o n  details t he 5 attri b utes of t he pri mar y efficac y esti ma n d. 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 6 /1 5 9  
 
 
 
T he 5  esti ma n d attri b utes  acc or di n g t o  I C H E 9( R 1) are: 
•  E n d p oi nt : A R R base d o n q ualifie d rela ps es u p t o 1 5 6 wee ks. 
T he patie n t-le v el data re q uire d t o a d dress t he cli nical q uesti o n are: ( 1) n u m ber of q ualifie d 
rela pse e ve nts, as a dj u dicate d b y t he E A C, o bser ve d u p t o Wee k 1 5 6 a n d ( 2) t he ti me (i n  
years) o v er w hic h t h os e e ve nts were o bs er ve d u p t o Wee k  1 5 6.  
•  Tre at me nt c o n diti o n of i nterest : E v o br uti ni b 4 5 m g t wice d ail y f or u p t o 1 5 6 wee ks; 
alter nati ve treat me nt c o n diti o n t o w hic h c o m p aris o n will be m a de: t erifl u n o mi de 1 4 m g 
o nce dail y f or u p t o 1 5 6 wee ks.  
•  P o p ul ati o n : Partici pa nts wit h R M S as defi ne d b y i ncl usi o n/e xcl usi o n criteria. 
•  Str ate gies use d t o a d dress I C Es:  
o  Treat me nt disc o nti n uati o n: Treat me nt P olic y str ate g y.  
o  Deat h attri b uta ble t o M S or treat me nt: C o m p osite varia ble strat e g y  
o  Deat h u nattri b uta ble t o M S or treat me nt: W hile ali ve strate g y  
o  U krai ne crisis: H y p ot heti cal  strate g y 
o  C O VI D -1 9  i nfecti o n, C O VI D -1 9  vacci nati o n a n d e mer ge nc y 
u n bli n di n g: 
Treat me nt P olic y strate g y.  
•  P o p ul ati o n -le vel s u m m ar y f or t he e n d p oi nt, pr o vi di n g a basis f or assessi n g st u d y 
i nter ve nti o n effect: Rela pse rate rati o, base d o n a N B m o del f or q ualifie d rela pse c o u nt, 
wit h ter ms f or i nter ve nti o n gr o u p a n d ra n d o mi zati o n strata, wit h offset e q ual t o l o g 
f oll o w-u p  ti me (i n years) o ver w hic h t h e q ualifie d rela pses e x perie n ce d b y a partici pa nt are 
o bser ve d.  
T he N B re gressi o n will be c o m p ute d wit h t he S A S ® G E N M O D pr oce d ure, usi n g t he 
dist = N B o pti o n i n t he M O D E L stat e me nt.  If t he m o del fails t o c o n ver ge, t he f oll o wi n g 
ste ps will be a p plie d se q ue ntiall y u ntil t he c o n ver ge n ce is reac h e d : use of a m ore efficie nt 
al g orit h m i n t he G LI M MI X pr oce d ure, re m o val of t he ter m f or t he re gi o n ra n d o mizati o n 
strat u m, re m o val of t he ter m f or t he b aseli ne E D S S  ra n d o mizati o n strat u m, use of t he 
P oiss o n m o del  wit h t he r o b ust varia nce esti mat i o n, see Ta ble 9  f or det ails. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 7 /1 5 9  
 
 
 
T a ble 9   
Det ails of S te ps t o be Ap plie d W he n t he P ri m a r y M o del F ails t o 
C o n ver ge   
(0 )* 
P R O C G E N M O D  
M o d el i n cl u d e s t er m s f or tr e at m e nt a n d f or b ot h r e gi o n a n d b a s eli n e E D S S 
ra n d o mi z ati o n str at a / di st = N B  
(1 ) 
P R O C G LI M MI X  
M o d el i n cl u d e s t er m s f or tr e at m e nt a n d f or b ot h r e gi o n a n d b a s eli n e E D S S 
ra n d o mi z ati o n str at a / di st = N B  
(2 ) 
P R O C G LI M MI X  
M o d el i n cl u d e s t er m s f or tr e at m e nt a n d t h e b a s eli n e E D S S r a n d o mi z ati o n 
str at u m / di st = N B  
(3 ) 
P R O C G LI M MI X  
M o d el i n cl u d e s o nl y  t h e t er m f or tr e at m e nt / di st = N B 
(4 ) 
P R O C G LI M MI X  
M o d el i n cl u d e s o nl y t h e t er m f or tr e at m e nt / di st = P OI S S O N / o pti o n 
‘ e m piri c al’ i n ‘ P R O C G LI M MI X’ st at e m e nt 
* I niti al m o d el 
Missi n g D at a H a n dli n g  
F or partici pa nts w h o ha v e n ot bee n treat e d a n d f oll o we d u ntil t he pla n ne d e n d of treat me nt  (i.e. 
P A c ut off or 1 5 6  w ee ks  p ost ra n d o mizati o n  ( Secti o n 9. 1 3 ), w hic he ver occ urs first) , t he missi n g 
data will be ass u me d t o be M A R; treat me nt disc o nti n uers will be ass u me d t o e x perie nce rela ps e 
t hr o u g h t h e pla n n e d e n d of tr eat me nt at t he sa me rate as partici pa nts wit h D B T P tr eat me nt 
o n g oi n g/ c o m pleted  wit hi n t he sa me i nter ve nti o n gr o u p a n d strat u m.  
H a n dli n g of I CEs  
I n acc or da nce wit h Treat me nt P olic y strat e g y, f or partici pa nts e x perienci n g t he  I C E pre m at ure 
treat me nt disc o ntin uati o n, a n y q u alifie d rela ps es occ urri n g t hr o u g h Safet y  F oll o w -u p will be 
i ncl u de d i n t he a nal ysis u p t o t he pla n ne d e n d of tr eat me nt (i.e. P A c ut off d ate or 1 5 6 wee ks p ost 
ra n d o mizati o n, w hic he ver occ urs first). If a partici pa nt is a treat me nt c o m pleter, i.e. d oes n ot 
e x perie nce t he I C E of pre mat ure treat me nt disc o nti n uati o n, t he n t he Treat me nt P olic y strate g y f or 
ha n dli n g t his I C E d oes n ot a p pl y, a n d o nl y d ata c ollecte d o n -tr eat me nt (i.e. n o data fr o m 
Safet y  F oll o w -u p  V isit) will be i ncl u de d i n t he a n al ysis (see Secti o n 9. 1 0 ). 
I n acc or da n ce wit h t he C o m p osite Varia ble str ate g y, f or partici pa nts e x perie nci n g t h e I C E deat h 
attri b uta ble t o M S or treat me nt, t he deat h will be c o u nte d as a q ualifie d rela pse. I n acc or da nce wit h 
t he W hile Ali ve strate g y, f or p artici pa nts e x perie nci n g t h e I C E d eat h u nattri b uta ble t o M S or 
treat me nt, t he deat h will n ot be c o u nte d as a q u alifie d rela ps e.  
Deat hs wit h pri mar y reas o n e ntere d as ‘ pr o gressi ve disease a n d/ or disease relate d c o n diti o n’ i n t he 
e C R F Deat h F or m will be c o nsi dere d as attri b ut a ble t o M S. Deat hs  wit h pri mar y reas o n set t o 
‘e ve nt relate d t o st u d y tr eat me nt’ will b e c o nsi d ere d as attri b uta ble t o st u d y i nter ve nti o n. Ot her 
deat hs (i.e. pri mar y reas o n e q ual t o ‘e ve nt u nrelate d t o st u d y treat me nt’ a n d ‘ u n k n o w n’) will b e 
c o nsi dere d as u nattri b uta ble t o M S or treat me nt.  
P artici pa nts at sites n ot f ull y o perati o nal  d ue t o t he U krai ne crisis , p ost start of U krai ne crisis  will 
be c o nsi dere d t o ha ve e x perie nce d t he I C E ‘ U krai ne crisis’.  T his I C E will be h a n dle d usi n g t h e 
H y p ot hetic al strate g y, w here t he h y p ot hetical sce nari o e n visa ge d is o ne i n w hic h t he crisis ha d 
ne ver ha p p e ne d. T he d ata fr o m s uc h partici pa nts will be ce ns ore d at t he ti me at w hic h t he site l os t 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 8 /1 5 9  
 
 
 
f ull y o perati o nal stat us. Ce ns ori n g at t he e n d of t he pre -crisis peri o d is n o n -i nf or mati ve f or t he 
o utc o me of i nterest (rela pse).  
Sit es n ot f ull y o perati o nal  p ost start of t he crisis al o n g wit h c orres p o n di n g ce ns ori n g dat e will be 
i de ntifie d bef ore D B L a n d liste d i n a n I A P A p pe n di x w here t he l o n git u di nal a nal ysis of site stat us 
is d oc u me nte d. 
I n acc or da n ce wit h Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C Es ‘C O VI D -1 9  
i nfecti o n’, ‘C O VI D -1 9  v acci nati o n ’, or ‘e mer ge n c y u n bli n di n g ’, t he occ urre nce of t hes e I C Es is 
c o nsi dere d irrele v a nt i n t he pri mar y a n al ysis of q ualifie d rela ps e.  
I nfere nti al a n al ysis 
T he p o p ulati o n -le vel s u m mar y c o m p ari n g t he i nter ve nti o n gr o u ps is q ualifie d rela pse rate rati o, 
base d o n a N B m o del f or q ualifie d rela pse c o u nt  o v er 1 5 6 wee ks , wit h ter ms f or i nter ve nti o n gr o u p 
a n d c o variat es defi ne d b y  ra n d o mizati o n strata, wit h offset e q ual t o l o g f oll o w-u p  ti me f or a 
partici pa nt  d uri n g t h e 1 5 6 wee ks p ost ra n d o mizati o n . T he a dj uste d q ualifie d rel a pse rate rati o 
c o m pari n g e v o br uti ni b t o terifl u n o mi de esti mate d fr o m t he N B m o del, 9 5 % 2 -si de d CI, a n d 
1 -si de d p-val ue will be re p orte d, t o get h er wit h a dj uste d A R R  f or eac h i nter ve nti o n gr o u p a n d 
ass ociate d 9 5 % 2 -si de d CI. I n a d diti o n, t he A R R rati o will be e x presse d as perce nta ge re d ucti o n 
relati ve t o terifl u n o mi de. T he a nal ysis of A R R will be base d o n F A S dat a fr o m a si n gle st u d y 
( 0 0 8 0 or  
). 
T he f oll o w -u p ti me , i n years, is defi n e d as f oll o ws: 
•  F or partici pa nts wit h treat me nt o n g oi n g at ti me of P A c ut off date:  
(𝐷𝑢𝑟𝑎 𝑡𝑖 𝑜𝑛𝑜𝑓 𝐸𝑣𝑜𝑏𝑟𝑢𝑡 𝑖𝑛𝑖𝑏𝑜𝑟𝑇𝑒𝑟𝑖 𝑓𝑙𝑢𝑛𝑜𝑚 𝑖ℎ𝑑 𝑒𝑑 𝑎𝑡𝑒𝑜𝑓𝑙 𝑎𝑠𝑡𝑑 −𝑜𝑠𝑒𝑑𝑎𝑡𝑒𝑜𝑓𝑓𝑖𝑟𝑠 𝑡𝑑𝑜𝑠) + 1
3 6 5 .2 5
 
•  F or partici pa nts w h o c o m plete d 1 5 6 wee ks of treat me nt:   
(𝑒𝑑𝑎 𝑦𝑠 𝐷𝑎𝑖𝑙𝑦𝑑𝑜𝑠𝑒 𝐶𝑢𝑚𝑢 −𝑙𝑎𝑡𝑖𝑣𝑒𝑎𝑐𝑡𝑢𝑎𝑙𝑑 𝑜𝑠𝑒𝑓) + 1
3 6 5 .2 5
 
•  F or earl y treat me nt disc o nti n uers:  
(𝑜𝑟𝐸𝑣 𝑜𝑏 𝑟𝑢𝑡𝑖 𝑛𝑖𝑏𝑜𝑟𝑇𝑒 𝑟𝑖𝑓𝑙𝑢𝑛𝑜𝑚𝑖𝑑∗  − 𝑒𝑚𝑔𝑆𝑢𝑚𝑜𝑓𝑑𝑜𝑠𝑒𝑝 𝑒𝑟𝑑𝑎) + 1
3 6 5 .2 5
 
•  F or partici pa nts wit h n o p ost ra n d o mizati o n rela pse assess me nt bef ore t he P A c ut off date: 
0. 1/ 3 6 5. 2 5  
*  wit hi n 1 5 6  wee ks p ost ra n d o mizati o n or bef ore t he P A c ut off dat e,  w hic h e ver occ urs first . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
5 9 /1 5 9  
 
 
 
T he M A R ass u m pti o n u n der pi ns t he rate rati o esti mat or i m ple me nte d b y t h e N B m o del t hat us es 
o bser ve d q u alifie d rela ps e e ve nts a n d o bser ve d f oll o w-u p  ti me f or eac h partici pa nt, re gar dless of 
treat me nt c o m plete d/disc o nti n ue d/ o n g oi n g stat us. 
T he c o variat es de fi ne d b y ra n d o mizati o n strata are re gi o n ( 4 le vels: N ort h A merica, 
Wester n 
E ur o pe, E aster n E ur o pe, R O W) a n d baseli ne  ( Da y 1) E D S S (2  le vels: < 4. 0, ≥ 4. 0 ). T he N B m o del 
ass u mes a c o m m o n dis persi o n para meter f or all partici pa nts, i n de pe n de nt of i nter ve nti o n  gr o u p or 
baseli ne  c o variat es. T he a dj uste d q ualifie d rela ps e rate rati o esti mate is gi ve n b y e x p o ne ntiati o n 
of t he esti mate f or t he treat me nt c oefficie nt fr o m t he N B m o del. I n t h e P A, o nl y o bs er ve d e ve nts 
a n d o bser vati o n ti me will be i ncl u de d i n t he a n al y sis; t here will be n o i m p utati o n of e ve nts f or 
partici pa nts disc o nti n ui n g st u d y earl y.  
Descri pti ve a n al ysis  
Descri pti ve statistics of t he rela pses will be pr o vi de d b y st u d y i nter ve nti o n gr o u p o n F A S, 
i ncl u di n g t he n u m ber a n d perce nta ge of rela ps es re q uiri n g h os pitalizati o n, n u m ber a n d perce nta ge 
of rela pses treate d wit h c ortic oster oi ds (as re p ort e d o n t he R E L A P S E D T e C R F pa ge) o ut of t he 
t otal n u m ber of rela ps es, a n d t his will be re peat e d o ut of t he t otal n u m ber of q ualifie d rel a pses. 
Des cri pti ve st atistics f or A R R u p t o 1 5 6 wee ks will be pr o vi de d b y st u d y i nter ve nti o n gr o u p  o n 
F A S . N o ce ns ori n g will be a p plie d f or descri pti v e statistics. A t t he treat me nt-gr o u p -le vel, t otal 
n u m ber of q ualifie d rela pses, t otal n u m ber of rela pses, f oll o w-u p  (i n partici pa n t-years), a n d 
u na dj uste d A R R (as n u m ber of all rela pses di vi de d b y p ers o n -ti me (i n years)), wit h 9 5 % 2-si de d 
CI (calc ulate d usi n g t he Gar w o o d met h o d), will  be re p orte d. I n a d diti o n, descri pti ve statistics of 
n u m ber of partici pa n t-le vel q ualifie d rela pses a n d partici pa n t-le vel A R R ( n u m ber of q ualifie d 
rela pses e x perie nce d b y a partici pa nt  u p t o 1 5 6 wee k s, di vi de d b y t he f oll o w-u p  e x perie nce d b y a 
partici pa nt  u p t o 1 5 6 w ee k s) will be s u m marize d f or eac h st u d y i nter ve nti o n gr o u p, i n t er ms of 
mea n, S D, me dia n, Q 1, Q 3, mi n, a n d ma x.  
N u m ber a n d p erce nta ges of partici pa nts e x perie n ci n g i nterc urre nt e ve nts will als o be prese nte d.  
A R R u p t o 1 5 6 wee ks will be prese nte d as a b y -tr eat me nt gr o u p bar c h art, wit h a vertical li ne 
se g me nt f or eac h b ar re prese nti n g 9 5 % 2-si de d CI, a n d wit h t h e p-v al u e f or t he c o m paris o n 
bet wee n ev o br uti ni b a n d terifl u n o mi de  ( base d o n N B m o del) dis pla ye d a b o ve t he bar p air .  
1 4. 1. 2  
Se nsiti vit y A n al yses of A R R   
T he f oll o wi n g se nsiti vit y a nal ys es f or A R R u p t o 1 5 6  wee ks  are pla n ne d , wit h t he sa me ha n dli n g 
of I C Es as i n t he pri mar y a nal ysis , u nless ot her wis e s pecifie d : 
1.  A nal ysis t o e val uate t he p ote ntial i nfl ue nce of i nf or mati ve treat me nt disc o nti n uati o n acc or di n g 
t o disc o nti n uati o n reas o n.  
T his se nsiti vit y a nal ysis will use t he sa me  N B m o del use d  i n t he pri mar y a nal ysis a n d re p ort 
t he sa me i nfere ntial res ults. I n a d ditio n, a f orest pl ot will prese nt t he q ualifie d rela pse rate rati o , 
9 5 % CI a n d p-val u e f or eac h delta. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 0 /1 5 9  
 
 
 
T he f oll o wi n g a p plies t o partici pa nts i n t he e v o br uti ni b i nter ve nti o n gr o u p. If a p artici pa nt’s 
disc o nti n uati o n is u nrelate d t o treat me nt ( i.e. u nrelate d t o  efficac y or safet y iss ues), t he 
partici pa nt’s rela pse c o u nt will be m ulti pl y i m p ute d usi n g A R R i n t he c o m parat or gr o u p  
(a dj uste d f or t he partici pa nt’s strat u m) base d o n C R MI met h o d , f or t he i nter val bet wee n 
disc o nti n uati o n a n d pla n ne d e n d of treat me nt ( i.e. P A c ut off or 1 5 6 wee ks p ost ra n d o mizati o n, 
w hic he ver occ urs first) . If a partici pa nt’s disc o nti n uati o n is relate d t o treat m e nt, rela ps e c o u nt 
will be m ulti pl y i m p ute d at a rate hi g her t ha n A R R i n t he c o m parat or gr o u p  (a dj uste d f or t he 
partici pa nt’s strat u m) , f or t he i nter val bet w ee n dis c o nti n uati o n a n d pla n ne d e n d of treat me nt . 
T he c o m parat or  rate aft er wit h dra wal will be m ulti plie d b y delta, ra n gi n g fr o m 1 t o 3. 1 
( ~tri pli n g of rela pse rat e) i n ste ps of 0. 3. F or p arti ci pa nts wit h disc o nti n uati o n of tr eat me nt (all 
reas o ns) i n t he terifl u n o mi de gr o u p, t h e rela ps e c o u nt will be m ulti pl y i m p ute d u n der t he M A R 
ass u m pti o n.   
MI met h o ds f or c o u nt d ata will be  a p plie d f oll o wi n g t he a p pr oac h fr o m K ee ne 2 0 1 4 , s ee 
A p pe n di x  1 8. 9  f or details. 
Treat me nt ter mi nati o n wit h pri mar y reas o n e ntere d as ‘a d v erse e ve nt’, ‘lac k of efficac y’ a n d 
‘ deat h’ i n t he e C R F T T E R M for m will be c o nsi dere d as relate d t o treat me nt. Ot her treat me nt 
ter mi nati o ns (i.e. pri mar y reas o n e q ual t o ‘l ost t o f oll o w-u p ’, ‘ pr ot oc ol n o n-c o m plia nce’, 
‘ wit h dra wal b y s u bject’ a n d ‘ ot her’) will be c o nsi dere d as u nrelate d t o treat me nt. 
2.  A nal ysis i n w hic h earl y treat me nt disc o nti n uati o n is i m p ute d as q ualifie d rela pse.  
T his se nsiti vit y a n al ysis will use t he s a me N B m o del use d i n t he pri mar y a nal ysis of A R R u p 
t o 1 5 6 wee ks a n d re p ort t he sa me i nfere ntial res ults .  
If a partici pa nt disc o nti n ue d treat me nt earl y d uri n g t he o n -treat me nt p eri o d wit h o ut q ualifie d 
rela pse i n t he 3 0 da ys pri or t o disc o nti n uati o n, t he partici pa nt is ass u me d t o ha ve a q ualifie d 
rela pse e ve nt at t he dat e of disc o nti n uati o n. 
3.  A nal ysis t o e v al uate t he p ote ntial i m pact of m o del miss pecificati o n . 
T his se nsiti vit y a nal ysis will a d d t he f oll o wi n g c o variates t o t he N B m o d el: n u m ber of rela pses 
i n pre vi o us 2 years bef ore Scree ni n g , prese nce/a bse nce of T 1 G d + lesi o ns wit hi n 6  m o nt hs 
pri or t o ra n d o mizati o n, pri or D M T  ( y/ n), a n d a ge, as defi ne d i n Secti o n 8. 2 . T he sa m e 
i nfere ntial r es ults will be re p orte d as f or t he pri mary a n al ysis.  
4.  A nal ysis t o e v al uate t he p ote ntial i m pact of C O VI D -1 9  i nfecti o n. 
T his se nsiti vit y a nal ysis will ha n dle t he I C E of C O VI D -1 9  i nfecti o n wit h t he H y p ot he tical 
strate g y, i.e. all of a partici pa nt’s data o n t he da y of a n d after t h e i nfecti o n will be ce ns ore d. 
T his is i n c o ntrast t o t he pri mar y a nal ysis i n w hic h a n y C O VI D -1 9 -relate d I C Es are i g n ore d i n 
t he a nal ysis (i.e. Treat me nt P olic y str ate g y).  Ce ns ori n g at t he ti me of i nf ecti o n will be  ass u me d 
t o be n o n -i nf or mati ve f or t he e ve nt of i nterest (rel a pse). 
T he I C E ‘C O VI D -1 9  vacci nati o n’ will be  ha n dle d via Treat me nt P olic y strate g y  as i n pri mar y 
a nal ysis . Partici pa nts e x perie nci n g t he I C E ‘ C O VI D -1 9  i nf ecti o n’ will b e i de ntifie d as t h ose 
wit h A Es relate d t o C O VI D -1 9  as defi ne d i n Secti o n  1 5. 2. 4 . T he h y p ot hetical sce nari o 
e n visa ge d is t hat C O VI D -1 9  i nfecti o n d oes n ot occ ur b ut C O VI D -1 9  v acci nati o n d oes.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 1 /1 5 9  
 
 
 
5.  A nal ysis t o e val uate t he p ote ntial i m pact of e mer ge nc y u n bli n di n g of a partici pa nt pri or t o 
st u d y disc o nti n uati o n of t he partici pa nt . 
T his  se nsiti vit y a nal ysis will ha n dle t he I C E of e mer ge nc y u n bli n di n g wit h t he H y p ot hetical 
strate g y, i.e. all of a p arti c i pa nt’s data o n t he d a y of a n d after t h e e mer ge n c y u n bli n di n g will 
be ce ns or e d. T his is i n c o ntrast t o t he pri mar y a nal ysis i n w hic h t he I C E of e mer ge nc y 
u n bli n di n g is i g n ore d i n t he a nal ysis ( i.e. Treat me nt P olic y strat e g y).  Ce ns ori n g at t he ti me of 
e mer ge n c y u n bli n di n g will be ass u me d t o b e n o ni nf or mati ve f or t he e ve nt of i nterest (rela pse) . 
Partici pa nts e x perie nci n g t he I C E e m er ge n c y u n bli n di n g will be i de ntifi e d as t h ose ha vi n g a 
Yes i n t he q uesti o n ‘ Was ra n d o mizati o n c o de br o ke n b y t h e site?’ i n t he S T E R M  e C R F pa ge.  
6.  A nal ys es t o e val uat e t he p ote ntial i m pact of t he war i n U krai n e. 
I n the pri mar y a n al ysis  of A R R , o nl y p artici pa nts at sites n ot f ull y o perati o nal p ost start of t h e 
U krai ne crisis, will be c o nsi dere d t o ha ve e x perie n ce d t he I C E ‘ U krai ne crisis’. T he data fr o m 
s uc h partici pa nts will be  ce ns ore d at t he date  at w hic h t he site l os t f ull y o p erati o nal stat us.  
I n t h e first se nsiti vit y a nal ysis  of A R R relate d t o t he i m pact of t he war i n U krai ne , all 
partici pa nts fr o m sites i n U krai ne  will ha ve t heir data ce ns ore d at t he start of t he crisis  (i.e. 
2 4  Fe br uar y  2 0 2 2 ). T he h y p ot hetical sce n ari o e n visa ge d is o ne i n w hic h t he crisis (affecti n g 
o nl y U krai ne partici pa nts) ha d n ot occ urre d . In a sec o n d se nsiti vit y a nal ysis  relat e d t o t he 
i m pact of war i n U krai ne, all partici pa nts fr o m sites i n U krai ne, R ussia n Fe d erati o n, a n d 
Belar us will ha ve t h eir data ce ns ore d  at t he start of t he cris is. T he h y p ot hetical sce n ari o 
e n visa ge d is o ne i n w hic h t he crisis (affecti n g partici pa nts fr o m U krai ne, R ussia n Fe derati o n, 
a n d Bel ar us) h a d n ot occ urre d.   
7.  m F A S  a nal ysis  
I n t his se nsiti vit y a n al ysis, t he pri mar y a nal ysis of A R R will be re peate d o n t he m F A S.  
8.  A nal ysis o n all rela pses.  
T his se nsiti vit y a n al ysis will use t he s a me N B m o del use d i n t he pri mar y a nal ysis of A R R u p 
t o 1 5 6 wee ks a n d re p ort t he sa me i nfere ntial res ults. 
All rela pses will be c o u nt e d, re gar dless of q u alificati o n stat us.  
9.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he sec o n d recr uit me nt c o h ort.  
T his se nsiti vit y a n al ysis will a d d t he f oll o wi n g c o variate t o t he N B m o del: me m bers hi p i n 
sec o n d recr uit me nt c o h ort ( yes/ n o), as defi n e d i n S ecti o n  8. 2 . T he s a me i nf ere ntial res ults will 
be re p ort e d as f or t h e pri mar y a nal ysis wit h t he p -val ue of t he a d diti o nal c o variate re p orte d.  
1 0.  A nal ysis wit h a ce ns ori n g dat e of 0 1  J u ne 2 0 2 3 f or all partici pa nts still o n g oi n g at t hat dat e.  
T o assess t he i m pact of t he P A tri g ger d ela y, partici pa nts will be ce ns ore d o n t he ori gi nall y 
pr ojecte d dat e of  t he P A tri g ger: 0 1  J u ne 2 0 2 3. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 2 /1 5 9  
 
 
 
1 4. 1. 3  
S u b gr o u p A n al yses of A R R   
T he a nal ysis of  t he pri mar y e n d p oi nt assess me nt, as descri be d i n Secti o n  1 4. 1. 1 , will be re peate d 
f or all s u b gr o u p le vels defi ne d i n Secti o n  8. 2  “ S u b gr o u p D efi niti o n a n d P ara metrizati o n ”. 
A d diti o nall y, a l ar ger m o del t hat a dj usts f or s u b gr o u p a n d i nter ve nti o n-b y -s u b gr o u p i nteracti o n 
will be fitte d, a n d t he p -v al ue of t he i nteracti o n r e p orte d. 
1 4. 2  
Sec o n d ar y Esti m a n ds   
T his secti o n pr o vi des d etaile d i nf or mati o n relat e d t o t he a nal ysis of t h e sec o n d ar y effi cac y 
esti ma n ds, i ncl u di n g pri mar y, s e nsiti vit y, s u p ple me ntar y, a n d s u b gr o u p a nal yses.  
1 4. 2. 1  
Ti me t o C o nfir me d Dis a bilit y Pr o gressi o n   
T he 5  esti ma n d attri b utes of sec o n dar y efficac y esti ma n ds ti me t o first occ urre nce of 1 2 -wee k a n d 
2 4 -wee k C D P  are:  
•  E n d p oi nt : Ti me t o first occ urre nce of 1 2 -wee k/ 2 4 -wee k C D P as meas ure d b y t he E D S S 
u p t o 1 5 6 wee ks  
•  Tre at me nt c o n diti o n of i nterest : E v o br uti ni b 4 5 m g t wice d ail y f or u p t o 1 5 6 wee ks; 
alter nati ve treat me nt c o n diti o n t o w hic h c o m p aris o n will be m a de: t e rifl u n o mi de 1 4 m g 
o nce dail y f or u p t o 1 5 6 wee ks.  
•  P o p ul ati o n : Partici pa nts wit h R M S as defi ne d b y i ncl usi o n/e xcl usi o n criteria. 
•  Str ate gies use d t o a d dress  I C Es:  
o  Treat me nt disc o nti n uati o n: Treat me nt p olic y strat e g y.  
o  Deat h attri b uta ble t o M S or treat me nt: C o m p osite varia ble strat e g y  
o  Deat h u nattri b uta ble t o M S or treat me nt: W hile ali ve strate g y  
o  U krai ne crisis: H y p ot heti cal strate g y  
o  C O VI D -1 9  i nfecti o n, C O VI D -1 9  vacci nati o n a n d e mer ge nc y 
u n bli n di n g: 
Treat me nt P olic y strate g y.  
•  P o p ul ati o n -le vel s u m m ar y c o m pari n g t he i nter ve nti o n gr o u ps is t he hazar d rati o a n d CI 
base d o n a stratifie d C o x m o del f or hazar d rat e, wit h ter m f or i nter ve nti o n gr o u p, a n d strata 
defi ne d b y ra n d o mizati o n strata a n d st u d y I D. Test is base d o n stratifie d l o gra n k test wit h 
strata defi ne d b y ra n d o miz ati o n strata a n d st u d y I D. Data are p o ole d fr o m t he F A S of t he 
st u dies 0 0 8 0 a n d 
. 
E D S S is assesse d i n all partici pa nt s b y t h e E x a mi ni n g I n vesti gat or at Scree ni n g  a n d Baseli ne  V isit, 
a n d e ver y 1 2  wee ks  u p t o a n d i ncl u di n g t he Safet y  F oll o w -u p  Visit . U nsc he d ule d E D S S 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 3 /1 5 9  
 
 
 
assess me nts f or i n di vi d ual partici pa nts ma y b e p erf or me d bet w ee n s c he d ule d assess me nts ( i.e. 
d uri n g a M S rela pse).  
Disa bilit y pr o gressi o n is defi ne d as a n i ncreas e of ≥ 1. 0 p oi nt fr o m t he baseli ne  E D S S sc ore w he n 
t he baseli ne  sc ore is 5. 0 or less a n d a n i ncrease of ≥ 0. 5 w he n t he baseli ne  sc ore is 5. 5. I nitial 
pr o gressi o n ca n h a p pe n at a n y visit d uri n g t he D B T P  u ntil t he P A c ut off date . 
1 4. 2. 1. 1  
Ti me t o 1 2 -wee k C D P   
Disa bilit y pr o gressi o n is c o nsi dere d s ustai ne d f or 1 2  wee ks w he n t he i nitial i ncrease i n t he E D S S 
is c o nfir me d at a re g ularl y sc he d ul e d visit at least 1 2  wee ks after t he i nitial d oc u me ntati o n of 
ne ur ol o gi cal w ors e ni n g .  
C o nfir mati o n of disa bilit y pr o gressi o n m ust occ ur at t he re g ularl y sc he d ul e d visit t hat is at least 
1 2  wee ks ( 8 4 da ys) after i nitial pr o gressi o n. If a p artici pa nt has a missi n g E D S S at t he sc he d ule d 
visit occ urri n g at least 8 4 da ys after a n i nitial pr o gressi o n or t he sc he d ul e d visit occ urs s e veral 
da ys bef ore t he 8 4 -da y wi n d o w after a n i nitial pr o gressi o n, c o nfir m ati o n of t he disa bilit y 
pr o gressi o n m ust be o n t he basis of t he ass ess me nt at t he ne xt sc he d ule d visit.  
E D S S assess me nts at u nsc he d ule d or sc he d ule d visits t hat are less t ha n 8 4 da y s aft er t he i nitial 
pr o gressi o n  are c o nsi dere d n o n -c o nfir mat or y E D S S assess me nts . F or disa bilit y pr o gressi o n t o be 
c o nfir me d at a re g ularl y sc h e d ule d visit at least 1 2  wee ks 
aft er i nitial pr o gressi o n , a n y 
n o n -c o nfir mat or y E D S S assess me nts s h o ul d be at leas t as hi g h as t he mi ni m u m c ha n ge re q uire d 
f or pr o gressi on.  T his me a ns t hat after a s c he d ule d or u nsc he d ule d visit at w hic h t he partici pa nt 
f ulfills t he i nitial disa bilit y pr o gressi o n (I D P), all s u bse q ue nt E D S S assess me nts (sc he d ule d a n d 
u nsc he d ule d) n ee d t o als o f ulfill t he w orse ni n g criteria u ntil t he w orse ni n g ca n be c o nfir me d at t he 
first sc he d ule d visit t hat occ urs at least 8 4 da ys  after o nset of t he w orse ni n g.  
Ti me t o 1 2 -wee k C D P is defi ne d as t he ti me fr o m ra n d o mizati o n date t o t he I D P date  w he n a n 
e ve nt is prese nt , a n d fr o m ra n d o mizati o n date t o ce ns ori n g date w he n a n e ve nt is n ot prese nt. 
Ce ns ori n g occ urs i n t h ose partici pa nts w h o di d n ot e x perie nce a 1 2 -wee k c o nfir me d disa bilit y 
pr o gressi o n  u p t o P A c ut off or 1 5 6 wee ks p ost ra n d o mizati o n , w hic he ver occ urs first; t his i ncl u des 
partici pa nts w h o h a d a “te ntati ve” disa bilit y pr o gressi o n  t hat c o ul d n ot b e c o nfir me d d ue t o a n 
earl y disc o nti n uati o n or a n y ot her reas o n. T h e ce ns ori n g d ate is t h e date of t he last E D S S 
assess me nt . Partici pa nts wit h n o p ost ra n d o mizati o n  E D S S assess me nt  will be ce ns ore d o n t he d a y 
of ra n d o mizati o n .  
Missi n g D at a H a n dli n g  
Partici pa nts w h o di d n ot e x perie nce 1 2 -wee k C D P b y 1 5 6 wee ks p ost ra n d o mizati o n, b y ti me of 
P A c ut off, b y ti me of earl y st u d y disc o nti n uati o n, or bef ore bei n g l ost t o f oll o w u p, will be 
ce ns ore d at t he date of t he last E D S S assess me nt d uri n g t he 1 5 6 wee ks p ost ra n d o mizati o n. I n t he 
pri mar y a nal ysis of 1 2 -w ee k C D P, ce ns ori n g will be ass u me d t o be n o ni nf or mat i ve, c o n diti o nal 
o n i nter ve nti o n gr o u p, ra n d o mizati o n strat u m, a n d st u d y I D.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 4 /1 5 9  
 
 
 
H a n dli n g of I CEs  
I n acc or da nce wit h Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C E pre m at ure 
treat me nt disc o nti n uati o n, all E D S S d at a t hr o u g h Safet y  F oll o w -u p will b e i ncl u de d i n t h e a n al ysis 
u p t o t he pla n ne d e n d of treat me nt (i.e. P A c ut off or 1 5 6 wee ks p ost  ra n d o mizati o n , w hic he ver 
occ urs first) .  
I n acc or da n ce wit h t he C o m p osite Varia ble str ate g y, f or partici pa nts e x perie nci n g t h e I C E deat h 
attri b uta ble t o M S or treat me nt, t he deat h will be c o u nte d as 1 2 -wee k C D P. I n acc or da n ce wit h t he 
W hile Ali ve strate g y, f or partici pa nts e x perie n ci n g 
t he I C E deat h u n attri b uta ble t o 
M S or 
treat me nt, partici pa nts will be ce ns ore d at ti me of d eat h.  (i.e. deat h will n ot b e  c o u nte d as 1 2 -wee k 
C D P ). 
Deat hs wit h pri mar y reas o n e ntere d as ‘ pr o gressi ve disease a n d/ or disease relate d c o n diti o n’ i n t he 
e C R F Deat h F or m will be c o nsi dere d as attri b ut a ble t o M S. Deat hs  wit h pri mar y reas o n set t o 
‘e ve nt relate d t o st u d y tr eat me nt’ will b e c o nsi d ere d as attri b uta ble t o st u d y i nter ve nti o n. Ot her 
deat hs ( i.e. pri mar y reas o n e q ual t o ‘e ve nt u nrelate d t o st u d y treat me nt’ a n d ‘ u n k n o w n’) will b e 
c o nsi dere d as u nattri b uta ble t o M S or treat me nt.  
Partici pa nts at sites n ot f ull y o p erati o nal p ost start of U krai ne crisis will be c o nsi dere d t o ha v e 
e x perie nce d t h e I C E ‘ U krai ne crisis’. T his I C E will be ha n dle d usi n g t h e H y p ot hetical strate g y, 
w here t he h y p ot h etical sce nari o e n visa ge d is o ne i n w hic h t he crisis ha d ne ver ha p pe n e d.  T he d ata 
fr o m s uc h partici pa nts will be ce ns ore d at t he ti me at w hic h t he site l os t f ull y o perati o nal stat us. 
Ce ns ori n g at t he e n d of t he pre -crisis peri o d is n o n -i nf or mati ve f or t he o utc o me of i nterest ( C D P). 
I n acc or da n ce wit h t he Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C Es 
‘C O VI D -1 9  i nf ecti o n’, ‘C O VI D -1 9  vacci nati o n’  or ‘e mer ge nc y u n bli n di n g ’ t h e occ urre n ce of 
t hese I C Es is c o nsi dere d irrele va nt i n t he pri mar y a nal ysis of C D P. 
Assess me nt of p o oli n g v ali dit y   
P ri or t o p o oli n g data fr o m st u dies 0 0 8 0 a n d 
, t he vali dit y of p o oli n g data will be assesse d b y 
re vie wi n g c o nsiste nc y of de m o gra p hi cs, baseli ne  c haracteristics, A R R a n d 1 2 -wee k C D P res ults.  
F or c o nsiste nc y, t he treat me nt effect  o n A R R a n d 1 2 -wee k C D P  m ust be i n t he sa me directi o n i n 
b ot h st u dies . 
Infere nti al a n al ysis  
T he P A of ti me t o 1 2 -w ee k C D P will be b ase d o n data p o ole d fr o m t he F A S of t he 2  P hase  3  
st u dies usi n g a stratifie d l o g ra n k test wit h i nter ve nti o n gr o u p as m ai n effect a n d stratificati o n 
varia bles use d i n ra n d o mi zati o n a n d st u d y I D (i.e. St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 or 
) as c o variates . 
T he 1 -si de d p-val ue ( α = 0. 0 2 4 3 7 5) fr o m t he str atifie d l o g ra n k test f or c o m paris o n b et wee n 
e v o br uti ni b vs . terifl u n o mi de will be re p orte d. I n a d diti o n, the  hazar d rati o c o m pari n g e v o br uti ni b 
t o terifl u n o mi de will be esti mate d via a stratifie d C o x m o del wit h a ter m f or i nter ve nti o n gr o u p 
a n d strata d efi ne d b y ra n d o mizati o n strata  a n d st u d y I D  (i.e. St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 or  
) , 
al o n g wit h 9 5 % 2 -si de d CI, a n d (al p ha-c o m p ati ble) 9 5. 1 2 5 % 2 -si de d CI. A n e x pa n de d m o del wit h 
a treat me n t-b y -st u d y i nteracti o n will be fit t o t he data a n d bet w ee n-st u d y heter o ge n eit y will be 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 5 /1 5 9  
 
 
 
teste d as t he t y p e-3 test of t he treat me n t-b y -st u d y i nteracti o n; t he c orres p o n di n g p-val u e will be 
pr o vi de d.  
T he ass u m pti o n of n o n -i nf or mati ve ce ns ori n g u n der pi ns t he hazar d rati o esti mat or i m ple me nte d 
b y t he stratifie d C o x m o del t hat uses o bs er ve d f oll o w-u p  ti me f or eac h partici pa nt, re gar dless of 
treat me nt c o m pleted / disc o nti n ued/ o n g oi n g  stat us, w here partici pa nts are ce ns ore d f or 1 2-wee k 
C D P at t he  E D S S assess me nt.  
T he trial -wise a n d fa mil y -wis e -t y pe-1 err or will be preser ve d at t he 0. 0 2 5 1 -si de d le vel i n t he 
prese nce of m ulti ple testi n g d u e t o m ulti ple e n d p oi nts ( pri mar y a n d sec o n dar y) , as d escri be d i n 
Secti o n  9. 1 6 . I n t he setti n g of s u peri orit y trials, a n I A f or B S S R has a mi ni mal or n o n -e xiste nt 
effect o n t y pe -1 err or rate i nflat i o n (Fri e de 2 0 1 9 ), s o t here is n o n ee d t o a dj ust f or t he I A f or B S S R 
c o n d ucte d i n A u g ust 2 0 2 1 . 
Descri pti ve a n al ysis  
K M esti mates ( pr o d uc t-li mit esti mates) of t he c u m ulati ve pr o ba bilit y of e x perie nci n g 1 2 -wee k 
C D P o ver ti me will be prese nte d b y i nter ve nti o n gr o u p , t o get her wit h a s u m mar y of p erce ntiles 
( 5t h, 1 0t h, 1 5t h) a n d c orres p o n di n g 2 -si de d 9 5 % CIs . T he K M c ur ves will als o be pr o vi de d f or eac h 
i nter ve nti o n gr o u p. 
N u m ber a n d p erce nta ges of partici pa nts e x perie n ci n g i nterc urre nt e ve nts will als o be prese nte d.  
B y -visit d escri pti ve statistics f or E D S S a bs ol ute a n d C F B val u es treate d as c o nti n u o us varia bles 
(i.e. mea n, me dia n, a n d ra n ge) will be re p orte d. D escri pti ve statistics f or cate g ori cal E D S S C F B, 
i.e. n u m ber a n d pr o p ort i o n i m pr o vi n g, sta ble, or w orse ni n g, will als o be re p orte d f or eac h ti me 
p oi nt. Here i m pr o ve me nt is defi ne d as a decrease of 1. 0 p oi nt or m ore, sta ble c o n diti o n as a c ha n ge 
of n o m ore t ha n half a p oi nt i n eit her directi o n, a n d w orse ni n g as a n i ncreas e of 1 . 0 p oi nt or m ore. 
1 4. 2. 1. 2  
Ti me t o 2 4 -wee k C D P   
Disa bilit y pr o gressi o n is c o nsi dere d s ustai ne d f or 2 4  wee ks w he n t he i nitial i ncrease i n t he E D S S 
is c o nfir me d at a re g ularl y sc he d ul e d visit at least 2 4 wee ks after t he i nitial d oc u me ntati o n of 
ne ur ol o gi cal w ors e ni n g.  
T he r ules f or c o nfir mi n g disa bilit y pr o gressi o n f or 2 4 -wee k C D P are t he sa m e as t h os e f or 1 2 -wee k  
C D P, wit h “1 6 8 da ys ” re placi n g “8 4 da ys ”. 
I n all ot her res pects, t he a nal ysis of t he 2 4-wee k C D P e n d p oi nt will be t he sa me as t hat of t he 
1 2 -wee k  C D P e n d p oi nt.  
1 4. 2. 1. 3  
Se nsiti vit y 
A n al yses: 
Ti me 
t o 
C o nfir me d 
Dis a bilit y 
Pr o gressi o n   
T he f oll o wi n g se nsiti vit y a nal ys es f or ti me t o 1 2 -wee k  C D P  are pl a n ne d , wit h t he sa me ha n dli n g 
of I C Es as i n t he pri mar y a nal ysis u nless ot her wise s pecifie d,  base d o n p o ole d data fr o m t he 
2  P hase  3  st u dies: 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 6 /1 5 9  
 
 
 
1.  A nal ysis t o e val uate t he p ote ntial i nfl ue nce of i nf or mati ve treat me nt disc o nti n uati o n acc or di n g 
t o disc o nti n uati o n reas o n or occ urre nce of i nitial pr o gressi o n e ve nt at last assess me nt .  
T his se nsiti vit y a nal ysis will use t he sa me C o x m o del use d i n  t he pri mar y a nal ysis of 1 2 -wee k  
C D P a n d re p ort t he res ulti n g H R, 9 5 % CI  a n d p -v al ue .  I n a d diti o n, a f orest pl ot will prese nt 
t he hazar d rati o, 9 5 % CI a n d p-val ue f or eac h delt a.  
T he f oll o wi n g a p plies t o partici pa nts i n t he e v o br uti ni b i nter ve nti o n gr o u p.  If a p artici pa nt’s 
disc o nti n uati o n is u nrelate d t o treat me nt ( i. e. u nrelate d t o effi cac y or safet y iss u es) a n d n o 
i nitial pr o gressi o n e ve nt occ urre d, t he partici pa nt’s ti me t o C D P will be m ulti pl y i m p ute d usi n g 
hazar d rate i n t he c o m parat or gr o u p  (a dj usted f or partici pa nt’s strat u m) , f or t he i nter val 
bet wee n dis c o nti n uati o n a n d pla n ne d e n d of tr eat me nt ( i.e. P A c ut off or 1 5 6  wee ks p ost 
ra n d o mizati o n, w hic he ver occ urs first). If a p artici pa nt’s disc o nti n uati o n is relate d t o treat me nt 
or a n i nitial u nc o nfir me d pr o gressi o n e ve nt occ urre d, t he partici pa nt’s ti me t o C D P will be 
m ulti pl y i m p ute d usi n g hazar d rate hi g h er t ha n t hat i n t he c o m parat or gr o u p  (a dj uste d f or 
partici pa nt’s  strat u m), f or t he i nter val bet w ee n dis c o nti n uati o n a n d pla n ne d e n d of treat me nt . 
T he c o m parat or  hazar d rate after wit h dra wal will be m ulti plie d b y delta, ra n gi n g fr o m 1 t o 3. 1 
( ~tri pli n g of hazar d rate) i n ste ps of 0. 3. F or partici pa nts wit h disc o nti n uati o n of treat me nt (all 
reas o ns) i n t he terifl u n o mi de gr o u p, t he ti me t o C D P will be m ulti pl y i m p ute d u n der t h e M A R 
ass u m pti o n.   
MI met h o d s f or ti me-t o-e ve nt data will be  a p plie d f oll o wi n g t he a p pr oac h fr o m Li p k o vic h  
2 0 1 6  ( delta a dj ust me nt), see A p pe n di x  1 8. 9  f or details.   
Treat me nt ter mi nati o n wit h pri mar y reas o n e ntere d as ‘a d v erse e ve nt’, ‘lac k of efficac y’ a n d 
‘ deat h’ i n t he e C R F T T E R M f or m will be c o nsi dere d as relate d t o treat me nt. Ot her treat me nt 
ter mi nati o ns (i.e. pri mar y reas o n e q ual t o ‘l ost t o f oll o w-u p ’, ‘ pr ot oc ol n o n -c o m plia nce’, 
‘ wit h dra wal b y s u bject’ a n d ‘ ot her’) will be c o nsi dere d as u nrelate d t o treat me nt. 
2.  A nal ysis i n w hic h i nitial disa bilit y pr o gressi o n n ot c o nfir me d d ue t o earl y treat me nt 
disc o nti n uati o n is i m p ute d as c o nfir me d disa bilit y pr o gressi o n.   
T his se nsiti vit y a nal ysis will use t he sa me C o x  m o del use d i n t he pri mar y a nal ysis of 1 2 -wee k  
C D P a n d re p ort t he res ulti n g H R a n d 9 5 % CI .  
If a partici p a nt disc o nti n ue d treat me nt earl y d uri n g t h e o n -treat me nt p eri o d after ha vi n g a n 
i nitial pr o gressi o n e ve nt, b ut pri or t o 1 2 -wee k  c o nfir mati o n, t he partici pa nt is ass u me d t o ha ve 
a 1 2 -wee k  C D P e ve nt at t he date of i nitial pr o gressi o n.  
3.  A nal ysis t o e v al uate t he p ote ntial i m pact of m o del miss pecificati o n.  
T his se nsiti vit y a nal ysis will a d d t he f oll o wi n g c o variates t o t he C o x  m o del: n u m ber of rela pses 
i n pre vi o us 2 years bef ore Scree ni n g , prese nce/a bse nce of T 1 G d + lesi o ns wit hi n 6  m o nt hs  
pri or t o ra n d o mizati o n, pri or D M T  ( y/ n), a n d a ge. T he res ulti n g H R f or treat me nt effect a n d 
9 5 % CI will be re p orte d .  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 7 /1 5 9  
 
 
 
4.  A nal ysis t o e v al uate t he p ote ntial i m pact of C O VI D -1 9  i nfecti o n. 
T his se nsiti vit y a nal ysis will ha n dle t he I C E of C O VI D -1 9  i nfecti o n wit h t he H y p ot hetical 
strate g y, i.e. all of a partici pa nt’s data  o n t he da y of a n d  after t h e i nfecti o n will be ce ns ore d. 
T his is i n c o ntrast t o t he pri mar y a nal ysis i n w hic h a n y C O VI D -1 9 -relate d I C Es are i g n ore d i n 
t he a nal ysis (i.e. Treat me nt P olic y str ate g y).  Ce ns ori n g at t he ti me  of t he i nfecti o n will be 
ass u me d t o be n o ni nf or m ati ve f or t he o utc o m e of i nterest ( C D P) .  
T he  I C E ‘C O VI D -1 9  vacci nati o n’ will be ha n dle d via Treat me nt P olic y strate g y as i n pri mar y 
a nal ysis . Partici pa nts e x perie nci n g t he I C E ‘C O VI D -1 9  i nf ecti o n’ will b e i de ntifie d as t h ose 
wit h A Es relate d t o C O VI D -1 9  as defi ne d i n Secti o n  1 5. 2. 4 . T he h y p ot hetical sce nari o 
e n visage d is t hat C O VI D -1 9  i nfecti o n d oes n ot occ ur, b ut C O VI D -1 9  v acci nati o n d oes.  
5.  A nal ys es t o e val uat e t he p ote ntial i m pact of t he war i n U krai n e. 
I n t he first se nsiti vit y a nal ysis of C D P relate d t o t he i m pact of t he war i n U krai ne, all 
partici pa nts fr o m sites  i n U krai ne will ha ve t heir data ce ns ore d at t he start of t he crisis (i.e. 
2 4  Fe br uar y  2 0 2 2 ). T he h y p ot hetical sce n ari o e n visa ge d is o ne i n w hic h t he crisis (affecti n g 
o nl y U krai ne partici pa nts) ha d n ot occ urre d.  In a sec o n d se nsiti vit y a nal ysis relat e d t o  t he 
i m pact of war i n U krai ne, all partici pa nts fr o m sites i n U krai ne, R ussia n Fe d erati o n, a n d 
Belar us will ha ve t heir data ce ns ore d at t he st art of t he crisis ( i.e. 2 4  Fe br uar y  2 0 2 2 ). T h e 
h y p ot hetic al sce nari o e n visa ge d is o ne i n w hic h t he crisis (affecti n g partici pa nts fr o m U krai ne, 
R ussia n Fe derati o n, a n d Belar us) ha d n ot occ urre d.  
6.  m F A S  a nal ysis . 
I n t his se nsiti vit y a n al ysis, t he pri mar y a nal ysis of C D P  will be re peate d o n t he m F A S.  
7.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he sec o n d recr uit me nt c o h ort.  
T his se nsiti vit y a nal ysis will a d d t he f oll o wi n g c o variate t o t h e C o x m o del: me m bers hi p i n 
sec o n d recr uit me nt c o h ort ( yes/ n o), as d efi ne d i n Secti o n  8. 2 . T he res ulti n g H R f or treat me nt 
effect a n d 9 5 % CI will be re p ort e d , al o n g wit h t he p-val ue f or t he a d diti o n al c o variat e . 
T he s e nsiti vit y a nal ys es a b o ve will be re p eate d f or ti me t o 2 4-wee k C D P.  
8.  A nal ysis wit h a ce ns ori n g dat e of 0 1  J u ne 2 0 2 3 f or all partici pa n ts still o n g oi n g at t hat dat e.  
T o assess t he i m pact of t he P A tri g ger d ela y, partici pa nts will be ce ns ore d o n t he ori gi nall y 
pr ojecte d date of t h e P A tri g ger: 0 1  J u ne 2 0 2 3. T his se nsiti vit y a n al ysis will be p erf or m e d f or 
ti me t o 1 2-wee k C D P  o nl y . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 8 /1 5 9  
 
 
 
1 4. 2. 2  
Ti me t o 2 4 -Wee k C o nfir me d Dis a bilit y I m pr o ve me nt   
T he 5  esti ma n d attri b utes of sec o n dar y effi cac y esti ma n ds ti me t o first occ urre nce of 2 4 -wee k C D I 
are:  
•  E n d p oi nt : Ti me t o first occ urre nce of 2 4 -wee k C D I as meas ure d b y t he E D S S u p t o 
1 5 6  wee ks  
•  Tre at me nt c o n diti o n of i nterest : E v o br uti ni b 4 5 m g t wice d ail y f or u p t o 1 5 6  wee ks ; 
alter nati ve treat me nt c o n diti o n t o w hic h c o m p aris o n will be m a de: t erifl u n o mi de 1 4 m g 
o nce dail y f or u p t o 1 5 6  wee ks . 
•  P o p ul ati o n : Partici pa nts wit h R M S as defi ne d b y i ncl usi o n/e xcl usi o n criteria w h o ha v e 
baseli ne  E D S S ≥ 2 . 
•  Str ate gies use d t o a d dress I C Es :  
o  Treat me nt disc o nti n uati o n: Treat me nt p olic y strat e g y.  
o  Deat h (a n y ca us e): W hile ali ve strate g y 
o  U krai ne crisis: H y p ot heti cal strate g y  
o  C O VI D -1 9  i nfecti o n, C O VI D -1 9  vacci nati o n a n d e mer ge nc y 
u n bli n di n g: 
Treat me nt P olic y strate g y.  
•  P o p ul ati o n -le vel s u m m ar y c o m pari n g t he i nter ve nti o n gr o u ps is t he hazar d rati o a n d CI 
base d o n a stratifie d C o x m o del f or hazar d rat e, wit h ter m f or i nter ve nti o n gr o u p, a n d strata 
defi ne d b y ra n d o mizati o n strata a n d st u d y I D. Test is base d o n stratifie d l o gra n k test wit h 
strata defi ne d b y ra n d o miz ati o n strata a n d st u d y I D. Data are p o ole d fr o m t he F A S of t he 
st u dies 0 0 8 0 a n d  
. 
T his e n d p oi n t will be an al yz e d f or t he s u b gr o u p of partici pa nts fr o m t he F A S p o ole d st u dies wit h 
baseli ne  E D S S sc ore ≥ 2. 0.  
F or partici pa nts wit h a b aseli ne  E D S S sc ore ≥ 2 a n d ≤ 6 , disa bilit y i m pr o ve me nt is defi ne d as a 
re d ucti o n i n E D S S sc ore ≥ 1. 0 c o m pare d t o bas eli ne  E D S S sc ore. F or parti ci pa nts wit h a baseli ne  
E D S S sc ore ≥ 6. 5 a n d ≤ 9. 5 , disa bilit y i m pr o ve m e nt is defi ne d as a re d ucti o n i n E D S S sc ore of ≥ 
0. 5.  
T he sa me a p pr oac h t o t he ti mi n g of 2 4 -wee k c o nfir mati o n of disa bilit y i m pr o ve me nt is a p plie d as 
f or 2 4 -wee k disa bilit y pr o gressi o n. C o nfir mati o n of disa bilit y i m pr o ve m e nt m ust occ ur at t he 
re g ularl y sc h e d ule d visit t hat is at least 2 4 wee ks ( 1 6 8  da ys) after i nitial i m pr o ve me nt. If a 
partici pa nt  has a missi n g E D S S at t he sc he d ule d visit occ urri n g at least  1 6 8  da ys aft er a n i nitial 
i m pr o ve me nt or t he s c he d ule d visit occ urs se v eral da ys bef ore t he 1 6 8 -da y wi n d o w after a n i nitial 
i m pr o ve me nt, c o nfir mati o n of t he disa bilit y i m pr o ve me nt m ust be base d o n  t he assess me nt at t he 
ne xt sc he d ule d visit.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
6 9 /1 5 9  
 
 
 
E D S S assess me nts at u nsc he d ule d or sc h e d ule d visits t hat are l ess t ha n 1 6 8  da ys after t he i nitial 
i m pr o ve me nt are c o nsi dere d n o n -c o nfir mat or y E D S S assess me nts. F or disa bilit y i m pr o ve me nt t o 
be c o nfir me d at a re g ul arl y sc h e d ule d visit at l east 2 4  wee ks after i nitial i m p r o ve me nt, a n y 
n o n -c o nfir mat or y E D S S assess me nts s h o ul d be at least as l o w as t he mi ni m u m c ha n ge re q uir e d 
f or i m pr o ve me nt. T his m ea ns t hat after a sc he d ul e d or u nsc he d ule d visit at w hic h t he partici pa nt 
f ulfills t he i nitial disa bilit y i m pr o ve me nt, all s u bseq ue nt E D S S assess me nts (sc he d ule d a n d 
u nsc he d ule d) nee d t o als o f ulfill t he i m pr o ve m e nt criteria u ntil t he i m pr o ve me nt ca n be c o nfir me d 
at t he first sc he d ule d visit t hat occ urs at least 1 6 8  da ys after o nset of t he i m pr o ve me nt.  
Ti me t o 2 4 -wee k C DI  is defi ne d as t h e ti me fr o m ra n d o mizati o n date t o t he i nitial disa bilit y 
i m pr o ve me nt date w he n a n e ve nt is prese nt, a n d fr o m ra n d o mizati o n date t o ce ns ori n g date w he n 
a n e ve nt is n ot prese nt. C e ns ori n g o cc urs i n t h ose partici pa nts w h o di d n ot e x perie nce a  2 4 -wee k  
c o nfir me d disa bilit y i m pr o ve me nt d uri n g 1 5 6  wee ks  p ost ra n d o mizati o n ; t his i ncl u des partici pa nts 
w h o ha d a “te ntati ve” disa bilit y i m pr o ve me nt t hat c o ul d n ot be c o nfir me d d ue t o a n earl y 
disc o nti n uati o n or a n y ot her reas o n. T he ce ns ori n g d ate is t he dat e of t he l ast E D S S assess me nt. 
Partici pa nts wit h n o p ost ra n d o mizati o n  E D S S assess me nt  will be ce ns ore d o n t he da y of 
ra n d o mizati o n. 
Missi n g D at a H a n dli n g  
Partici pa nts w h o di d n ot e x perie nce 2 4 -wee k C DI b y 1 5 6  wee ks  p ost ra n d o mizati o n, b y ti me of 
P A c ut off, b y ti me of earl y st u d y disc o nti n uati o n, or bef ore bei n g l ost t o f oll o w u p, will be 
ce ns ore d at t he date of t he last E D S S assess me nt d uri n g t he 1 5 6  wee ks  p ost ra n d o mizati o n. I n t he 
pri mar y a n al ysis of 2 4 -w ee k C DI, ce ns ori n g will b e ass u me d t o be n o n i nf or mati ve, c o n diti o nal o n 
i nter ve nti o n gr o u p, ra n d o mizati o n strat u m, a n d st u d y I D.  
H a n dli n g of I C Es 
I n acc or da nce wit h Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C E pre m at ure 
treat me nt disc o nti n uati o n, all E D S S d at a t hr o u g h Safet y  F ol l o w-u p will b e i ncl u de d i n t h e a n al ysis 
u p t o t he pla n ne d e n d of treat me nt (i.e. P A c ut off or 1 5 6  wee ks  p ost ra n d o mizati o n , w hic he ver 
occ urs first) .  
I n acc or da n ce wit h t he W hile Ali ve strate g y, f or partici pa nts e x perie nci n g t he I C E deat h (a n y 
ca use), p artici pa nts will be ce ns or e d at ti me of deat h . 
Partici pa nts at sites n ot f ull y o p erati o nal p ost start of U krai ne crisis will be c o nsi dere d t o ha v e 
e x perie nce d t h e I C E ‘ U krai ne crisis’. T his I C E will be ha n dle d usi n g t h e H y p ot hetical strate g y, 
w here t he h y p ot h etical sce nari o e n visa ge d is o ne i n w hic h t he crisis ha d ne ver ha p pe n e d.  T he d ata 
fr o m s uc h partici p a nts will be ce ns ore d at t he ti me at w hic h t he site l ost f ull y o perati o nal stat us.  
I n acc or da n ce wit h t he Treat me nt P olic y strat e g y, f or partici pa nts ex perie nci n g t he I C Es 
‘C O VI D -1 9  i nfecti o n’, ‘C O VI D -1 9  v acci n ati o n’  or ‘e mer ge n c y u n bli n di n g’ , t he occ urre nce of 
t hese I C Es is c o nsi dere d irrele va nt i n t he pri mar y a nal ysis of C DI. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 0 /1 5 9  
 
 
 
I nfere nti al a n al ysis 
T he P A of ti me t o 2 4 -wee k C DI will be bas e d o n data p o ol e d fr o m t he F A S of t he 2  P hase  3  st u dies 
usi n g a stratifie d l o g ra n k test wit h i nter ve nti o n gr o u p as mai n effect a n d stratificati o n vari a bles 
use d i n ra n d o mizati o n a n d st u d y I D (i.e. St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 or _ 
) as c o variates . T h e 
1 -si de d p-val ue ( α = 0. 0 2 4 3 7 5 ) fr o m t he stratifie d l o g ra n k test f or c o m paris o n bet wee n e v o br uti ni b 
vs . terifl u n o mi de will be re p ort e d. I n a d diti o n, t he hazar d rati o c o m pari n g e v o br uti ni b t o 
terifl u n o mi de will be esti mate d via a stratifie d C o x m o del wit h a ter m f or i nter ve nti o n gro u p a n d 
strata defi n e d b y ra n d o mizati o n strata a n d st u d y I D (i.e. St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 or _ 
), al o n g 
wit h 9 5 % 2 -si de d CI, a n d (al p ha-c o m pati ble) 9 5. 1 2 5 % 2 -si de d CI.  
T he ass u m pti o n of n o n -i nf or mati ve ce ns ori n g u n der pi ns t he hazar d rati o esti mat or i m ple mente d 
b y t he stratifie d C o x m o del t hat uses o bs er ve d f oll o w-u p  ti me f or eac h partici pa nt, re gar dless of 
treat me nt c o m pleted / disc o nti n ued/ o n g oi n g  stat us, w here partici pa nts are ce ns ore d f or 2 4-wee k 
C D I at t he t hir d t o last E D S S assess me nt.  
Descri pti ve a n al y sis 
K M esti mates ( pr o d uct -li mit esti mates) of t he c u m ulati ve pr o ba bilit y of e x perie nci n g 2 4-wee k 
C DI o v er ti me will be prese nte d b y i nter ve nti o n gr o u p, t o get h er wit h a s u m mar y of p erce ntiles 
( 5t h, 1 0t h, 1 5t h) a n d c orres p o n di n g 2 -si de d 9 5 % CIs b ase d . T he K M c ur ves will als o be pr o vi de d 
f or eac h i nter ve nti o n gr o u p. 
N u m ber a n d p erce nta ges of partici pa nts e x perie n ci n g I C Es will als o be pres e nte d. 
Se nsiti vit y a n al ysis  
Se nsiti vit y a nal yses d escri be d f or ti me t o 1 2 -wee k  a n d 2 4-wee k C D P i n Secti o n  1 4. 2. 1. 3  will be 
a p plie d t o ti me t o 2 4 -wee k C DI e x ce pt f or t he se nsiti vit y a n al ys es 2 a n d 8.  
F or se nsiti vit y a nal ysis # 1, t he hazar d rate after wit h dra wal will be di v i de d b y d elta, ra n gi n g fr o m 
1 t o 3. 1  (re d ucti o n of haz ar d rat e) i n ste ps of 0. 3 . 
1 4. 2. 3  
P R O MI S Sc ores   
P F is assesse d wit h t he P R O MI S n q S h ort F or m v 2. 0 –  P h ysi cal F u n cti o n –  M ulti ple Scler osis 1 5a 
(P R O MI S n q P F( M S) 1 5a ). Fati g ue is assesse d wit h t he P R O MI S S h ort F or m v 1. 0 –  Fati g ue –  
M ulti ple Scler osis 8a (P R O MI S Fati g u e ( M S)  8a ). P R O MI S P F a n d Fati g u e sc ore s are ass esse d i n 
all partici pa nts at Baseli ne  V isit, a n d e ver y 1 2 wee ks u ntil t he e n d of t he st u d y peri o d u p t o 
1 5 6  wee ks .  
1 4. 2. 3. 1  
P R O MI S P F Sc ore C F B  o ver 9 6  Wee k s  
T he 5  esti ma n d attri b utes of sec o n dar y efficac y esti ma n ds C F B i n P R O MI S P F sc ore are:  
•  E n d p oi nt : C F B i n P R O MI S P F sc ore o ver 9 6  wee ks  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 1 /1 5 9  
 
 
 
•  Tre at me nt c o n diti o n of i nterest : E v o br uti ni b 4 5 m g t wice d ail y f or u p t o 1 5 6  wee ks ; 
alter nati ve treat me nt c o n diti o n t o w hic h c o m p aris o n will be m a de: t erifl u n o mi de 1 4 m g 
o nce dail y f or u p t o 1 5 6  wee ks . 
•  P o p ul ati o n : Partici pa nts wit h R M S as defi ne d b y i ncl usi o n/e xcl usi o n criteria. 
•  Str ate gies use d t o a d dress I C Es :  
o  Treat me nt disc o nti n uati o n: Treat me nt P olic y str ate g y.  
o  Deat h (a n y ca us e): W hile ali ve strate g y  
o  U krai ne crisis: H y p ot heti cal strate g y  
o  C O VI D -1 9  i nfecti o n, C O VI D -1 9  vacci nati o n a n d e mer ge nc y 
u n bli n di n g: 
Treat me nt P olic y strate g y.  
•  P o p ul ati o n -le vel s u m m ar y c o m pari n g t he i nter ve nti o n gr o u ps is t he differe nce of a v era ge 
least-sq uares mea ns of s c ore C F B (a v era ge o ver Wee ks 7 2, 8 4 a n d 9 6) a n d CI bas e d o n a 
M M R M, wit h test of treat me nt effect base d o n differe n ce of a vera ge least -s q uares mea ns. 
Data are p o ole d fr o m t he F A S of t he st u dies 0 0 8 0 a n d  
.  
Meas ures fr o m t h e P R O MI S P F it e m ba n k are s c ore d o n a T -sc ore metri c ( hi g her sc ores = hi g h er 
P F).  
Missi n g D at a H a n dli n g  
F or partici pa nts wit h missi n g P R O MI S P F d ata, t he missi n g data will be ass u me d t o be M A R; 
s uc h partici p a nts will b e ass u me d t o ha v e t he s a me mea n P R O MI S P F sc ore C F B  tr aject or y 
t hr o u g h 9 6  w ee ks as p artici pa nts wit h a vaila ble data wit hi n t he sa me i nter ve nti o n gr o u p a n d 
strat u m, a n d ha vi n g t he s a me baseli ne  s c ore a n d st u d y I D. 
H a n dli n g of I C Es 
I n t his st u d y, t h e I C E of treat me nt disc o nti n uati o n is ha n dle d b y t he Treat me nt P olic y str ate g y, i n 
w hic h data p ost pre mat ure treat me nt disc o nti n uati o n, i.e. at Safet y  F oll o w -u p  V isit, are us e d i n t h e 
a nal ysis. H o we v er, P R O MI S sc ores are n ot assess e d  at t he Safet y  F oll o w -u p  V isit. T h us, t he data 
t o i ncl u de i n t he a nal ysis of P R O MI S sc ores are t he sa me, re gar dless of w het her t he partici pa nt  is 
a treat me nt disc o nti n uer or has treat me nt o n g oi n g/ c o m pleted : all a v aila ble assess me nts  w hile o n 
treat me nt o ver 9 6  wee ks p ost ra n d o mizati o n  are i ncl u de d i n t he a nal ysis.  
I n acc or da n ce wit h t he W hile Ali ve strate g y, f or partici pa nts e x perie nci n g t he I C E deat h  (a n y 
ca use), all P R O MI S P F d ata u p t o t he ti me of deat h will be use d i n t he a nal ysis.  
Partici pa nts at sites n ot f ull y o p erati o nal p ost start of U krai ne crisis will be c o nsi dere d t o ha v e 
e x perie nce d t h e I C E ‘ U krai ne crisis’. T his I C E will be ha n dle d usi n g t h e H y p ot hetical strate g y, 
w here t he h y p ot h etical sce nari o e n visa ge d is o ne i n w hic h t h e crisis ha d ne ver ha p pe n e d.  T he d ata 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 2 /1 5 9  
 
 
 
fr o m s uc h partici pa nts will be ce ns ore d at t he ti me at w hic h t he site l ost f ull y o perati o nal stat us. 
Ce ns ori n g at t he e n d of t he pre -crisis peri o d is n o ni nf or mati ve f or t he o utc o me of i nterest 
( P R O MI S P F Sc ore C F B). 
I n acc or da n ce wit h t he Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C Es 
‘C O VI D -1 9  i nfecti o n’, ‘C O VI D -1 9  v acci n ati o n’  or ‘e mer ge n c y u n bli n di n g’ , t he occ urre nce of 
t hese I C Es is c o nsi dere d irrele va nt i n t he pri mar y a nal ysis of P R O MI S P F Sc ore C F B.  
I nfere nti al a n al ysis 
T he p o p ulati o n -le vel s u m mar y c o m p ari n g t he i nter ve nti o n gr o u ps will be t he differe n ce i n a vera ge 
least-sq uares mea ns, b as e d o n a M M R M f or C F B,  wit h a vera ge ta ke n o ver Wee ks 7 2 , 8 4  a n d 9 6, 
w here t h e m o del i ncl u des ter ms f or i nter ve nti o n gr o u p, visit, i nter ve nti o n gr o u p b y visit 
i nteracti o n, baseli ne  sc ore, baseli ne  sc ore b y visit i nteracti o n, ra n d o mizati o n strata, a n d st u d y I D, 
a n d w here t h e data are p o ole d fr o m t he F A S of st u dies 0 0 8 0 a n d 
. Data u p t o a n d i ncl u di n g 
a nal ysis vis it Wee k  9 6 will be i ncl u de d i n t he m o de l. T he u nstr uct ur e d c o varia nce matri x will be 
c o nsi dere d. D e n o mi nat or de grees of free d o m will be c o m p ute d usi n g Ke n war d a n d R o ger’s 
met h o d  (Ke n w ar d 1 9 9 7 ). If t he m o del fails t o c o n v er ge, t he b aseli ne  s c ore b y visit i nteracti o n will 
be o mitte d.  
T he differe nce (c o m pari n g e v o br uti ni b a n d terifl u n o mi de) i n a vera ge least-sq uares mea n C F B, 
9 5 % 2 -si de d CI, (al p ha-c o m pati ble) 9 5. 1 2 5 % CI a n d 1-si de d p-val ue will be r e p orte d. F or eac h 
i nter ve nti o n gr o u p, t h e a dj uste d a vera ge least-sq uares mea n sc ore C F B a n d ass ociate d 9 5 % 2 -si de d 
CI will be re p orte d.  I n a d diti o n, t he res ults of t he M M R M will be pres e nte d gra p hicall y b y 
i nter ve nti o n gr o u p wit h p oi nts f or t he esti mates per visit a n d err or bars f or t he 9 5 % CIs.  
T he M A R ass u m pti o n u n der pi ns  t he esti mat or of differe n ce of a vera ge L S mea ns i m ple me nte d b y 
t he M M R M t hat uses o bser ve d s c ore C F B d ata fr o m eac h partici p a nt, re gar dless of tr eat me nt 
c o m pleted / disc o nti n ued/ o n g oi n g  stat us.  
Descri pti ve a n al ysis  
A fi g ure will be pr o vi de d descri bi n g t he distri b uti o n of a vera ge C F B  ta ke n o ver Wee ks  7 2, 8 4 a n d 
9 6 , wit h o ne c ur ve f or eac h i nter ve nti o n gr o u p. T he esti mate d e m pirical c u m ulati ve distri b uti o n 
f u ncti o n c ur ve f or a vera ge C F B will dis pla y pr o p orti o n of partici p a nt s ha vi n g a v al ue u p t o  a v era ge 
C F B.  
Descri pti ve statistics f or P R O MI S sc ore s a n d C F B at eac h visit  (i ncl u di n g visits p ost Wee k 9 6) 
will be pr o vi de d b y i nter ve nti o n gr o u p.  
N u m ber a n d p erce nta ges of partici pa nts e x p erie n ci n g I C Es will als o be pres e nte d. 
•  I n a d diti o n, t he ra w m ea n sc ore o ver ti me will be prese nte d as a b y -visit b o x pl ot f or eac h st u d y 
i nter ve nti o n gr o u p i n a si n gle fi g ure.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 3 /1 5 9  
 
 
 
1 4. 2. 3. 2  
P R O MI S F ati g ue Sc ore C F B  o ver 9 6  Wee k s  
Meas ures fr o m t he fati g ue ite m ba n k are sc ore d o n a 
T -sc ore metric ( hi g her sc ores =  hi g her 
fati g u e).  
•  T he sec o n dar y esti ma n d , C F B i n P R O MI S Fati g ue sc ore o ver  9 6  wee ks , will be a nal yz e d i n t he 
sa me ma n ner as C F B i n P R O MI S P F sc ore o ver  9 6  wee ks, e x ce pt t hat t he a vera ge will be ta ke n 
o ver Wee ks 4 8, 6 0 , 7 2, 8 4 a n d 9 6.   
1 4. 2. 3. 3  
Se nsiti vit y A n al yses: P R O MI S Sc ore C F B   
T he f oll o wi n g se nsiti vit y a nal ys es f or P R O MI S P F sc ore C F B o ver  9 6  wee ks  are pla n ne d , wit h 
t he sa me ha n dli n g of I C Es as i n t he pri mar y a nal ysis , u nless ot her wise s pecifie d,  base d o n p o ole d 
data fr o m t he 2  P hase  3  st u dies: 
1.  A nal ysis t o e val uate t he p ote ntial i nfl ue nce of i nf or mati ve treat me nt disc o nti n uati o n acc or di n g 
t o disc o nti n uati o n reas o n. 
T his se nsiti vit y a nal ysis will use t he sa me M M R M m o del use d i n t he pri mar y a n al ysis of 
P R O MI S P F Sc ore C F B a vera ge d o ver  Wee k s 7 2, 8 4 a n d 9 6 a n d re p ort t h e res ulti n g differe nce 
i n a vera ge L S mea ns  d ue t o treat me nt , 9 5 % CI, a n d 1 -si de d p -val ue  f or t he si g nifica n ce of t h e 
treat me nt effect. I n a d diti o n, a f orest pl ot will prese nt t he differe nce i n a v era ge L S mea ns, 9 5 % 
CI a n d p -val ue f or eac h d elta.  
T he f oll o wi n g a p plies t o partici pa nts i n t he e v o br uti ni b i nter ve nti o n gr o u p. If a p artici pa nt’s 
disc o nti n uati o n is u nrelate d t o treat me nt ( i.e. u nrelate d t o efficac y or safet y iss ues), t he 
partici pa nt’s s c ore C F B at eac h ti me p oi nt will be m ulti pl y i m p ute d usi n g C F B distri b uti o n at 
t hat ti me p oi nt i n t he c o m parat or gr o u p  (a dj uste d f or t he partici pa nt’s strat u m a n d baseli ne  
sc ore), f or t he i nter val bet wee n disc o nti n uati o n a n d 9 6  wee ks p ost ra n d o mizati o n  or P A c ut off, 
w hic he ver occ urs first . If a partici pa nt’s dis c o nti n uati o n is relate d t o treat me nt, t h e 
partici pa nt’s sc ore C F B at eac h ti me p oi nt will be m ulti pl y i m p ute d usi n g a w orse C F B 
distri b uti o n at t hat ti me p oi nt t ha n t hat i n t he c o m parat or gr o u p  (a dj uste d f or t he p artici pa nt’s 
strat u m a n d baseli ne  s c ore), f or t he i nter val bet wee n disc o nti n uati o n a n d 9 6  wee ks p ost 
ra n d o mizati o n or P A c ut off, w hic he ver occ urs first. T he c o m parat or C F B after wit h dra wal will 
be s hifte d b y delta ra n gi n g fr o m 1 t o a ma xi m u m of 1 0 i n ste ps of 1 (st o p pe d at t he p oi nt at 
w hic h t he differe n ce c o m pari n g e v o br uti ni b a n d terifl u n o mi de  is n ot statisticall y si g nifica nt). 
T he s hift i n dicati n g w ors e C F B distri b uti o n is gi ve n  as decrease d sc ore f or P R O MI S P F a n d 
as i ncrease d sc ore  f or P R O MIS Fati g u e. F or partici pa nts wit h disc o nti n uati o n o f treat me nt (all 
reas o ns) i n terifl u n o mi de gr o u p, t he C F B will be m ulti pl y i m p ute d u n der t he M AR  ass u m pti o n.  
C o ntr ol -base d patter n i m p utati o n a n d delta -a dj uste d patter n i m p utati o n will be a p plie d  
(Little  1 9 9 6 , O' K ell y  2 0 1 4 , Ratitc h  2 0 1 3 ) see A p pe n di x  1 8. 9  f or details.  
Treat me nt ter mi nati o n wit h pri mar y reas o n e ntere d as ‘a d v erse e ve nt’, ‘lac k of efficac y’ a n d 
‘ deat h’ i n t he e C R F T T E R M f or m will be c o nsi dere d as relate d t o treat me nt. Ot her treat me nt 
ter mi nati o ns (i.e. pri mar y reas o n e q ual t o ‘l ost t o f oll o w-u p ’, ‘ pr ot oc ol n o n -c o m plia nce’, 
‘ wit h dra wal b y s u bject’ a n d ‘ ot her’) will be c o nsi dere d as u nrelate d t o treat me nt. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 4 /1 5 9  
 
 
 
2.  A nal ysis t o e v al uate t he p ote ntial i m pact of m o del mi ss pecificati o n. 
T his se nsiti vit y a n al ysis will a d d t he f oll o wi n g c o variates t o t he mi x e d m o del: n u m ber of 
rela pses i n t he 2  years bef ore Scree ni n g , pres e nce/ a bsence of T 1 G d + lesi o ns wit hi n 6  m o nt hs  
pri or t o ra n d o mizati o n, pri or D M T  ( y/ n), a n d a ge, as defi ne d i n Secti o n  8. 2 . T he sa me 
i nfere ntial r es ults will be re p orte d as f or t he pri mar y a n al ysis.  
3.  A nal ysis t o e v al uate t he p ote ntial i m pact of C O VI D -1 9  i nfecti o n. 
T his se nsiti vit y a na l ysis will ha n dle t he I C E of C O VI D -1 9  i nfecti o n wit h t he H y p ot hetical 
strate g y, i.e. all of a partici pa nt’s data o n t he da y of a n d after t h e i nfecti o n will be ce ns ore d.  
T his is i n c o ntrast t o t he pri mar y a nal ysis i n w hic h a n y C O VI D -1 9 -relate d I C Es are i g n ore d i n 
t he a nal ysis (i.e. Treat me nt P olic y str ate g y).  Ce ns ori n g at t he ti me of i nf ecti o n will be  ass u me d 
t o be n o n -i nf or mati ve f or t he o utc o me of i nterest ( P R O MI S sc ore C F B) . 
T he I C E ' C O VI D -1 9  vacci nati o n' will be h a n dle d via Treat me nt P olic y strate g y as i n pri mar y 
a nal ysis . Partici pa nts e x perie nci n g t he I C E 'C O VI D -1 9  i nf ecti o n' will be i de ntifie d as t h ose 
wit h A Es relate d t o C O VI D -1 9  as defi ne d i n Secti o n  1 5. 2. 4.  T he h y p ot hetical sce nari o 
e n visa ge d is t hat C O VI D -1 9  i nfecti o n d oes n ot occ ur, b ut C O VI D -1 9  v acci nati o n d oes.  
4.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he war i n U krai n e. 
I n t he first se nsiti vit y a nal ysis of P R O MI S sc ore C F B rel ate d t o t he i m pact of t he war i n 
U krai ne, all partici pa nts fr o m sites i n U krai ne will ha ve t heir data ce ns ore d at t he start of t he 
crisis (i.e. 2 4  Fe br uar y  2 0 2 2 ). T he h y p ot hetical sce nari o e n visa ge d is o n e i n w hic h t he crisis 
(affecti n g o nl y U krai ne p artici pa nts) ha d n ot o cc urre d. I n a sec o n d se nsiti vit y a nal ysis relate d 
t o t he i m pact of war i n U krai ne, all partici pa nts fr o m sites i n U krai ne, R ussia n Fe derati o n, a n d 
Belar us will ha ve t h eir data ce ns ore d at t he start of t he crisis. T he h y p ot hetical sce n ari o 
e n visa ge d is o ne i n w hic h t he crisis (affecti n g partici pa nts fr o m U krai ne, R ussia n Fe derati o n, 
a n d Bel ar us) ha d n o t occ urre d. T he ce ns ore d data will n ot be i m p ute d; ce ns ori n g at t he ti me of 
t he start of t he crisis will be ass u me d t o be n o ni nf or mati ve f or t he o utc o me of i nterest 
( P R O MI S Sc ore C F B). 
5.  m F A S anal ysis.  
I n t his se nsiti vit y a nal ysis, t he pri mar y a nal ysis of P R O MI S sc ore C F B  will be re peat e d o n t he 
m F A S.  
6.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he sec o n d recr uit me nt c o h ort.  
T his se nsiti vit y a n al ysis will a d d t he f oll o wi n g c o variate t o t he mi x e d m o del: me m bers hi p i n 
sec o n d recr uit me nt c o h ort ( yes/ n o), as d efi ne d i n Secti o n  8. 2 . T h e sa m e i nf ere ntial res ults will 
be re p ort e d as f or t h e pri mar y a nal ysis wit h t he p -val ue of t he a d diti o nal c o variate re p orte d.  
T he s e nsiti vit y a n al ys es f or P R O MI S Fati g ue sc ore C F B a vera ge d o ver Wee ks  4 8, 6 0, 7 2, 8 4 a n d 
9 6 will be si milar.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 5 /1 5 9  
 
 
 
1 4. 2. 4  
M RI Lesi o n Me as ures   
T he 5  esti ma n d attri b utes of sec o n dar y M RI lesi o n meas ure efficac y esti ma n ds are:  
•  E n d p oi nt :  
o  T otal n u m ber of T 1 G d + lesi o ns base d o n all a vail a ble M RI sca n.  
o  N u m ber of ne w or e nl ar gi n g T 2 (acti ve T 2) lesi o ns base d o n t he last a vaila ble M RI 
sca n rel ati ve t o t he baseli ne  M RI s ca n.  
•  Tre at me nt c o n diti o n of i nte rest: E v o br uti ni b 4 5 m g t wice d ail y f or u p t o 1 5 6  wee ks ; 
alter nati ve treat me nt c o n diti o n t o w hic h c o m p aris o n will be m a de: t erifl u n o mi de 1 4 m g 
o nce dail y f or u p t o 1 5 6  wee ks . 
•  P o p ul ati o n : Partici pa nts wit h R M S as defi ne d b y i ncl usi o n/e xcl usi o n criteria. 
•  Str ate gies use d t o a d dress I C Es :  
o  Treat me nt disc o nti n uati o n: Treat me nt p olic y strat e g y.  
o  Deat h (a n y ca us e): W hile ali ve strate g y 
o  U krai ne crisis: H y p ot heti cal strate g y  
o  C O VI D -1 9  i nfecti o n, C O VI D -1 9  vacci nati o n a n d e mer ge nc y 
u n bli n di n g: 
Treat me nt P olic y strate g y.  
•  P o p ul ati o n -le vel s u m m ar y c o m pari n g t he i nter ve nti o n gr o u ps is lesi o n rate rati o a n d CI 
base d o n N B m o del, wit h test of treat me nt effect base d o n test of l esi o n rate rati o, wit h 
offset defi n e d i n Secti o ns 1 4. 2. 4. 1  a n d 1 4. 2. 4. 2 . 
Brai n 
M RIs are sc h e d ule d  at Scree ni n g  a n d 
Wee ks 2 4, 4 8, 9 6, 1 5 6 a nd earl y tr eat me nt  
d isc o ntin uati o n . Vari o us M RI deri ve d para meters ha ve bee n relat e d t o disease acti vit y, i ncl u di n g 
T 1 G d + lesi o ns a n d acti ve T 2 lesi o ns.  
1 4. 2. 4. 1  
T ot al N u m ber of T 1 G d + lesi o ns B ase d o n All A v ail a ble M RI 
Sc a ns   
T he t otal n u m ber of T 1 G d + lesi o ns f or a p artici p a nt will be calc ulate d as t he s u m of ne w T 1 G d +  
lesi o ns fr o m n o n -missi n g p ost  b aseli ne  s ca ns. L o g n u m b er of n o n -missi n g s ca ns c ontri b uti n g t o 
t he t otal is use d as t he offset i n N B m o deli n g . A nal yses are pres e nte d f or eac h st u d y se paratel y 
base d o n F A S.   
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 6 /1 5 9  
 
 
 
Missi n g D at a H a n dli n g  
F or partici pa nts missi n g o ne or m ore s ca ns, t he missi n g data will be ass u me d t o be M A R; s uc h a 
partici pa nt will be ass u me d t o e x perie nce lesi o ns t hr o u g h pla n ne d e n d of treat me nt ( i.e. P A c ut off 
or 1 5 6  wee ks  ( Secti o n 9. 1 3 ), w hic he ver occ urs first) at t he sa me rate as partici pa nt s wit h  a vaila ble 
data wit hi n t he sa me i nter ve nti o n gr o u p a n d str at u m a n d ha vi n g t he sa m e b aseli ne  lesi o n acti vit y 
( prese n ce/a bs e nce).  
H a n dli n g of I CEs  
I n t his st u d y, t h e I C E of treat me nt disc o nti n uati o n is ha n dle d b y t he Treat me nt P olic y str ate g y, i n 
w hic h data p ost pre mat ure treat me nt disc o nti n uati o n, i.e. at Safet y  F oll o w -u p  V isit, are us e d i n t h e 
a nal ysis. H o we v er, M RI sca ns are n ot sc h e d ule d at t he Safet y  F oll o w -u p  V isit. T h us, t he data t o 
i ncl u de i n t he a nal ysis of T 1 G d + lesi o ns are t he sa me, re gar dless of w het h er t he partici pa nt  is a 
treat me nt disc o nti n uer or has  tr eat me nt o n g oi n g/c o m plete d : all a v aila ble sca ns w hile o n treat me nt 
are i ncl u de d i n t he a nal ysis.  
I n acc or da n ce wit h t he W hile Ali ve strate g y, f or partici pa nts e x perie nci n g t he I C E deat h  (a n y 
ca use), all T 1 G d + lesi o n data u p t o t he ti me of deat h will be use d i n t he a n al ysis.  
Partici pa nts at sites n ot f ull y o perati o nal, p ost start of U krai ne crisis will be c o n si dere d t o ha v e 
e x perie nce d t h e I C E ‘ U krai ne crisis’. T his I C E will be ha n dle d usi n g t h e H y p ot hetical strate g y, 
w here t he h y p ot h etical sce nari o e n visa ge d is o ne i n w hic h t he crisis ha d ne ver ha p pe n e d.  T he d ata 
fr o m s uc h partici pa nts will be ce ns ore d at t he ti me at w hic h t he site l ost f ull y o perati o nal stat us. 
Ce ns ori n g at t he e n d of t he pre -crisis peri o d is n o n -i nf or mati ve f or t he o utc o me of i nterest ( T 1 
G d + lesi o ns).  
I n acc or da n ce wit h t he Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C Es 
‘C O VI D -1 9  i nfecti o n’, ‘C O VI D -1 9  v acci n ati o n’  or ‘e mer ge n c y u n bli n di n g’ , t he occ urre nce of 
t hese I C Es is c o nsi dere d irrele va nt i n t he pri mar y a nal ysis of T 1 G d + lesi o ns. 
I nfere nti al a n al ysis 
T he p o p ulati o n -le vel s u m mar y c o m pari n g t he i nter ve nti o n gr o u ps is lesi o n rate rati o, base d o n a 
N B m o del f or lesi o n c o u nt, wit h ter ms f or i nter ve nti o n gr o u p, ra n d o mizati o n strata, a n d baseli ne  
lesi o n acti vit y (i. e. pres e nce/a bs e nce of T 1 G d + lesi o ns at bas eli ne ), wit h offset e q u al t o l o g 
n u m ber of t otal a vaila ble sca ns over w hic h t he lesi o ns e x perie nce d b y a partici pa nt are o bser ve d . 
T he a dj uste d lesi o n R R c o m pari n g e v o br uti ni b t o terifl u n o mi de esti mate d fr o m t he N B m o del, 
9 5 % 2 -si de d CI, a n d 1-si de d p-val u e will be re p orte d, t o get her wit h a dj uste d lesi o n rate f or eac h 
i nter ve nti o n gr o u p a n d ass ociate d 9 5 % 2-si de d CI. I n a d diti o n, t he lesi o n R R will be e x presse d as 
perce nt a ge re d ucti o n relati ve t o terifl u n o mi de. T he a nal ysis of t otal n u m ber of T 1 G d + lesi o ns will 
be base d o n d ata fr o m a si n gle st u d y ( 0 0 8 0 or  
).  
T he M A R  ass u m pti o n u n der pi ns t he rate rati o esti mat or i m ple me nte d b y t h e N B m o del t hat us es 
o bser ve d l esi o n c o u nt a n d n u m ber of sca ns gi vi n g rise t o t hat c o u nt f or eac h partici pa nt, re gar dl ess 
of treat me nt c o m plete d /disc o nti n ue d/ o n g oi n g stat us. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 7 /1 5 9  
 
 
 
Descri pti ve a n al ys is 
 
Descri pti ve statistics f or t he n u m ber of ne w T 1 G d + lesi o ns b y ti me p oi nt u p t o 1 5 6  wee ks  will be 
pr o vi de d b y i nter ve nti o n gr o u p.   
N u m ber a n d p erce nta ges of partici pa nts e x perie n ci n g I C Es will als o be pres e nte d. 
Mea n n u m ber of T 1 G d + lesi o ns at a gi ve n visit will be prese nte d as a b y -visit li ne pl ot f or eac h 
i nter ve nti o n gr o u p, wit h a vertical li ne se g m e nt at eac h visit re prese nti n g ± S E (jittere d if nee de d 
f or le gi bilit y), a n d wit h b ot h i nter ve nti o n gr o u ps i ncl u de d i n a si n gle fi g ure. Pr o p ort i o n of 
partici pa nt s w h o are T 1 G d + lesi o n -free will be prese nt e d as a b y-visit li ne pl ot f or eac h 
i nter ve nti o n gr o u p ( verti cal li ne se g me nt at eac h visit re prese nti n g 9 5 % CI ma y be o mitte d f or 
le gi bilit y), a n d wit h b ot h i nter ve nti o n gr o u ps i n cl u de d i n a si n gle fi g ure.  I n t hese fi g ures, t he 
s paci n g of tic k mar ks o n t he h oriz o ntal a xis s h o ul d reflect t he ti me i nter val bet wee n visits ( i.e. 
visits t hat are n o n u nif or ml y s pace d i n ti me s h o ul d be n o n u nif or ml y s pace d o n t he h oriz o ntal a xis).   
Mea n n u m ber of T 1 G d + lesi o ns per  sca n esti mate d base d o n t he N B m o del , will be prese nte d as 
a gr o u pe d bar c hart  b y i nter ve nti o n gr o u p, wit h a vertical li ne se g me nt f or eac h bar re prese nti n g 
9 5 % 2 -si de d CI, a n d wit h t he p-val ue f or t he c o m p aris o n wit h terifl u n o mi de  ( base d o n N B m o del) 
dis pla ye d a b o ve t he gr o u pe d bar  c h art pair .  
1 4. 2. 4. 2  
N u m ber of ne w or e nl ar gi n g T 2 lesi o ns o n t he L ast A v ail a ble 
M RI Sc a n Rel ati ve t o t he B aseli ne  M RI Sc a n   
T he n u m ber of ne w/e nlar gi n g T 2 lesi o ns o n t he last a vaila ble sca n  relati ve t o t he baseli ne  sca n 
will be calc ulate d as t he s u m of ne w/e nlar gi n g T 2 lesi o ns fr o m n o n -missi n g sca ns. F or eac h sca n 
c ollecte d, N e ur o R x re p orts t he n u m ber of ne w/e nl ar gi n g T 2 lesi o ns relati v e t o t he pre vi o us scan.  
T h us , f or e x a m ple, s u m mi n g t he ne w/e nlar gi n g T 2 lesi o ns fr o m t he Wee k  2 4  a n d Wee k  4 8  sca ns 
pr o vi des t he s u m of ne w/e nlar gi n g T 2 l esi o ns at Wee k  2 4  relati ve t o bas eli ne  (i.e. Scree ni n g) a n d 
ne w/e nlar gi n g T 2 lesi o ns at Wee k  4 8  relati ve t o Wee k  2 4 .  
If a p artici pa nt h as sca ns o nl y at Wee k  2 4  a n d W ee k  9 6 , t he Ne ur o R x M RI rea d er will i de ntif y 
ne w/e nlar gi n g T 2 lesi o ns at Wee k  9 6  relati ve t o t he pre vi o usl y  a vaila ble s ca n at Wee k  2 4 . T h us,  
s u m mi n g t he ne w/e nlar gi n g T 2 lesi o ns fr o m t he W ee k  2 4  a n d Wee k  9 6  sca ns pr o vi des t he s u m of 
ne w/e nlar gi n g T 2 lesi o ns at Wee k  2 4  relati ve t o baseli ne  (i. e. Scree ni n g) a n d ne w/ e nlar gi n g T 2 
lesi o ns at Wee k  9 6  relati ve t o Wee k  2 4 .  
T he ti me bet w ee n t h e last a vaila ble sca n a n d t h e baseli ne  sca n (i n years) is use d as t he offs et i n t he 
N B m o deli n g.  T he ti me (i n years) fr o m Scree ni n g  s ca n will be calc ulate d as ( date of last sc h e d ule d 
M RI sca n wit h a n o n -missi n g val ue f or t he n u m ber of ne w or e nlar gi n g T 2 lesi o ns –  date of 
Scree ni n g  sca n + 1)/ 3 65. 2 5.  
T he s a me missi n g data h a n dli n g  a n d I C E str ate g y use d i n t he a n al ysis of T otal n u m ber of T 1 G d + 
lesi o ns will be use d i n t he a nal ysis of N u m ber of ne w/e nlar gi n g T 2 lesi o ns . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 8 /1 5 9  
 
 
 
I nfere nti al a n al ysis 
T he p o p ulati o n -le vel s u m mar y c o m pari n g t he i nter ve nti o n gr o u ps is lesi o n rate rati o, base d o n a 
N B re gressi o n m o del f or lesi o n c o u nt, wit h ter ms f or i nter ve nti o n gr o u p, ra n d o mizati o n strata, a n d 
baseli ne  v ol u me of T 2 lesi o n  (as c o nti n u o us c o variate ), wit h offset e q ual t o l o g ti me bet wee n t he 
last a vaila ble sca n a n d b aseli ne  sca n (i n years). T h e a dj uste d lesi o n R R c o m pari n g e v o br uti ni b t o 
terifl u n o mi de esti mate d fr o m t he N B m o del, 9 5 % 2-si de d CI, a n d 1-si de d p-val ue will be re p orte d, 
t o get her wit h a dj uste d lesi o n rate f or eac h i nter ve nti o n gr o u p a n d ass ociat e d 9 5 % 2 -si de d CI. I n 
a d diti o n, t he lesi o n R R will be e x presse d as perce nta ge re d ucti o n relati v e t o terifl u n o mi de. T he 
a nal ysis of t otal n u m ber of ne w or e nlar gi n g T 2  lesi o ns will be bas e d o n d ata fr o m a si n gle st u d y 
( 0 0 8 0 or  
). 
Descri pti ve a n al ysis  
Descri pti ve statistics f or t he n u m ber of n e w/e nlar gi n g T 2  lesi o ns b y ti me p oi nt u p t o 1 5 6  wee ks  
will be pr o vi de d b y i nter ve nti o n gr o u p.   
N u m ber a n d p erce nta ges of partici pa nts e x perie n ci n g I C Es will als o be pres e nte d.  
Mea n n u m ber of ne w/e nl ar gi n g  lesi o ns at a gi ve n visit will be prese nte d as a b y-visit li ne pl ot f or 
eac h i nter ve nti o n gr o u p, wit h a v ertical li ne se g me nt at eac h visit re pres e nti n g ± S E (jittere d if 
nee de d f or le gi bilit y) , a n d wit h b ot h i nter ve nti o n gr o u ps i ncl u de d i n a si n gle fi g ure. Pr o p orti o n of 
partici pa nts w h o are ne w/e nlar gi n g T 2  lesi o n-free will be prese nte d as a b y-visit li ne pl ot f or eac h 
i nter ve nti o n gr o u p ( verti cal li ne se g me nt at eac h visit re prese nti n g 9 5 % CI ma y be o mi tte d f or 
le gi bilit y), a n d wit h b ot h i nter ve nti o n gr o u ps i ncl u de d i n a si n gle fi g ure. T h e  s paci n g of tic k mar ks 
o n t he h oriz o ntal a xis s h o ul d reflect t he ti me i nter val bet wee n visits . 
Mea n n u m ber of ne w/ e nlar gi n g T 2  lesi o ns per year esti mate d bas e d o n t he N B m o del  will be 
prese nte d as a gr o u pe d b ar c hart b y i nter ve nti o n gr o u p, wit h a vertical li ne se g m e nt f or eac h bar 
re pres e nti n g 9 5 % 2-si de d CI, a n d wit h t he p-val ue f or t he c o m paris o n wit h terifl u n o mi de ( base d 
o n N B m o del) dis pla ye d a b o ve t he gr o u pe d bar c h art pair.  
1 4. 2. 4. 3  
Se nsiti vit y / S u p ple me nt ar y A n al yses: M RI Lesi o n Me as ures   
T he f oll o wi n g se nsiti vit y a nal ys es f or t otal n u m ber of  T 1 G d + lesi o ns  are pla n ne d , wit h t he sa me 
ha n dli n g of I C Es as i n t he pri mar y a n al ysis , u nless ot her wise s pecifie d : 
1.  A nal ysis t o e val uate t he p ote ntial i nfl ue nce of i nf or mati ve treat me nt disc o nti n uati o n acc or di n g 
t o disc o nti n uati o n reas o n. 
T his se nsiti vit y a n al ysis will use t he sa me N B m o del us e d i n t he pri mar y a nal ysis of t otal T 1 
G d + lesi o ns base d o n all a vaila ble M RI sca ns . T he lesi o n rate rati o f or treat me nt effect will be 
re p orte d, t o get her wit h 9 5 % 2-si de d CI, a n d 1-si de d p-val ue f or t he si g nifica nce of t he 
treat me nt effect. I n a d diti o n, a f orest pl ot will prese nt t he lesi o n rate rati o, 9 5 % CI a n d p-val ue 
f or eac h delta. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
7 9 /1 5 9  
 
 
 
T he f oll o wi n g a p plies t o partici pa nts i n t he e v o br uti ni b i nter ve nti o n gr o u p. If a p artici pa nt’s 
disc o nti n uati o n is u nrelate d t o treat me nt ( i.e. u nrelate d t o efficac y or saf et y iss ues), t he 
partici pa nt’s lesi o n c o u nt will be m ulti pl y i m p ut e d usi n g t h e rat e i n t he co m parat or gr o u p  
(a dj uste d f or t he p artici p a nt’s strat u m a n d baseli n e  lesi o n acti vit y) b ase d o n C R MI m et h o d , 
f or t he i nter val bet wee n disc o nti n uati o n a n d pla n ne d e n d of tr eat me nt ( i.e. P A c ut off or 
1 5 6  wee ks  p ost ra n d o mizati o n , w hic he ver occ urs first). If a partici p a nt’s disc o nti n uati o n is 
relate d t o treat me nt, lesi o n c o u nt will be m ulti pl y i m p ute d at a rate hi g her t ha n t hat i n 
c o m parat or gr o u p  (a dj uste d f or t he partici pa nt’s strat u m a n d bas eli ne  lesi o n acti vit y), f or t he 
i nter val bet wee n disc o nti n uati o n a n d pla n ne d e n d of treat me nt . T he c o m parat or rate after 
wit h dra wal will be m ulti plie d b y delta, ra n gi n g fr o m 1 t o 3. 1 ( ~tri pli n g of rela pse rate) i n ste ps 
of 0. 3. F or partici p a nts wit h disc o nti n uati o n of treat me nt (all reas o ns) i n t he terifl u n o mi de 
gr o u p, t h e rela ps e c o u nt will be m ult i pl y i m p ute d u n der t he M A R ass u m pti o n.   
MI met h o ds f or c o u nt data are a p plie d f oll o wi n g t he a p pr oac h fr o m 
Kee ne 2 0 1 4 , s ee 
A p pe n di x  1 8. 9  f or details. 
Treat me nt ter mi nati o n wit h pri mar y reas o n e ntere d as ‘a d v erse e ve nt’, ‘lac k of efficac y’ a n d 
‘ deat h’ i n t he e C R F T T E R M f or m will be c o nsi dere d as relate d t o treat me nt. Ot her treat me nt 
ter mi nati o ns (i.e. pri mar y reas o n e q ual t o ‘l ost t o f oll o w-u p ’, ‘ pr ot oc ol n o n -c o m plia nce’, 
‘ wit h dra wal b y s u bject’ a n d ‘ ot her’) will be c o nsi dere d as u nrelate d t o treat me nt. 
2.  A nal ysis t o e v al uate t he p ote ntial i m pact of C O VI D -1 9  i nfecti o n. 
T his se nsiti vit y a nal ysis will ha n dle t he I C E of C O VI D -1 9  i nfecti o n wit h t he H y p ot hetical 
strate g y, i.e. all of a partici pa nt’s data o n t he da y of a n d after t h e i nfecti o n will be ce ns ore d. 
T his is i n c o ntrast t o t he pri mar y a nal ysis i n w hic h a n y C O VI D -1 9 -relate d I C Es are i g n ore d i n 
t he a nal ysis (i.e. Treat me nt P olic y str ate g y).  Ce ns ori n g at t he ti me of i nf ecti o n will be  ass u me d 
t o be n o n -i nf or mati ve f or t he o utc o me of i nterest (T 1 G d +  lesi o ns). 
T he  I C E 'C O VI D -1 9  vacci nati o n' will be h a n dle d via Treat me nt P olic y strate g y as i n pri mar y 
a nal ysis . Partici pa nts e x perie nci n g t he I C E ' C O VI D -1 9  i nf ecti o n' will be i de ntifie d as t h ose 
wit h A Es relate d t o C O VI D -1 9  as defi ne d i n Secti o n  1 5. 2. 4.  T he h y p ot hetical sce nari o 
e n visa ge d is t hat C O VI D -1 9  i nfecti o n d oes n ot occ ur b ut C O VI D -1 9  v acci nati o n d oes.  
3.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he war i n U krai n e . 
I n t he first se nsiti vit y a n al ysis of T 1 G d + lesi o ns relate d t o t he i m pact of t he war i n U krai ne, 
all partici pa nts fr o m sites i n U krai ne will ha ve t heir data ce ns ore d at t he start of t he crisis ( i.e. 
2 4  Fe br uar y  2 0 2 2 ). T he h y p ot hetical sce n ari o e n visa ge d is o ne i n w hic h t he crisis (affecti n g 
o nl y U krai ne partici pa nts) ha d n ot occ urre d.  I n a sec o n d se nsiti vit y a nal ysis relat e d t o t he 
i m pact of war i n U krai ne, all partici pa nts fr o m sites i n U krai ne, R ussia n Fe d erati o n, a n d 
Belar us will ha ve t h eir data ce ns ore d at t he start of t he crisis. T he h y p ot hetical sce n ari o 
e n visa ge d is o ne i n w hic h t he crisis (affecti n g partici pa nts fr o m U krai ne, R ussia n Fe derati o n, 
a n d Bel ar us) ha d n ot occ urre d. T he ce ns ore d data will n ot be i m p u te d; ce ns ori n g at t he ti me of 
t he start of t he crisis will be ass u me d t o be n o ni nf or mati ve f or t he o utc o me of i nterest ( T 1 G d + 
lesi o ns). 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 0 /1 5 9  
 
 
 
4.  m F A S  anal ysis.  
I n t his se nsiti vit y a nal ysis, t he pri mar y a n al ysis of T 1 G d + lesi o ns will be re p eate d o n t he 
m F A S.   
5.  A na l ysis t o e v al uate t he p ote ntial i m pact of t he sec o n d recr uit me nt c o h ort.  
T his se nsiti vit y a n al ysis will a d d t he f oll o wi n g c o variate t o t he N B m o del: me m bers hi p i n 
sec o n d recr uit me nt c o h ort ( yes/ n o), as defi n e d i n S ecti o n  8. 2 . T he s a me i nf ere ntial res ults will 
be re p ort e d as f or t h e pri mar y a nal ysis wit h t he p -val ue of t he a d diti o nal c o variate re p orte d.  
T he f oll o wi n g s u p ple me ntar y a nal ysis is pla n ne d t o e val uate t he p ote ntial i m pact of m o del 
miss pecificati o n : 
A nal ysis w h erei n lesi o n c o u nt at a si n gle sca n are c o nsi dere d as N B -distri b ute d l o n git u di nal 
data a n d a nal yze d usi n g a mi x e d effect m o del , wit h a ra n d o m effect f or partici pa nt, a n d ter ms 
f or i nter ve nti o n gr o u p, ra n d o mizati o n strata, a n d baseli ne  lesi o n acti vit y. T his m o del will 
c o m pare treat me nt o n t h e basis of c o n diti o nal a dj uste d lesi o n rate rati o, w here c o n diti o ni n g is 
o n t he ra n d o m effect.  See A p pe n di x  1 8. 9  f or details. 
Se nsiti vit y a n al ys es f or n u m ber of ne w or e nlar gi n g T 2 lesi o ns o n t he last a vaila ble M RI sca n 
relati ve t o t h e bas eli ne  M RI s ca n  will be si milar , e x ce pt t hat t he offs et i n t he m o del will be l o g 
ti me fr o m baseli ne  sca n t o last a vaila ble sca n (i n years), i n place of l o g n u m bers of sca ns . I n t he 
s u p ple me ntar y a nal ysis i n w hic h ne w/e nlar gi n g T 2 lesi o n c o u nt at a si n gle sca n is m o dele d as N B -
distri b ute d , t he offset para meter will be  e q ual t o t h e ti me (i n years) bet w ee n t he sca n i n q uesti o n 
a n d t he pre vi o us  a vaila bl e sca n , re prese nti n g t he ti me i nter val o ver w hic h ne w/e nlar gi n g T 2 lesi o ns 
accr ue d . 
1 4. 2. 5  
Ne ur ofil a me nt Li g ht C h ai n C o nce ntr ati o n at Wee k  1 2   
T he 5  esti ma n d attri b utes of t his sec o n dar y efficac y esti ma n d are:  
•  E n d p oi nt : Nf L c o nce ntr ati o n at 1 2  w ee ks  
•  Tre at me nt c o n diti o n of i nterest : E v o br uti ni b 4 5 m g t wice d ail y f or u p t o 1 5 6  wee ks ; 
alter nati ve treat me nt c o n diti o n t o w hic h c o m p aris o n will be m a de: t erifl u n o mi de 1 4 m g 
o nce dail y f or u p t o 1 5 6  wee ks . 
•  P o p ul ati o n : Partici pa nts wit h R M S as defi ne d b y i ncl usi o n/e xcl usi o n criteria. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 1 /1 5 9  
 
 
 
•  Str ate gies use d t o a d dress I C Es :  
o  Treat me nt di sc o nti n uati o n: Treat me nt p olic y strat e g y. 
o  Deat h (a n y ca us e): W hile ali ve strate g y  
o  U krai ne crisis: H y p ot heti cal strate g y  
o  C O VI D -1 9  i nfecti o n, C O VI D -1 9  vacci nati o n a n d e mer ge nc y 
u n bli n di n g: 
Treat me nt P olic y strate g y.  
•  P o p ul ati o n -le vel s u m m ar y c o m pari n g t he i nter ve nti o n gr o u ps is t he rati o of ge o metric 
mea ns at 1 2  wee ks a n d CI b ase d o n a M M R M m o del  f or l o g( Nf L c o nce ntrati o n), wit h test 
of treat me nt effect base d o n differe n ce of least -s q u ares me a ns.  
Ser u m Nf L c o n ce ntrati o ns are assesse d i n all partici pa nts at Baseli ne  V isit a n d Wee ks 1 2, 2 4, 4 8, 
7 2, 9 6,  1 2 0, 1 4 4, 1 5 6 , e n d of D B T P a n d earl y tr eat me nt disc o nti n uati o n.  
Missi n g D at a H a n dli n g  
F or partici p a nts wit h missi n g Nf L c o n ce ntr ati o n data, t he missi n g data will be ass u me d t o be M A R; 
s uc h partici pa nts will be ass u me d t o ha ve t he sa me mea n Nf L c o nce ntr ati o n traject or y t hr o u g h 
pla n ne d e n d of treat me nt ( i.e. P A c ut off  or 1 5 6  wee ks , w hic he v er o cc urs first)  as partici pa nts wit h 
a vaila ble data wit hi n t he sa me i nter ve nti o n gr o u p a n d strat u m, a n d ha vi n g t he sa me b aseli ne  
c o nce ntr ati o n . 
H a n dli n g of I C Es 
In t his st u d y, t h e I C E of treat me nt disc o nti n uati o n is ha n dle d b y t he Treat me nt P olic y str ate g y, i n 
w hic h data p ost pre mat ure treat me nt disc o nti n uati o n, i.e. at Safet y  F oll o w -u p  V isit, are us e d i n t h e 
a nal ysis.  H o we ver, Nf L assess me nts  are n ot sc he d ule d at t h e Safet y  F oll o w -u p  V isit. T h us, t he 
data t o i ncl u de i n t he a nal ysis of Nf L c o nce ntr ati o n  are t he sa me, re gar dless of w het her t he 
partici pa nt  is a treat me nt disc o nti n uer or has  treat me nt o n g oi n g/ c o m plete d : all a vaila ble 
assess me nts  w hile o n treat me nt are i ncl u d e d i n t he a nal ysis.  
I n acc or da n ce wit h t he W hile Ali ve strate g y, f or partici pa nts e x perie nci n g t he I C E deat h (a n y 
ca use), all Nf L c o n ce ntr ati o n  data u p t o t he ti me of deat h will be use d i n t h e a nal ysis.  
Partici pa nts at sites n ot f ull y o p erati o nal p ost start of U krai ne crisis will be c o nsi dere d t o ha v e 
e x perie nce d t h e I C E ‘ U krai ne crisis’. T his I C E will be ha n dle d usi n g t h e H y p ot hetical strate g y, 
w here t he h y p ot h etical sce nari o e n visa ge d is o ne i n w hic h t he crisis ha d ne ver ha p pe n e d.  T he d ata 
fr o m s uc h partici pa nts will be ce ns ore d at t he ti me at w hic h t he site l ost f ull y o perati o nal stat us. 
Ce ns ori n g at t he e n d of t he pre -crisis p eri o d is n o n -i nf or mati ve f or t he o ut c o me of i nterest ( Nf L 
c o nce ntr ati o n).  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 2 /1 5 9  
 
 
 
I n acc or da n ce wit h t he Treat me nt P olic y strat e g y, f or partici pa nts e x perie nci n g t he I C Es 
‘C O VI D -1 9  i nfecti o n’, ‘C O VI D -1 9  v acci n ati o n’  or ‘e mer ge n c y u n bli n di n g’ , t he occ urre nce of 
t hese I C Es is c o nsi dere d irrele va nt i n t he pri mar y a nal ysis of Nf L c o nce ntr ati o n. 
I nfere nti al a n al ysis 
T he p o p ulati o n -le vel s u m mar y c o m pari n g t he i nter ve nti o n gr o u ps will be t he rati o of ge o metri c 
mea ns , base d o n a M M R M f or l o g( Nf L c o n ce ntrati o n), w here t he m o del i ncl u des ter ms f or 
i nter ve nti o n gr o u p, visit, i nter ve nti o n gr o u p b y visit i nteracti o n, l o g(b aseli ne  c o nce ntrati o n ) a n d  
ra n d o mizati o n strata. T he u nstr uct ure d c o varia n ce matri x will be c o nsi dere d . De n o mi nat or de grees 
of free d o m will be c o m p ute d usi n g Ke n war d a n d R o ger’s met h o d  (Ke n war d 1 9 9 7 ). T he a nal ysis 
of Nf L c o n ce ntr ati o n will be base d o n F A S data fr o m a si n gle st u d y ( 0 0 8 0 or  
).  
T he rati o (c o m p ari n g e v o br utini b a n d terifl u n o mi de) of ge o metri c  mea n s, 9 5 % 2-si de d CI, a n d 
1 -si de d p-val ue will be re p orte d. F or eac h i nter ve nti o n gr o u p, t he a dj uste d ge o m etric  mea n at 
Wee k  1 2  a n d ass ociate d 9 5 % 2 -si de d CI will be re p orte d. I n a d diti o n, t he res ults of t he M M R M 
will b e prese nte d gra p hic all y b y i nter ve nti o n gr o u p wit h p oi nts f or t he esti mates per visit a n d err or 
bars f or t he 9 5 % C Is. 
T he M A R ass u m pti o n u n der pi ns t he esti mat or of rati o of ge o metric  mea ns t hr o u g h Wee k  1 2  
i m ple me nte d b y t he M M R M t hat uses o bser ve d Nf L c o nce ntrati o n  dat a fr o m eac h partici pa nt, 
re gar dl ess of treat me nt c o m pleted /disc o nti n ue d/ o n g oi n g stat us.  
Descri pti ve a n al ysis  
T he me a n a n d me dia n ( mi n, ma x) o bser ve d v al ues f or eac h i nter ve nti o n gr o u p will b e pl otte d 
vers us visit  till t he pla n ne d e n d of treat me nt (i.e. P A c ut off or 1 5 6  W ee ks p ost ra n d o mizati o n, 
w hic he ver occ urs first) . Me dia n perce nt c ha n ge fr o m baseli ne  li ne pl ot will als o be pr o vi de d. 
Descri pti ve statistics f or Nf L c o nce ntrati o n data  will be pr o vi de d b y i nter ve nti o n gr o u p.  
N u m ber a n d p erce nta ges of partici pa nts e x perie n ci n g I C Es will als o be pres e nte d. 
1 4. 2. 5. 1  
Se nsiti vit y 
A n al yses: 
Ne ur ofil a me nt 
Li g ht 
C h ai n 
C o nce ntr ati o n   
T he f oll o wi n g s e nsiti vit y a nal ys es f or Nf L c o n ce ntrati o n are pla n ne d , wit h t he sa me ha n dli n g of 
I C Es as i n t he pri mar y a n al ysis , u nless ot her wise s pecifie d : 
1.  A nal ysis t o e v al uate t he p ote ntial i m pact of C O VI D -1 9  i nfecti o n. 
T his se nsiti vit y a nal ysis will ha n dle t he I C E of C O VI D -1 9  i nfecti o n wit h t he H y p ot hetical 
strate g y, i.e. all of a partici pa nt’s data o n t he da y of a n d after t h e i nfecti o n will be ce ns ore d. 
T his is i n c o ntrast t o t he pri mar y a nal ysis i n w hic h a n y C O VI D -1 9 -relate d I C Es are i g n ore d i n 
t he a nal ysis (i.e. Treat me nt P olic y str ate g y).  Ce ns ori n g at t he ti me of i nfecti o n is ass u me d t o 
be n o ni nf or mati ve f or t he o utc o me of i nterest ( Nf L c o n ce ntr ati o n) . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 3 /1 5 9  
 
 
 
T h e I C E 'C O VI D -1 9  vacci nati o n' will be h a n dle d via Treat me nt P olic y strate g y as i n pri mar y 
a nal ysis. Partici pa nts e x perie nci n g t he I C E 'C O VI D -1 9  i nf ecti o n' will be i de ntifie d as t h ose 
wit h A Es relate d t o C O VI D -1 9  as defi ne d i n Secti o n  1 5. 2. 4.  T he h y p ot hetical sce nari o 
e n visa ge d is t hat C O VI D -1 9  i nfecti o n d oes n ot occ ur b ut C O VI D -1 9  v acci nati o n d oes.  
2.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he war i n U krai n e. 
I n t he first se nsiti vit y a n al ysis of Nf L c o nce ntrati o n relate d t o t he i m pact of t he war i n U krai ne, 
all partici pa nts fr o m sites i n U krai ne will ha ve t heir data ce ns ore d at t he start of t he crisis ( i.e. 
2 4  Fe br uar y  2 0 2 2 ). T he h y p ot hetical sce n ari o e n visa ge d is o ne i n w hic h t he crisis (affecti n g 
o nl y U krai ne partici pa nts) ha d n ot occ urre d.  I n a sec o n d se nsiti vit y a nal ysis relat e d t o t he 
i m pact of war i n U krai ne, all partici pa nts fr o m sites i n U krai ne, R ussia n Fe d erati o n, a n d 
Belar us will ha ve t h eir data ce ns ore d at t he start of t he crisis. T he h y p ot hetical sce n ari o 
e n visa ge d is o ne i n w hic h t he crisis (affecti n g partici pa nts fr o m U krai ne, R ussia n Fe derati o n, 
a n d Bel ar us) ha d n ot occ urre d. T he ce ns ore d data will n ot be i m p u te d; ce ns ori n g at t he ti me of 
t he start of t he crisis will be ass u me d t o be n o ni nf or mati ve f or t h e o utc o m e of i nterest ( Nf L 
c o nce ntr ati o n).  
3.  m F A S  anal ysis.  
I n t his se nsiti vit y a nal ysis, t he pri mar y a nal ysis of Nf L c o nce ntrati o n will be re peat e d o n t he 
m F A S .   
4.  A nal ysis t o e v al uate t he p ote ntial i m pact of t he sec o n d recr uit me nt c o h ort.  
T his se nsiti vit y a nal ysis will a d d t he f oll o wi n g c o variate t o t he M M R M m o del: me m bers hi p 
i n sec o n d recr uit me nt c o h ort ( yes/ n o), as d efi ne d i n Secti o n 8. 2 . T h e sa me i nfere ntial res ults 
will be re p orte d as f or t he pri mar y a nal ysis wit h t he p -val u e of t he a d diti o nal c o variate 
re p orte d. 
1 4. 2. 6  
S u b gr o u p A n al yses f or Sec o n d ar y Esti m a n ds   
T he a nal ysis of t he sec o n dar y esti ma n ds, 1 2 -wee k  C D P, 2 4 -wee k C D P,  a n d 2 4 -wee k C DI,  as 
descri be d i n Secti o n s 1 4. 2. 1. 1 , 1 4. 2. 1. 2  a n d 1 4. 2 . 2, will be re p eate d f or all s u b gr o u p l e vels defi ne d 
i n Secti o n  8. 2  “ S u b gr o u p Defi niti o n a n d Para m etrizati o n”.  A d diti o n all y, a lar ger m o del t hat 
a dj usts f or s u b gr o u p a n d i nter ve nti o n-b y -s u b gr o u p i nteracti o n will be fitte d, a n d t he p-val ue of t he 
i nteracti o n re p orte d. 
1 4. 3  
Terti ar y/ E x pl or at or y E n d p oi nts   
A nal ys es of tertiar y/ e x pl orat or y e n d p oi nts will be base d o n t he F A S.  T he ha n dli n g of I C E s will be 
a nal o g o us t o t he pri mar y a n d sec o n d ar y e n d p oi nts  i n Secti o n s 1 4. 1. 1  a n d 1 4. 2 . Details are pr o vi de d 
i n eac h s u bse cti o n bel o w.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 4 /1 5 9  
 
 
 
1 4. 3. 1  
A R R at Wee ks 4 8 a n d 9 6   
T he a nal ysis of A R R u p t o 4 8 wee ks (9 6  wee ks) will f oll o w t hat of A R R u p t o 1 5 6  wee ks  des cri be d 
i n Secti o n  1 4. 1. 1 . F or partici pa nts disc o nti n ui n g treat me nt, a n y q u alifie d rela pses occ urri n g 
t hr o u g h Safet y  F oll o w -u p will be i ncl u de d i n t he a nal ysis u p t o 4 8  ( 9 6 res pecti vel y) wee ks p ost 
ra n d o mizati o n (see S ecti o ns 9. 1 1  a n d 9. 1 2  res pecti vel y). 
1 4. 3. 2  
Ti me t o F irst Q u alifie d R el a pse  o ver 1 5 6  Wee ks   
Ti me t o first q u alifie d rel a pse is d efi ne d as t he ti m e fr o m ra n d o mizati o n dat e t o t he first q u alifie d 
rela pse d ate. T he h a n dli n g of I C Es will be a nal o g o us t o t he pri mar y e n d p oi nt, descri be d i n 
Secti o n  1 4. 1. 1 . Partici pa nts 
w h o di d n ot e x perie nce q ualifie d rela pse b y 1 5 6  wee ks p ost 
ra n d o mizati o n, b y ti me of P A c ut off, b y ti me of earl y st u d y disc o nti n uati o n, or bef ore bei n g l ost 
t o f oll o w u p, will be ce ns ore d at t he date of t he last rela pse assess me nt d uri n g t he 1 5 6  wee ks p ost 
ra n d o mizati o n. Ce ns ori n g will be ass u me d t o be n o ni nf or mati ve f or q ualifi e d rela pse, c o n diti o nal 
o n i nter ve nti o n gr o u p, a n d ra n d o mizati o n strat u m.  
T he hazar d rati o c o m pari n g e v o br uti ni b t o terifl u n o mi de will be esti mate d via a stratifie d C o x 
m o del wit h a ter m f or i nter ve nti o n gr o u p a n d strata defi ne d b y ra n d o mizati o n strata, al o n g wit h 
9 5 % 2 -si de d CI. A t est of treat me nt effect will be base d o n a stratifie d l o g ra n k t est  wit h strata 
defi ne d b y ra n d o mizati o n strata .  
T he c u m ulati ve distri b uti o n f u ncti o n will be esti mate d b y K M met h o d b y i nter ve nti o n gr o u p .  
1 4. 3. 3  
Q u alif yi n g Rel a pse -free S t at us at Wee k  9 6   
T he pr o p orti o n of partici pa nts q ualif yi n g  rela ps e-free at Wee k  9 6  ( meas ure d fr o m ra n d o mizati o n, 
see Secti o n 9. 1 2 ) will be c o m pare d b et wee n i nter ve nti o n gr o u ps usi n g C oc hra n -Ma ntel -Hae nszel 
( C M H) χ2 test stratifie d b y ra n d o mizati o n strata.  
Partici pa nts w h o disc o nti n ue st u d y pri or t o Wee k  9 6 , wit h o ut ha vi n g a q ualifie d rela pse will be 
c o u nte d as n ot bei n g q ualifie d rela pse -free. T he ha n dli n g of I C Es will be a nal o g o us t o t he pri mar y 
e n d p oi nt, descri be d i n Secti o n  1 4. 1. 1 . 
F or eac h i nter ve nti o n gr o u p, t he pr o p orti o n will be re p orte d, wit h 9 5 % 2 -si de d CI.  
I n a d diti o n, t he esti mate d pr o ba bilit y of bei n g q u alifie d rela pse-free at Wee k  9 6 , base d o n t he K M 
met h o d (c orres p o n di n g t o t he a nal ysis i n Secti o n 1 4. 3. 2 ) will be re p orte d, wit h 9 5 % 2 -si de d CI.  
1 4. 3. 4  
1 2 -wee k  ( 2 4-w ee k) C o nfir me d E D S S P r o gressi o n -F ree S t at us 
at Wee k  9 6   
T he pr o p orti o n of partici pa nts t hat are 1 2 -wee k  c o nfir me d E D S S pr o gressi o n -free (i.e. 1 2 -wee k  
C D P -free) at Wee k  9 6  ( m eas ure d fr o m ra n d o mizati o n, see Secti o n 9. 1 2 ) will be c o m pare d bet wee n 
i nter ve nti o n gr o u ps usi n g C M H χ2 test, stratifie d b y ra n d o mizati o n strata a n d st u d y I D, bas e d o n 
data p o ole d fr o m b ot h P h ase  3  st u dies.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 5 /1 5 9  
 
 
 
T he ha n dli n g of I C Es will be a nal o g o us t o t he sec o n dar y e n d p oi nt, des cri b e d i n Secti o n  1 4. 2. 1. 1 . 
Partici pa nts w h o disc o nti n ue st u d y pri or t o Wee k  9 6  or ha vi n g n ot reac h e d Wee k  9 6  at ti me of 
pla n ne d e n d of treat me nt , wit h o ut ha vi n g 1 2 -wee k  c o nfir me d E D S S pr o gressi o n will be c o u nte d 
as n ot bei n g 1 2 -wee k  c o nfir me d E D S S pr o gressi o n -free. 
F or eac h i nter ve nti o n gr o u p, t he pr o p orti o n will be re p orte d, wit h 9 5 % 2 -si de d CI.  
I n a d diti o n, t he esti mate d pr o ba bilit y of bei n g 1 2 -wee k  c o nfir m e d E D S S pr o gress i o n-free at 
Wee k  9 6 , base d o n t he K M met h o d (c orres p o n di n g t o t he a n al ysis i n Secti o n 1 4. 2. 1. 1 ) will be 
re p orte d, wit h 9 5 % 2 -si de d CI.  
T he sa me a p pr oac h will be use d  f or t he a nal ysis of 2 4-wee k c o nfir me d E D S S pr o gressi o n -free 
stat us.  
1 4. 3. 5  
2 4 -wee k 
C o nfir me d 
D is a bilit y Im pr o ve me nt 
S t at us at 
Wee k  9 6   
T his e n d p oi nt will be a nal yze d f or t he s u b gr o u p o f partici p a nts fr o m t he p o ole d st u dies wit h 
baseli ne  E D S S sc ore ≥ 2. 0.  T he ha n dli n g of I C Es will be a nal o g o us t o t he sec o n dar y e n d p oi nt, 
descri be d i n Secti o n  1 4. 2. 2 . 
F or pa rtici p a nts wit h a baseli ne  E D S S sc ore ≥ 2 a n d ≤ 6 , disa bilit y i m pr o ve me nt is defi ne d as a 
re d ucti o n i n E D S S sc ore ≥ 1. 0 c o m pare d t o bas eli ne  E D S S sc ore. F or pa rti ci pa nts wit h a baseli ne  
E D S S sc ore ≥ 6 . 5 a n d ≤ 9. 5 , disa bilit y i m pr o ve me nt is defi ne d as a re d ucti o n i n E D S S sc ore of 
≥ 0. 5.  
T he sa me a p pr oac h t o t he ti mi n g of 2 4 -wee k  c o nfir mati o n of disa bilit y i m pr o ve me nt is a p plie d as 
f or 2 4 -wee k  disa bilit y pr o gressi o n. C o nfir mati o n of disa bilit y i m pr o ve m e nt m ust occ ur at t he 
re g ularl y s c he d ule d visit t hat is at least 2 4  wee ks ( 1 6 8  da ys) after i nitial i m pr o ve me nt. If a 
partici pa nt  has a missi n g E D S S at t he sc he d ule d visit occ urri n g at least 1 6 8 da ys aft er a n i ni tial 
i m pr o ve me nt or t he s c he d ule d visit occ urs se v eral da ys bef ore t he 1 6 8 -da y wi n d o w after a n i nitial 
i m pr o ve me nt, c o nfir mati o n of t he disa bilit y i m pr o ve me nt m ust be o n t he basis of t he assess me nt 
at t he ne xt sc he d ule d visit.  
E D S S assess me nts at u nsc he d u le d or sc h e d ule d visits t hat are < 1 6 8 da ys after t he i nitial 
i m pr o ve me nt are c o nsi dere d n o n -c o nfir mat or y E D S S assess me nts . F or disa bilit y i m pr o ve me nt t o 
be c o nfir me d at a re g ul arl y s c he d ule d visit at least 2 4  wee ks after i nitial i m pr o ve me nt, a n y 
n o n -c o nfir mat or y E D S S assess me nts s h o ul d be at least as l o w as t he mi ni m u m c ha n ge re q uir e d 
f or i m pr o ve me nt. 
A  partici pa nt  wit h o ut c o nfir me d disa bilit y i m pr o ve me nt will be c o u nt e d as n ot i m pr o ve d, 
i n de pe n de nt of f oll o w-u p  ti me. T he i nter ve nti o n gr o u p c o m par is o n will be base d o n a C M H χ 2 test 
stratifie d acc or di n g t o ra n d o mizati o n strata a n d st u d y I D.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 6 /1 5 9  
 
 
 
1 4. 3. 6  
Lesi o n -F ree S t at us at Wee k  9 6   
T he pr o p orti o n of partici pa nts ha vi n g lesi o n -free stat us at We e k 9 6  will be c o m pare d bet wee n 
i nter ve nti o n gr o u ps usi n g C M H χ2 test str atifie d b y ra n d o mizati o n strata. T he stat us at Wee k  9 6 
will be base d o n me as ure me nts perf or me d  fr o m ra n d o mizati o n u p t o da y 6 9 4 ( w hic h c orres p o n ds 
t o t he st u d y d a y of Wee k 9 6 Visit [ 6 73] + 2 1  da ys). If t he Wee k  9 6 sca n was perf or me d pri or t o 
da y  6 6 6 ( da y  6 7 3 –  7  da ys)  a n d w as n ot re p eate d pri or t o da y  6 9 4, it will be c o nsi dere d as missi n g 
f or t his a nal ysis. 
T he ha n dli n g of I C Es will be a nal o g o us t o t he sec o n dar y e n d p oi nt, descri be d i n Secti o n  1 4. 2. 4. 1 . 
Partici pa nts w h o disc o nti n ue d st u d y earl y a n d / or are missi n g o ne or m or e of t he 3 sca ns pla n ne d 
t hr o u g h Wee k  9 6  (i.e. at Wee ks  2 4, 4 8, 9 6), will be c o u nte d as n ot l esi o n -free, i n de pe n de nt of 
f oll o w-u p  ti me. 
F or eac h i nter ve nti o n gr o u p, t he pr o p orti o n will be re p orte d, wit h 9 5 % 2 -si de d CI.  
T his a nal ysis will be d o n e f or t he f oll o wi n g e n d p oi nts:  
•  Ne w T 1 G d + lesi o n -free stat us 
•  Ne w or  e nlar gi n g T 2 lesi o n -free stat us 
•  C U A lesi o n -free stat us 
1 4. 3. 7  
T ot al N u m ber of L esi o ns B ase d o n All A v ail a ble M RI S c a ns   
T he a n al ysis of t otal n u m ber of C U A lesi o ns b ase d o n all a vaila ble sca ns, will f oll o w t hat of t he 
n u m ber of ne w/e nlar gi n g T 2 lesi o ns descri be d i n  Secti o n  1 4. 2. 4. 2  i ncl u di n g t he ha n dli n g of I C Es. 
Baseli ne  lesi o n acti vit y will be a dj uste d f or usi n g t he f oll o wi n g c o vari ates: baseli ne  T 1 G d + 
lesi o ns (a bse nce/ pres e n ce) a n d bas eli ne  T 2 l esi o n v ol u me ( c o nti n u o us ). F or partici pa nts 
disc o nti n ui n g treat me nt, all a vaila ble lesi o n data will be i ncl u de d i n t he a nal ysis u p t o t he pla n ne d 
e n d of treat me nt ( i.e. P A c ut off or 1 5 6  wee ks p ost ra n d o mizati o n , w hic he ver occ urs first). 
A si milar a nal ysis will be a p plie d t o t otal n u m ber of ne w T 1 h y p o -i nte ns e lesi o ns base d o n all 
a vaila ble M RI s ca ns , wit h baseli ne  lesi o n acti vit y a dj uste d f or usi n g bas eli ne  T 1 G d + lesi o ns 
(a bse nce/ pres e nce). 
1 4. 3. 8  
C h a n ge i n V ol u me of Lesi o ns fr o m B aseli ne  t o Wee k  9 6   
V ol u me of lesi o ns is  ass esse d i n all partici p a nts at Scree ni n g , Wee ks 2 4, 4 8, 9 6, 1 5 6 a n d earl y 
disc o nti n uati o n of treat me nt.  T he ha n dli n g of I C Es will be a nal o g o us t o t he sec o n dar y e n d p oi nt, 
descri be d i n Secti o n  1 4. 2. 4. 1 . 
C u be -r o ot tra nsf or me d lesi o n v ol u me C F B will be m o dele d  via M M R M, wit h i nter ve nti o n gr o u p, 
visit, i nter ve nti o n gr o u p b y visit i nteracti o n, baseli ne  val ue of c u be -r o ot e d v ol u me, i nteracti o n 
b et wee n baseli ne  val ue a n d visit, a n d c o variates defi ne d b y ra n d o mizati o n strata as fi x e d effects. 
Esti mati o n of treat me nt effect (a n d 9 5 % 2 -si de d CI) will be base d o n a dj uste d differe nce i n 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 7 /1 5 9  
 
 
 
least-sq uares mea ns fr o m t he m o del.  A ll a vail a ble v ol u me of l esi o ns data (irres pecti ve of 
disc o nti n uati o n) will be i ncl u de d i n t he a nal ysis u p t o  a n d i ncl u di n g t he W ee k 9 6  a n al ysis visit . 
T his a nal ysis will be d o n e f or t he f oll o wi n g e n d p oi nts:  
•  c ha n ge i n v ol u me of T 1 G d + lesi o ns fr o m Baseli ne  t o Wee k 9 6  
•  c ha n ge i n v ol u me of T 2 l esi o ns fr o m Baseli ne  t o Wee k 9 6  
Descri pti ve statistics b y visit a n d i nter ve nti o n gr o u p will be pr o vi de d.  
1 4. 3. 9  
Perce nt a ge 
C h a n ge i n Br ai n 
V ol u me fr o m 
Wee k 2 4 t o 
Wee k  9 6   
Perce nt c ha n ge i n v ol u me ( brai n v ol u me, t hala mic v ol u me, or c ortical gre y m atter v ol u me), 
relati ve t o Wee k 2 4, is assesse d i n all partici pa nts at Wee ks 4 8, 9 6, 1 5 6, a n d earl y disc o nti n uati o n 
of treat me nt, d uri n g t he d o u ble -bli n d peri o d.  
Brai n v ol u me is rec or de d as a n a bs ol ute “ n or malize d” val ue at t he Baseli ne  V isit t he n rec or de d at 
s u bse q ue nt visits as a perce nt a ge c h a n ge rel ati ve t o t he a bs ol ute val ue at t he Baseli ne  V isit. 
T heref ore, brai n v ol u me at Wee k 2 4 will be calc ulate d as t he brai n v ol u m e at t he Baseli ne  V isit 
m ulti plie d b y 1 + ([ perce nta ge c h a n ge i n brai n v ol u me fr o m Baseli ne  visit t o Wee k 2 4]/ 1 0 0). T his 
val ue will be use d t o deter mi ne t he p erce nta ge c ha n ge i n brai n v ol u me at Wee ks 4 8 a n d 9 6 rel ati ve 
t o W ee k 2 4. 
T he ha n dli n g of I C Es will  be a nal o g o us t o t he sec o n dar y e n d p oi nt, descri be d i n Secti o n  1 4. 2. 4. 1 . 
P B V C fr o m  Wee k 2 4 will be m o dele d  via M M R M, wit h i nter ve nti o n gr o u p, visit, i nter ve nti o n 
gr o u p b y visit i nteracti o n, Wee k 2 4 val ue of v ol u me, i nteracti o n b et wee n Wee k 2 4 val ue a n d visit, 
a n d c o variat es defi ne d b y ra n d o mizati o n strata as fi x e d effects. A n u nstr uct ure d c o varia nce matri x 
wil l be ass u me d. S h o ul d t he m o del fail t o c o n ver ge, c o nsi d erati o n will be gi ve n t o usi n g a 
c o varia n ce str u ct ure wit h fe w er p ara met ers ( i. e. c o m p o u n d s y m metr y), or o mitti n g t he b aseli ne  
val ue -visit i nteracti o n fr o m t he m o del. De n o mi nat or de grees of free d o m wil l be c o m p ute d usi n g 
Ke n war d a n d R o ger’s met h o d  (Ke n war d 1 9 9 7 ). Missi n g sca n assess me nts will be ha n dle d via t he 
M A R ass u m pti o n. C o nti n u o us c o variates will be ce ntere d b y t h e mea n, w here mea n is base d o n 
all partici pa nts i n FA S.  
Esti mati o n of treat me nt effect (a n d 9 5 % 2 -si de d CI) a n d p-val ue c o m pari n g i nter ve nti o n gr o u ps,  
base d o n a dj uste d differe nce i n P B V C least-sq u ares mea ns will be re p orte d f or Wee k  4 8  a n d 
Wee k  9 6 ti me p oi nts. I n a d diti o n, t he a dj uste d P B V C least-sq uares me a ns esti mate (a n d 9 5 % 
2 -si de d CI) f or eac h i nter ve nti o n gr o u p will be re p orte d at Wee k  4 8  a n d Wee k  9 6 . All a vaila ble 
data (irres pecti ve of dis c o nti n uati o n) will be i n cl u de d i n t he a nal ysis u p t o a n d i ncl u di n g t he 
Wee k  9 6 a nal ysis visit . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 8 /1 5 9  
 
 
 
T his a nal ysis will be d o n e f or t he f oll o wi n g e n d p oi nts:  
•  perce nt a ge c h a n ge i n B V fr o m Wee k 2 4 t o Wee ks 4 8 a n d 9 6  
•  perce nt a ge c h a n ge i n t hal a mic v ol u me fr o m Wee k 2 4 t o Wee ks 4 8 a n d 9 6  
•  perce nt a ge c h a n ge i n c ortical gre y matter fr o m Wee k 2 4 t o Wee ks 4 8 a n d 9 6  
Descri pti ve statistics b y visit a n d i nter ve nti o n gr o u p will be pr o vi de d. 
1 4. 3. 1 0  
C h a n ge i n 
N or m alize d T 1 I nte nsit y 
wit hi n Pre -E xisti n g 
N o n -E n h a nci n g T 2 Wei g hte d Lesi o n V ol u me fr o m B aseli ne  t o 
Wee k  9 6   
C ha n ge i n n T 1 i nte nsit y wit hi n pre -e xisti n g n o n -e n ha nci n g T 2 wei g ht e d lesi o n v ol u me, fr o m 
baseli ne  t o Wee k  9 6 , is a “ti me c o urse” varia ble re p orte d i n n or malize d T 1 u nits. T hese u nits 
re pres e nt a scal e of relati ve i nte nsit y w here t he m e dia n i nte nsit y of n or mal a p peari n g gre y matter 
fr o m a gi ve n p artici pa nt is ma p pe d t o zer o a n d t he me dia n i nte nsit y of n or mal a p peari n g w hite 
matter is ma p pe d t o 1. A val ue bel o w zer o re prese nts a n or malize d i nte nsit y t hat is l o wer t ha n t he 
partici pa nt’s n or mal a p peari n g gre y matter a n d li ke wise a val ue a b o ve 1 is a n or malize d i nte nsit y 
a b o ve t hat of t he partici pa nt’s n or mal a p peari n g w hite matter. T he i nte nsit y at eac h assess me nt 
visit is defi ne d o nce at t he e n d of t he peri o d.  Partici pa nts re q uire a mi ni m u m of 2 sca ns t o ha v e a n 
assess me nt of n T 1 i nte nsit y. Missi n g val ues will n ot be i m p ute d . 
T he ha n dli n g of I C Es will be a nal o g o us t o t he sec o n dar y e n d p oi nt, descri be d i n Secti o n  1 4. 2. 4. 1 . 
C ha n ge fr o m baseli ne  t o p ost b aseli ne visit i n n T 1 i nte nsit y f or p os t b aseli ne  at Wee k 2 4, Wee k  4 8 
a n d Wee k  9 6  Vi sits will be deri ve d. T he H o d ges-Le h m a n esti mate (a n d 9 5 % 2 -si de d CI) of s hift 
i n distri b uti o n of Wee k  9 6  n T 1 i nte nsit y C F B bet wee n i nter ve nti o n gr o u ps, stratifie d acc or di n g t o 
ra n d o mizati o n strata a n d baseli ne  T 2 lesi o n v ol u m e cate g or y ( base d o n tertiles) will be re p orte d. 
T he Wilc o x o n ra n k s u m test, stratifie d acc or di n g t o ra n d o mizati o n strata a n d baseli ne  T 2 lesi o n 
v ol u me cate g or y ( bas e d o n tertiles), will be use d t o c o m pare t he i nter ve nti o n gr o u ps.  All a vaila ble 
data (irres pecti ve of dis c o nti n uati o n) will be i n cl u de d i n t he a nal ysis u p t o a n d i ncl u di n g t he 
Wee k  9 6 a nal ysis visit . 
I n a d diti o n, i nter ve nti o n gr o u p differe n ces acr oss t he distri b uti o n of t he c h a n ge fr o m bas eli ne  i n 
n T 1 i nte nsit y will be pres e nte d base d o n me di a n  re gressi o n r u n o n t he 5 0t h q ua ntile .  
Descri pti ve statistics will be pr o vi de d b y st u d y i nter ve nti o n gr o u p.  I n a d diti o n, b o x pl ots of t he 
c ha n ge fr o m baseli ne b y i nter ve nti o n gr o u p a n d ti me p oi nt will be pr o vi de d.   
1 4. 3. 1 1  
V ol u me of S E Ls B ase d o n Sc a ns at Wee ks 2 4, 4 8, a n d 9 6   
V ol u me of S E Ls base d o n sca ns t hr o u g h Wee k  9 6  is a “ti me c o urse” varia ble re p orte d i n m m3 
u nits: a si n gle val ue is a vaila ble per partici pa nt f or t he D B T P , eit her at Wee k  9 6  if partici pa nt 
c o m plete d t hat visit or at Earl y  Disc o nti n uati o n  V isit if partici pa nt disc o nti n ue d treat me nt earl y. 
Partici pa nts re q uire a mi ni m u m of 3 sca ns t o ha v e a S E L assess me nt. Missi n g val ues will n ot be 
i m p ute d. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
8 9 /1 5 9  
 
 
 
S E Ls are i de ntifie d as areas of pre -e xisti n g T 2 l esi o ns of at l east 1 0 c o nti g u o us v o x els ( v o xel size 
is ~ 3 m m3) s h o wi n g gra d ual a n d c o nsta nt c o nce ntric e x pa nsi o n (Elli ott 2 0 1 9 ). S E Ls ma y q u alif y 
as a p ote ntial rea d -o ut f or pr o gressi ve acc u m ulati o n of irre versi ble ne ural tiss ue da ma ge a n d 
es peciall y a x o nal l oss ( va n Wal der vee n 1 9 9 8 ; Fili p pi 2 0 1 2 ). 
T he ha n dli n g of I C Es will be a nal o g o us t o t he sec o n dar y e n d p oi nt, descri be d i n Secti o n  1 4. 2. 4. 1 . 
T he H o d ges -Le h ma n esti mate (a n d 9 5 % 2 -si de d CI) of s hift i n distri b uti o n of S E L v ol u me bet wee n 
i nter ve nti o n gr o u ps, stratifie d acc or di n g t o ra n d o mizati o n strata a n d baseli ne  T 2 lesi o n v ol u me 
cate g or y ( bas e d o n tertiles) will be re p orte d f or W ee k  9 6  (Earl y  Disc o nti n u ati o n  Vi sit assess me nt 
w o ul d be i ncl u de d o nl y if it falls i n t he Wee k 9 6 a nal ysis visit wi n d o w ). T h e Wilc o x o n ra n k s u m 
test, stratifie d acc or di n g t o ra n d o mizati o n strata a n d baseli ne  T 2 lesi o n v ol u me cate g or y will be 
use d t o c o m pare t h e i nter ve nti o n gr o u ps at Wee k  9 6 . All a vaila bl e data (irres p ecti ve of 
disc o nti n uati o n) will be i ncl u de d i n t he a nal ysis u p t o a n d i ncl u di n g t he W ee k  9 6 a n al ysis visit . 
I n a d diti o n, i nter ve nti o n gr o u p differe nces acr oss t he distri b uti o n of S E L v ol u me will be prese nte d 
base d o n me dia n  re gressi o n  r u n o n t he 5 0t h q ua ntiles.  
S E Ls v ol u me as a perce nta ge of bas eli ne  T 2 lesi o n v ol u me will be deri v e d a n d a n al yze d i n t he 
sa me wa y t h a n v ol u me of S E Ls. Perce nt S E L v ol u me is base d o n t he rati o of S E L v ol u me t o 
baseli ne  T 2 lesi o n v ol u me.  
Descri pti v e statistics will be pr o vi de d b y st u d y i nter ve nti o n gr o u p.  
1 4. 3. 1 2  
C h a n ge i n N u m ber of P h ase Ri m Lesi o n s at Wee ks 2 4, 4 8 a n d 
9 6   
T he c ha n ge i n n u m ber of P hase Ri m Lesi o ns  e n d p oi nt will n ot be a nal yze d as part of t he P A b ut 
will be a nal yze d l ater. T h e c orres p o n di n g a nal ysis will t heref ore b e des cri be d i n a se parate IA P.  
1 4. 3. 1 3  
C h a n ge i n Cere br al Bl o o d Fl o w i n N or m al -A p pe ari n g W hite 
M atter at Wee ks 2 4, 4 8 a n d 9 6   
T he Cere bral Bl o o d Fl o w  e n d p oi nt will n ot be a nal yze d as part of t he P A b ut will be a nal yz e d 
later. T he c orres p o n di n g a nal ysis will t heref ore be descri be d i n a s e parate IA P.  
1 4. 3. 1 4  
Ti me t o ≥ 2 0 % Incre ase (C o nfir me d at 1 2  W ee ks) i n T 2 5 -F W  
(9 -H P T ) u p t o 1 5 6  Wee ks   
Ti me t o ≥ 2 0 % i ncreas e, c o nfir me d at 1 2  wee ks, i n T 2 5 -F W  is defi n e d as t he ti me fr o m 
ra n d o mizati o n date t o t he date of the i nitial w orse ni n g of ≥ 2 0 % . T he w ors e ni n g is defi n e d bas e d 
o n t he baseli ne  val ue. I n ge neral, t he v al ue of T 2 5-F W is ta ke n t o be t he a vera ge sc ores of 
2  T 2 5 -F W atte m pts . If t h e test res ult is missi n g  d ue t o “ p h ysic al li mitati o n”,  t he ma xi m u m p ossi ble 
val ue  o n t he scal e  is t o b e i m p ute d (i.e. 1 8 0  sec o n ds). If t he test res ult of o ne atte m pt  is missi n g, 
b ut n ot d ue t o a “ p h ysical li mitati o n,” t he res ult fr o m t he ot her atte m pt  will be  use d t o i m p ute t he 
missi n g val ue.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 0 /1 5 9  
 
 
 
T he ha n dli n g of I C Es will be a nal o g o us t o t h e sec o n dar y e n d p oi nt, ti me t o 1 2-wee k C D P, 
descri be d i n Secti o n  1 4. 2. 1. 1 . I n acc or da nce wit h t he C o m p osite Varia ble strate g y, f or p artici pa nts 
e x perie nci n g t h e I C E d eat h attri b uta ble t o M S or treat me nt, t he deat h will be c o u nte d as 1 2 -wee k 
≥ 2 0 % i ncreas e. I n acc or da nce wit h t he W hile Ali ve strate g y, f or partici pa nts e x perie nci n g t he I C E 
deat h u nattri b uta ble t o M S or treat me n t, partici pa nts will be ce ns ore d at ti me of deat h. (i.e. deat h 
will n ot be c o u nte d as 1 2 -wee k ≥ 2 0 % i ncrease).  
Partici pa nts w h o di d n ot e x perie nce ≥ 2 0 % i ncrease, c o nfir me d at 1 2  wee ks,  b y 1 5 6  wee ks p ost 
ra n d o mizati o n ( Secti o n 9. 1 3 ), b y ti me of P A c ut off, b y ti me of earl y st u d y disc o nti n uati o n, or 
bef ore b ei n g l ost t o f oll o w u p, will be ce ns ore d at t he date of t he last T 2 5 -F W  assess me nt d uri n g 
t he 1 5 6  wee ks p ost ra n d o mizati o n. Ce ns ori n g will be ass u m e d t o b e n o ni nf or mati ve f or 1 2 -wee k  
c o nfir me d w ors e ni n g i n T 2 5 -F W , c o n diti o nal o n i nter ve nti o n gr o u p, ra n d o mizati o n strat u m, a n d 
st u d y I D. C o nfir mati o n of ≥ 2 0 % i n crease m ust occ ur at t he re g ularl y sc he d ule d visit t hat is  at 
least 1 2  wee ks ( 8 4  da ys) after i nitial w orse ni n g. All s u bse q ue nt assess me nts (sc he d ule d a n d  
u nsc he d ule d) fr o m i nitial w orse ni n g nee d t o als o f ulfill t he w orse ni n g criteria u ntil t he w orse ni n g 
ca n be c o nfir me d at t h e first sc h e d ule d visit t hat occ urs at  least 8 4  d a ys after o nset of t he 
w orse ni n g.  
Base d o n d ata p o ole d fr o m b ot h P hase  3  st u dies, t he hazar d rati o c o m pari n g e v o br uti ni b t o 
terifl u n o mi de will be esti mate d via a stratifie d C o x m o del wit h a t er m f or i nter ve nti o n gr o u p, strat a 
defi ne d b y ra n d o miz ati o n strata , st u d y I D, a n d b aseli ne  T 2 5 -F W sc ore as c o nti n u o us c o variate,  
al o n g wit h 9 5 % 2 -si de d CI. A test of treat me nt effect will be bas e d o n a str atifie d l o g ra n k test .  
T he c u m ulati ve distri b uti o n f u ncti o n will be esti mate d b y K M  met h o d b y i nter ve nti o n gr o u p .  
A si milar a nal ysis will b e a p plie d t o Ti me t o ≥ 2 0 % i ncrease (c o nfir me d at 1 2  wee ks) i n 9 -H P T. 
I n ge neral, t he v al ue of 9-H P T is ta ke n t o be  t he a v era ge s c ores of t he 4  9 -H P T atte m pts ( 2  atte m pts 
o n t he ri g ht h a n d a n d 2  attem pts o n t he l ef t-ha n d ). If t he t est res ult is missi n g d u e t o “ p h ysical 
li mitati o n”, t he ma xi m u m p ossi ble val ue o n t he scale is t o be i m p ute d (i.e. 3 0 0 sec o n ds). If t he test 
res ult of o ne atte m pt is missi n g, b ut n ot d ue t o a “ p h ysic al li mitati o n,” t he res ult fr o m t he ot her 
atte m pt o n t he sa me ha n d will be use d  t o i m p ute t he missi n g val ue. If res ults fr o m b ot h atte m pts 
of t he sa me ha n d are missi n g, t he n t he a vera ge sc ore fr o m t he ot her ha n d will be use d t o i m p ute 
t he missi n g val ue. 
1 4. 3. 1 5  
N E D A -3 at Wee k  4 8 , Wee k  9 6   
N E D A at a ti me p oi nt is defi ne d as me eti n g t h e f oll o wi n g 3  criteria at t hat ti me p oi n t: 
•  Q ualif yi n g rela pse -free st at us  
•  Ne w T 1 G d + lesi o ns free stat us a n d ne w or e nlar gi n g T 2 lesi o n free stat us   
•  1 2 -wee k  c o nfir me d E D S S pr o gressi o n free stat us   
 
T he ha n dli n g of I C Es will be a nal o g o us t o t he pri mar y (f or rela ps es) a n d sec o n d ar y (f or M RI 
lesi ons a n d 1 2 -wee k C D P) e n d p oi nts, descri be d i n Secti o ns 1 4. 1. 1  a n d 1 4. 2. 1. 1 , res pecti vel y. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 1 /1 5 9  
 
 
 
Partici pa nts w h o reac h t he ti me p oi nt of i nterest will be c o nsi dere d as h a vi n g e vi d e nce of diseas e 
acti vit y if at least o ne q u alifie d rela pse, at least o ne M RI sca n s h o wi n g dise ase acti vit y ( defi ne d as 
G d + T 1 lesi o ns, or ne w or e nlar gi n g T 2 l esi o ns), or at l east o ne 1 2 -wee k  C D P e ve nt, was re p orte d 
u p t o t he ti me p oi nt of i nterest. Ot her wise t he partici pa nt will be c o nsi dere d t o ha ve N E D A.  
Partici pa nts w h o disc o nti n ue st u d y earl y wit h at l east o ne e ve nt bef ore earl y dis c o nti n uati o n will 
be c o nsi dere d as ha vi n g e vi de nce of disease acti vit y.  
E ve n if a n e ve nt w as n ot re p orte d bef ore earl y st u d y disc o nti n uati o n, t he partici p a nt will b e 
c o nsi dere d t o s h o w e vi de nce of disease acti vit y if t he reas o n f or earl y disc o nti n uati o n is lac k of 
effic ac y or d eat h; ot her wise, t he partici pa nt’s N E D A stat us will be c o nsi dere d a missi n g  
o bser vati o n.  
T he pr o p orti o n of partici pa nts wit h N E D A will be c o m pare d bet w ee n i nter ve nti o n gr o u ps  usi n g 
t he C M H χ2 test stratifie d b y ra n d o mizati o n strata.  
Descri pti ve statistics will be pr o vi de d b y i nter ve nti o n gr o u p.  
T he a nal ysis will be re p eate d c o ns i deri n g all rela pses, n ot o nl y q ualifie d rel a pses. 
1 4. 3. 1 6  
Ti me t o 1 2 -wee k  C o nfir me d Dis a bilit y B ase d o n C o m p osite 
Sc ore   
Ti me t o first occ urre nce of 1 2 -wee k  C D P u p t o 1 5 6  wee ks base d o n a c o m p osite sc ore is defi ne d 
b y 3  c o m p o n e nts:  
•  1 2 -wee k  C D P o n E D S S or;  
•  1 2 -wee k  c o nfir me d pr o gressi o n ( ≥ 2 0 %) i n T 2 5 -F W vers us baseli ne  or;  
•  1 2 -wee k  c o nfir me d pr o gressi o n ( ≥ 2 0 %) i n 9 -H P T vers us baseli ne . 
T he ha n dli n g of I C Es will be a nal o g o us  t o t he s ec o n dar y (f or 1 2-wee k C D P) a n d tertiar y (f or 
1 2 -wee k c o nfir m e d pr o gressi o n i n T 2 5 -F W a n d 9 -H P T) e n d p oi nts, descri be d i n Secti o ns 1 4. 2. 1. 1  
a nd 1 4. 3. 1 4 , res pecti vel y. 
T his e n d p oi nt is a nal yze d f or partici p a nts p o ole d fr o m b ot h P hase  3  st u dies. T he hazar d rati o 
c o m pari n g e v o br uti ni b t o terifl u n o mi de will be esti mate d via a stratifie d C o x m o del wit h a ter m 
f or i nter ve nti o n gr o u p a n d strata defi ne d b y ra n d o mizati o n strata a n d st u d y I D (i.e. St u d y 
M S 2 0 0 5 2 7 _ 0 0 8 0 or _ 
), al o n g wit h 9 5 % 2 -si de d CI. T h e test of tr eat m e nt effect will be b ase d 
o n a stratifi e d l o gra n k test of distri b uti o n of ti me t o e ve nt wit h strata d efi ne d b y ra n d o mizati o n 
strata a n d st u d y I D. C u m ulati ve distri b uti o n f u ncti o n will be esti mate d via K M  m et h o d b y 
i nter ve nti o n gr o u p.  
T he ass u m pti o n of n o n -i nf or mati ve ce ns ori n g u nder pi ns t he C o x m o del a n d K M esti mat or.  
Descri pti ve statistics will i n dicate pr o p orti o n of c o m p osite e ve nts d ue t o eac h of t he 3  c o m p o ne nt 
e ve nts, b y st u d y i nter ve nti o n gr o u p.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 2 /1 5 9  
 
 
 
1 4. 3. 1 7  
N E P at Wee k  4 8 , Wee k  9 6   
N E P at a ti me p oi nt is defi ne d as meeti n g t he f oll o wi n g 3  criteria at t hat ti me p oi nt:  
•  N o 1 2 -wee k  C D P o n E D S S  
•  N o 1 2 -wee k  c o nfir m e d pr o gressi o n ( ≥ 2 0 %) i n 9-H P T sc ore  
•  N o 1 2 -wee k  c o nfir m e d pr o gressi o n ( ≥ 2 0 %) i n T 2 5-F W ti me  
T he ha n dli n g of I C Es will be a nal o g o us t o t he s ec o n dar y (f or 1 2 -wee k C D P) a n d tertiar y (f or 
1 2 -wee k c o nfir m e d pr o gressi o n i n T 2 5 -F W a n d 9 -H P T) e n d p oi nts, descri be d i n Secti o ns 1 4. 2. 1. 1  
a n d 1 4. 3. 1 4 , res pecti vel y. 
Partici pa nts w h o reac h t he ti me p oi nt of i nterest will be c o nsi dere d as ha vi n g e vi de nce of 
pr o gress i o n if at least o ne 1 2 -wee k  C D P e ve nt, at least o ne 1 2 -wee k  c o nfir me d 9 -H P T sc ore 
w orse ni n g e v e nt or at le ast o ne 1 2 -wee k  c o nfir m e d T 2 5 -F W sc ore w ors e ni n g e v e nt was re p ort e d 
u p t o t he ti me p oi nt of i nterest. Ot her wise t he partici pa nt will be c o nsi dere d t o h a ve N E P.  
Partici pa nts w h o disc o nti n ue st u d y earl y wit h at l east o ne e ve nt bef ore earl y disc o nti n uati o n  a n d 
t he ti me p oi nt of i nterest will be c o nsi dere d as ha vi n g e vi de nce of pr o gressi o n.  
E ve n if a n e ve nt w as n ot re p orte d bef ore earl y st u d y disc o nti n uati o n  a n d t h e ti me p oi nt of i nterest , 
t he partici pa nt will be c o nsi dere d t o s h o w e vi de nce of pr o gressi o n if t he reas o n f or earl y 
disc o nti n uati o n is lac k of efficac y or deat h; ot her wise, t h e partici pa nt’s N E P stat us will be 
c o nsi dere d a missi n g o bs er vati o n.  
T he p r o p orti o n of partici pa nts wit h N E P will be c o m pare d bet wee n i nter ve nti o n gr o u ps  usi n g t he 
C M H χ 2 test stratifie d b y ra n d o mizati o n strata.  
Descri pti ve statistics will be pr o vi de d b y i nter ve nti o n gr o u p.  
1 4. 3. 1 8  
N E P A D at Wee k  4 8 , Wee k  9 6   
N E P A D at a ti me p oi nt is defi ne d as me eti n g t h e f oll o wi n g 5  criteria at t hat ti me p oi nt:  
•  N o q ualifie d  rel a pses o n treat me nt 
•  N o 1 2 -wee k  C D P  o n E D S S  
•  N o 1 2 -wee k  c o nfir m e d pr o gressi o n  ( ≥ 2 0 %) i n 9-H P T sc ore  
•  N o 1 2 -wee k  c o nfir m e d pr o gressi o n ( ≥ 2 0 %) i n T 2 5-F W ti me  
•  N o ne w or e nlar gi n g T 2 l esi o ns a n d n o ne w T 1 G d + lesi o ns o n M RI  
T he ha n dli n g of I C Es will be a nal o g o us t o t he pri m ar y (f or rel a pses), sec o n d ar y (f or 1 2 -wee k C D P 
a n d 
M RI lesi o ns) a n d t ertiar y (f or 1 2-wee k c o nfir me d pr o gressi o n i n T 2 5 -F W a n d 9 -H P T) 
e n d p oi nts, descri be d i n Secti o ns 1 4. 1. 1 , 1 4. 2. 1. 1 , 1 4. 2. 4. 1  a n d 1 4. 3. 1 4 , res pecti vel y. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 3 /1 5 9  
 
 
 
Partici pa nts w h o reac h t he ti me p oi nt of i nterest will be  c o nsi dere d as ha vi n g e vi de n ce of 
pr o gressi o n or acti ve acti vit y if at least o ne q ualifi e d rela ps e, at l east o ne 1 2 -wee k  C D P e ve nt, at 
least o ne 1 2 -wee k  c o nfir me d 9 -H P T sc ore w ors e ni n g e v e nt, at least o ne 1 2 -wee k  c o nfir me d T 2 5 -
F W sc ore w ors e ni n g e ve nt, or at least o ne M RI s ca n s h o wi n g dise ase acti vit y ( defi ne d as G d + T 1 
lesi o ns or ne w or e nlar gi n g T 2 lesi o ns) was re p ort e d u p t o t he ti me p oi nt of i nterest. Ot her wise t h e 
partici pa nt will be c o nsi d ere d t o ha v e N E P A D.  
Partici pa nts w h o disc o nti n ue st u d y earl y wi t h at l east o ne e ve nt bef ore earl y disc o nti n uati o n a n d 
ti me p oi nt of i nterest will be c o nsi dere d as ha vi n g e vi de nce of pr o gressi o n or acti ve dise ase.  
E ve n if a n e ve nt w as n ot re p orte d bef ore earl y st u d y disc o nti n uati o n  a n d ti me p oi nt of i nterest , t he 
partici pa nt will be c o nsi dere d t o s h o w e vi de nce of pr o gressi o n or acti ve disease if t h e reas o n f or 
earl y disc o nti n uati o n is lac k of effi cac y or deat h; ot her wise, t he p artici pa nt’s N E P A D stat us will 
be c o nsi dere d a missi n g o bser vati o n.  
T he pr o p orti o n of p artici pa n ts wit h N E P A D will be c o m pare d bet w ee n i nt er ve nti o n gr o u ps  usi n g 
t he C M H χ2 test stratifie d b y ra n d o mizati o n strata.  
Descri pti ve statistics will be pr o vi de d b y i nter ve nti o n gr o u p.  
T he a nal ysis will be re p eate d c o nsi deri n g all rela pses, n ot o nl y q ualifie d  rel a pses. 
1 4. 3. 1 9  
C F B i n S D M T sc ore at Wee k  4 8  a n d Wee k  9 6   
S D M T  sc ores are assesse d i n all partici pa nts at Scree ni n g , Bas eli ne  V isit, a n d e ver y 1 2  wee ks u ntil 
t he e n d of t he D B T P  at Wee k  1 5 6 .  
Base d o n data p o ol e d fr o m b ot h P hase  3  st u dies, t he a nal ysis of S D M T s c ore C F B at Wee k 4 8 a n d 
Wee k  9 6  a nal ysis visits , 
will f oll o w t hat of P R O MI S sc ore C F B at a gi ve n ti me p oi nt 
(Secti o n  1 6. 4. 1 ), i ncl u di n g t he h a n dli n g of I C Es.  
I n a d diti o n, a nal yses o n i m pr o ve me nt  or w orse ni n g stat us  will be perf or me d  (Be n e dict 2 0 2 1 ). 
P artici pa nts will be classifie d  i nt o t he f oll o wi n g cate g ori es, at Wee k 4 8 a n d Wee k  9 6  base d o n t he 
i nitial date of i m pr o ve me nt or w orse ni n g: 
•  S ustai ne d i m pr o veme nt: d efi ne d as a ≥ 4 -p oi nt i ncrease fr o m bas eli ne s ustai ne d f or 
6  m o nt hs u ntil en d  of  D B T P , re gar dless of w ors e ni n g at earlier visits.  He nce all res ults 
m ust meet t he criteria f or 6 m o nt hs a n d o n war ds, u ntil t he E n d of  Treat me nt assess me nt  or 
P A c ut off, w hic he v er occ urs first. 
•  S ustai ne d w orse ni n g: d efi ne d as a ≥ 4 -p oi nt d ecrease fr o m baseli ne s ustai ne d f or 6  m o nt hs 
u ntil E n d  of  Treat me nt  or P A c ut off, w hic he v er occ urs first. 
•  Sta ble: d efi ne d as n ot me eti n g s ustai ne d i m pr o ve me nt or w orse ni n g . 
If a partici pa nt is missi n g t h e bas eli ne res ult or p ost -baseli ne res ults at least 6 m o nt hs after t he 
baseli ne meas ur e me nt , t h eir stat us will be c o nsi dere d missi n g. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 4 /1 5 9  
 
 
 
T he ha n dli n g of I C Es will be a nal o g o us t o t h e sec o n dar y e n d p oi nt, ti me t o 1 2 -wee k C D P, 
descri be d i n Secti o n  1 4. 2. 1. 1 . In acc or da nce wit h t he C o m p osite Varia ble strate g y, f or p artici pa nts 
e x perie nci n g t h e I C E deat h attri b uta ble t o M S or treat me nt, t he deat h will be c o u nte d as sustai n e d 
w orse ni n g . I n acc or da n ce wit h t he W hile Ali ve strate g y, f or partici p a nts e x perie nci n g t he I C E 
deat h u nattri b uta ble t o M S or treat me nt, partici pa nts will be ce ns ore d at ti me of d eat h (i.e. d eat h 
will n ot be c o u nte d as sustai ne d w orse ni n g ). 
Descri pti ve statistics will be pr o vi de d f or all cate g ories b y i nter ve nti o n gr o u p.  
T he pr o p orti o n of partic i pa nts wit h s ustai ne d i m pr o ve me nt/ w orse ni n g will be c o m pare d b et wee n 
i nter ve nti o n gr o u ps usi n g t he C M H χ 2 test stratifie d b y ra n d o mizati o n strata. 
1 4. 3. 2 0  
PI R A u p t o Wee k  1 5 6   
PI R A u p t o  Wee k  1 5 6 is defi ne d d uri n g t he o n -tr eat me nt peri o d f or t hese 2 pr o gressi o n criteria 
se parat el y: 
•  1 2 -wee k  C D P o n E D S S  
•  1 2 -wee k  c C D P d efi ne d b y 3  c o m p o ne nts ( 1 2 -wee k  C D P o n E D S S, 1 2 -wee k  c o nfir me d 
w orse ni n g i n T 2 5 -F W a n d 9 -H P T vers us baseli ne , see Secti o n  1 4. 3. 1 6 )  
PI R A (L u bli n 2 0 2 2 ) is defi ne d as a 1 2 -wee k  C D P e ve nt (res pecti vel y 1 2 -wee k  c C D P) wit h eit her 
n o pri or q ualifie d rela pse, or a n o nset m ore t ha n 3 0 da ys after t he start date of t he last q ualifie d  
rela pse (irres pecti ve of t he E D S S c o nfir m ati o n). I n a d diti o n, t o q ualif y as PI R A, n o rela ps e m ust 
occ ur wit hi n 3 0 da ys bef ore or after t he E D S S c o nfir mati o n. If a r ela pse wit h i nc o m plete rec o v er y 
occ urre d ( mea ni n g t hat t he E D S S is n ot t he sa me as bef ore t he rela ps e), t he baseli ne  (i.e. t he 
refere nce E D S S val ue) is reset > 3 0 d a ys aft er t he rela pse o nset t o i de ntif y t he ne xt PI R A. I n a n 
i n di vi d ual partici pa nt , t he bas eli ne c o ul d be reset m ulti ple ti mes (i.e. after eac h rela pse) u ntil eit her 
a PI R A e ve nt is dis c o vere d, or u ntil t he i n di vi d ual E D S S pr ofile e n de d . I n case of missi n g E D S S 
bef ore or after t he rela ps e, t he rela pse will be ass u me d t o be rec o vere d a n d t he base li ne will n ot be 
reset. 
T he ha n dli n g of I C Es will be a nal o g o us t o t he pri mar y (f or rela ps es), s ec o n dar y (f or 1 2 -wee k 
C D P) a n d tertiar y (f or 1 2 -wee k c o nfir me d pr o gressi o n i n T 2 5 -F W a n d 9 -H P T) e n d p oi nts, 
descri be d i n Secti o ns 1 4. 1. 1 , 1 4. 2. 1. 1  a n d 1 4. 3. 1 4 , res pecti vel y. 
T his e n d p oi nt is a nal yze d f or partici pa nts p o ole d fr o m b ot h P hase  3  st u dies. Ti me t o PI R A is 
defi ne d as t he ti me fr o m ra n d o mizati o n date t o t he first 1 2 -wee k s C D P (c C D P res pecti vel y) e ve nt 
date w he n a n e ve nt is prese nt, a n d fr o m ra n d o mi zati o n t o ce ns ori n g dat e w he n a n e ve nt is n ot 
prese nt. Ce ns ori n g occ urs i n t h ose partici pa nts w h o di d n ot e x perie nce a n y of t he 1 2 -wee k  
c o nfir me d disa bilit y pr o gressi o n  e ve nts u p t o t he P A c ut off or  1 5 6  wee ks p ost ra n d o mizati o n , 
w hic he ver o cc urs first ; t his i ncl u des partici pa nts w h o ha d a “te ntati ve” disa bilit y pr o gressi o n t hat 
c oul d n ot be c o nfir me d d ue t o a n earl y dis c o nti n uati o n or a n y ot her reas o n. T he ce ns ori n g d ate is 
t he date of t he last assess me nt a m o n g E D S S . F or c C D P, t he ce ns ori n g date is t he mi ni m u m of t he 
last a vaila ble E D S S assess me nt date, t he last a vaila ble 9-H P T assess m e nt date a n d t he last 
a vaila ble T 2 5 -F W assess me nt date.   
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 5 /1 5 9  
 
 
 
T he hazar d rati o c o m pari n g e v o br uti ni b t o terifl u n o mi de will be esti mate d via a stratifie d C o x 
m o del wit h a ter m f or i nt er ve nti o n gr o u p a n d strat a defi ne d b y ra n d o mizati o n strata a n d st u d y I D 
(i.e. St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 or _ 
), al o n g wit h 9 5 % 2 -si de d CI. T he test of tr eat me nt effect 
will be bas e d o n a str atifie d l o gra n k test of distri b uti o n of ti me t o e v e nt wit h strata d efi ne d b y 
ra n d o mizati o n strata a n d st u d y I D. C u m ulati ve distri b uti o n f u ncti o n will be esti mate d via K M  
met h o d b y i nter ve nti o n gr o u p.  
T he ass u m pti o n of n o n -i nf or mati ve ce ns ori n g u n der pi ns t he C o x m o del a n d K M esti mat or. 
Descri pti ve statistics will i n dicate pr o p orti o n of c o m p osite e ve nts d ue t o eac h of t he 3  c o m p o ne nt 
e ve nts, b y i nter ve nti o n gr o u p. 
T he a nal ysis c o nsi d eri n g t he ti me t o C D P will be re p eate d c o nsi deri n g all rela ps es, n ot o nl y 
q ualifie d  rela ps es. 
I n a d diti o n, a se nsiti vit y a nal ysis will be c o nsi deri n g ti me t o PI R A as t he ti me t o C D P (c C D P) i n 
t he h y p ot hetical sce nari o f or t he I C E ‘rela pse’. C o nsi deri n g t hat t he q ualifie d rela pse w o ul d n ot 
ha p pe n, t he a nal yses d escri be d a b o v e will be re peate d ce ns ori n g p artici pa nts wit h a q ualifie d 
rela pse at t he ti me of t he first q ualifie d rela ps e. 
1 4. 3. 2 1  
PI R M A u p t o Wee k  1 5 6   
PI R M A u p t o 
Wee k  1 5 6 is defi ne d as m eeti n g t he f oll o wi n g criteria d uri n g t h e o n -tr eat me nt 
peri o d:  
•  1 2 -wee k  C D P o n E D S S  
•  1 2 -wee k  c C D P  d efi ne d b y 3  c o m p o ne nts ( 1 2 -wee k  C D P o n E D S S, 1 2 -wee k  c o nfir me d 
w orse ni n g i n T 2 5 -F W a n d 9 -H P T vers us baseli ne , see Secti o n  1 4. 3 . 1 6)  
PI R M A is defi ne d as a 1 2 -wee k  C D P e ve nt (res pecti vel y 1 2 -wee k  c C D P)  wit h eit her n o pri or 
q ualifie d rel a pse a n d n o ne w or e nlar gi n g T 2 lesi o ns a n d n o ne w T 1 G d + l esi o ns, or a n o ns et  (i.e. 
I D P) m ore t ha n 3 0 d a ys after t he start d ate of t he l ast q ualifie d  rela pse or t he date ne w or e nlar gi n g 
T 2 lesi o ns or ne w T 1 G d + lesi o ns are i de ntifie d (irres pecti ve of t he E D S S c o nfir mati o n). I n 
a d diti o n, t o q ualif y as PI R M A, n o rela pse a n d n o ne w or e nlar gi n g T 2 l esi o ns a n d n o ne w T 1 G d + 
lesi o ns o n M RI m ust occ ur wit hi n 3 0 d a ys bef ore or aft er t h e 1 2 -wee k c o nfir mati o n. If a rela ps e 
wit h i nc o m plete rec o v er y occ urre d ( mea ni n g t hat t he E D S S is n ot t he sa me as bef ore t he rela pse), 
t he baseli ne  (i.e. t he refere nce E D S S val ue) is res et > 3 0 d a ys after t h e rela ps e o nset t o i de ntif y t h e 
ne xt PI R M A. I n a n i n di vi d ual partici pa nt , t he baseli ne  c o ul d be reset m ulti ple ti mes (i.e. after eac h 
rela pse) u ntil eit her a PI R M A e ve nt is disc o vere d, or u ntil t he i n di vi d ual E D S S pr ofile e n de d. I n 
case of missi n g E D S S bef ore or after t he rela pse, t he rela ps e will be ass u me d t o be rec o vere d a n d 
t he baseli ne will n ot be reset. 
T he ha n dli n g of I C Es will be a nal o g o us t o t he pri m ar y (f or rel a pses), sec o n d ar y (f or 1 2 -wee k C D P 
a n d 
M RI lesi o ns) a n d t ertiar y (f or 1 2 -wee k c o nfir me d pr o gressi o n i n T 2 5 -F W a n d 9 -H P T) 
e n d p oi nts, descri be d i n Secti o ns  1 4. 1. 1 , 1 4. 2. 1. 1 , 1 4. 2. 4. 1  a n d 1 4. 3. 1 4 , res pecti vel y. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 6 /1 5 9  
 
 
 
T his e n d p oi nt is a n al yze d f or partic i pa nts p o ole d fr o m b ot h P hase 3  st u di es. Ti me t o PI R M A is 
defi ne d as t he ti me fr o m ra n d o mizati o n date t o t he first 1 2 -we eks C D P (c C D P res pecti vel y)  e ve nt 
date w he n a n e ve nt is prese nt, a n d fr o m ra n d o mi zati o n t o ce ns ori n g dat e w he n a n e ve nt is n ot 
prese nt. Ce ns ori n g occ urs i n t h ose partici pa nts w h o di d n ot e x perie nce a n y of t he 1 2 -wee k  
c o nfir me d disa bilit y pr o gressi o n e ve nts u p t o t he P A c ut off or  1 5 6  wee ks p ost ra n d o mizati o n , 
w hic he ver o cc urs first ; t his i ncl u des partici pa nts w h o ha d a “te ntati ve” disa bility pr o gressi o n t hat 
c o ul d n ot be c o nfir me d d ue t o a n earl y dis c o nti n uati o n or a n y ot her reas o n. T he ce ns ori n g d ate is 
t he date of t he last assess me nt a m o n g E D S S. F or c C D P, t he ce ns ori n g date is t he mi ni m u m of t he 
last a vaila ble E D S S assess me nt date, t he last a vaila ble 9-H P T assess m e nt date a n d t he last 
a vaila ble T 2 5 -F W assess me nt date.  
T he hazar d rati o c o m pari n g e v o br uti ni b t o terifl u n o mi de will be esti mate d via a stratifie d C o x 
m o del wit h a ter m f or i nt er ve nti o n gr o u p a n d strat a defi ne d b y ra n d o mizati o n str ata a n d st u d y I D 
(i.e. St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 or _ 
), al o n g wit h 9 5 % 2 -si de d CI. T he test of tr eat me nt effect 
will be bas e d o n a str atifie d l o gra n k test of distri b uti o n of ti me t o e v e nt wit h strata d efi ne d b y 
ra n d o mizati o n strata a n d st u d y I D. C u m ulati ve distri b uti o n f u ncti o n will be esti mate d via K M  
met h o d b y i nter ve nti o n gr o u p.  
T he ass u m pti o n of n o n -i nf or mati ve ce ns ori n g u n der pi ns t he C o x m o del a n d K M esti mat or. 
Descri pti ve statistics will i n dicate pr o p orti o n of c o m p osite e ve nts d ue t o eac h of t he 3  c o m po ne nt 
e ve nts, b y i nter ve nti o n gr o u p.  
T he a nal ysis c o nsi d eri n g t he ti me t o C D P will be re p eate d c o nsi deri n g all rela ps es, n ot o nl y 
q ualifie d  rela ps es. 
I n a d diti o n, a s e nsiti vit y a nal ysis will be c o nsi deri n g ti me t o PI R M A as t he ti me t o C D P (c C D P) 
i n t he h y pot hetical s ce nari o f or t he I C Es  ‘rela pse’, ‘ne w or e nlar gi n g T 2 lesi o ns ’ a n d ‘T 1 G d + 
lesi o ns’. C o nsi deri n g t hat t he I C Es w o ul d n ot ha p pe n, t he a nal yses descri be d a b o ve will be 
re peat e d ce ns ori n g partici pa nts wit h a rela pse at t he ti me of t he first rela pse or wit h ne w or 
e nlar gi n g T 2 lesi o ns at t he ti me of t he lesi o n or wit h T 1 G d + lesi o ns at t he ti me of t he lesi o n, 
w hic he ver occ ur first.  
1 5  
S afet y A n al yses   
T his  secti o n i ncl u des s pecificati o ns f or s u m mari zi n g safet y e n d p oi nts t h at are c o m m o n acr oss 
cli nical st u dies s uc h as A Es , la b orat or y tests a n d vital si g ns. If n o partici pa nts  are e x cl u de d fr o m 
t he S A F d ue t o lac k of s afet y d ata r o b ust ness, t h e n t here will b e n o disti nct m S A F a nal ysis set, 
a n d all safet y a n al ys es will be prese nte d f or eac h st u d y s e paratel y o n t he S A F. If a n m S A F is 
defi ne d via e x cl usi o n of S A F partici pa nts d ue t o lac k of safet y d ata r o b ust ness , safet y a nal yses 
will be prese nte d f or eac h st u d y se paratel y  o n t he m S A F  a n d S A F. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 7 /1 5 9  
 
 
 
Data ha n dli n g f or s afet y e n d p oi nts is descri be d i n Ta ble 1 0  f or t he P A. 
T a ble 1 0  
D at a H a n dli n g f or S afet y A n al ysis   
D at a s u m m ari z e d  
A n al y si s  
A n al y si s 
s et s  
P eri o d c o v er e d  
Tr e at m e nt gr o u p s  
A E s  
L a b or at or y d at a  
Vit al si g n s  
E C G s  
Ot h er s af et y e v al u ati o n s  
P A  
 
 
S A F  
 
 
 
 
All d at a fr o m t h e 
o n -tr e at m e nt p eri o d u ntil 
t h e P A c ut off  d at e  
(S af et y  F oll o w -u p 
i n cl u d e d) 
 
 
 
E v o br uti ni b 4 5 m g t wi c e d ail y  
T erifl u n o mi d e 1 4 m g o n c e d ail y  
1 5. 1  
A E s  
All a nal ys es descri be d i n t his secti o n will be base d o n T E A Es if n ot ot her wise s pecifie d.  
T E A Es f or t he o n -treat m e nt peri o d will be defi n e d as:  
•  A Es starti n g o n or after first st u d y i nter ve nti o n a d mi nistrati o n of a n y st u d y i nter ve nti o n 
u ntil t he P A c ut off date   
•  or if it was prese nt pri or t o a n y st u d y i nter ve nti o n a d mi nistrati o n b ut e x acer bati n g after.  
•  A n y A E w hic h starte d b ef ore first a d mi nistrati o n of a n y st u d y i nter ve nti o n b ut i m pr o ve d d uri n g 
t he o n -treat me nt p eri o d will n ot be c o u nte d as T E A E.  
A E s wit h c ha n ges i n t o xicit y gra de/se verit y, s eri o us ness or o utc o me of A Es are rec or de d as 
se parat e e ntri es i n t he e C R F wit h ass ociate d e n d a n d start d ates (start d ate e q u als e n d d ate of 
pre vi o us e ntr y, s u p p orte d i n e C R F b y ‘ A E N E WI D’ i n S U P P A E). Rec or ds of t he sa me A E will be 
c o nsi dere d as o n e e ve nt i n t he a n al ysis. If t he s e verit y of t he re p orte d e ve nt w orse ns aft er start of 
st u d y i nter ve nti o n, t he T E AE fla g will be re -e val uate d f or t he w orse a n d t he s u bse q ue nt rec or ds 
as per t he T E A E defi niti o n. If t he w ors e rec or d starts o utsi de of t he o n -treat me nt peri o d, it will n ot 
a p pear o n t h e s u m mari es/listi n gs of T E A Es, u nless ot her wise s pecifie d. T h ese e v e nts will be ke pt 
as se parate rec or ds i n t he data base i n or der t o mai ntai n t he f ull detaile d hist or y of t he e ve nts. W he n 
s uc h A Es are liste d, start a n d e n d date s h o ul d be pr o vi de d t o get her wit h c ha n ge date, t o xicit y 
gra de/se v erit y , o ut c o me a n d seri o us ness per e pis o de.  
1 5. 1. 1  
All A E s  
A Es will be c o de d acc or di n g t o t he latest Me d D R A versi o n a vaila ble at t he ti me of a nal ysis. T he 
se verit y of A Es will be gra de d usi n g N CI-C T C A E versi o n 5. 0  t o xicit y gra des. A Es wit h missi n g 
classificati o n c o ncer ni n g st u d y i nter ve nti o n relati o ns hi p will be c o nsi dere d relate d t o t he st u d y 
i nter ve nti o n.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 8 /1 5 9  
 
 
 
1 5. 1. 1. 1  
3  Tier A p pr o ac h   
T he 3 -tier a p pr oac h is a s yste matic w a y t o s u m marize a n d a nal yz e A Es i n cli nical st u dies (Cr o we  
2 0 0 9 ). A Es i n differe nt tiers are a nal yze d usi n g differe nt le v els of statistical a nal ys es.  
T he A Es defi ne d b y t h e Be nefit Ris k Acti o n Tea m f or Tier 1 re p orti n g i n t his st u d y are i n  T a ble 
1 1 .  
T a ble 1 1  
Tier 1 A Es   
Ti er 1 A E ( P T)  
Wit hi n 
gr o u p 
s u m m ar y  
B et w e e n gr o u p c o m p ari s o n 
( E v o br uti ni b - T erifl u n o mi d e ) 9 5 % CI 
Dr u g I n d u c e d Li v er I nj ur y  
 
n ( %)  
∆ [ x x %, x x %] 
Tier 1 A E : DI LI is a n u m brella ter m a n d will be i de ntifie d usi n g s p o ns or -defi ne d list of searc h 
ter m as d efi ne d i n A p p e n di x  1 8. 5  a n d all c orres p o n di n g P Ts will be i ncl u de d i n t he Tier 1 
s u m mar y. 
T his ta ble will be re peate d f or A Es starti n g wit hi n 6 m o nt h s (1 8 0 da ys ) of treat me nt start.  
All T E A Es (i ncl u di n g t h ose i n Tier 1) will be classifie d i nt o Tier 2 or Tier 3 base d o n t he R ule -of -
4 . If t here are 4  or m ore partici pa nt s wit h t he re p orte d ter m i n a n y st u d y i nter ve nti o n gr o u p, t hat 
ter m will be i ncl u de d i n Tier 2. Ot her wise, it will be i ncl u de d i n Tier 3. 
T he Tier 1 a n d Tier 2 A Es will be ass esse d wit h a 9 5 % CI f or bet wee n -gr o u p c o m paris o ns. F or 
t he differe nce i n cr u de rates, e x presse d i n perce nta ges, t he CIs will be base d o n M N met h o d 
(Mietti ne n  & N ur mi ne n  1 9 8 5 ). F or Tier 1 e v e nts w hic h were o bs er ve d f or less t ha n 4  partici pa nts 
t he CI will n ot be dis pla ye d i n t he Tier 1 ta ble. T h e a nal yses will be d o n e f or all Tier 2 T E A Es.  
E AI R of T E A Es will als o be se p arat el y pres e nte d f or eac h Tier, b y P T (see Secti o n  1 5. 1  f or 
m ulti ple e ve nts ha n dli n g). D iffere nce i n E AI R will be s u m marize d. F or Tier 1 a n d Tier 2 A Es, t he 
CIs will be calc ulate d usi n g t he P oiss o n base d met h o d . E AI R are cal c ulate d as n u m ber of 
partici pa nts wit h A E di vi de d b y t he s u m of t h e i n di vi d ual ti mes of all p artici pa nts i n t he s afet y 
p o p ulati o n fr o m start of treat me nt t o first o nset of A E. If a p artici pa nt has m ulti ple e ve nts, t he 
e x p os ure peri o d of t he first e ve nt after first a d mi nistrati o n of st u d y i nter ve nti o n is use d. F or a 
partici pa nt wit h n o e ve nt, t he e x p os ure peri o d is ce ns ore d at t he l ast f oll o w-u p  ti me f or t he A E 
s u m marizati o n peri o d. T he i nci de nce rate m ulti plie d wit h 1 0 0 w o ul d gi ve t he n u m ber of A Es 
e x pecte d i n 1 0 0 partici pa nts wit hi n 1 -ti me u nit (f or e x a m ple 1 year). A n e x a m ple of S A S c o de is 
a vaila ble i n t he Statistical Met h o d ol o g y d oc u me nt n ote d i n A p pe n di x  1 8. 9 . 
N o m ulti plicit y a dj ust me nt will be a p plie d f or Tier 1 a n d 2 A Es. T he Tier 3 A Es will be ass esse d 
via s u m mar y statistics a n d ris k differe n ces  w it h o ut a n y CIs. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
9 9 /1 5 9  
 
 
 
F or t he c o m paris o n of e v o br uti ni b wit h terifl u n o mi de, f orest trees f or Tier 1 a n d Tier 2 A Es, a n d 
E AI R A Es will be pr o vi de d as well, dis pla yi n g t he i nci de nce rate a n d ass ociate d 9 5 % CI of 
differe n ce.  
1 5. 1. 1. 2  
O ver vie w of T E A Es   
2  t y pes of s u m mar y ta ble of T E A Es will be pr o vi d e d as descri be d i n Ta ble 1 2 . 
T a ble 1 2  
S u m m ar y T a bles of T E A Es   
S u m m ar y  
M o d aliti e s  
O v er vi e w of T E A E s  
•  
A n y T E A E  
•  
R el at e d T E A E  
•  
S eri o u s T E A E  
•  
R el at e d s eri o u s T E A E  
•  
T E A E wit h N CI -C T C A E Gr a d e  ≥1  
•  
R el at e d T E A E wit h N CI -C T C A E Gr a d e  ≥1  
•  
T E A E wit h N CI -C T C A E Gr a d e  ≥2  
•  
R el at e d T E A E wit h N CI -C T C A E Gr a d e  ≥2  
•  
T E A E wit h N CI -C T C A E Gr a d e  ≥3  
•  
R el at e d T E A E wit h N CI -C T C A E Gr a d e  ≥3  
•  
T E A E wit h N CI -C T C A E Gr a d e  ≥4  
•  
R el at e d T E A E wit h N CI -C T C A E Gr a d e  ≥4  
•  
T E A E l e a di n g t o d e at h  
•  
R el at e d T E A E l e a di n g t o d e at h  
O v er vi e w of T E A E s l e a di n g t o 
A cti o n s:  
•  
C h a n g e i n d o s e  
•  
S t u d y i nt er v e nti o n i nt err u pti o n 
or wit h dr a w al  
•  
A d mi ni str ati o n of m e di c ati o n  
•  
Pr o c e d ur e  
•  
St u d y t er mi n ati o n  
•  
T E A E wit h n o c h a n g e of d o s e  
•  
R el at e d T E A E wit h n o c h a n g e of d o s e  
•  
T E A E l e a di n g t o i nt err u pti o n of st u d y i nt er v e nti o n  
•  
R el at e d T E A E l e a di n g t o i nt err u pti o n of st u d y i nt er v e nti o n  
•  
T E A E l e a di n g t o wit h dr a w al of st u d y i nt er v e nti o n  
•  
R el at e d T E A E l e a di n g t o wit h dr a w al of st u d y i nt er v e nti o n   
•  
T E A E l e a di n g t o a d mi ni str ati o n of c o n c o mit a nt m e di c ati o n  
•  
R el at e d T E A E l e a di n g t o a d mi ni str ati o n of c o n c o mit a nt m e di c ati o n  
•  
T E A E l e a di n g t o c o n c o mit a nt pr o c e d ur e  
•  
R el at e d T E A E l e a di n g t o c o n c o mit a nt pr o c e d ur e  
•  
T E A E l e a di n g t o st u d y t er mi n ati o n  
•  
R el at e d T E A E l e a di n g t o st u d y t er mi n ati o n  
 
 
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 0 /1 5 9  
 
 
 
1 5. 1. 1. 3  
T a b ul ati o n of A E s b y S O C a n d P T  
T he T E A E ta bles t o be pre pare d  are liste d bel o w : 
T a ble 1 3  
T E A E T a bles   
 
O v er all 
fr e q u e n c y 
B y pri m ar y 
S O C a n d P T  
B y P T o nl y  
B y pri m ar y S O C, P T 
a n d w or st gr a d e  
T E A E o v er vi e w s u m m ar y  
✓ 
N A  
N A  
N A  
T E A E l e a di n g t o 
di s c o nti n u ati o n of st u d y 
i nt er v e nti o n / st u d y o v er vi e w 
s u m m ar y  
✓ 
N A  
N A  
N A  
All T E A E s  
✓ 
✓ 
✓ 
✓ 
S eri o u s T E A E s  
✓ 
✓ 
 
 
N o n -s eri o u s T E A E s*  
✓ 
✓ 
 
 
T E A E s l e a di n g t o st u d y 
i nt er v e nti o n wit h dr a w al 
✓ 
✓ 
 
 
T E A E s l e a di n g t o st u d y 
t er mi n ati o n 
✓ 
✓ 
 
 
T E A E s l e a di n g t o d e at h  
✓ 
✓ 
 
 
Tr e at m e n t-r el at e d T E A E s  
✓ 
✓ 
✓ 
✓ 
Tr e at m e n t-r el at e d s eri o u s 
T E A E s  
✓ 
✓ 
 
 
Tr e at m e n t-r el at e d T E A E s 
l e a di n g t o tr e at m e nt 
wit h dr a w al  
✓ 
✓ 
 
 
Tr e at m e n t-r el at e d T E A E 
l e a di n g t o st u d y t er mi n ati o n 
✓ 
✓ 
 
 
Tr e at m e n t-r el at e d T E A E s 
l e a di n g t o d e at h 
✓ 
✓ 
 
 
(*): 2  t a bl e s will b e pr o vi d e d: 1) a t a bl e wit h all n o n -s eri o u s T E A E s b y S O C a n d P T, a n d 2) a t a bl e wit h  
o nl y T E A E s e x c e e di n g a fr e q u e n c y of 5 % o n t h e P T l e v el i n at l e a st o n e of t h e i nt er v e nti o n gr o u p s 
( > 5 %), b y S O C a n d P T.  
 
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 1 /1 5 9  
 
 
 
E AI R will als o be s u m mariz e d as descri be d i n Secti o n  1 5. 1. 1. 3 . T he E AI R of T E A Es t o be 
pre pare d are list e d bel o w:  
T a ble 1 4  
E AI R of T E A E T a bles   
 
O v er all fr e q u e n c y  
B y pri m ar y S O C a n d 
P T  
B y pri m ar y S O C, P T 
a n d w or st gr a d e  
All T E A E s  
✓ 
✓ 
✓ 
S eri o u s T E A E s  
✓ 
✓ 
N A  
St u d y i nt er v e nti o n -r el at e d 
T E A E s  
✓ 
✓ 
N A  
St u d y i nt er v e nti o n-r el at e d 
S eri o u s T E A E s  
✓ 
✓ 
N A  
S pecific r ules f or S O C/ P T t a b ul ati o n  
All A Es rec or de d d uri n g t he st u d y (i.e. assesse d fr o m si g nat ure of i nf or me d c o nse nt u ntil t he e n d 
of t he F oll o w -u p/ E n d  of  St u d y  V isit) will be c o de d acc or di n g t o t he Me d D R A a n d assi g n e d t o a 
S O C a n d P T.  
S O C ter ms will be  s orte d al p ha beticall y. F or t he P A, eac h i nter ve nti o n gr o u p will be dis pla ye d i n 
t he ta ble. P Ts wit hi n eac h S O C will be s orte d b y d esce n di n g fre q u e n c y of t he e v o br uti ni b 
i nter ve nti o n gr o u p , a n d t he n al p ha beticall y if m ulti ple P Ts ha ve t he sa me fre q ue nc y.  
If a partici pa nt  e x perie nces m ore t ha n o ne o cc urre nce of t he sa me T E A E (sa me S O C a n d sa me 
P T) d uri n g t he st u d y, t h e partici pa nt  will be c o u nte d o nl y o n ce f or t hat st u d y i nter ve nti o n (t he 
w orst se verit y a n d t he w orst relati o ns hi p t o st u d y i nter ve nti o n will be ta b ulate d).  
I n case a partici pa nt  ha d e ve nts wit h missi n g a n d n o n -missi n g gra des, t he ma xi m u m of t he 
n o n -missi n g gra d es will be dis pla ye d.  
I n c o m plete A E-relate d d ates will be ha n dle d as s p ecifie d i n Secti o n  9. 1 4 . 
E AI R of T E A Es will be prese nte d b y S O C a n d P T.  
P artici p a nt d at a listi n gs  
A listi n g of T E A Es le a di n g t o wit h dra wal of st u d y i nter ve nti o n a n d lea di n g t o st u d y ter mi nati o n, 
if a n y, will be pr o vi de d as well. 
1 5. 1. 1. 4  
Se nsiti vit y A n al yses of A Es   
T here will be 2  se nsiti vit y a nal ys es t o e val uate t he p ote ntial i m pact of t he war i n U krai ne o n 
T E A E /seri o us T E A E E AI R. T he first s e nsiti vit y a nal ysis will c o nsi der t hat all partici pa nts i n 
U krai ne e x perie n ce t he I C E ‘ U krai ne crisis’ o n 2 4  Fe br uar y  2 0 2 2 . T he I C E will be han dle d b y t h e 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 2 /1 5 9  
 
 
 
H y p ot hetic al strate g y ( i.e. all U krai ne partici pa nts will ha ve t heir d ata ce ns ore d p ost start of crisis).  
T he sec o n d se nsiti vit y a n al ysis will c o nsi der t hat all partici pa nts i n U krai ne, R ussia n Fe derati o n, 
a n d Belar us e x perie nce t he I C E ‘ U krai ne crisis’ o n 2 4  Fe br uar y  2 0 2 2 . A gai n, t h e I C E will be 
ha n dle d b y t he H y p ot hetical strate g y ( i.e. all parti ci pa nts fr o m U krai ne, R ussia n Fe d erati o n, a n d 
Belar us will ha ve t heir d ata ce ns ore d p ost start of crisis).  
1 5. 2  
De at hs, Ot her Seri o us A E s, a n d Ot her Si g nific a nt A E s  
1 5. 2. 1  
De at hs   
A s u m mar y of deat hs will be pr o vi de d i ncl u di n g (cli nicaltrials. g o v re q uire me nt):  
•  N u m ber a n d p erce nta ge of (all) deat hs  
•  N u m ber a n d perce nt a ge of t he pri mar y ca use of d eat h (cate g ories: pr o gress i ve disease 
a n d/ or disease relate d c o n diti o n , e ve nt u nrelate d t o st u d y i nter ve nti o n, e ve nt relate d t o 
st u d y i nter ve nti o n, u n k n o w n) 
T he ta b ulati o n of T E A Es lea di n g t o deat h is descri be d i n Secti o n  1 5. 1. 1. 3 . A listi n g of deat hs, if 
a n y, will be pr o vi de d.  
I n case t h ere is n o deat h i n t he st u d y, o nl y t he s u m mar y of deat h re q uir e d b y cli nicaltrials. g o v will 
be perf or me d, neit her t a b ulati o n of T E A E lea di n g t o deat h will be pr o d uce d, n or t he listi n g of 
deat h.  
1 5. 2. 2  
Seri o us A E s  
T h e ta b ulati o n of seri o us T E A Es is descri b e d i n Secti o n  1 5. 1. 1. 3 . A partici pa nt  listi n g of seri o us 
T E A Es will be pr o vi de d.  
1 5. 2. 3  
T E A Es of S peci al I nterest   
T he f oll o wi n g e ve nts are defi ne d as A E SI:  
•  Li ver relat e d A Es  
•  I nfecti o ns: 
o  All I nfecti o ns re p orte d as Seri o us A Es or Gra d e ≥ 3  
o  All o p p ort u nistic i nfecti o ns  
•  A m ylase a n d l i pase ele vati o ns i ncl u di n g ac ute pa n creatitis  
•  Seiz ures  
A E SI will be i de ntifie d usi n g S M Q if a vaila ble or s p o ns or -defi ne d list of searc h ter m (refer t o 
A p pe n di x  1 8. 5 ). 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 3 /1 5 9  
 
 
 
A n o ver vie w of A E SI wil l be prese nte d b y i nter ve nti o n gr o u p s h o wi n g n u m ber a n d perce nta ge of 
partici pa nts e x perie nci n g A E SI. St u d y i nter ve nti o n relate d A E SI will als o be prese nte d. A E SIs 
will be fla g ge d i n t he A E listi n gs .  
1 5. 2. 4  
Ot her Si g nific a nt T E A Es   
Ta bles a n d a listi n g of partici pa nts wit h C O VI D -1 9  rel ate d T E A Es will be pr o d uce d. T E A Es 
relate d t o C O VI D -1 9  will be retrie ve d fr o m  C O VI D -1 9  S M Q ( narr o w sc o pe). T E A Es relate d t o 
C O VI D -1 9  vacci nati o ns (see defi niti o n bel o w) will n ot be c o nsi dere d as relate d t o C O VI D -1 9 . 
A d diti o nall y, ta bles of partici pa nts wit h T E A E s ass ociate d wit h C O VI D -1 9  vacci nati o ns will be 
pr o d uce d b y i nter ve nti o n gr o u p. T E A Es ass oci ate d wit h C O VI D -1 9  vacci n ati o ns wi ll be defi ne d 
as T E A Es meeti n g all of t he f oll o wi n g criteria:  
1.  Hi g h le vel ter m e q ual t o “ Vacci n ati o n relate d c o m plicati o ns” O R “ Vacci nati o n site 
reacti o ns” O R l o west le v el ter m e q ual t o “ Vacci nati o n a d verse reacti o n”  
2.  Fla g ge d i n S D T M A E: “ Ca usalit y fact ors ot her t ha n st u d y treat me nt” free te xt fiel d 
c o ntai ni n g s pecific ter ms relate d t o C O VI D -1 9  vacci nati o n   
T he T E A E ta bles t o be pre pare d are liste d bel o w:  
T a ble 1 5  
T E A E T a bles t o be pr o d uce d   
 
B y pri m ar y 
S O C a n d P T  
B y pri m ar y 
S O C, P T a n d 
w or st gr a d e  
T E A E s r el at e d t o C O VI D -1 9  
 
✓ 
✓ 
T E A E s r el at e d t o C O VI D -1 9  l e a di n g t o wit h dr a w al of 
st u d y i nt er v e nti o n  
 
✓ 
N A  
S eri o u s T E A E s r el at e d t o C O VI D -1 9  
 
✓ 
N A  
St u d y i nt er v e nti o n -r el at e d T E A E s r el at e d t o C O VI D -1 9  
✓ 
✓ 
T E A E s a s s o ci at e d wit h v a c ci n ati o n s f or C O VI D -1 9  
✓ 
✓ 
S eri o u s T E A E s a s s o ci at e d wit h v a c ci n ati o n s f or 
C O VI D -1 9  
✓ 
N A  
St u d y i nt er v e nti o n -r el at e d T E A E s a s s o ci at e d wit h 
v a c ci n ati o n s f or C O VI D -1 9  
✓ 
N A  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 4 /1 5 9  
 
 
 
1 5. 3  
Cli nic al L a b or at or y E v al u ati o n   
T he f oll o wi n g la b orat or y p ara met ers will be m eas ure d d uri n g t he st u d y as part of t he s afet y 
e val uati o n:  
•  He mat ol o g y  
•  Bi oc he mistr y, i ncl u di n g t he f oll o wi n g L F T: 
o  As partate a mi n otra nsferase  
o  Ala ni ne a mi n otra nsf eras e  
o  Al kali ne p h os p hatase  
o  γ-Gl uta m yl -tra nsf eras e 
o  T otal Bilir u bi n  
•  Uri nal ysis  
•  C oa g ulati o n  
T he cli nical la b orat or y safet y tests t o be meas ure d i n t his st u d y are pr o vi de d i n t he pr ot oc ol (refer 
t o A p pe n di x  5  of t he C T P). Para meters fr o m A p pe n di x  5  of t he C T P t o be s u m marize d a n d liste d 
i n t he T L Fs are pr o vi de d i n A p pe n di x  1 8. 6 . 
Listi n gs a n d s u m mar y statistics a t eac h assess m e nt ti me will be prese nt e d usi n g t he SI u nits. 
N or mal ra n ges will be pr o vi de d b y t h e ce ntral l a b orat or y, a n d o ut of ra n ge fla gs will be calc ulate d 
base d o n t he n or mal ra n ges. La b orat or y d ata n ot tr a nsferre d fr o m t he ce ntr al la b orat or y i n SI u nits 
will be c o n v erte d t o SI u nits bef ore pr ocessi n g. B ot h ori gi nal u nits a n d SI u nits will be pr o vi de d 
i n t he S D T M d o mai n.  
F or h e mat ol o g y, bi oc h e mistr y a n d c o a g ulati o n  des cri pti ve statistics b y visit , data fr o m ce ntr al la bs 
will be utilize d f or all ta ble s a n d fi g ures. If t he ce ntral la b is missi n g f or a visit b ut a l ocal la b is 
prese nt, t he l ocal la b v al ues will be use d.  T he l ocal la b res ults will be assi g n e d t o a nal ysis visits as 
descri be d i n Secti o n  9. 8 . N or mal ra n ges pr o vi d e d b y t he l ocal la b will be use d f or f urt her 
deri vati o ns. B ot h c e ntral a n d l ocal la b data will be liste d.  
F or uri nal ysis, l ocal la b data will be utilize d f or T L Fs . A s pecific listi n g f or uri ne micr osc o p y will 
be pr o vi de d (ce ntral la b data).  
C o nti n u o us cli nical la b orat or y dat a  ( he mat ol o g y, bi oc he mistr y, uri nal ysis, c oa g ulati o n) will be 
s u m marize d b y st u d y i nt er ve nti o n usi n g des cri pti ve statistics at baseli ne  a n d eac h p ost  b aseline  
visit f or a bs ol ute val ue a n d c ha n ges fr o m baseli ne  (see Secti o n  9. 2  a n d A p pe n di x  1 8. 6 ). 
He mat ol o g y, bi oc he mistr y a n d uri nal ysis d ata will be pres e nte d b y a nal ysis visit , w hile 
c oa g ulati o n data will be prese nte d b y n o mi nal visit (see Secti o n  9. 8  a n d A p pe n di x  1 8. 4 ). 
As a se nsiti vit y a nal ysis, descri pti ve statistics b y visit will be re peate d usi n g o nl y ce ntr al la b data 
f or t he f oll o wi n g para meters: Ne utr o p hil c o u nt, A m ylase, Li p ase, A L T, A S T. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 5 /1 5 9  
 
 
 
S o me la b orat or y res ults will be classifie d acc or di n g t o N CI -C T C A E Versi o n  5. 0 . S o me of t he 
t o xicit y gra di n gs are base d o n la b orat or y meas ure me nts i n c o nj u n cti o n wit h cli nical fi n di n gs. 
N o n -n u meric al q ualifiers ( e x ce pt f or fasti n g fla gs) will n ot be ta ke n i nt o c o nsi derati o n i n t he 
deri vati o n of C T C A E criteria ( e. g. h y p o kale mia Gra de  1 a n d Gra de  2 are o nl y disti n g uis he d b y a 
n o n -n u merical q ualifier a n d t heref ore Gra d e 2 will n ot be deri ve d). I n cas e a la b orat or y para meter 
has bi -directi o nal t o xicities ( e. g. P otassi u m ) b ot h directi o ns will be prese nte d f or t he gi ve n 
para meter ( i.e. P otassi u m  L o w a n d P otassi u m  Hi g h).  
A d diti o nal la b orat or y res ults t hat are  n ot part of N CI -C T C A E will be prese nte d acc or di n g t o t he 
cate g ories: bel o w n or mal li mit, wit hi n n or mal li mits a n d a b o ve n or mal li mit (acc or di n g t o t he 
la b orat or y n or mal ra n ges). La b orat or y res ults c o ntai ni n g a m o difier s uc h as “ <” or “ > =” will be 
ha n dle d as per A p pe n di x  1 8. 7  f or s u m mar y statistics a n d b ot h res ults as c ollecte d i n t he data base 
a n d as i m p ute d will be re p orte d i n partici pa nt  data listi n gs.  
S hift ta bles  of baseli ne  v ers us p os t b aseli ne will be prese nte d b y i nter ve nti o n gr o u p f or h e mat ol o g y 
a n d bi oc he mistr y.  
•  La b orat or y gra da ble p ara meters part of N CI -C T C A E will be use d t o s u m marize c ha n ges fr o m 
baseli ne  Gra de  t o w orst o n-treat me nt gra de.  
o  I n case of gra di n gs i n v ol vi n g baseli ne  meas ure m e nts f or t he i de ntificati o n of gra des 
d uri n g t h e o n -tr eat me nt peri o d, t he s hift t a ble will prese nt baseli ne  n or mal a n d 
a b n or mal. N or mal will i ncl u de meas ure m e nts bel o w a n d wit hi n n or mal ra n ge 
( directi o n i ncrease), or meas ure me nts wit hi n a n d a b o ve n or mal ra n ge ( directi o n 
decrease).  
•  La b orat or y p ara m eters t hat are n ot p art of N CI -C T C A E will be use d t o s u m marize c ha n ges 
fr o m baseli ne  fi n di n g t o w orst o n-treat me nt fi n di n g. 
Partici pa nt data listi n gs 
will be pr o vi de d,  wit h a fla g f or a b n or m al val ues, al o n g 
wit h 
c orres p o n di n g n or m al ra n ges:  
•  La b orat or y gra da ble para meters part of N CI -C T C A E will be prese nte d acc or di n g t o t he 
cate g ories b ase d o n n or mal ra n ges al o n g wit h t he gra d e. A b n or mal v al ues will be fla g ge d 
acc or di n g t o t he dir ecti o n of t o xicit y as d etaile d i n A p pe n di x  1 8. 6  (e. g. f or a para meter s u c h 
as P otassi u m L o w, o nl y val ues bel o w t he L L N will  be  fla g ge d). 
•  La b orat or y para me ters t hat are n ot part of N CI-C T C A E will be prese nte d acc or di n g t o t he 
cate g ories b ase d o n n or mal ra n ges: b el o w n or mal li mits ( L o w), wit hi n n or m al li mits ( N or mal), 
a n d a b o ve n or mal li mits ( Hi g h). Val ues t hat are eit her a b o v e U L N or b el o w L L N will be 
fla g ged.  
B o x pl ots of t he la b orat or y v al ues b y i nter ve nti o n gr o u p a n d ti me p oi nt will be pr o vi de d f or t he 
f oll o wi n g para meters i ncl u de d i n Ta ble 1 6 : 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 6 /1 5 9  
 
 
 
T a ble 1 6  
L a b or at or y P ar a meters   
B o x pl ots f or la b orat or y para meters w here t o xicit y gra des are defi n e d bas e d o n t he rati o of t he 
para meter val ues a n d t he U L N will n ot be dis pla ye d usi n g t he u nit of meas ure me nt b ut i nstea d 
usi n g t he rati o of t he me as ure d val u e o ver U L N. T his c o m prises A L P, A L T, A S T, bilir u bi n, G G T, 
Li pas e a n d A m ylas e . W here feasi ble, a refere nce li ne f or C T C A E gra de ≥ 3  s h o ul d be a d de d t o 
gra p hical dis pla ys.  
Li ver f u ncti o n tests : A L T, A S T, a n d t otal bilir u bi n are use d t o assess p ossi ble dr u g i n d uce d li ver 
t o xicit y. T h e rati os of t est res ult o ver U L N will b e calc ul ate d a n d classifie d f or t hes e 3  para meters 
d uri n g t he o n -treat me nt p eri o d. 
S u m mar y of li ver f u ncti o n tests will i ncl u de t he f oll o wi n g cate g ories. T he n u m ber a n d perce nta ge 
of partici p a nts wit h eac h of t he f oll o wi n g cate g ories d uri n g t h e o n -tr eat me nt peri o d will be 
s u m marize d b y st u d y i nt er ve nti o n gr o u p: 
•  A L T ≥ 3 × U L N, A L T ≥ 5 × U L N, A L T ≥ 8 × U L N, A L T ≥ 1 0 × U L N, A L T ≥ 2 0 × U L N  
•  A S T ≥ 3 × U L N, A S T ≥ 5 × U L N, A S T ≥ 8 × U L N, A S T ≥ 1 0 × U L N, A S T ≥ 2 0 × U L N  
•  ( A L T or A S T) ≥ 3 × U L N, ( A L T or A S T) ≥ 5 × U L N, (A L T  or A S T)  ≥ 8 × U L N , ( A L T or 
A S T)  ≥ 1 0 × U L N, ( A L T or A S T) ≥ 2 0 × U L N  
•  T BI LI  ≥ 1. 5 × U L N, T BI LI ≥ 2 × U L N  
C at e g or y  
L a b or at or y p ar a m et er  
C o n v e nti o n al U nit  
SI U nit s  
H e m at ol o g y  
H e m o gl o bi n  
g/ d L  
g/ L  
R e d bl o o d c ell c o u nt  
1 0 6 / µ L 
1 0 1 2 / L 
R eti c ul o c yt e c o u nt  
1 0 3 / µ L 
1 0 9 / L 
W hit e bl o o d c ell c o u nt  
1 0 3 / µ L 
1 0 9 / L 
N e utr o p hil c o u nt  
1 0 3 / µ L 
1 0 9 / L 
L y m p h o c yt e c o u nt  
1 0 3 / µ L 
1 0 9 / L 
Pl at el et c o u nt  
1 0 3 / µ L 
1 0 9 / L 
Bi o c h e mi str y  
Al a ni n e  a mi n otr a n sf er a s e 
( A L T) 
U/ L  
U/ L  
Al b u mi n  
g/ d L  
g/ L  
A s p art at e 
a mi n otr a n sf er a s e ( A S T)  
U/ L  
U/ L  
G a m m a -gl ut a m yl 
tr a n sf er a s e ( G G T) 
U/ L  
U/ L  
Al k ali n e p h o s p h at a s e  
U/ L  
U/ L  
T ot al bilir u bi n  
m g/ d L  
µ m ol/ L  
A m yl a s e  
U/ L  
U/ L  
Li p a s e  
U/ L  
U/ L  
e G F R  
m L/ mi n/ 1. 7 3 m
2  
m L/ mi n/ 1. 7 3 m
2  
Bl o o d ur e a nitr o g e n 
( B U N) 
m g/ d L  
m m ol/ L  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 7 /1 5 9  
 
 
 
•  C o nc urre nt A L T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N  
•  C o nc urre nt A L T ≥ 3 × U L N a n d T BI LI ≥ 1. 5 × U L N  
•  C o nc urre nt A S T ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N  
•  C o nc urre nt A S T ≥ 3 × U L N a n d T BI LI ≥ 1. 5 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 1. 5 × U L N   
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N a n d A L P > 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 1. 5 × U L N a n d A L P > 2 × U L N  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 2 × U L N a n d A L P ≤ 2 × U L N or missi n g  
•  C o nc urre nt ( A L T or A S T) ≥ 3 × U L N a n d T BI LI ≥ 1. 5 × U L N a n d A L P ≤ 2 × U L N or missi n g  
I n a d diti o n, t he f oll o wi n g cate g ories will be s u m marize d i n a se parate t a ble, li mite d t o t he first 6 
m o nt hs  (1 8 0 da ys ) after treat me nt start dat e:  
•  A L T ≥ 5 × U L N  
•  A L P ≥ 2 × U L N  
•  C o nc urre nt A L T ≥ 5 × U L N a n d T BI LI ≥ 2 × U L N  
•  C o nc urre nt A L P  ≥ 2 × U L N a n d T BI LI ≥ 2 × U L N  
C o nc urre nt meas ure me nts are t h ose occ urri n g o n t he sa me date.  
Cate g ories will be c u m ulati ve, i.e. a partici pa nt wit h a n ele vati o n of A S T ≥ 1 0 × U L N will als o 
a p pear i n t he cate g ories ≥ 8 × U L N , ≥ 5 × U L N a n d ≥ 3 × U L N.  
A listi n g will be pr o d uce d, dis pla yi n g all A L T, A S T, T BI LI a n d A L P res ults f or partici pa nts wit h 
a n y L F T ele vati o n (A S T  ≥ 3 × U L N, A L T  ≥ 3 × U L N or T BI LI  ≥ 1. 5 × U L N ). 
I n a d diti o n, t he f oll o wi n g gra p hical dis pla ys will be pr o vi de d f or t he o n -treat me nt peri o d : 
•  A L T v al ues o ver ti me will be prese nte d i n a s pa g hetti pl ot f or partici pa nt s wit h A L T Gra d e  2 
or hi g her ele v ati o n (i.e. Gra de  ≥ 2) b y i nter ve nti o n gr o u p  
•  Ti me i n wee ks fr o m first d ose t o first A L T occ urre nce of Gra de  2 or hi g her ele vati o n (i.e. 
Gra de  ≥ 2) f or all partici pa nt s b y i nter ve nti o n gr o u p ( K M pl ot)  
•  Ti me i n wee ks fr o m first d ose t o first e G F R o cc urre nce e q ual t o less t ha n 6 0  m L/ mi n/ 1. 7 3 m 2 
f or partici pa nt s wit h bas eli ne  e G F R ≥ 6 0 m L/ mi n/ 1. 7 3 m 2 b y i nter ve nti o n gr o u p ( K M pl ot)  
•  e-DI S H fi g ure, as descri be d i n Merz et al ( 2 0 1 4)  will be prese nte d i ncl u di n g 2  pa nels  (f or P A): 
o ne f or eac h i nter ve nti o n gr o u p.  
F or t he 2  ti me-t o-e ve nt fi g ures, at t he ti me of P A, a partici pa nt  o n g oi n g a n d  wit h o ut e x perie nci n g 
t he e ve nt will ha ve t he e ve nt ti me ri g h t-ce ns ore d at t he ti me of t he l ast A L T/e G F R assess me nt  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 8 /1 5 9  
 
 
 
bef ore c ut off. T o be i ncl u de d i n a ti me -t o-e ve nt fi g ure, a gr o u p m ust ha v e at least o ne e ve nt. Bel o w 
t he h oriz o ntal a xis of t he ti me-t o-e ve nt fi g ure, n u m ber of partici p a nt s at ris k will be dis pla ye d. T he 
vertical a xis ma y b e restricte d t o 0. 5 0 –  1. 0, if n o ne of t he c ur ves r eac h 5 0 %.  
I n t hese st u dies, cli nicall y si g nifi ca nt la b a b n or malities were rec or de d as A E s. I n lie u of a listi n g 
of cli nicall y si g nifica nt l a b a b n or malities f or eac h d o mai n, t he f oll o wi n g b y -p artici pa nt  la b val ue 
listi n gs will be pr o vi de d: 
•  Listi n g of p os t b aseli ne Gra de ≥ 3 h e mat ol o g y v al ues  
•  Listi n g of p os t b aseli ne Gra de ≥ 3 bi oc h e mistr y v al ues  
•  Listi n g of p os t b as eli ne uri nal ysis val ues wit h a n i ncreas e of “ + +” f or n o n -gra da ble para meters 
w he n a p plica bl e.  
•  Listi n g of p os t b as eli ne  Gra d e ≥ 2 A S T, A L T or Bilir u bi n.  F or eac h para m eter, w he n a 
partici pa nt  has a n i n creas e t o Gra de 2, all p osteri or val ues will be i ncl u de d i n t he listi n g.  
Per Secti o n  7. 1 of t he M S 2 0 0 5 2 7 -0 0 8 0/ 
 P r ot oc ol V ersi o n 6 , st u d y i nter ve nti o n is t o be 
te m p oraril y disc o nti n ue d i n t he f oll o wi n g sce nari os: 
•  If a partici pa nt ha d  a n i ncreas e i n A L T or A S T t o > 3 x t o < 5 U L N.  A rec hec k of t h e val u e 
wit hi n 7 2 h o urs is re q uire d, t o c o nfir m t he re p orte d ele vati o n.  
•  If A S T a n d/ or A L T > 3 × U L N t o < 5 × U L N are c o nfir me d wit hi n 7 2 h o urs a n d ha ve i ncrease d 
b y m ore t ha n 5 0 % (c o m pare d t o latest c o nfir me d val ue), t he i nterr u pti o n of t he st u d y 
i nter ve nti o n c o nti n ues, wit h a n a d diti o nal rec hec k 7 2 h o urs later. 
•  If t he rec hec ke d val u e i n t he sec o n d rec hec k has d ecrease d t o < U L N or < p artici pa nt’s 
baseli n e, rec halle n ge ca n be c o nsi dere d i n t he a bs e nce of h y p er bilir u bi ne mia.  
•  I n all ot her cases, st u d y i nter ve nti o n is t o be per m a ne ntl y disc o nti n ue d. 
•  If A S T a n d/ or A L T > 3 × U L N t o < 5 × U L N are c o nfir me d wit hi n 7 2 h o urs a n d ha ve i ncrease d 
b y less t ha n 5 0 % (c o m pare d t o latest c o nfir me d val ue), t he i nterr u pti o n of t he st u d y 
i nter ve nti o n c o nti n ues wit h a n a d diti o n al rec h ec k i n 1 wee k. 
•  If rec hec ke d val ue i n t he sec o n d rec hec k has d ecrease d t o < U L N or < p artici pa nt’s 
baseli ne, rec halle n ge ca n be c o nsi dere d i n t he a bs e nce of h y p er bilir u bi ne mia . 
•  I n all ot her cases, st u d y i nter ve nti o n is t o be per m a ne ntl y disc o nti n ue d. 
T o s u p p ort assess me nt of t he fracti o n of te m p oraril y disc o nti n ue d partici pa nts w h o c o ul d rei nitiate 
treat me nt if all o we d 1 w ee k, 2 wee ks, 3 wee ks, 4 wee ks  t o rec o v er, t he ti me t o first A L T a n d A S T 
meeti n g rec h alle n gi n g criteri o n  is t o be c haract erize d a m o n g partici pa nts w h o disc o nti n ue d 
treat me nt (te m p or aril y or per ma ne ntl y) f or A L T or A S T > 3 x U L N b ase d o n S A F . 
( 1) F or a partici pa nt w h o h as at least o ne dat e w here A L T or A S T > 3 x U L N (l ocal la b 
A L T/ A S T assess me nts ta ke n i nt o c o nsi derati o n), x 1 is defi ne d as t he earliest ele vati o n date.  
( 2) T he treat me nt disc o nti n u ati o n date x 2 is defi n e d as t he earliest d ate a m o n g (i) " N o d ose" 
date ≥ x 1 fr o m ‘ Dr u g A d mi nistrati o n’ C R F, (ii) " Start" date ≥ x 1 f or A E rec or d i n dicati n g 
" Dr u g I nterr u pte d" f or " Acti o n ta ke n wit h st u d y treat me nt" fr o m ‘ A E’ C R F, a n d (iii) "last 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 0 9 /1 5 9  
 
 
 
a d mi nistrati o n date" ≥ x 1 fr o m ‘ Treat me nt Ter mi n ati o n’ C R F. Partici pa nts f or w h o m b oth 
x 1 a n d x 2 ca n be defi ne d c o m prise t he s u b gr o u p of i nterest f or ti me t o e ve nt a nal ysis.  
A partici pa nt is c o nsi dere d t o ha ve " A L T or A S T > 3 x U L N" if (a) A L T > 3 x U L N, ( b) A S T > 3 
x U L N, or (c) b ot h A L T > 3 x U L N a n d A S T > 3 x U L N. F or t he partici pa nt  to be c o nsi dere d 
rec o vere d, t he p artici pa nt  m ust ha ve b ot h A L T ≤ 3 x U L N a n d A S T ≤ 3 x U L N.  
Partici pa nts i n t he s u b gr o u p of i nterest w h o ha ve A L T a n d A S T rec o v er y b y t he pla n ne d e n d of 
treat me nt, will ha ve t he ti me t o first A L T a n d A S T rec o ver y calc ul ate d as "( x 1 earliest date at 
w hic h b ot h A L T ≤ 3 x U L N a n d A S T ≤ 3 x U L N ) –  (x 2 date of treat me nt disc o nti n uati o n d ue t o 
A L T or A S T ele vati o n ) + 1". N ote t hat t he "earliest" date of rec o v er y is relati ve t o t he date of 
treat me nt disc o nti n uati o n d ue t o A L T or A ST ele vati o n.  
Partici pa nts i n t he s u b gr o u p of i nterest w h o d o n ot ha ve A L T a n d A S T rec o ver y b y t he P A c ut off 
date or pri or t o st u d y ter mi nati o n, or are l ost t o f oll o w u p, will be ce ns ore d at t he date of t he last 
a vaila ble A L T or A S T assess me nt. T he ce ns ori n g ti me will be calc ulat e d as " (d ate of ce ns ori n g ) 
–  (date of tr eat me nt disc o nti n uati o n d ue t o A L T or A S T ele vati o n ) + 1".  
K M esti mates ( pr o d uc t-li mit esti mates) of t he c u m ulati ve pr o ba bilit y of first meeti n g rec halle n ge 
criteri o n o ver ti me will b e prese nt e d b y i nter ve nti o n gr o u p, t o get h er wit h a s u m mar y of p erce ntiles 
(2 5 t h, 5 0 t h, 7 5t h) a n d c orres p o n di n g 2 -si d e d 9 5 % CIs. S u m mar y statistics ( mea n, S D, me di a n, 
mi ni m u m a n d ma xi m u m) will be prese nte d f or f oll o w-u p  ti me. T he K M c ur ves will als o b e 
pr o vi de d f or e ac h i nter ve nti o n gr o u p.  T he K M fi g ure a n d s u p p orti ve K M ta bles will be re peate d 
base d o n t he f oll o wi n g 2 s u b gr o u ps of p artici pa nts:  
•  Partici pa nts w h o ha d A L T/ A S T ele vati o n > 3 - < 5 x U L N at treat me nt disc o nti n uati o n  
•  Partici pa nts w h o ha d A L T/ A S T ele vati o n ≥ 5 x U L N at treat me nt disc o nti n uati o n  
Partici pa nts wit h A L T/ A S T val ues ≤ 3 x U L N at treat me nt disc o nti n uati o n are i ncl u d e d i n t he 
s u b gr o u p A L T/ A S T > 3 - < 5 x U L N a n d re p ort e d i n f o ot n otes.  
T reat me nt ga p a nal ysis will e x pl ore w het her l o n ger tr eat me nt p a use i n st u d y i nter ve nti o n affects 
effic ac y. T his a nal ysis will als o be pr o d u ce d o n p o ole d data fr o m b ot h st u di es.  Treat me nt ga ps of 
i nterest will be cate g orize d as f oll o wi n g: 
( 1) Ga p bet wee n E n d  of  Treat me nt a n d E n d  of  St u d y  V isits (ga p  1 ): 
a. Earl y  treat me nt disc o nti n uati o n f oll o we d b y Safet y  F oll o w -u p (ga p  1 a ) 
b.  Pla n ne d E n d  of  Treat me nt f oll o we d b y S afet y F oll o w -u p (ga p  1 b ).  
I n case E n d  of  Treat me nt  reas o n is " Deat h" or " L ost t o f oll o w-u p ", it will n ot be 
c o nsi dere d as a ga p.  
( 2) Treat me nt ga p after first st u d y i nter v e nti o n a d mi nistrati o n d ue t o a n y reas o n, o btai ne d fr o m 
C R F as f oll o wi n g (ga p  2 ): 
a. ‘Dr u g A d mi n istrati o n’ rec or ds w here " N o d ose", wit h reas o n " A d verse e v e nt" or 
" Ot her", is select e d i n res p o nse t o t he q uesti o n "Is t here a c h a n ge i n d os e?" (ga p  2 a ).  
b.  ‘A E ’ rec or ds w here " Dr u g I nterr u pte d" or " Dr u g 
Wit h dra w n" is selecte d f or 
" Acti o n ta k e n wit h st u d y treat me nt" (ga p  2 b ).  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 0 /1 5 9  
 
 
 
Ga p start f or cat e g or y 1 (i.e. ga p 1) is E n d  of  Treat me nt  date a n d ga p e n d d ate will be i m p ute d as 
S afet y F oll o w -u p  V isit e n d date e ve n t h ou g h dr u g is n ot a d mi nistere d d uri n g t his visit. T o 
deter mi ne n o n -o v erla p pi n g ga ps, ga p start f or cat e g or y 2 (i.e. ga p  2) is d efi ne d as t he earliest of 
" N o d os e" date (i.e. ga p  2a) a n d A E st art dat e (i.e. ga p  2 b) a n d e n ds wit h first st u d y i nter ve nti o n 
a d mi nistrati o n rec or d aft er t he ga p start date. I n case ga p  1 a n d ga p  2 o cc ur o n t he sa me da y, 
i nf or mati o n f or ga p 1 will be prese nte d. M ulti ple n o n -o verla p pi n g ga ps ca n occ ur f or cate g or y  ga p 
2, all ga ps fr o m cat e g or y 2a a n d all ga ps fr o m cate g or y 2 b will be p rese nte d. 
Partici pa nts  i n t he s u b gr o u p of i nterest will ha ve t he ga p d urati o n i n da ys calc ul ate d as t he 
differe n ce b et wee n st art a n d st o p dates pl us 1 ( g a p d urati o n [da ys ] = g a p e n d date - g a p start date 
+ 1). O nl y ga ps wit h d urati o n l o n ger t ha n 7 da ys a n d  d urati o n s h orter or e q ual t o 3 0 da ys will be 
prese nte d.  
Reas o n f or ga p is pre m at ure E n d  of  Treat me nt  reas o n f or ga p 1a, treat me nt c o m pleti o n f or ga p 1 b, 
n o d ose a d mi nistrati o n reas o n f or ga p 2 a a n d A E  f or ga p 2 b. I n case ga p 2 a a n d ga p 2 b start o n t he 
sa me da y, A E  is pr ese nte d as t he reas o n f or ga p. 
Efficac y assess me nts (e. g. rela ps e, E D S S a n d M RI) at st art of ga p a n d at e n d of ga p will b e 
prese nte d f or t he partici pa nts  i n t he s u b gr o u p of i nterest. F or rela pse/ E D S S assess me nt/ M RI res ult 
at start of ga p, t he l ast n o n -missi n g rel a pse/ E D S S assess me nt/ M RI res ult o n or bef ore t h e start of 
ga p is sele cte d. F or rela pse/ E D S S assess me nt/ M RI res ult at e n d of ga p, t he first n o n -mis si n g 
rela pse/ E D S S assess me nt/ M RI res ult o n or after t he e n d of ga p is s electe d.  
Details of treat me nt ga ps a n d c orres p o n di n g efficac y i nf or mati o n bef ore/ after treat me nt ga p will 
be prese nt e d i n a listi n g base d o n t he S A F. S u m mar y t a bles will als o be pr o d uc e d t o des cri be 
n u m ber of ga ps a n d reas o n, as well as treat me nt ga p i m pact o n efficac y ass ess me nt.   
Effic ac y E v al u ati o n of P artici p a nts w h o Rest arte d St u d y I nter ve nti o n  after I nterr u pti o n d ue 
t o A L T/ A S T Ele v ati o n  
T hese a nal yses are mea nt t o i n vesti gate t he effect of i nterr u pti o n of treat me nt o n A R R a n d E D S S 
pr o gressi o n, b y pres e nti n g 3 s u b gr o u ps si de b y si d e:   
( 1) 
Partici pa nts w h o i nterr u pte d I M P d ue t o A L T/ A S T ele vati o ns a n d restarte d treat me nt after 
t he rec h alle ngi n g criteri o n were met;  
( 2) 
T he c o m ple me ntar y F A S  s u b gr o u p ( partici pa nts i n F A S  t hat are n ot i n ( 1)); 
(2a ) 
A  s u bset of ( 2) w h o di d n ot e x perie nce L F T ele vati o ns. 
T he a nal ys es will be perf or me d usi n g t he F A S. A R R ( descri pti ve statistics a n d res ults of ne ga ti ve 
bi n o mial m o del) a n d E D S S ( descri pti ve statistics a n d ti me t o 1 2 -wee k  c o nfir me d pr o gressi o n ) will 
be dis pla ye d b y st u d y i nt er ve nti o n gr o u p.  F urt her details re gar di n g t he m o delli n g will b e i ncl u de d 
i n t he Statistical Met h o d ol o g y d oc u me nt ( A p pe n di x 1 8. 9 ). 
D uri n g t he D B T P, terifl u n o mi de le vel deter mi nati o n mi g ht be c o m plete d f or safet y reas o ns o nl y, 
t hese terifl u n o mi de le vels will be prese nte d i n a listi n g. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 1 /1 5 9  
 
 
 
1 5. 4  
Vit al Si g ns   
Vital si g ns ( hei g ht ( cm), wei g ht ( k g), B MI ( k g/ m²), b o d y te m perat ure (° C), S B P  ( m m H g), D B P  
( m m H g), res pirat or y rat e ( breat hs/ mi n) a n d p ulse rat e ( beats/ mi n)) will be s u mmarize d b y 
i nter ve nti o n gr o u p usi n g descri pti ve statistics (see Secti o n  9 ).  
T he descri pti ve statistics will be prese nte d as f oll o ws:  
•  T he baseli ne  will be pres e nt e d first   
•  T he n eac h sc h e d ule d ti me p oi nt will be prese nte d o n partici pa nt s w h o ha ve reac h e d t his 
ti me p oi nt: a bs ol ute val u es a n d C F B will be dis pla ye d (e x ce pt f or hei g ht a n d B MI as 
t he y are o nl y prese nt at S cree ni n g  visit).  
B MI (k g/ m² ) = 
𝐷𝑢𝑟𝑎ℎ𝑡 [𝑖𝑜] 
ℎ𝑛𝑜𝑓ℎ𝐸[𝑣𝑜]2 × 1 0 0 0 0  
B o d y te m perat ure, S B P, D B P, res pir at or y rate a n d p ulse rate will be a n al yze d wit h s hift ta bles of 
ma xi m u m C F B usi n g t he cate g ories d efi ne d i n  T a ble 1 7 : 
T a ble 1 7  
Vit al Si g ns C ate g ories   
P ar a m et er  
U nit  
S hift  
B a s eli n e  c at e g ori e s  
P o s t b a s eli n e  c at e g ori e s 
( a b s ol ut e c h a n g e) 
T e m p er at ur e  
° C 
I n cr e a s e 
< 3 7 / ≥3 7 - < 3 8 / ≥3 8 - 
< 3 9 / ≥3 9 - < 4 0 / ≥ 4 0  
≤0* / > 0 - < 1 / ≥1 - < 2 / ≥2 - < 3 / 
≥3  
P ul s e r at e  
b p m  
I n cr e a s e 
a n d d e cr e a s e  
< 1 0 0 / ≥1 0 0  
≤0* / > 0 - ≤2 0 / > 2 0 - ≤4 0 / > 4 0  
S B P  
m m H g  
I n cr e a s e 
a n d d e cr e a s e  
< 1 4 0 / ≥1 4 0  
≤0* / > 0 - ≤2 0 / > 2 0 - ≤4 0 / > 4 0  
D B P  
m m H g  
I n cr e a s e 
a n d d e cr e a s e  
< 9 0 / ≥9 0  
≤0* / > 0 - ≤ 2 0 / > 2 0 - ≤4 0 / > 4 0  
R e s pir at or y r at e  
br e at h s/ mi n  I n cr e a s e 
a n d d e cr e a s e  
< 2 0 / ≥2 0  
≤0* / > 0 - ≤5 / > 5 - ≤1 0 / > 1 0  
* T hi s c at e g or y will i n cl u d e t h e p arti ci p a nt s wit h n o c h a n g e s or d e cr e a s e/i n cr e a s e i n t h e i n cr e a s e/ d e cr e a s e p art of t h e 
t a bl e r e s p e cti v el y. 
A listi n g of ma xi m u m C F B a n d a listi n g of all vital si g ns data will be pr o vi de d.  
1 5. 5  
1 2 -Le a d E C G   
O nl y l o cal  E C G rea ds w ere c ollecte d at t he st u d y start, h o we v er all l ocal rea ds will n o w be se nt t o 
be rea d ce ntrall y. He n ce f or a n al ys es p ur p oses  (i ncl u di n g c h a n ge fr o m b aseli ne  c o m p utati o n), 
ce ntral r ea d d ata will be use d as s o urce data.  
Descri pti ve statistics (a b s ol ute a n d c ha n ge fr o m b aseli ne ) o ver ti me f or 1 2-lea d E C G para meters 
will be pr o vi de d. Para meters t o be i ncl u de d are: Q Tc F, H R, P R a n d Q R S. Baseli ne  assess me nt s as 
defi ne d i n Secti o n  9. 4  will be c o nsi dere d t o be pre -d ose.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 2 /1 5 9  
 
 
 
A d diti o nall y, a s u m mar y ta ble of a b n or mal val ues ( o utliers) f or 1 2 -lea d E C G para meters will be 
prese nte d:  
•  H R:  
o  A bs ol ute <  5 0 b p m, <  4 0 b p m, <  3 0 b p m  
o  C ha n ge fr o m bas eli ne  >  2 0 b p m, >  3 0 b p m, >  4 0 b p m  
o  A bs ol ute < 5 0 b p m a n d d ecrease fr o m baseli ne  > 2 5 %  
o  A bs ol ute > 1 0 0 b p m a n d i ncreas e fr o m bas eli ne  > 2 5 %  
•  P R:  
o  A bs ol ute >  2 0 0 msec a n d >  2 2 0 msec  
o  I n crease fr o m baseli ne  > 3 0 msec  
o  A bs ol ute > 2 0 0 msec a n d i ncrease fr o m bas eli ne  > 2 5 %  
•  Q R S:  
o  A bs ol ute >  1 1 0 msec  
o  A bs ol ute > 1 2 0 msec a n d i ncreas e fr o m bas eli ne  > 2 5 %  
•  Q Tc F:  
o  A bs ol ute ≤ 4 5 0 msec, >  4 5 0 msec  a n d ≤ 4 8 0 msec , > 4 8 0 msec  a n d ≤ 5 0 0 msec , a n d > 5 0 0 
msec  
o  I n crease fr o m baseli ne  ≤ 3 0 msec, >  3 0 msec a n d ≤ 6 0 msec, a n d > 6 0 msec  
B y -visit fre q ue n c y t a bles b y di a g n osis ter m will be pr o vi de d, dis pla yi n g all ter ms, o nl y t he first 
ter m a n d o nl y t h e sec o n d ter m se paratel y. T he perce nta ge of dia g n osis ter ms will be base d o n t he 
t otal n u m ber of partici pa nts wit h res ults at the visit.  
A s hift ta ble of m or p h ol o gical assess me nts, fr o m baseli ne  t o t he w orst o bser vati o n of t he 
o n -treat me nt peri o d, of t he n u m ber a n d p erce nta ge of partici pa nt s f or eac h i nter pretati o n cate g or y 
( N or mal, 
A b n or mal-I nsi g nifica nt, 
A b n or mal-Si g nifica nt , 
Missi n g, a n d T otal) 
will als o be 
pr o vi de d.  Res ults rec or de d as "i nc o m plete a nal ysis" or " u ni nter preta ble" will be c o u nte d u n der t he 
" Missi n g" cate g or y. 
Listi n gs of E C G q ua ntitati ve val ues, m or p h ol o gical a n d r h yt h m res ults will be pr o d uce d i ncl u di n g 
res ults fr o m b ot h ce ntr al a n d l ocal rea ds.  
1 5. 6  
P h ysic al E x a mi n ati o n   
N o s u m mar y ta ble will be pr o vi de d si nce p h ysical e x a mi nati o n fi n di n gs d uri n g Scree ni n g  will be 
rec or de d as me dical hist or y e ve nts a n d fi n di n gs d uri n g t he st u d y as A Es.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 3 /1 5 9  
 
 
 
1 5. 7  
Pre g n a nc y Test   
Res ults of pre g na nc y test ( uri ne or ser u m) will be liste d.  
1 5. 8  
S afet y/ P h ar m ac o d y n a mic  E n d p oi nts: I m m u n o gl o b uli n le vels   
B o x pl ots of Ser u m I g G, I g A a n d I g M le vels ( g/ L) b y i nter ve nti o n gr o u p a n d ti me p oi nt will be 
pr o vi de d, as well as li ne pl ots of me dia n val ue a n d  me dia n perce nt c ha n ge fr o m baseli ne  b y ti me 
p oi nt a n d i nter ve nti o n gr o u p.  
Descri pti ve statistics (a bs ol ute val ue, c ha n ge fr o m baseli ne  a n d perce nt c ha n ge fr o m baseli ne ) b y 
i nter ve nti o n gr o u p a n d ti me p oi nt will be prese nte d as well.  
L i ne pl ots of me dia n val ue a n d me dia n perce nt c ha n ge fr o m baseli ne b y ti me p oi nt a n d 
i nter ve nti o n gr o u p will als o be pr o vi d e d f or s er u m I g E a n d I g G s u b class le vels  ( w here a p plica ble). 
Ser u m I g G, I g A, I g M , I g E a n d I g G s u bclass le vels  ( w here a p plica ble) will be liste d b y i nter ve nti o n 
gr o u p, p artici pa nt a n d ti me p oi nt ( w here a p plica ble) . I g G val ues 
< 3 g/ L (se vere 
h y p o ga m ma gl o b uli ne mia) a n d I g G val ues < 6 g/ L ( h y p o ga m ma gl o b uli ne mia) will be fla g ge d i n 
t he listi n g. 
1 5. 9  
Uri n al ysis Micr osc o pic E v al u ati o n   
Uri nal ysis Micr osc o pic E val uati o n data will be liste d b y i nter ve nti o n gr o u p a n d ti me p oi nt ( w here 
a p plica ble).  
1 5. 1 0  
C -S S R S   
T he C -S S R S is a n u merical sc ore deri ve d fr o m 1 0 cate g ories. T he C -S S R S assesses t he s uici dal 
be ha vi or a n d s uici d al i deati o n i n partici pa nt s.  
T he C -S S R S o utc o me cate g ories are pr o vi de d b el o w. Eac h cate g or y h as a bi nar y res p o ns e ( yes/ n o) 
a n d are n u m bere d, pr o vi di n g a sc o re. A sc ore of 0 is assi g ne d if t here is n o s uici dal i deati o n or 
s uici dal be ha vi or prese nt. 
I d eati o n: 
1.  Wis h t o be Dea d  
2.  N o n -s pecific Acti ve S uici dal T h o u g hts 
3.  Acti ve S uici dal I deati o n wit h A n y Met h o ds ( N ot Pla n) wit h o ut I nte nt t o A ct  
4.  Acti ve S uici dal I deati o n wit h S o me I nte nt t o Act, wit h o ut S pecific Pla n  
5.  Acti ve S uici dal I deati o n wit h S pecific Pla n a n d I nte nt  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 4 /1 5 9  
 
 
 
Be ha vi or:  
6.  Pre parat or y Acts or Be h a vi or  
7.  A b orte d Atte m pt  
8.  I nterr u pte d Atte m pt 
9.  Act ual Atte m pt ( n o n -fatal) 
1 0.  C o m plete d S uici de  
Occ urre nce of s uici dal be ha vi or is defi ne d as ha vi n g a ns were d “ yes ” t o a least 1 of t he 4 s uici dal 
be ha vi or s u bcate g ories f or Baseli ne /Scree ni n g  assess me nt s a n d t o at least 1 of t he 5 s uici dal 
be ha vi or s u bcat e g ories f or p os t b aseli ne “si nce last visit” assess me nts . N ote t hat n o n -s uici dal self-
i nj uri o us be ha vi or is n ot c o nsi dere d i n t he deri vati o n of s uici dal be ha vi or a n d occ urre n ce will be 
re p orte d se p aratel y. 
Occ urre nce of s uici dal i deati o n is defi ne d as h a vi n g a ns were d “ yes ” t o at least o ne of t he s uici da l 
i deati o n s u b-cate g ories.  
Occ urre nce of s uici dalit y is defi ne d as ha vi n g at least o ne occ urre nce of s uici dal i deati o n or at 
least o ne occ urre n ce of s uici dal be ha vi or. 
T he  n u m ber a n d perce nt a ge of p artici pa nt s wit h occ urre n ce of s uici dal b e ha vi or at a n y ti me d uri n g 
treat me nt, occ urre n ce of s uici dal i deati o n at a n y ti me d uri n g tr eat me nt, occ urre nce of s uici dalit y  
at a n y ti me d uri n g tr eat me nt a n d occ urre nce of self -i nj uri o us be ha vi or wit h o ut s uici dal i nte nt at 
a n y ti me d uri n g tr eat me nt  will be s u m marize d.   
S hifts fr o m baseli ne  ( ma xi m u m sc ore fr o m "Baseli ne /Scree ni n g " assess me nt) t o t he w orst o n 
treat me nt o utc o me ( ma xi m u m sc ore fr o m "si nc e l ast visit" assess me nts) will be prese nte d. T he 
f oll o wi n g cate g ories will be s u m marize d:  
•  N o i deati o n (sc ore 0)  
•  N o n -seri o us s uici dal i deati o n (sc ore 1-3)  
•  Seri o us s uici dal i deati o n (sc ore 4 -5)  
•  S uici dal be ha vi or (sc ore 6 -1 0).  
Partici pa nt data listi n gs will be als o pr o vi de d.  
1 5. 1 1  
H B V D N A   
H B V D N A P C R testi n g res ults will be liste d b y i nter ve nti o n gr o u p a n d ti me p oi nt ( w here 
a p plica ble). A s hift ta ble fr o m baseli ne  t o hi g hest p ost b aseli ne val ues i ncl u di n g t he cat e g ories < 
2 0  I U/ m L v ers us ≥ 2 0 I U/ m L will be pr o vi de d. T his s u m mar y will be bas e d o n partici pa nts  wit h 
ne gati ve H e patitis B s urface a nti ge n at Scree ni n g b ut p ositi ve He patitis B s urface a nti b o d y or  
He patitis B c ore a nti b o d y.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 5 /1 5 9  
 
 
 
1 5. 1 2  
L oc al L a b or at or y Res ults   
L ocal l a b orat or y res ults t hat are n ot descri be d i n Secti o n  1 5. 3  will be liste d b y i nter ve nti o n gr o u p 
a n d ti me p oi nt ( w here a p plica ble).  
1 5. 1 3  
A nti -S A R S -C o V -2 A nti b o dies L e vels   
All partici pa nts i n t he F A S  a nal ysis set wit h a f ull C O VI D -1 9  v acci n ati o n  a n d si g ne d i nf or m e d 
c o nse nt  f or Pr ot oc ol Versi o n  5 will be i ncl u de d i n t he a nal ysis re gar dless of t he vacci ne t y pe. 
C o mi rnat y, S pi ke va x, Val ne va C O VI D -1 9  Vacci ne or V L A 2 0 0 1, N u va x o vi d or C o v o va x, 
Va x ze vria or C o vis hiel d re q uire 2 d oses t o be c o nsi dere d f ull y vacci nate d w hile J c o v de n re q uires 
o nl y 1.  
I n a d diti o n, partici pa nts nee d t o ha ve e x p os ure t o e v o br uti ni b or terifl u n o mi de ≥ 2  wee ks at t he 
ti me of first C O VI D-1 9 vacci nati o n a n d t o re mai n o n treat me nt at t he ti me of t he sec o n d 
C O VI D -1 9 vacci nati o n (if 2 d oses are re q uire d)  a n d at t he ti me a b o oster d ose is recei ve d (as 
a p plica ble). 
Pre -vacci nati o n ti me p oi nt c orres p o n ds t o t he l ast assess me nt bef ore t he date of t he first v acci n e 
d ose  a n d ca n occ ur pri or t o first a d mi nistrati o n of acti ve st u d y i nter ve nti o n . P ost-vacci nati o n 
ti me p oi nt c orres p o n ds t o t he first assess me nt after t he last dose of f ull vacci nati o n +  at least  
2 8  da ys  f or all C O VI D -1 9  vacci nes.  F or J c o v de n, t his is t he date of t he first vacci ne d os e +  at least  
2 8  da ys.   
P ost -b o oster ti me p oi nt c orres p o n ds t o t he first assess me nt after a b o oster vacci nati o n + at least  7 
da ys . 
S A R S -C o V -2 vacci nati o n dates are rec or de d o n t he C o nc o mita nt Me dicati o n  e C R F pa ge. I n cas e 
of m ulti ple dates, t he first o ne will be use d t o d eri ve t he first d os e of S A R S -C o V -2 vacci nati o n 
a n d t he sec o n d vacci ne date will be c o nsi dere d f or all a nal yses p ost  vacci nati o n. A d diti o nal 
vacci ne d ates after t he f ull vacci nati o n will be c o nsi dere d as b o oster d oses.  
Val ues of I g G a nti -S 1/ S 2 le vels f or S A R S C o V -2 a b o ve a n d bel o w t he L L R of 3. 8 A U/ m L  will 
be ha n dle d as f oll o ws i n t he a nal yses:  
•  Val ues > L L R will be us e d  as o bser v e d  
•  All n o n -missi n g val ues ≤ L L R will be set as L L R val ue (i.e. t he y will be s et as 3. 8 A U/ m L ) 
•  Val ues of I g G a nti -S 1 /S 2 le vels re p ort e d as " > 2, 9 0 0  A U/ m L " (u p p er li mit of re p orti n g ) will be 
set t o a n u meric val u e of “2, 9 0 0 + 1”.  
T he f oll o wi n g s u b gr o u ps will be use d f or a n al ysis, w here s p ecifie d:  
•  Ser ostat us at pre -v ac ci n ati o n: 
o  Ser o ne gati ve ( pre -vac ci n ati o n a nti -I g G a nti b o dies t o S A R S-C o V -2 < 1 5. 0 A U/ m L ) 
o  Ser o p ositi ve ( pre -vac ci nati o n a nti -I g G a nti b o dies t o S A R S-C o V -2 ≥ 1 5. 0 A U/ m L ) 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 6 /1 5 9  
 
 
 
•  D urati o n of ti me bet w ee n t he f ull C O VI D -1 9  vacci nati o n c ycl e a n d t he p os t-vacci nati o n 
sa m ple a nti b o d y assess me nt:  
o  >  4  t o ≤ 8  wee ks  
o  >  8 t o ≤ 1 2 wee ks  
o  > 1 2  wee ks  
W here d urati o n will be calc ulat e d as t he differe nce b et wee n t he d ate of t he f ull 
C O VI D -1 9  
vacci nati o n a n d t h e date of t he p os t-vacci nati o n sa m ple pl us 1, di vi de d b y 7 . 
 
•  D urati o n of ti me bet w ee n t he b o oster v acci nati o n a n d t he p ost -b o oster  sa m ple a nti b o d y 
assess me nt:  
o  ≥ 1 t o <  4 wee ks  
o  ≥ 4 t o ≤ 8 wee ks  
o  > 8 t o ≤ 1 2 wee ks  
o  > 1 2  wee ks    
W here d urati o n will be calc ulate d as t he differe nce bet w ee n t he d ate of t he b o oster C O VI D -1 9 
vacci nati o n a n d t h e date of t he p os t-vacci nati o n sa m ple pl us 1, di vi de d b y 7.  
 
•  T y pe of vacci ne:  
o  m R N A: i ncl u di n g C o mi rnat y or S pi ke v a x vacci nes  
o  N o n -m R N A: i ncl u di n g Val ne v a C O VI D -1 9  Vacci ne or V L A 2 0 0 1, N u va x o vi d or 
C o v o va x, Va xze vria or C o vis hiel d a n d J c o v de n vacci nes  
o  If a n y p artici pa nts recei v e a mi x of m R N A a n d n o n -m R N A vacci nes f or t he f ull 
vacci nati o n c ycl e, a t hir d gr o u p will be create d: B ot h m R N A a n d n o n -m R N A.  
T he dis p ositi o n of partici pa nts will be s u m marize d b y d escri pti ve statistics: N u m ber of p artici pa nts  
w h o recei v e d t he c o m plete vacci nati o n c ycl e, o verall, b y c o u ntr y a n d b y t y pe of vacci n e, n u m ber 
of partici pa nts w h o recei ve d t he b o oster d ose, o v erall a n d b y t y p e  of vacci n e.  
T o assess t he de m o gra p hics a n d baseli ne  c haracteristics of partici pa nts i ncl u de d i n t his a nal ysis, 
t he f oll o wi n g ta bles will be re p eate d o n all partici pa nts i n t he FA S  a n al ysis set wit h a f ull 
C O VI D -1 9 vacci nati o n  a n d si g ne d i nf or me d c o ns e nt f or Pr ot oc ol V ersi o n  5 : 
•  De m o gra p hic characteristics  
•  R M S  b aseli ne d isease ch aract eristics  
•  Hist or y of D M T  
I n or der t o assess t he d urati o n of treat me nt e x p os ure at t he ti me of C O VI D vacci nati o n, t he 
d urati o n of treat me nt at t he ti me of C O VI D -1 9  v acci nati o n  ( wee ks) is deri ve d as f oll o ws: 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 7 /1 5 9  
 
 
 
𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐸𝑣𝑜𝑏𝑟𝑢𝑡𝑖𝑛𝑖𝑏 𝑜𝑟 𝑇𝑒𝑟𝑖𝑓𝑙𝑢𝑛𝑜𝑚𝑖𝑑𝑒 ( w e e ks) = 
(𝑑𝑎𝑡𝑒 𝑜𝑓 𝑙𝑎𝑠𝑡𝑑 𝑜𝑠𝑒𝑑𝑎-1 9  𝑡𝑒𝑜𝑓𝑓𝑖𝑟𝑠𝑡𝑑𝑜 − 𝑠𝑒𝑑𝑎 𝑦𝑠 𝐷𝑎𝑖𝑙𝑦 𝑑𝑜𝑠𝑒 +  1 )
7
 
T he d urati o n of e x p os ure t o e v o br uti ni b or terifl u n o mi de at t he ti me of first C O VI D -1 9  vacci nati o n 
will be a nal yze d b y s u m mar y st atistics a n d b y fre q ue ncies acc or di n g t o t he f oll o wi n g cate g ories:  
•  ≥ 2  t o 1 2  wee ks  
•  >  1 2  t o 2 4 wee ks 
•  >  2 4 t o 3 6 wee ks  
•  >  3 6 t o 4 8 wee ks  
•  >  4 8 t o 6 0 wee ks  
•  >  6 0 t o 7 2 wee ks  
•  >  7 2 t o 8 4 wee ks  
•  >  8 4 t o 9 6  wee ks  
•  >  9 6 t o 1 0 8 wee ks  
•  >  1 0 8 t o 1 2 0 wee ks  
•  >  1 2 0 t o 1 3 2 wee ks  
•  >  1 3 2 t o 1 4 4 wee ks  
•  >  1 4 4 t o 1 5 6  wee ks  
•  >  1 5 6  wee ks  
Wit h res pect t o t he ti me bet wee n t he f ull C O VI D -1 9  vacci nati o n c ycle a n d t he p os t-vacci nati o n 
sa m ple a nti b o d y assess me nt (i n wee ks) t he f oll o wi n g deri v ati o n r ule a p plies:  
𝐶𝑢𝑚𝑢 𝑙𝑎𝑡𝑖𝑣𝑒𝑎 𝑐𝑡𝑢𝑎 𝑙𝑑𝑜𝑠𝑒𝑓𝑜𝑟𝐸𝑣𝑜 𝑏𝑟𝑢𝑡𝑖 𝑛𝑖𝑏 𝑜𝑟𝑇𝑒𝑟𝑖𝑓𝑙 𝑢𝑛𝑜𝑚𝑖𝑑𝑒𝑚𝑔𝑆 ( w e e ks) = 
(𝑢𝑚𝑜𝑓 𝑑𝑜 𝑠𝑒𝑝𝑒-𝑟𝑑𝑎𝑦𝑓𝑜𝑟𝐸𝑣𝑜𝑏 𝑟𝑢𝑡𝑖𝑛𝑖 − 𝑏𝑜𝑟𝑇 𝑒𝑟 𝑖𝑓𝑙𝑢 𝑛𝑜𝑚𝑖𝑑-1 9  𝑒𝑟𝑒𝑐𝑜𝑟𝑑𝑠𝐶𝑢𝑚 𝑢𝑙𝑎𝑡𝑖 +  1 )
7
 
T he d urati o n of t he ti me bet wee n t he f ull C O VI D -1 9  vacci nati o n c ycl e a n d t he p os t-vacci nati o n 
sa m ple a nti b o d y assess m e nt will be a nal yze d b y s u m mar y st atistics a n d b y fre q ue n cies acc o r di n g 
t o t he f oll o wi n g cate g ori es:  
•  >  4 t o ≤ 8 wee ks  
•  >  8 t o ≤ 1 2  wee ks  
•  >  1 2  wee ks  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 8 /1 5 9  
 
 
 
Wit h res pect t o t he ti me bet wee n t he b o oster C O VI D -1 9  v acci nati o n a n d p ost -b o oster  vacci nati o n 
sa m ple a nti b o d y assess me nt (i n wee ks) t he f oll o wi n g deri v ati o n r ule a p plies:  
𝐷𝑢𝑟𝑎 𝑡𝑖𝑜𝑛𝑜𝑓𝐸 𝑣𝑜𝑏𝑟𝑢𝑡𝑖 𝑛𝑖𝑏𝑜𝑟𝑇𝑒𝑟𝑖𝑓𝑙 𝑢𝑛𝑜 𝑚𝑖𝑑𝑒𝑑𝑎𝑡𝑒 𝑜𝑓𝑙𝑎𝑠𝑡𝑑𝑜𝑠𝑒 ( w e e ks) = 
(𝑑𝑎𝑡𝑒 𝑜𝑓 𝑓𝑖𝑟𝑠-𝑡𝑑𝑜𝑠𝑒𝑑𝑎 𝑦𝑠𝐷𝑎𝑖𝑙𝑦𝑑𝑜𝑠𝑒 𝐶𝑢𝑚𝑢𝑙𝑎 − 𝑡𝑖𝑣𝑒 𝑎𝑐 𝑡𝑢𝑎𝑙𝑑𝑜𝑠 𝑒𝑓𝑜𝑟𝐸𝑣𝑜𝑏𝑟𝑢𝑡 +  1 )
7
 
T he d urati o n of t he ti me bet wee n t he b o oster vacci nati o n a n d t he p ost -b o oster  sa m ple a nti b o d y 
assess me nt will be a nal yze d b y s u m mar y statistics a n d b y fre q u e ncies acc or di n g t o t he f oll o wi n g 
cate g ories:  
•  >  1 t o <  4 wee ks  
•  >  4 wee ks t o ≤ 8 w ee ks  
•  >  8 t o <  1 2 w ee ks  
•  >  1 2 wee ks  
A listi n g will i ncl u de partici pa nt i de ntifier, a ge, s e x, race, 
st u d y i nter ven ti o n start date, 
pre -vac ci nati o n a nti b o d y ass ess me nt date, C O VI D -1 9  v acci nati o n dates, p os t-vacci nati o n 
a nti b o d y ass ess me nt dat e, p ost -b o oster  sa m ple c ollecti o n date, d urati o n of st u d y i nter ve nti o n at 
t he ti me of first C O VI D -1 9  vacci nati o n, ti me bet wee n t h e f ull C O VI D -1 9  vacci nati o n c ycl e a n d 
t he p ost-vacci n ati o n sa m ple a nti b o d y assess me nt, as well as ti me bet wee n t he b o oster vacci nati o n 
a n d t he p ost -b o oster  sa m ple a nti b o d y assess me nt. 
T o c haracteriz e S A R S -C o V -2 vacci ne res p o ns e, i.e. le vel of a nti-S 1/ S 2 I g G a nti b o dies, i n 
partici pa nts wit h R M S, s u m mar y statistics (i ncl u di n g ge o metric mea n a n d c orres p o n di n g 9 5 % 
CIs) of a nti-S 1/ S 2 I g G a nti b o d y le vels at pre-v a cci nati o n, p os t-vacci nati o n a n d p ost -b o oster  
ti me p oi nts will be pr o vi de d b y st u d y i nter ve nti o n ar m . T he pre -v ac ci nati o n a n d p os t-vacci nati o n 
ti me p oi nts will be  s u m marize d se paratel y f or all p artici pa nts w h o recei ve d a b o oster v acci nati o n.  
2 -si de d 9 5 % CIs for ge o metric mea n will be calc ulate d as f oll o ws: t he l o g -tra nsf or me d le vels of 
a nti-S 1/ S 2 I g G a nti b o dies will be use d a n d t he arit h metic mea n a n d u p per a n d l o wer li mits of t he 
2 -si de d 9 5 % CIs f or t he arit h metic mea n will be c o m p ute d b y use of p erce ntiles o f t-distri b uti o n; 
t he e x p o ne ntiate of t hese li mits a n d t he arit h metic mea n itself are t he ge o metric mea n a n d li mits 
of t he CI  f or t he ge o metric mea n, res p ecti vel y. 
F or a vis ual re prese ntati o n of a nti-S 1/ S 2 I g G a nti b o dies pre -vacci nati o n, p os t-vacci nati o n a n d 
p ost -b o oster  b o x pl ots will be pr o vi de d i n a d diti o n. T he fi g ure will be re peate d c o nsi deri n g o nl y 
partici pa nts wit h C O VI D -1 9  vacci n ati o n b o oster.  
A n e x pl orat or y a n al ysis will be c o n d u cte d t o i n v esti gate w het h er a nti-S 1/ S 2 I g G a nti b o d y le vels 
after a f ull vacci nati o n c ycle are i m pacte d b y c o variates. A li near re gressi o n m o del wit h  t he 
f oll o wi n g i n de p e n de nt varia bles will be esti mate d: i nter ve nti o n gr o u p, a ge, ge n der, a nti-S 1/ S 2 I g G 
a nti b o d y le vels bef ore v acci nati o n (i.e. ser o -p ositi ve or ser o -ne gati ve ), d urati o n of e x p os ure t o 
terifl u n o mi de / e v o br uti ni b at t he ti me of t he first C O VI D -1 9  v acci n ati o n, ti me bet wee n t he f ull 
vacci nati o n c ycle a n d a nti b o d y assess me nt. I n cas e dia g n ostic met h o ds ( e. g. Q Q -pl ots) s h o w t hat 
a nti b o d y le vels are n ot n or mall y dis tri b ute d, l o g-tr a nsf or me d val ues of a nti b o d y le vels will be use d 
f or t he a n al ysis. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 1 9 /1 5 9  
 
 
 
T he f ol d c ha n ge is t he rati o bet wee n t he p os t-vacci nati o n I g G a nti -S 1/ S 2 a nti b o d y l e vels a n d t he 
pre -vac ci nati o n a nti -S 1/ S 2 I g G a nti b o d y le vels.  
S u m mar y statistics of t he f ol d c ha n ges will be pr o vi de d.  
A d diti o nall y, t he n u m ber a n d perce nta ge of partici pa nts i n eac h of t he f oll o wi n g f ol d c ha n ge 
cate g ories will be prese nt e d:  
•  ≤ 1 x - partici pa nts ha vi n g a f ol d i ncrease ≤ 1  
•  > 1 x - ≤ 1 0 x; partici pa nts ha vi n g a f ol d i ncrease great er t ha n 1 a n d less or e q ual t ha n 1 0  
•  > 1 0 x - ≤ 3 0 x; partici pa nts ha vi n g a f ol d i ncrease greater t ha n 1 0 a n d less or e q ual t ha n 3 0  
•  > 3 0 x - ≤ 6 0 x; partici pa nts ha vi n g a f ol d i ncrease greater t ha n 3 0 a n d less or e q ual t ha n 6 0  
•  > 6 0 x - ≤ 1 0 0 x; partici pa nts ha vi n g a f ol d i ncrease greater t ha n 6 0 a n d less or e q ual t ha n 1 0 0  
•  > 1 0 0 x ; partici pa nts ha vi n g a f ol d i ncrease > 1 0 0  
A listi n g of a nti-S 1/ S 2 I g G a nti b o d y le vels wit h pre - a n d p os t-v acci nati o n , a n d if a v aila ble p ost -
b o oster  sa m ples will be prese nte d p er p artici pa nt. T he listi n g will c o ntai n partici pa nt n u m ber, 
para meter na me, date of sa m ple ta ke n, visit, ser ostat us at pre -v ac ci nati o n, res ult, f ol d c ha n ge  t o 
p os t-vacci nati o n, f ol d c h a n ge t o p ost -b o oster  vacci nati o n, f ol d c ha n ge fr o m p os t-vacci nati o n t o 
p ost -b o oster  vacci nati o n , vacci nati o n d ates of t he partici pa nt a n d w het her t he sa m ple is a pre- or 
p os t-vacci nati o n sa m ple , t y pe a n d na me of v acci ne.  
All descri be d a nal ys es will be re p eate d o n t he s u b gr o u ps “ Ser ostat us at pre -vac ci natio n”, “ti me 
bet wee n t he f ull C O VI D -1 9  v acci n ati o n c ycl e a n d t he p os t-v acci n ati o n sa m ple a nti b o d y 
assess me nt”, “ti me bet w ee n t he b o oster v acci n ati o n a n d t he p ost -b o oster  vacci n ati o n sa m ple 
a nti b o d y ass ess me nt” as well as f or “t y p e of vacci ne” as defi ne d a b o v e.  
Perce nta ges  f or t he s u b gr o u p a nal ys es will be base d o n t he n u m ber of partici pa nts wit hi n t he 
s u b gr o u p of i nterest. 
F or s u b gr o u p a nal yses b y “ti me bet wee n t he f ull C O VI D -1 9  vacci nati o n a n d t he p os t-vacci nati o n 
sa m ple”, o nl y pre- a n d p os t-vacci nati o n ti m e p oi nts will be  c o nsi dere d. F or s u b gr o u p a nal yses b y 
“ti me bet wee n b o oster C O VI D -1 9  vacci ne a n d p ost -b o oster  sa m ple”, o nl y pre -b o oster  a n d 
p ost -b o oster  ti me p oi nts will be  c o nsi dere d. F or t he s u b gr o u p “ Ser ostat us at pre -vac ci nati o n” a 
scatter pl ot of a nti-S 1 / S 2 I g G a nti b o d y l e vels at pre -vac ci n ati o n, p os t-vacci nati o n a n d p ost -b o oster  
ti me p oi nts will be als o pr o vi de d.  
I m m u n o gl o b uli n le vels (ser u m I g G, I g A a n d I g M le vels [g/ L ]) will be s u m marize d at t he ti me of 
t he first C O VI D -1 9  vacci nati o n d ose, b y st u d y i nter ve nti o n gr o u p. T he s u m maries will be s plit b y 
t he ti mi n g of t he ass ess me nt bef ore t he first C O VI D -1 9  vacci nati o n: u p t o a n d i ncl u di n g 3  m o nt hs 
bef ore a n d bet w ee n 3  a n d 6  m o nt hs  bef ore. T he ti mi n g will be deri ve d as descri be d i n Secti o n  9. 6 . 
If t h e assess me nt occ urs o n t he sa me date as t he first C O VI D-1 9 vacci nati o n, t he assess me nt will 
be i ncl u de d i n t he “ u p t o a n d i nc l u di n g 3 m o nt hs b ef ore” gr o u p. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 0 /1 5 9  
 
 
 
1 5. 1 4  
F oc use d Ge netic Testi n g   
F or partici pa nts wit h res ults of f oc use d ge netic testi n g perf or me d as per t h e Pr ot oc ol Secti o n 7. 1 
f or vari a nts i n t he Hi g h Ir o n Fe ( h u ma n he m oc hr o mat osis pr otei n; H F E) ge n e ( C 2 8 2 Y, H 6 3 D), 
t he s u m mar y of n u m ber of partici pa nts wit h detecte d varia nts will be pr o d uce d, base d o n t he S A F 
a nal ysis s et. T he res ults will be als o liste d.  
 
1 6  
A n al yses of Ot her E n d p oi nts   
1 6. 1  
P K   
1 6. 1. 1  
Ge ner al 
S pecific ati o ns f or 
P K 
C o nce ntr ati o n a n d 
P K 
P ar a meter D at a   
P K sa m ples will be c ollecte d acc or di n g t o t he Sc he d ule of Acti vities (Secti o n  1. 3. 1 of t he pr ot oc ol) 
fr o m all partici pa nts i n t he mai n st u dies a n d i n a P K s u bst u d y ( M S 2 0 0 5 2 7_ 0 0 8 0 o nl y) .  
T he f oll o wi n g  c hec ks  f or e v o br uti ni b a n d met a b olite 
M S C 2 7 2 9 9 0 9 A c o nce ntr ati o ns will be 
perf or me d . T his is n ot a c o m pre he nsi ve list a n d a d diti o nal c hec ks ma y be re q uire d. 
•  If a n e pis o de of v o miti n g occ urs o n t he d a y of P K c ollecti o n, t he c o n ce ntr ati o n res ults f or t hat 
da y will be fla g ge d a n d i de ntifie d i n a listi n g. If it is k n o w n t hat t he ti me of v o miti n g is after 
t he ti me of e v o br uti ni b d osi n g , a n d pri or t o c ollecti o n of a P K sa m ple o n t he da y of t h e P K 
c ollecti o n, t he c o nce ntrati o n res ults f oll o wi n g t he ti me of v o miti n g will be e x cl u de d fr o m t he 
calc ulati o n of s u m mar y statistics  a n d esti mati o n of P K para met ers . 
•  Meal i nf or mati o n i n relati o n t o e v o br uti ni b d osi n g o n t he da y of P K c ollecti o n : If e v o br uti ni b 
is n ot ta ke n wit h a m eal o n t he da y of t he P K c ollecti o n, c o n ce ntrati o n res ults will be fla g ge d 
a n d i de ntifie d i n a listi n g, b ut n o data will be e x cl u de d fr o m t he calc ulati o n of s u m mar y 
statistics or t he esti mati o n of P K para meters . C o n ce ntrati o n res ults will  als o be fla g ge d  w he n 
t he d ose is ta ke n > 1  h o ur pri or t o a meal or t he d ose is ta ke n 2  h o urs aft er a meal.  
•  Meal i nf or mati o n i n relati o n t o e v o br uti ni b d osi n g o n t he pre vi o us da y of P K c ollecti o n: If 
e v o br uti ni b is n ot ta ke n wit h a meal o n t he pre vi o us da y of t he P K c ollecti o n, pre -d ose 
c o nce nt rati o n res ults will be fla g ge d a n d i de ntifie d i n a listi n g, b ut n o dat a will be e x cl u de d 
fr o m t he calc ulati o n of s u m mar y statistics. Pre-d ose c o nce ntrati o n res ults will als o be fla g ge d 
w he n t he pre vi o us d ose is ta ke n > 1  h o ur pri or t o a meal or t he pre vi o us  d ose is ta ke n > 2  h o urs 
after a meal.  
•  D osi n g : If t he m ost rece nt e v o br uti ni b d ose wa s ta ke n 1 8  h o urs or 6  h o urs pri or pre d os e 
sa m pli n g ti me, t he pre d ose P K sa m ple will be fla g ge d a n d i d e ntifie d i n a listi n g , b ut n o dat a 
will be e x cl u de d fr o m t he calc ulati o n of s u m mar y statistics . T here will be n o fla g f or p ost d ose 
c o nce ntr ati o ns if t he d ose o n t he da y of P K sa m pl e is ta ke n acc or di n g t o pr ot oc ol.  
•  C o nc o mita nt me dicati o n : If P K c o nce ntrati o n  data is c ollecte d w hile a m o derate or str o n g 
C Y P 3 A i n d ucer or i n hi bit or is ta ke n , or s h ortl y aft er disc o nti n uati o n  of t he m o derate or str o n g 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 1 /1 5 9  
 
 
 
C Y P 3 A i n d ucer or i n hi bit or , affecte d c o nce ntrati o n res ults a n d a n y esti mat e d para meters will 
be fla g ge d a n d e x cl u de d fr o m t he calc ulati o n of s u m mar y st atistics.  If P K c o nce ntrati o n data 
is c ollecte d w he n a pr ot o n p u m p i n hi bit or, H 2 bl oc ker, or a ntaci d is ta ke n, affect e d 
c o nce ntr ati o n res ults a n d a n y esti mate d para meters will be fla g ge d  a n d i de ntifie d i n a listi n g 
b ut n o t e x cl u de d fr o m s u m mar y statistics. 
•  P K bl o o d c ollecti o n : D esi g nate d p re d ose P K sa m ples c ollecte d j ust after d osi n g of e v o br uti ni b 
a n d sa m ples c ollecte d o ut of or der  (as s pecifie d i n t he pr ot oc ol) will be e x cl u de d fr o m t h e 
calc ulati o n of s u m mar y statistics. T he 2 n d d u plicate P K sa m ple  i n a se q ue n ce  will be e x cl u de d 
fr o m t he calc ulati o n  of descri pti ve statistics a n d esti mati o n of P K para meters . If a P K sa m ple 
is c ollecte d o utsi de of t he c ollecti o n wi n d o ws defi ne d bel o w, see Ta ble 1 8  a n d Ta ble 1 9 , t he 
affecte d c o n ce ntr ati o n res ults a n d a n y esti mate d p ara meters will be fla g ge d a n d i de ntifie d i n a 
listi n g b ut will n ot be e x cl u de d fr o m cal c ulati o n of s u m mar y statistics.  
T a ble 1 8  
P K S a m pli n g Ti me Wi n d o ws  –  M ai n St u d y   
 
D a y 1  
W e e k 4, 2 4, 
9 6 [ a] 
W e e k 1 2,  4 8, 
7 2 [ a] 
W e e k 1 5 6 [ a] 
S c h e d ul e d 
Ti m e  
Wi n d o w  
Pr e d o s e  
M u st b e c oll e ct e d 
pri or t o d o si n g  
M u st b e c oll e ct e d 
pri or t o d o si n g  
M u st b e c oll e ct e d 
pri or t o d o si n g  
M u st b e c oll e ct e d 
pri or t o d o si n g  
0. 5 h  
0 –  1 h  
N/ A  
N/ A  
N/ A  
0. 7 5 –  1. 5 h [b ] 
N o wi n d o w  
N o wi n d o w  
N/ A  
N/ A  
1 h  
0. 5 h –  2 h  
N/ A  
N/ A  
N/ A  
1 h –  6 h  
N/ A  
N/ A  
N o wi n d o w  
N/ A  
2 h  
1 h –  4 h  
N/ A  
N/ A  
N/ A  
4 h  
2 h –  1 2  h  
N/ A  
N/ A  
N/ A  
a A s s p e cifi e d i n t h e pr ot o c ol, v i sit wi n d o w i s ±  3 d a y s f or all vi sit s fr o m W e e k  2 t o W e e k  4 4, i n cl u si v e. Vi sit wi n d o w i s 
±  7 d a y s f or all vi sit s fr o m W e e k  4 8 t o W e e k  1 5 6 i n cl u si v e. E x c e pti o n: W e e k  4 h a s a vi sit wi n d o w of ±  2 d a y s.  
b T o b e c oll e ct e d o n D a y  1, W e e k  4, W e e k  2 4, a n d W e e k  9 6. S a m pl e t o b e c oll e ct e d wit hi n 3 0  mi n ut e s aft er E C G 
a s s e s s m e nt w hi c h s h o ul d b e r e c or d e d a p pr o xi m at el y 4 5  mi n ut e s t o 6 0  mi n ut e s aft er d o si n g.  
N/ A = n ot a p pli c a bl e  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 2 /1 5 9  
 
 
 
T a ble 1 9  
P K S a m pli n g Ti me Wi n d o ws –  S u bst u d y   
 
D a y 1, W e e k  2, 4, 2 4[ a , b] 
W e e k 8, 1 2, 4 8, 7 2 [ b] 
W e e k  9 6 [ b] 
S c h e d ul e d 
Ti m e  
Wi n d o w  
Pr e d o s e  
M u st b e c oll e ct e d pri or t o 
d o si n g  
M u st b e c oll e ct e d pri or t o 
d o si n g  
M u st b e c oll e ct e d pri or t o 
d o si n g  
0. 2 5 h  
0 –  0. 5 h  
N/ A  
N/ A  
0. 5 h  
0. 2 5 h –  1  h  
N/ A  
N/ A  
0. 7 5 –  1. 5 h [c ] 
N o wi n d o w  
N/ A  
N o wi n d o w  
1 h  
0. 5 h –  2 h  
N/ A  
N/ A  
1 h –  6 h  
N/ A  
N o wi n d o w  
N/ A  
2 h  
1 h –  4 h  
N/ A  
N/ A  
4 h  
2 h –  6 h  
N/ A  
N/ A  
6 h  
4 h –  1 2 h  
N/ A  
N/ A  
a P K s a m pl e s will o nl y b e c oll e ct e d u p t o 4 h p o st d o s e f or W e e k 2 4.  
b A s s p e cifi e d i n t h e pr ot o c ol, v i sit wi n d o w i s ± 3 d a y s f or all vi sit s fr o m W e e k  2 t o W e e k  4 4, i n cl u si v e. Vi sit wi n d o w i s 
±  7  d a y s f or all vi sit s fr o m W e e k  4 8 t o W e e k  1 5 6 i n cl u si v e. E x c e pti o n:  W e e k  4 h a s a vi sit wi n d o w of ±  2  d a y s.  
c T o b e c oll e ct e d aft er E C G a s s e s s m e nt o n D a y  1, W e e k  4, W e e k  2 4, a n d W e e k  9 6. S a m pl e t o  b e c oll e ct e d wit hi n 
3 0  mi n ut e s aft er E C G a s s e s s m e nt w hi c h s h o ul d b e r e c or d e d a p pr o xi m at el y 4 5  mi n ut e s t o 6 0  mi n ut e s aft er d o si n g.  
N/ A = n ot a p pli c a bl e  
Data listi n gs , s u m maries of e v o br uti ni b a n d M S C 2 7 2 9 9 0 9 A c o nce ntrati o ns , a n d ass ociat e d fi g ures 
will be t he res p o nsi bilit y of I Q VI A, O verla n d Par k, Ka nsas. F or t he descri pti ve statistical 
prese ntati o n of e v o br uti ni b a n d M S C 2 7 2 9 9 0 9 A c o nce ntrati o ns, all c o nce ntrati o ns t hat are B L Q 
will be assi g ne d a n u merical val ue of zer o pri or t o calc ulati o n of statistics. F o r da ys w he n a P K 
sa m ple is sc he d ule d t o be c ollecte d bet wee n 1 a n d 6  h o urs p ost d ose, t he statistical prese ntati o n of 
c o nce ntr ati o ns will use t he f oll o wi n g ti me i nter vals f or s u m marizati o n:  pre d ose , ≥1 t o 2  h o urs 
p ost d ose, > 2 t o 4  h o urs p ost d ose, a n d > 4 t o 6  h o urs p ost d ose. Gra p hical dis pla ys of i n di vi d ual a n d 
mea n ( ± S D f or li near pr ofiles o nl y) plas m a c o nce ntrati o n -ti me pr ofiles f or Da y  1 ( mai n st u dies) 
a n d Da y  1, Wee k  2, Wee k  4, a n d Wee k  2 4  ( P K s u bst u d y) will be prese nt e d o n li near a n d se mi-
l o garit h mic scales. I n di vi d ual a n d mea n (li near o nl y) tr o u g h ( pre d os e) c o nce ntrati o n -da y pr ofiles 
will be prese nte d.  
1 6. 1. 2  
Esti m ati o n of P K P ar a meters   
E v o br uti ni b a n d M S C 2 7 2 9 9 0 9 A P K para m eters will be calc ulat e d f or Da y 1 a n d 
Wee k  4 of 
partici pa nts i n t he P K s u bst u d y usi n g t he act ual ela pse d ti me si nce d osi n g. I n cases w here t he 
act ual sa m pli n g ti me is missi n g, calc ulati o ns ma y be p erf or me d usi n g t he n o mi nal ti me. Details 
(e. g. n u mber of sa m ples, partici pa nts affecte d) will be d escri be d i n t he C S R. I n case act ual d osi n g 
ti me is missi n g, sc he d ul e d ti me mi g ht b e use d f or N C A after perf or ma nce of a de q u ate pl a usi bilit y 
c hec ks a n d a gree me nt wit h t he s p o ns or. Decisi o n a n d rati o nal e s h o ul d b e i ncl u de d i n t he C S R. 
Ot her wise, t here will be n o f urt her i m p utati o n of missi n g data.  
T he f oll o wi n g plas ma P K para meters will be calc ulate d f or e v o br uti ni b a n d M S C 2 7 2 9 9 0 9 A f or 
Da y  1 a n d Wee k  4 w h ere a p pr o priate : 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 3 /1 5 9  
 
 
 
S y m b ol  
D efi niti o n  
C al c ul ati o n  
C m a x 
M a xi m u m 
o b s er v e d 
c o n c e ntr ati o n  
 
tm a x  
T h e ti m e t o r e a c h 
t h e C m a x i n a 
d o si n g i nt er v al  
I n c a s e of m ulti pl e/i d e nti c al C m a x v al u e s, t h e fir st o c c urr e n c e will b e 
u s e d.  
A U C 0 -6  
T h e p arti al A U C 
fr o m ti m e z er o 
( = d o si n g ti m e) t o 
6  h o ur s aft er 
d o si n g  
C al c ul at e d u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g 
d o w n).  
I n c a s e s w h er e t h e a ct u al o b s er v ati o n ti m e i s n ot e q u al t o t h e 
s c h e d ul e d o b s er v ati o n ti m e A U C 0 -6 will b e c al c ul at e d b a s e d o n t h e 
e sti m at e d c o n c e ntr ati o n at 6  h o ur s a n d n ot t h e c o n c e ntr ati o n  at t h e 
a ct u al o b s er v ati o n ti m e.  
A U C 0 -1 2  
T h e p arti al A U C 
fr o m ti m e z er o 
( = d o si n g ti m e) t o 
1 2  h o ur s aft er 
d o si n g  
C al c ul at e d u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g 
d o w n).  
A U C 0 -1 2 will b e c al c ul at e d b a s e d o n t h e e sti m at e d c o n c e ntr ati o n at 
1 2  h o ur s . 
A U C 0 -tl a st 
T h e A U C fr o m 
ti m e z er o 
( = d o si n g ti m e) t o 
t h e ti m e of t h e l a st 
q u a ntifi a bl e 
c o n c e ntr ati o n 
(tl a st). 
C al c ul at e d u si n g t h e mi x e d l o g -li n e ar tr a p e z oi d al r ul e (li n e ar u p, l o g 
d o w n).  
A U C 0 -∞ 
T h e A U C fr o m 
ti m e z er o 
( = d o si n g ti m e) u p 
t o i nfi nit y wit h 
e xtr a p ol ati o n of 
t h e t er mi n al 
p h a s e.  
A U C 0 -∞ =  A U C 0 -tl a st +  C l a st pr e d  / λ z, w h er e Cl a st pr e d  i s t h e pr e di ct e d 
c o n c e ntr ati o n at t h e t l a st, c al c ul at e d fr o m t h e l o g-li n e ar r e gr e s si o n li n e 
f or λz d et er mi n ati o n.  
t½  
T h e t er mi n al h alf -
lif e. 
t½  =  l n ( 2) / λ z, w h er e λz i s t h e t er mi n al fir st or d er ( eli mi n ati o n) r at e 
c o n st a nt d et er mi n e d fr o m t h e t er mi n al sl o p e of t h e l o g -tr a n sf or m e d 
c o n c e ntr ati o n c ur v e u si n g li n e ar r e gr e s si o n o n t er mi n al d at a p oi nt s of 
t h e c ur v e. 
C L/ F  
T h e a p p ar e nt t ot al 
b o d y cl e ar a n c e 
f oll o wi n g 
e xtr a v a s c ul ar 
a d mi ni str ati o n.  
C L/ F  =  D o s e  / A U C 0 -∞ F or D a y  1  
C L s s/ F 
T h e a p p ar e nt 
b o d y cl e ar a n c e at 
st e a d y st at e 
f oll o wi n g 
e xtr a v a s c ul ar 
a d mi ni str ati o n.  
C L s s/ F =  D o s e  / A U C 0 -1 2  F or W e e k  4.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 4 /1 5 9  
 
 
 
S y m b ol  
D efi niti o n  
C al c ul ati o n  
V z/ F 
T h e a p p ar e nt 
v ol u m e of 
di stri b uti o n d uri n g 
t h e t er mi n al p h a s e 
f oll o wi n g 
e xtr a v a s c ul ar 
a d mi ni str ati o n.  
V z/ F =  D o s e  / (A U C 0 -∞ ×  λ z) F or D a y 1  
V z/ F =  D o s e  / (A U C 0 -1 2  ×  λ z) F or W e e k 4  
M/ P( C
m a x ) 
M ol e c ul ar w ei g ht -
c orr e ct e d r ati o of 
m et a b olit e 
( M S C 2 7 2 9 9 0 9 A) 
C m a x  t o p ar e nt 
( e v o br uti ni b) Cm a x . 
M/ P( C
m a x ) =  ( Cm a x m et a b olit e  ×  M W p ar e nt)  / ( Cm a x p ar e nt  ×   
M W m et a b olit e)  
M/ P( A U C
0 -6 ) 
M ol e c ul ar w ei g ht -
c orr e ct e d r ati o of 
m et a b olit e 
( M S C 2 7 2 9 9 0 9 A) 
A U C 0 -6  t o p ar e nt 
( e v o br uti ni b) 
A U C 0 -6  
M/ P( A U C
0 -6 ) =  ( A U C0 -6 m et a b olit e  ×  M W p ar e nt)  / ( A U C0 -6 p ar e nt  ×   
M W m et a b olit e)  
M/ P( A U C
0 -1 2 ) 
M ol e c ul ar w ei g ht -
c orr e ct e d r ati o of 
m et a b olit e 
( M S C 2 7 2 9 9 0 9 A) 
A U C 0 -1 2  t o p ar e nt 
( e v o br uti ni b) 
A U C 0 -1 2  
M/ P( A U C
0 -1 2 ) =  ( A U C0 -6 m et a b olit e  ×  M W p ar e nt)  / ( A U C0 -1 2 p ar e nt  ×   
M W m et a b olit e)  
M/ P( A U C
0 -∞) 
M ol e c ul ar w ei g ht -
c orr e ct e d r ati o of 
m et a b olit e 
( M S C 2 7 2 9 9 0 9 A) 
A U C 0 -∞ t o p ar e nt 
( e v o br uti ni b) 
A U C 0 -∞ 
M/ P( A U C
0 -∞) =  ( A U C0 -∞m et a b olit e  ×  M W p ar e nt)  / ( A U C0 -∞p ar e nt  ×   
M W m et a b olit e)  
A d diti o nal P K para meters ma y be calc ul ate d w here a p pr o pri ate.  
U nits f or P K para meter o ut p ut will be base d o n c o nce ntr ati o n a n d d ose u nits use d i n t he st u d y, 
u nless ot her wise s pecifie d. I n case c o nce ntrati o n data u nits c ha n ge wit hi n t he st u d y, P K para meters 
will be re p orte d usi n g c o nsiste nt u nits t hr o u g h o ut st u d y o ut p uts.  
T he para meters C ma x  a n d t ma x  will be o btai ne d directl y fr o m t he c o nce ntrati o n -ti me pr ofiles.  
I n cas es w here t he act ual o bser vati o n ti me is n ot e q ual t o t he sc he d ule d o bser vati o n ti me, A U C 0 -6 
will be calc ul ate d b y esti mate d c o nce ntrati o n  at 6  h , pr o vi de d λ z is esti ma ble. I n case s uita ble 
re gressi o n ca n n ot be perf or me d, partial areas ma y be calc ulate d usi n g t he c o nce ntrati o n at act ual 
sa m pli n g ti me if act ual s a m pli n g ti me is wit hi n 1 0 % of t he n o mi nal sa m pli n g ti me. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 5 /1 5 9  
 
 
 
At stea d y state, if A U C 0 -1 2 is n ot esti ma ble via e xtra p olati o n, t he pre -d ose c o nce ntr ati o n ma y b e 
d u plicate d a n d us e d as t h e tr o u g h c o n ce ntr ati o n f or calc ul ati o n of A U C 0 -1 2. I n s u c h cases, A U C0 -tlast 
s hall be esti mate d base d o n o bser ve d C last. 
•  I n cases B L Q c o nce ntrati o ns occ ur at t he e n d of t he c ollecti o n i nter val, t hese c o nce ntrati o ns 
mi g ht be set t o missi n g f or calc ulati o ns of partial A U Cs after a gree me nt wit h t he S p o ns or. T his 
is a n e x e m pti o n t o t he ge neral B L Q h a n dli n g r ul e a n d s h o ul d be a p plie d i n case its a p plicati o n 
w o ul d res ult i n esti mati o n of i m pla usi ble partial A U C val ues. I m pla usi bilit y is c o nsi dere d i n 
cases partial A U Cs are greater t ha n A U C 0 -∞.   
T he f oll o wi n g P K p ara m eters will be calc ulate d f or dia g n ostic p ur p oses a n d liste d, b ut will n ot be 
s u m marize d: 
•  First ( λ z l o w) a n d last ( λz u p) t i me p oi nt of t he ti me i nter val of t he l o g-li near re gressi o n t o 
deter mi ne λ z.  
•  N u m ber of dat a p oi nts ( N λ) i ncl u de d i n t he l o g -li near re gressi o n a n al ysis t o deter mi ne λz. 
•  G o o d ness of fit statistic (a dj uste d Rs q) f or calc ulati o n of λ z. 
•  A U C fr o m ti me t last e xtra p olate d t o i nfi nit y gi ve n as perce nta ge of A U C0 -. ( A U Ce xtra %) 
•  S pa n rati o of i nter val o ver w hic h t ½  was esti mate d  / t½  
T he re gressi o n a nal ysis s h o ul d c o ntai n data fr o m at least 3 differe nt ti me p oi nts i n t he ter mi nal 
p hase c o nsiste nt wit h t he assess me nt of a str ai g ht li ne o n t he l o g -tra nsf or me d scale. P h oe ni x 
Wi n N o nli n “ best fit” met h o d ol o g y will b e use d as sta n dar d. If warra nte d, f urt her a dj ust me nt ma y 
be ma de b y t h e p har mac o ki neticist, after a gree me nt wit h t he S p o ns or. T he l ast q ua ntifia ble 
c o nce ntr ati o n > L L O Q s h o ul d al wa ys b e i ncl u de d i n t he re gressi o n a nal ysis, 
w hile t he 
c o nce ntr ati o n at t ma x  a n d a n y c o nce ntrati o ns B L Q w hic h occ ur aft er t he l ast q ua ntifia ble data p oi nt 
> L L O Q s h o ul d n ot be us e d.  
If A U Ce xtra %> 2 0 %  a n d/ or  t he c oefficie nt of c orrelati o n ( Rs qa dj) of λz is < 0. 8 a n d/or t he o bser vati o n 
peri o d o ver w hic h t he re gressi o n li ne is esti mate d (s pa n rati o) is less t ha n 2 -f ol d t he res ulti n g t½ , 
t he rate c o nsta nts a n d all deri ve d para meters (e. g. t½ , A U C0 -, C L et c.) will be liste d, fla g ge d a n d 
i ncl u de d i n t he para meter o ut p uts. S h o ul d m ore t ha n 1 0 % of partici pa nts be fla g ge d f or A U Ce xtra % 
a n d/ or Rs q a dj (f or a partic ular a nal yt e), a se nsiti vit y a nal ysis e x cl u di n g fla g ge d para meters ma y be 
perf or me d after disc ussi o n wit h t he S p o ns or.  
T he m olec ular wei g hts  of e v o br uti ni b  a n d M S C 2 7 2 9 9 0 9 A t o be use d i n t he calc ul ati o n of M/ P 
rati os are as f oll o ws:  
•  e v o br uti ni b = 4 2 9. 5 2 1 3  
•  M S C 2 7 2 9 9 0 9 A = 4 6 3. 5 2 8 9  
T he P K of e v o br uti ni b will als o be c h aracterize d usi n g p o p ulati o n 
m o deli n g. Pleas e see 
Secti o n  1 6. 3  f or details. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 6 /1 5 9  
 
 
 
1 6. 1. 3  
Prese nt ati o n of P K P ar a meter D at a   
Data listi n gs a n d s u m maries of e v o br uti ni b a n d 
M S C 2 7 2 9 9 0 9 A P K para meters will be t he 
res p o nsi bilit y of I Q VI A, O verla n d Par k, Ka ns as. A ta ble of d escri pti ve statistics of P K para met ers 
will be pr o d uce d a n d dis pla ye d b y a nal yte a n d d a y usi n g P K S U B a nal ysis set. I n a d diti o n, listi n g s 
of i n di vi d ual P K para meters a n d dia g n ostics will be pr o d uce d a n d dis pla ye d b y a n al yt e a n d 
da y / w ee k usi n g S A F a n al ysis set. T he P h oe ni x Wi n N o nli n N C A C ore O ut p ut will be i ncl u de d. N o 
fi g ures will be pr o d uce d f or P K para meters. 
1 6. 2  
P D   
1 6. 2. 1  
B T K Occ u p a nc y  at B aseli ne a n d Wee ks 2, 4, 8, 1 2 a n d 2 4  
Meas ure me nt of B T K (free a n d t otal) will be assesse d as part of t he P D s u bst u d y as i n dicate d i n 
t he pr ot oc ol f or M S 2 0 0 5 2 7 _ 0 0 8 0, Sc he d ule of Assess me nts. Data o n t hese varia bles will b e 
s u m marize d descri pti vel y i n ta b ular a n d/ or gra p hic f or mat a n d liste d as a p pr o priate f or t he d ata  
base d o n t he P D B T K O a nal ysis set .  
B T K e n d p oi nts (fr ee B T K, t otal B T K, a n d %  B T K  occ u p a nc y  as calc ul ate d wit h t he f or m ula 
bel o w) will be s u m mari ze d usi n g t he P D B T K O a nal ysis set. Des cri pti ve statistics f or B T K 
e n d p oi nts will be prese nt e d as descri be d i n Secti o n  9. 2 .  
Perce nt B T K occ u pa nc y is calc ulate d as f oll o ws  a n d will be retrie ve d fr o m e xter nal data : 
%  𝐷𝑢𝑟𝑎𝑡𝑖𝑜𝑛𝑜𝑓𝐸𝑣= ( 1 −
( 𝑜𝑏𝑟𝑢
𝑡𝑖𝑛𝑖)
𝑏𝑜𝑟𝑇𝑒𝑟𝑖𝑓𝑙𝑢𝑛𝑜
𝑚𝑖𝑑𝑒𝑑𝑎𝑡𝑒𝑜𝑓𝑙𝑎
) ∗1 0 0  
wit h B T K F de n oti n g free B T K, B T K T d e n oti n g t otal B T K, a n d bas eli ne  defi ne d as last 
n o n -missi n g meas ur e me nt pri or t o t he first d ose of st u d y i nter ve nti o n.  
Gi ve n t hat B T K  occ u pa n c y  is a val u e l yi n g i n t he u nit i nter val ( 0, 1), it is prefera ble t o m o del t he 
d ata as beta -distri b ute d, rat her t ha n n or mal -distri b ute d. T he mea n a n d 9 5 %, 9 0 %, a n d 8 0 % CIs f or 
t he mea n will be esti mate d usi n g a beta m o del f or B T K occ u p a nc y  at eac h ti me p oi nt. As a 
s u p p orti ve a nal ysis, t he c o n ve nti o nall y esti mate d mea n a n d CIs, i n w hich B T K  o cc u p a n c y val ues 
are tr eate d as n or mall y distri b ute d, will als o be pr o vi de d.  
T he B T K  occ u p a nc y  me dia n ( 5t h a n d 9 5t h perce ntiles ) val ues will be pl otte d vers us ti me p oi nt. 
T he B T K  occ u pa n c y  dat a ma y als o b e i ncl u de d i n e x p os ure -res p o nse a nal yses (refer t o Secti o n 
1 8. 3 ). 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 7 /1 5 9  
 
 
 
1 6. 2. 2  
Nf L C o nce ntr ati o n at B aseli ne a n d  Wee ks 2 4, 4 8, 7 2 , 9 6 , a n d 
1 2 0   
T he a nal ysis of Nf L c o n ce ntrati o n s at Wee ks 2 4, 4 8, 7 2 , 9 6  a n d 1 2 0 will f oll o w t hat of Nf L at 
Wee k  1 2  descri be d i n Secti o n  1 4. 2. 5  a n d will be prese nte d i n t he sa me o ut p ut . F or partici pa nts 
disc o nti n ui n g treat me nt, all a vaila ble Nf L c o nce ntrati o n data will be i ncl u d e d i n t he a nal ysis u p t o 
1 5 6  wee ks p ost ra n d o mizati o n .  
1 6. 2. 3  
O t her P D E n d p oi nt A n al ys es at B aseli ne a n d Wee ks 2, 4, 8, 1 2 
a n d 2 4  
P D e n d p oi nts i ncl u di n g cell ular f u ncti o n ( i.e.  B -cell acti vati o n  a n d  Fc RI II sti m ulati o n), 
i m m u n o p he n ot y pi n g (i.e., T B N K , a n d B-cell & plas ma cell s u bset  pa n el s) a n d ser u m c yt o ki nes  
(N = 1 6) ) will be assesse d i n a s u bset of partici pa nt s fr o m selecte d sites i n t he P D s u bst u d y as 
i n dicate d i n t he pr ot oc ol Sc he d ule of Assess me nts .  
T he A bs ol ute val ues, a n d A bs ol ute a n d P erce nta ge C ha n ge fr o m baseli ne  of eac h bi o mar ker 
para meter will be s u m m arize d descri pti vel y f or P D a nal ysis set b y visit. I n a d diti o n, t he n u m ber 
of partici pa nts wit h a val ue bel o w L L O Q will be prese nte d b y visit t o get h er wit h t he L L O Q li mit, 
if a vaila ble. N o i m p utati o n will be perf or me d f or val ues bel o w L L O Q. Descri pti ve statistics f or 
t hese varia bl es will be prese nte d as d escri be d i n S ecti o n  9. 2 . 
T he me dia n ( 5 t h a n d 9 5 t h perce ntiles ) o bser ve d val ues f or eac h i nter ve nti o n gr o u p will be pl otte d 
vers us ti me p oi nt i n a li ne pl ot f or mat f or t he P D e n d p oi nts. Me di a n perce nt c ha n ge fr o m baseli ne  
li ne pl ots will als o be pr o vi de d. 
Ge ne e x pressi o n will n ot be a nal yz e d as p art of t he P A b ut ma y  b e a nal yz e d later. T he 
c orres p o n di n g a nal ysis will t heref ore b e descri be d i n a se parate IA P.  
1 6. 3  
P o p ul ati o n P K M o deli n g  a n d E x p os ure -Res p o nse A n al yses  
T he p o p ulati o n P K  m o deli n g a n d e x p os ure-res p o nse a nal ys es will be t he res p o nsi bilit y of t he 
S p o ns or  ( ma y be c o n d u cte d b y a differe nt e xter nal ve n d or). T he pri m ar y o bj ecti ves of t h e 
p o p ulati o n P K  m o deli n g  a n d e x p os ure-res p o nse a nal ys es are: 1) t o des cri b e t he P K c o n ce ntr ati o n 
ti me pr ofile f oll o wi n g t he a d mi nistrati o n of ev o br uti ni b i n patie nts wit h rela psi n g M S , a n d 2 ) t o 
e x pl ore t he relati o ns hi p bet wee n ev o b r uti ni b e x p os ure a n d selecte d efficac y/safet y e n d p oi nts. 
Sec o n dar y o bje cti ves  i ncl u de: 
•  T o esti mate t y pic al p o p ulati o n para meters a n d ma g nit u de of t he i nter - a n d i ntrai n di vi d ual 
varia bilit y f or ev o br uti ni b P K para meters i n patie nts wit h rela psi n g m ulti ple s cler osis  
•  T o i de ntif y i ntri nsic a n d e xtri nsic c o variates (e. g. de m o gra p hic  fact ors, meal  etc.) t h at are 
si g nifica nt pr e dict ors of varia bilit y i n P K. 
T he a nal ysis will i ncl u de : a) p o p ulati o n P K m o deli n g a n d b) e x p os ure -res p o nse a nal ys es 
c o n d ucte d o n t he pri m ar y efficac y e n d p oi nt  A R R  a n d ot her select cli nicall y rele va nt efficac y a n d 
safet y e n d p oi nts.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 8 /1 5 9  
 
 
 
T he P K data of t he c urre nt st u d y will be c o m bi ne d wit h t he c orres p o n di n g data of ot her st u dies 
(i.e. t he alrea d y c o m plete d st u dies M S 2 0 0 5 2 7 _ 0 0 1 9, M S 2 0 0 5 2 7 _ 0 0 1 7, M S 2 0 0 5 2 7 _ 0 0 8 6,  a n d 
ot her s), d uri n g t he m o del de vel o p me nt pr ocess (e. g. t o hel p esti mate t he para meters of a n a de q uat e 
str uct ural m o del).  
R ele va nt e v o br uti ni b P K para meters a n d e x p os ures  (e. g. stea d y state A U C) will be pre dicte d f or 
all patie nts wit h e val u a ble P K usi n g t he p o p ulati o n P K m o deli n g a p pr oac h.  N ot all P K para meters 
(e. g. Vz/ F) ma y b e c o m p ute d f or e v er y patie nt.  
T here will be a n i nte grate d e x p os ure-res p o nse a nal ysis of t he c o m bi ne d data of t he 2  P hase  3  
st u dies f or all e n d p oi nts a nal yz e d. T he re s ults will be s u m marize d s e parat el y i n de dicate d 
p har mac o metric re p ort/s.  Details of t h e pla n n e d M & S w or k f or st u dies M S 2 0 0 5 2 7 _ 0 0 8 0 a n d 
 will be de vel o pe d i n P har m ac o metric M o deli n g A nal ysis Pla ns b y t he e xter nal 
ve n d or  t hat will perf or m t hese M & S tas ks  u n d er Merc k Cli nical P har mac o metr y g ui da nce a n d 
s u per visi o n. T he P har mac o metric M o deli n g A nal ysis Pla n s will be fi nalize d a n d si g ne d -off bef ore 
t he P A D B l oc k of t h e  2  P hase  3  st u dies. 
Earl y access of t he P K data usi n g mas k e d patie nt I Ds fr o m t he St u d y M S 2 0 0 5 2 7 _ 0 0 8 0 a n d 
 b y a n e xter nal ve n d or is pla n ne d pri or t o t he data base l oc k t o facilitate p o p ulati o n 
P K m o del de vel o p me nt. T he S p o ns or will re mai n bli n de d t o t he data d uri n g t his peri o d. Pri or t o 
e na bli n g earl y d ata access, t his p r ocess will be d oc u me nte d i n a n u n bli n di n g me m o. 
1 6. 4  
P R O  –  E x pl or at or y E n d p oi nts   
T his secti o n disc usses o nl y t h ose P R O e n d p oi nts t hat are e x pl orat or y. P R O e n d p oi nts t hat are 
sec o n dar y are disc uss e d i n Secti o n  1 4. 2 . F or t he a nal ysis i n t he f oll o wi n g s u bsecti o ns, data 
selecti o n f or P A will be ha n dle d as i n dicate d i n Ta ble 8 . A nal ys es pres e nte d at p o ole d le vel will 
als o be pr o d uce d f or eac h st u d y.  
1 6. 4. 1  
C h a n ge fr o m B aseli ne  i n P R O MI S S c ore at Wee k  4 8 , Wee k  9 6  
a n d Wee k 1 4 4   
T he a nal ysis of c ha n ge fr o m baseli ne  i n P R O MI S sc ore ( P F or fati g ue) at 
Wee k 4 8  
(Wee k  9 6 /Wee k  1 4 4)  will be i m ple me nte d vi a t he sa me m o del ( base d o n p o ole d data) use d f or t h e 
a nal ysis of c ha n ge fr o m b aseli ne  i n P R O MI S sc ore ( P F or fati g ue) o ver 9 6  wee ks (Secti o n  1 4. 2. 3 ), 
b y selecti n g a n a p pr o priate c o ntrast fr o m t he m o del s pecific t o Wee k  4 8  (Wee k  9 6/ Wee k  1 4 4) , 
a n d re p orti n g t he treat m e nt effect meas ure, 9 5 % 2 -si de d CI, a n d p-v al ue. T he ha n dli n g of I C Es 
wil l be a nal o g o us t o t he sec o n dar y e n d p oi nt, descri be d i n Secti o n 1 4. 2. 3. 1 . 
F or eac h P R O MI S sc ore  C F B at 
Wee k  4 8  (Wee k  9 6/ Wee k  1 4 4) , a fi g ure will be pr o vi d e d 
descri bi n g t he distri b uti o n of C F B at Wee k  4 8  (Wee k  9 6/ Wee k  1 4 4) , o n e c ur ve p er i nter ve nti o n 
gr o u p , as descri be d i n Secti o n  1 4. 2. 3 . 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 2 9 /1 5 9  
 
 
 
1 6. 4. 2  
C h a n ge  fr o m B aseli ne  i n S F-3 6 v 2 sc ore at Wee k  4 8 , Wee k  9 6  
a n d Wee k 1 4 4   
T he a nal ysis of c ha n ge fr o m baseli ne  i n S F-3 6 v 2 sc ore at Wee k s 4 8, 9 6  a n d 1 4 4  will be base d o n 
p o ole d data, a n d f oll o w t he sa me a p pr oac h use d f or t he a nal ysis of c h a n ge fr o m baseli ne  i n 
P R O MI S sc ore at Wee k  9 6  (Secti o n  1 4. 2. 3 ). T his a p plies t o t he i n di vi d ual d o mai n sc ores, as w ell 
as t he M C S a n d P C S. T he ha n dli n g of I C Es will als o be a nal o g o us t o t he P R O MI S sec o n dar y 
e n d p oi nt, descri be d i n Secti o n  1 4. 2. 3. 1 . 
T he a nal ysis of c ha n ge fr o m baseli ne  i n S F-3 6 v 2 sc ore at 
Wee k s 4 8 , 9 6 a n d 1 4 4 will be 
i m ple me nte d via t he s a me m o del des cri be d a b o ve, b y selecti n g a n a p pr o priate c o ntr ast fr o m t h e 
m o del s pecific t o W ee k s 4 8 , 9 6 a n d 1 4 4, a n d re p orti n g t he treat me nt effect meas ure, 9 5 % 2-si de d 
CI, a n d p -val ue .  
F or eac h i nter ve nti o n gr o u p, descri pti ve statistics will be prese nte d f or a bs ol ute (ra w) val ue, C F B, 
a n d perce nt C F B v al ue f or eac h visit, fr o m b aseli ne  t o 
Wee k 1 5 6  ( S afet y F oll o w -u p  V isits 
i ncl u de d).  
F or t he S F -3 6 M C S a n d P C S e n d p oi nt s, a fi g ure will be pr o vi de d descri bi n g t he distri b uti o n of 
C F B at Wee k  4 8 , o ne c ur ve per i nter ve nti o n gr o u p. T his will be re peate d f or 
Wee k 9 6  a n d 
Wee k  1 4 4 . T his will f oll o w t he sa me a p pr oac h d escri be d i n Secti o n 1 4. 2. 3 . 
F or eac h S F -3 6 e n d p oi nt ( d o mai n sc ores, M C S, P C S ), t he n u m ber ( pr o p orti o n) of partici pa nts n ot 
w orse ni n g, a n d n u m ber ( pr o p orti o n) of partici pa nts w orse ni n g ( decrease ≥ 5), bet wee n baseli ne  
a n d 
Wee k  4 8 , baseli ne  a n d 
Wee k  9 6 a n d baseli ne  a n d 
Wee k  1 4 4 will be s u m marize d b y 
i nter ve nti o n gr o u p.  
Mea n sc ore C F B will be prese nte d as a b y -visit li ne pl ot f or eac h i nter ve nti o n gr o u p, wit h b ot h 
i nter ve nti o n gr o u ps i ncl u de d i n a si n gle fi g ure, a n d h oriz o ntal a xis e xte n di n g t o Wee k 1 4 4 . 
A  bar  c hart fi g ure of M ea n sc ore C F B at Wee k  4 8 prese nti n g eac h S F -3 6 s u b -d o mai n sc ore ( P F, 
R P, B P, G H, V T, S F, R E, M H) f or eac h i nter ve nti o n will  be pr o vi de d. T his will be re p eate d f or 
Wee k  9 6  a n d Wee k  1 4 4 . 
1 6. 4. 3  
C h a n ge fr o m 
B aseli ne  i n E Q 5 D -5 L 
V A S a n d I n de x at 
Wee k  4 8 , Wee k  9 6  a n d Wee k 1 4 4   
T he a nal ysis of c ha n ge fr o m baseli ne  i n E Q 5 D-5 L V A S at Wee k  4 8 , Wee k  9 6  a n d Wee k 1 4 4 will 
be bas e d o n p o ol e d dat a a n d f oll o w t h e sa m e a p pr oac h use d f or a nal ysis of C F B i n S F -3 6 v 2 at 
Wee k s 4 8 , 9 6  a n d 1 4 4 (Secti o n  1 6. 4. 2 ), i ncl u di n g t he ha n dli n g of I C Es. T he a nal ysis of E Q  5 D -5 L 
I n d e x at Wee k  4 8 , Wee k  9 6  a n d Wee k 1 4 4 will als o f oll o w t his a p pr oac h.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 0 /1 5 9  
 
 
 
F or eac h i nter ve nti o n gr o u p, descri pti ve statistics will be prese nte d f or a bs ol ute (ra w) val ue, C F B, 
a n d perce nt C F B v al ue f or eac h visit, fr o m b aseli ne  t o 
Wee k 1 5 6  ( S afet y F oll o w -u p  V isits 
i ncl u de d).  
1 6. 4. 4  
Ti me t o 
F irst O cc urre nce of 1 2 -wee k  C o nfir me d 
P F 
D eteri or ati o n C o m p are d t o B aseli ne  u p t o 1 5 6  W ee ks   
T he M CI D f or t he P R O MI S n q P F( M S) 1 5a is re p orte d t o be 2. 3 –  2. 7 ( Ka m u d o ni 2 0 2 2 ). A M CI D 
c ut off of 2. 7 will be use d. P F deteri orati o n is defi n e d  as a re d ucti o n i n P R O MI S P F T -sc ore ≥ 2. 7 
c o m pare d t o baseli ne P R O MI S P F T -s c ore. C o nfir me d P F deteri orati o n is a deteri orati o n s ustai ne d 
f or at least 1 2 w ee ks.  
C o nfir mati o n of deteri or ati o n m ust occ ur at t he re g ularl y s c he d ule d visit t hat is at least 1 2  wee ks 
(8 4  da ys) after i nitial det eri orati o n. If a p artici pa nt  has a missi n g P F s c ore at t he s c he d ule d visit 
occ urri n g at least 8 4 d a ys after a n i nitial deteri or ati o n or t he sc h e d ule d visit occ urs se veral d a ys 
bef ore t he 8 4 -d a y wi n d o w after a n i nitial deteri or ati o n, c o nfir mati o n of t h e deteri orati o n m ust be 
o n t he ba sis of t he assess me nt at t he ne xt sc he d ule d visit.  
P F sc ore ass ess me nts at u nsc he d ule d or sc h e d ule d visits t hat are less t ha n 8 4  da ys after t he i nitial 
deteri orati o n are c o nsi d ere d n o n -c o nfir mat or y P F sc ore assess me nts . F or deteri orati o n t o be 
c o nfir me d at a re g ularl y s c he d ule d visit at least 1 2  wee ks after i nitial deteri orati o n, a n y 
n o n -c o nfir mat or y P F s c ore ass ess me nts s h o ul d be at least as m uc h w orse ni n g as t hat re q uire d f or 
deteri orati o n.  
T he a n al ysis of ti me t o first occ urre nce of 1 2 -wee k  c o nfir me d P F  det eri orati o n c o m pare d t o 
baseli ne  will be base d o n p o ole d data a n d f oll o w t he sa me a p pr oac h use d f or t he a nal ysis of ti me 
t o 1 2 -wee k  C D P ( Secti o n  1 4. 2. 1. 1 ).  
T he ha n dli n g of I C Es will als o be a nal o g o us t o t he sec o n d ar y e n d p oi nt, ti me t o 1 2 -wee k C D P, 
descri be d i n Secti o n  1 4. 2. 1. 1 . I n acc or da nce wit h t he C o m p osite Varia ble strate g y, f or p artici pa nts 
e x perie nci n g t he I C E d eat h attri b uta ble t o 
M S or treat me nt, t he d eat h will be c o u nt e d as 
c o nfir mati o n of d eteri or ati o n. I n  acc or da nce wit h t he 
W hile Ali ve strate g y, f or p artici pa nts 
e x perie nci n g t he I C E deat h u nattri b uta ble t o M S or treat me nt, partici p a nts will be ce ns ore d at ti me 
of deat h. (i.e. d eat h will n ot be c o u nte d as c o nfir mati o n of deteri orati o n).  
Descri pti ve statist ics will f oll o w t he sa me a p pr oac h use d f or t he 1 2 -wee k  C D P.  
1 6. 4. 5  
Ti me t o 
First 
Occ urre nce of 2 4 -wee k 
C o nfir me d 
P F 
I m pr o ve me nt C o m p are d t o B aseli ne  u p t o 1 5 6  Wee ks   
P R O MI S P F i m pr o ve me nt is defi ne d as a n i ncrease of at least 2. 7 p oi nts o n P R O MI S P F sc ore 
relati ve t o bas eli ne . C o nfir me d P F sc ore i m pr o ve me nt e ve nts are d efi ne d as P R O MI S P F 
i m pr o ve me nt s ustai ne d f or at least 2 4 wee ks.   
C o nfir mati o n of i m pr o ve me nt m ust occ ur at t he re g ularl y sc he d ule d visit t hat is at least 2 4  wee ks 
(1 6 8  da ys) after i nitial i m pr o ve me nt. If a partici pa nt has a missi n g P F sc ore at t he sc he d ule d visit 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 1 /1 5 9  
 
 
 
occ urri n g at least 1 6 8  da ys after a n i nitial i m pr o ve me nt or t h e sc h e d ule d visit occ urs se v eral da ys 
bef ore t he 1 6 8 -da y wi n d o w after a n i nitial i m pr o ve me nt, c o nfir mati o n of t he i m pr o ve me nt m ust 
be o n t he basis of t he ass ess me nt at t he ne xt sc he d ule d visit.  
P F sc ore assess me nts at u nsc he d ule d or sc he d ule d visits t hat are less t ha n 1 6 8 da ys aft er t he i nitial 
i m pr o ve me nt are c o nsi d ere d n o n -c o nfir m at or y P F sc ore ass ess me nts. F or i m pr o ve me nt t o be 
c o nfir me d at a re g ul arl y sc h e d ule d visit at least 2 4 wee ks after i nitial i m pr o ve me nt, a n y 
n o n -c o nfir mat or y P F sc ore assess me nts s h o ul d be at least as l o w as t he mi ni mal c ha n ge re q uire d 
f or i m pr o ve me nt. 
T he a nal ysis of ti me t o first occ urre nce of 2 4 -wee k c o nfir m e d P F i m pr o ve me nt c o m pare d t o 
baseli ne  will be base d o n p o ole d data a n d f oll o w t he sa me a p pr oac h use d f or t he a nal ysis of ti me 
t o 2 4-wee k C DI ( Secti o n  1 4. 2. 2 ). T he ha n dli n g of I C Es will als o be a nal o g o us t o t h e sec o n dar y 
e n d p oi nt. 
Descri pti ve statistics will f oll o w t he sa me a p pr oac h use d f or t he 2 4 -wee k C DI.  
1 6. 4. 6  
Ti me t o First Occ urre nce of 1 2 -wee k  C o nfir me d F ati g ue 
Deteri or ati o n C o m p are d t o B aseli ne  u p t o 1 5 6  Wee ks    
T he M CI D f or t he P R O MI S Fati g ue ( M S) 8 a is r e p orte d t o be 3. 4 - 4 ( Ka m u d o ni 2 0 2 1 ). A M CI D 
c ut off of 4 p oi nts will be use d. P R O MI S fati g u e deteri orati o n  is defi ne d as a n i ncreas e of at least 
4 p oi nts o n P R O MI S fati g ue sc ore relati ve t o b aseli ne . C o nfir me d fati g ue sc ore deteri orati o n 
e ve nts are defi ne d as det eri orati o ns i n P R O MI S fati g ue s ustai n e d f or at least 1 2  wee ks.  
T he a nal ysis of ti me t o first occ urr e n ce of 1 2 -wee k  c o nfir me d fati g ue det eri orati o n c o m pare d t o 
baseli ne  will be base d o n p o ole d data a n d f oll o w t he sa me a p pr oac h use d f or t he a nal ysis of ti me 
t o 1 2 -wee k  c o nfir me d P F deteri orati o n ( Secti o n  1 6. 4 . 4).  
T he ha n dli n g of I C Es will als o be a nal o g o us t o t he ti me t o 1 2-wee k c o nfir me d P F deteri or ati o n  
( Secti o n 1 6. 4. 4 ). I n acc or da nce 
wit h t he 
C o m p osite 
Varia ble strat e g y, f or partici pa nts 
e x perie nci n g t he I C E d eat h attri b uta ble t o 
M S or treat me nt, t he d eat h will be c o u nt e d as 
c o nfir mati o n of d eteri or ati o n. I n acc or da nce wit h t he 
W hile Ali ve strate g y, f or p artici pa nts 
e x perie nci n g t he I C E deat h u nattri b uta ble t o M S or treat me nt, partici p a nts will be ce ns ore d at ti me 
of deat h. (i.e. d eat h will n ot be c o u nte d as c o nfir mati o n of deteri orati o n).  
Descri pti ve stati stics will f oll o w t he sa me a p pr oac h use d f or t he 1 2 -wee k  c o nfir me d P F 
deteri orati o n.  
1 6. 4. 7  
Ti me t o First Occ urre nce of 2 4 -wee k C o nfir me d F ati g ue 
I m pr o ve me nt C o m p are d t o B aseli ne  u p t o 1 5 6  Wee ks   
P R O MI S fati g ue i m pr o ve me nt is defi ne d as a decreas e of at least 4 p oi nts o n P R O MI S fati g u e 
sc ore relati ve t o baseli ne . C o nfir me d fati g ue sc ore i m pr o ve me nt e ve nts are defi ne d as 
i m pr o ve me nts i n P R O MI S fati g ue s ustai ne d f or at least 2 4 wee ks. 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 2 /1 5 9  
 
 
 
T he a nal ysis of ti me t o first occ urre nce of 2 4 -wee k c o nfir me d fati g u e i m pr o ve me nt c o m pare d t o 
baseli ne  will be base d o n p o ole d data a n d f oll o w t he sa me a p pr oac h use d f or t he a nal ysis of ti me 
t o 2 4-wee k c o nfir me d P F i m pr o ve me nt ( Secti o n  1 6. 4. 5 ). T he ha n dli n g of I C Es will als o b e 
a nal o g o us.  
Descri pti ve statistics will f oll o w t he sa me a p pr oac h use d f or t he 2 4 -wee k c o nfir me d P F 
i m pr o veme nt.  
1 6. 4. 8  
P R O MI S F ati g ue Sc ore C F B o ver 9 6  Wee ks I n de pe n de nt of 
Rel a pse Acti vit y   
T he pri mar y a nal ysis of C F B i n P R O MI S Fati g u e sc ore o ver 9 6  wee ks defi ne d i n Secti o n  1 4. 2. 3. 2  
will be re peat e d c o nsi deri n g t he h y p ot hetical sce n ari o f or t he I C E ‘rel a pse’.  
T he ha n dli n g of I C Es will be a nal o g o us t o t he pri mar y (f or rel a pses) a n d s ec o n dar y  (f or P R O MI S 
fati g u e) e n d p oi nts, des cri be d i n Secti o ns 1 4. 1. 1  a n d 1 4. 2. 3. 1 , res pecti vel y. 
Partici pa nts wit h q ualifie d rela pse will be ce ns ore d at t he ti me of t he o nset of t he first q ualifie d 
rela pse. D escri pti ve statistics a n d i nfere ntial a nal ysis ( M M R M) will be prese nte d.  
T he a nal ysis will be re p eate d c o nsi deri n g all rela pses, n ot o nl y q ualifie d.  
1 6. 4. 9  
P R O MI S Res p o nse u p t o Wee k  1 5 6   
Res p o nse i n P R O MI S ( P F or fati g u e) will be a nal yze d base d o n differe nces i n pr o p orti o ns of 
res p o n ders b et wee n i nter ve nti o n gr o u ps.  
Res p o n der d efi niti o ns will be base d o n M CI D criteria f or i m pr o ve m e nt or deteri orati o n fr o m 
baseli ne  as descri be d i n Secti o ns 1 6. 4. 4 , 1 6. 4. 5 , 1 6. 4. 6  a n d 1 6. 4. 7 . T he h a n dli n g of I C Es will als o 
be a nal o g o us.  
T he f oll o wi n g a nal ysis will be re peate d f or t he 4  defi niti o ns of res p o nse ( P F i m pr o ve me nt, P F 
d eteri orati o n, fati g u e i m pr o ve me nt a n d fati g u e det eri orati o n):  
A l o gistic re gressi o n m o del wit h re peat e d meas ures will be a p plie d, wit h ter ms f or i nter ve nti o n 
gr o u p, visit, i nter ve nti o n gr o u p b y visit i nteracti o n, baseli ne  sc ore, b aseli ne  sc ore b y visit 
i nteracti o n, ra n d o mizati o n strata a n d st u d y I D, a n d w here t he dat a are p o ole d fr o m t he F A S of 
st u dies 0 0 8 0 a n d  
. T he u nstr uct ure d c o varia n ce matri x will be c o nsi dere d. T he esti mate d o d ds 
rati o at Wee k 4 8, Wee k  9 6 , Wee k  1 4 4  a n d Wee k  1 5 6 , t o get her wit h a n ass o ciate d 2 -si de d 9 5 % CI 
of t he esti mate d o d ds rati o  will be prese nte d.   
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 3 /1 5 9  
 
 
 
1 6. 5  
H R U   
H R U para met er data will be p o ole d fr o m b ot h P hase  3  st u dies a n d s u m marize d b y visit via 
descri pti ve statistics (mea n, S D, me dia n, mi ni m u m/ ma xi m u m, 2 5 t h a n d 7 5 t h perce ntile; 9 5 % CI) 
f or t he o n -tr eat me nt peri o d. T he f oll o wi n g p ara m eters will be s u m marize d: 
•  N u m ber of d oct or/cli nic visits  
•  N u m ber of h o me visits  
•  N u m ber of e m er ge n c y r o o m visits  
•  N u m ber of da ys i n h os pit al  
•  N u m ber of partici pa nt s w h o pai d s o me o ne t o assist t he m, n ( %): 
o  A vera ge n u m ber of da ys per wee k of pai d assista nce (restricte d o n p artici pa nt s w h o 
pai d s o me o ne t o assist t he m)  
o  A vera ge n u m ber of h o urs per d a y of pai d assista nce (restricte d o n part ici p a nts w h o 
pai d s o me o ne t o assist t he m)  
•  N u m ber of partici pa nt s wit h a relati ve or frie n d w h o misse d w or k beca us e of M S , n ( %): 
o  N u m ber of da ys of misse d w or k (restri cte d o n partici pa nt s wit h a relati ve or frie n d 
w h o misse d w or k beca us e of M S ) 
•  N u m ber of pa rtici pa nts w h o misse d at least o ne f ull da y of w or k beca use of M S , n ( %): 
o  N u m ber of da ys of misse d w or k (restricte d o n partici pa nt s w h o misse d at least o n e 
f ull da y of w or k beca us e of M S ) 
•  N u m ber of partici pa nt s w h o misse d at least o n e partial da y of w or k b eca us e of M S , n ( %): 
o  A vera ge n u m ber of h o urs per da y misse d fr o m w or k (restri cte d o n partici p a nt s w h o 
misse d at least o ne partial da y of w or k beca us e of M S ) 
•  N u m ber of partici pa nt s w h o acc o m plis he d less at w or k d ue t o M S , n ( %)  
•  Perce nt t hat best i n dicat es t he a m o u nt of w or k t he partici pa nt  was a ble t o acc o m plis h 
des pite M S  
H R U data will als o be liste d.  
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 4 /1 5 9  
 
 
 
1 7  
Refere nces   
Be ne di ct R H B, T o mic D, Cree B A, et al. Si p o ni m o d a n d C o g niti o n i n Sec o n dar y Pr o gressi ve 
M ulti ple 
Scler osis: 
E X P A N D 
Sec o n dar y 
A nal ys es. 
Ne ur ol o g y. 
2 0 2 1; 9 6( 3):e 3 7 6 -e 3 8 6. 
d oi: 1 0. 1 2 1 2/ W N L. 0 0 0 0 0 0 0 0 0 0 0 1 1 2 7 5   
Bretz F, M a urer W, Bra n nat h W, et al. A gra p hi cal a p pr oac h t o se q ue ntiall y rejecti ve m ulti ple test 
pr oce d ures. Stat Me d. 2 0 0 9; 2 8: 5 8 6 -6 0 4.   
Bretz F, Ma urer W, Xi D. Re plica bilit y,  re pr o d uci bilit y, a n d m ulti plicit y i n dr u g de vel o p me nt. 
C H A N C E. 2 0 1 9; 3 2: 4, 4 -1 1.  Cli nical St u d y 
Meas ures: htt ps:// w w w. nati o nal mss ociet y. or g/ F or -
Pr ofessi o nals/ Researc hers/ Res o urces -f or-Researc hers/ Cli nical -St u d y -Meas ures   
Cr o we BJ, Xia H A, Berli n J A, et al. Rec o m me n dati o ns f or s afet y pla n ni n g, dat a c ollecti o n, 
e val uati o n a n d re p orti n g d uri n g dr u g, bi ol o gic a n d vacci ne d e vel o p me nt: a re p ort of t h e safet y 
pla n ni n g, e v al uati o n, a n d re p orti n g tea m. Cli n Trials. 2 0 0 9; 6( 5): 4 3 0 -4 0.   
Elli ott C, Belac he w S, W oli ns k y J S, Ha user S L, Ka p p os L, B ar k h of F, Ber nasc o ni C, Fec k er J, 
M o del F, Wei Wei, Ar n ol d D L.  C hr o nic w hite matter lesi o n acti vit y pre di cts cli nical pr o gressi o n 
i n pri mar y pr o gressi ve m ulti ple scler osis. Brai n 2 0 1 9: 1 4 2; 2 7 8 7 -2 7 9 9  
Fili p pi M, R occa M A, Bar k h of F, Br uc k 
W, C he n J T, C o mi G, et al.  Ass ociati o n bet wee n 
pat h ol o gic al a n d M RI fi n di n gs i n m ulti ple scler osis.  La n cet N e ur ol 2 0 1 2; 1 1: 3 4 9 -6 0.   
Frie de  T, P o hl ma n n H, S c h mi dli H. Bli n de d sa m ple siz e resti mati o n i n e ve nt -dri ve n cli nical trials: 
Met h o ds a n d a n a p plicati o n i n m ulti ple scler osis. P har m Stat. 2 0 1 9; 1 8: 3 5 1 -6 5.   
H u n g H M J a n d 
Wa n g S. M ulti ple c o m paris o ns i n c o m ple x cli nical trial desi g ns. Bi o metrical 
J o ur nal. 2 0 1 3; 5 5( 3): 4 2 0-9.   
Ka m u d o ni P, A mt ma n n D, J o h ns J, et al. T he vali dit y, res p o nsi ve n ess, a n d sc ore i nter pretati o n of 
t he P R O MI S n q P h ysical F u ncti o n –  M ulti ple Scler osis 1 5 a s h ort f or m i n m ulti ple scler osis. 
M ulti ple  
Scler osis  
a n d  
Rel ate d  
Dis or ders  
.  
2 0 2 2; V ol.  
6 2 :1 0 3 7 5 3 
[ htt ps:// d oi. or g/ 1 0. 1 0 1 6/j. msar d. 2 0 2 2. 1 0 3 7 5 3]  
Ka m u d o ni P, He n k e C, Barrett A, et al. A ne w P R O MI S p h ysic al f u ncti o n s h ort f or m f or use i n 
rela pse a n d pr o gressi ve m ulti ple scler osis t y pes. Q ual Life Res. 2 0 1 8; 2 7( 1): S 1– S 1 9 0.   
Ka m u d o ni P, J o h ns J, C o o k K F et al. Sta n dar dizi n g fati g u e meas ure me nt i n m ulti ple scler osis: t he 
vali dit y, res p o nsi ve n ess a n d sc ore i nter pretati o n of t he P R O MI S S F v 1. 0 –  Fati g u e ( M S) 8a . 
M ulti ple  
Scler osis  
a n d 
Rel ate d  
Dis or ders  
.  
2 0 2 1 ; V ol. 
5 4 : 1 0 31 1 7  
[htt ps:// d oi. or g/ 1 0. 1 0 1 6/j. msar d. 2 0 2 1. 1 0 3 1 1 7 ]  
Kee ne O. N., R o ger J. H., Hartle y B. F., Ke n war d 
M. G. 
Missi n g dat a s e nsiti vit y a n al ysis f or 
recurre nt e v e nt data usi n g c o ntr olle d i m p utati o n. P har m. Stat. 2 0 1 4; 1 3: 2 5 8 -2 6 4 [ D OI : 
1 0. 1 0 0 2/ pst. 1 6 2 4]   
Ke n war d, M. G., & R o ger, J. H. ( 1 9 9 7). S mall Sa m ple I nfere nce f or Fi x e d Effec ts fr o m Restri cte d 
Ma xi m u m Li keli h o o d . Bi o metrics , 5 3 ( 3), 9 8 3 – 9 9 7. htt ps:// d oi. or g/ 1 0. 2 3 0 7/ 2 5 3 3 5 5 8   
Li p k o vic h I., Ratitc h B., O' K ell y M. Se nsiti vit y t o ce ns ore d -at-ra n d o m ass u m pti o n i n t he a nal ysis 
of ti me -t o-e ve nt e n d p oi nts. P har m. Stat. 2 0 1 6; 1 5( 3): 2 1 6 -2 9 [ D OI : 1 0. 1 0 0 2/ pst. 1 7 3 8].   
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 5 /1 5 9  
 
 
 
Little R, Ya u L. I nte nt -t o-treat a n al ysis f or l o n git u di nal st u dies wit h dr o p -o uts. Bi o metrics 
1 9 9 6; 2( 4): 1 3 2 4 -3 3.   
L u bli n F, Häri n g D, Ga nj ga hi H et al. H o w pati e nts wit h m ulti ple scler osis ac q uire disa bilit y . 
Brai n,  2 0 2 2; 1 4 5 (9 ), 3 1 4 7– 3 1 6 1  [htt p s:// d oi. or g/ 1 0. 1 0 9 3/ brai n/a wac 0 1 6].  
O’ Kell y 
M, 
Ratitc h 
B. 
Cli nical trials 
wit h 
missi n g data: a g ui de f or practiti o ners. 
1 0. 1 0 0 2/ 9 7 8 1 1 1 8 7 6 2 5 1 6.   
Merz, M., Lee, K. R., K ulla k -U blic k, G. A. et al. Met h o d ol o g y t o Assess Cli nical Li v er Safet y Data. 
Dr u g Saf 3 7 ( S u p pl 1), 3 3 – 4 5 ( 2 0 1 4).   
Mietti ne n O, N ur mi ne n M. C o m parati ve a nal ysis of t w o rates. Stat Me d 1 9 8 5; 4( 2): 2 1 3 -2 6  Ratitc h 
B, O’ K ell y M, T osiell o B. Missi n g d ata i n cli nical trials: fr o m cl nical ass u m pti o ns t o statistical 
a nal ysis usi n g patter n mi xt ure m o dels. P har m. Stat. 2 0 1 3; 1 2( 6): 3 3 7 -3 4 7 [ D OI : 1 0. 1 0 0 2/ pst. 1 5 4 9].  
Va n Wal der vee n M A, K a m h orst W, Sc helte ns P, va n Waes ber g h e J H, Ra vi d R, Val k J, et al. 
Hist o pat h ol o gic c orrelat e of h y p oi nte ns e lesi o ns o n T 1 -we i g ht e d s pi n-ec h o 
M RI i n m ulti ple 
scler osis.  Ne ur ol o g y 1 9 9 8; 5 0: 1 2 8 2-8.   
Ware J, K osi ns ki M, Bj or ner J., T ur ner -B o w ker D, Ga n de k B, Mer uis h M. I n User’s ma n ual f or 
t he S F-3 6 v 2 heal t h s ur ve y, Li nc ol n, RI, Q ualit y Metric I nc or p orate d, 2 0 0 7.  
Ware J, S her b o ur ne C. T he M O S 3 6 -lte m S h ort-F or m Healt h S ur ve y ( S F -3 6) I. C o nce pt ual 
Fra me w or k a n d Ite m Selecti o n. Me d Care. 1 9 9 2; 3 0( 6): 4 7 3 -8 3.    
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 6 /1 5 9  
 
 
 
1 8  
A p pe n dices   
1 8. 1  
P R O MI S Sc ores   
P R O MI S P F( M S) 1 5 a  
T he P R O MI S n q S h ort F or m v 2. 0 - P h ysical F u ncti o n - M ulti ple Scler osis 1 5a [ P R O MI S n q 
P F( M S) 1 5a]  is sc ore d o n a T sc ore metric, wit h a mea n of 5 0 a n d a S D of 1 0. Hi g her s c ores 
i n dicate hi g her p h ysic al f u ncti o n. T he T sc ore metric all o ws f or eas y i nter pretati o n of sc ores b y 
facilitati n g c o m paris o ns t o t he “a v era ge” pers o n, as refere nce d t o t he U S ge neral p o p ulati o n. F or 
e x a m ple, a pers o n wit h a T sc ore of 6 0 is o n e S D a b o ve a vera ge p h ysic al f u ncti o n. T his s h ort f or m 
has a n M CI D of 2. 3 t o 2. 7.  
P R O MI S F ati g ue ( M S) 8 a  
T he P R O MI S S h ort F or m v 1. 0 - Fati g ue - M ulti ple Scler o sis 8 a [ P R O MI S Fati g ue ( M S) 8 a] is 
sc ore d o n a T sc ore metri c, wit h a mea n of 5 0 a n d a sta n dar d de viati o n ( S D) of 1 0. Hi g h er sc ores 
i n dicate hi g her fati g ue. T he T sc ore metric all o ws f or eas y i nter pretati o n of sc ores b y facilitati n g 
c o m paris o ns t o t he “a ve ra ge” p ers o n, as refere nce d t o t he U S ge neral p o p ulati o n. F or e x a m ple, a 
pers o n wit h a T sc ore of 6 0 is o ne S D a b o ve a vera ge fati g u e. T his s h ort f or m has a n M CI D of 3. 4 
t o 4 (Ka m u d o ni 2 0 2 1 ) 
T -sc ores f or t he P R O MI S P F ( M S) an d t he P R O MI S Fati g u e  ( M S) are calc ulate d usi n g/a p pl yi n g 
a n ite m-res p o nse t he or y (i.e. gra de d res p o nse m o del) a p pr oac h, base d o n “res p o nse p atter n 
sc ori n g”, w hic h utilizes i n di vi d uals’ ite m res p o ns es a n d t he P R O MI S ite m ba n k gra de d res p o nse 
m o del para meter s f or eac h ite m. T hese i ncl u de a discri mi nati o n (sl o pe) para meter a n d a n ite m -
res p o nse diffic ult y para m eter (le v el of u n derl yi n g trait val ue at w hic h a res p o nse o pti o n has a 5 0 % 
c ha nce of bei n g sel ecte d), f or eac h ite m, res p ecti v el y.  
T he sc ori n g will be p erf or me d usi n g t he Healt h meas ures Assess me nt Ce ntre A p plicati o n 
Pr o gra m mi n g I nterface (accessi ble at: htt p:// w w w. healt h meas ures . n et), w hic h e val u ates t he 
patter n of i n di vi d uals’ res p o nses t o t he a d mi nistere d ite ms a n d ge nerates a n esti mate d sc ore bas e d 
o n t his patter n (t h us t he na me “res p o nse patter n s c ori n g”). Res p o nse p atter n sc ori n g is es peciall y 
usef ul w he n t here are missi n g res p o ns es ( i.e. s ki p p e d ite ms); a pers o n’s s c ore (i.e. P F/f ati g u e le vel) 
ca n be esti mate d usi n g a vaila ble res p o nse. O nl y q uesti o n naires wit h at least 8 ite ms (f or P F) or 4 
ite ms (fati g u e) re pres e nti n g 5 0 % of res p o ns es will be e val ua bl e. 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 7 /1 5 9  
 
 
 
1 8. 2  
3 6 -Ite m S h ort F or m S ur ve y ( S F-3 6) Sc ori n g I nstr ucti o ns   
T he S F -3 6 is a vali date d 3 6 -ite m, partici pa n t-re p orte d i n dicati o n of o verall healt h stat us n ot 
s pecific t o a n y a ge, disease, or i nter ve nti o n gr o u p ( Ware  1 9 9 2 ).  
T he 
S F -3 6 i ncl u des 
m ulti -ite m 
scales 
meas uri n g 
eac h 
of t he f oll o wi n g 
8 healt h 
c o nce pts:  ( 1) p h ysic al f u ncti o ni n g; ( 2)  r ole li mitati o ns beca use of p h ysi cal healt h pr o bl e ms; 
( 3) b o dil y pai n; ( 4)  s oci al f u ncti o ni n g; ( 5) ge neral me ntal healt h ( ps yc h ol o gical distres s a n d 
ps yc h ol o gical 
well bei n g); ( 6)  r ole li mitati o ns beca use of e m oti o nal pr o ble ms; ( 7) vitalit y 
(e ner g y/f ati g u e); a n d ( 8) ge n eral healt h perce pti o ns (see Ta ble 2 0 ). T hes e are s u m marize d i n 
2  s u m mar y me as ures of p h ysical a n d me ntal healt h: t he P C S a n d M C S. 
Q uesti o ns i n t he sta n dar d versi o n of t h e S F -3 6 refer t o a 4 -wee k ti me peri o d. Scales are s c ore d 
acc or di n g t o t he Li kert met h o d. L o w er sc ores e q u ate t o  hi g her disa bilit y a n d hi g her sc ores e q uate 
t o l o wer disa bilit y. 
T he S F -3 6 v 2 m ulti -ite m scales yiel d a healt h pr ofile ( 8 sc ores) or ca n be a g gre gate d i nt o 
2  s u m mar y sc ores, t he P C S sc ore a n d M C S sc ore o btai ne d t hr o u g h a li near c o m bi nati o n of 
wei g ht e d tra nsf or m e d sc ores fr o m t he 8 s u bscales. P C S a n d M C S are sta n dar dize d, wit h a n a vera ge 
of 5 0 a n d a sta n dar d d e viati o n of 1 0 i n t he ge n eral A meri ca n p o p ulati o n. P C S a n d M C S are 
c o m p ute d o nl y if all of t he 8 scal e sc ores are a vaila ble. T his A p pe n di x details h o w t hese 2  sc ores 
s h o ul d be calc ulate d, as descri be d i n Ware ( 2 0 0 7) . 
T a ble 2 0  
S F -3 6 –  A b bre vi at e d Ite m C o nt e nt f or t he S F-3 6 v 2 He alt h D o m ai n 
Sc ales   
S c al e  
Ori gi n al 
it e m # 
It e m # i n t h e 
M S 2 0 0 5 2 7 -0 0 8 0 
st u d y  
A b br e vi at e d It e m C o nt e nt  
P h y si c al 
F u n cti o ni n g ( P F)  
3 a  
3  
Vi g or o u s a cti viti e s, s u c h a s r u n ni n g, lifti n g h e a v y o bj e ct s, or 
p arti ci p ati n g i n str e n u o u s s p ort s  
3 b  
4  
M o d er at e a cti viti e s, s u c h a s m o vi n g a t a bl e, p u s hi n g a 
v a c u u m cl e a n er, b o wli n g, or pl a yi n g g olf  
3 c  
5  
Lifti n g or c arr yi n g gr o c eri e s  
3 d  
6  
Cli m bi n g s e v er al fli g ht s of st air s  
3 e  
7  
Cli m bi n g o n e fli g ht of st air s  
3f  
8  
B e n di n g, k n e eli n g, or st o o pi n g  
3 g  
9  
W al ki n g m or e t h a n a mil e  
3 h  
1 0  
W al ki n g s e v er al h u n dr e d y ar d s  
3i  
1 1  
W al ki n g o n e h u n dr e d y ar d s  
3j  
1 2  
B at hi n g or dr e s si n g o n e s elf  
R ol e -P h y si c al ( R P)  
4 a  
1 3  
C ut d o w n t h e a m o u nt of ti m e s p e nt o n w or k or ot h er 
a cti viti e s  
4 b  
1 4  
A c c o m pli s h e d l e s s t h a n y o u w o ul d li k e  
4 c  
1 5  
Li mit e d i n ki n d of w or k or ot h er a cti viti e s  
4 d  
1 6  
H a d diffi c ult y p erf or mi n g w or k or ot h er a cti viti e s ( e .g . it t o o k 
e xtr a eff ort)  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 8 /1 5 9  
 
 
 
S c al e  
Ori gi n al 
it e m # 
It e m # i n t h e 
M S 2 0 0 5 2 7 -0 0 8 0 
st u d y  
A b br e vi at e d It e m C o nt e nt  
B o dil y P ai n ( B P)  
7  
2 1  
I nt e n sit y of b o dil y p ai n 
8  
2 2  
E xt e nt p ai n i nt erf er e d wit h n or m al w or k  
G e n er al H e alt h 
( G H) 
1  
1  
I s y o ur h e alt h: e x c ell e nt, v er y g o o d, g o o d, f air, p o or 
1 1 a  
3 3  
S e e m t o g et si c k a littl e e a si er t h a n ot h er p e o pl e  
1 1 b  
3 4  
A s h e alt h y a s a n y b o d y I k n o w  
1 1 c  
3 5  
E x p e ct m y h e alt h t o g et w or s e  
1 1 d  
3 6  
H e alt h i s e x c ell e nt  
Vit alit y ( V T)  
9 a  
2 3  
F e el f ull of lif e  
9 e  
2 7  
H a v e a l ot of e n er g y  
9 g  
2 9  
F e el w or n o ut  
9i  
3 1  
F e el tir e d  
S o ci al F u n cti o ni n g 
( S F) 
6  
2 0  
E xt e nt h e alt h pr o bl e m s i nt erf er e d wit h n or m al s o ci al 
a cti viti e s  
1 0  
3 2  
Fr e q u e n c y h e alt h pr o bl e m s i nt erf er e d wit h s o ci al a cti viti e s  
R ol e -E m oti o n al 
( R E) 
5 a  
1 7  
C ut d o w n t h e a m o u nt of ti m e s p e nt o n w or k or ot h er 
a cti viti e s  
5 b  
1 8  
A c c o m pli s h e d l e s s t h a n y o u w o ul d li k e  
5 c  
1 9  
Di d w or k or ot h er a cti viti e s l e s s c ar ef ull y t h a n u s u al  
M e nt al H e alt h ( M H)  
9 b  
2 4  
B e e n v er y n er v o u s  
9 c  
2 5  
F elt s o d o w n i n t h e d u m p s t h at n ot hi n g c o ul d c h e er y o u u p  
9 d  
2 6  
F elt c al m a n d p e a c ef ul  
9f  
2 8  
F elt d o w n h e art e d a n d d e pr e s s e d  
9 h  
3 0  
B e e n h a p p y  
S elf -E v al u at e d 
Tr a n siti o n ( S E T)  
2  
2  
H o w h e alt h i s n o w c o m p ar e d t o 1 y e ar a g o  
Ste p 1: Rec o di n g Ite m Res p o nse V al ues  
S o me of t he S F -3 6 v 2 ite ms will be re-c o de d s o t hat acr oss all q uesti o ns, a hi g her sc ore will i n dicate 
a better h ealt h state. Q uesti o ns 2, 3a -3j, 4a -4 d, 5a -5 c, 9 b, 9c, 9f, 9 g, 9i, 1 0, 1 1a, 1 1c will be sc ore d 
as rec or de d; t he ot her q uesti o ns will ha ve t he sc ores tra nsf or me d as s h o w n i n  Ta ble 2 1 . If m ulti ple 
a ns wers are gi ve n t o t he sa me ite m, t he n t he ite m sc ore will be left as missi n g. 
T a ble 2 1  
S F -3 6 –  R ec o di n g  
 Q u e sti o n  
Ori gi n al c o d e a n d r e -c o d e r e s p o n s e  
Q u e sti o n n u m b er: 1  
    Ori gi n al r e s p o n s e  
1  
2  
3  
4  
5  
 
    R e -c o d e d r e s p o n s e  
5  
4. 4  
3. 4  
2  
1  
 
Q u e sti o n s n u m b er s:  6, 1 1 b, 1 1 d  
    Ori gi n al r e s p o n s e  
1  
2  
3  
4  
5  
 
    R e -c o d e d r e s p o n s e  
5  
4  
3  
2  
1  
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 3 9 /1 5 9  
 
 
 
 Q u e sti o n  
Ori gi n al c o d e a n d r e -c o d e r e s p o n s e  
Q u e sti o n n u m b er:  7  
    Ori gi n al r e s p o n s e  
1  
2  
3  
4  
5  
6  
    R e -c o d e d r e s p o n s e  
6  
5. 4  
4. 2  
3. 1  
2. 2  
1  
Q u e sti o n n u m b er:  8 (if q u e sti o n n u m b er 7 i s a n s w er e d)  
    Ori gi n al r e s p o n s e t o # 8  
1  
1  
2  
3  
4  
5  
    Ori gi n al r e s p o n s e t o # 7  
1  
2 -6  
1 -6  
1 -6  
1 -6  
1 -6  
    R e -c o d e d r e s p o n s e  
6  
5  
4  
3  
2  
1  
Q u e sti o n n u m b er:  8 (if q u e sti o n n u m b er 7 i s N O T a n s w er e d)  
    Ori gi n al r e s p o n s e  
1  
2  
3  
4  
5  
 
    R e -c o d e d r e s p o n s e  
6  
4. 7 5  
3. 5  
2. 2 5  
1  
 
Q u e sti o n s n u m b er:  9 a, 9 d, 9 e, 9 h  
    Ori gi n al r e s p o n s e  
1  
2  
3  
4  
5  
 
    R e -c o d e d r e s p o n s e  
5  
4  
3  
2  
1  
 
Ste p 2: Deter mi ni n g He alt h D o m ai n Sc ale Sc ores ( 0 -1 0 0 Sc ores)  
After ite m rec o di n g, a t otal ra w sc ore is c o m p ute d f or eac h h ealt h d o mai n scale. T he t otal ra w 
sc ore is t he si m ple al ge braic s u m of t he fi nal res p o nse val ues f or all ite ms i n a gi ve n scale, as 
s h o w n i n Ta ble 2 2 . T he t otal ra w sc ore f or eac h s cale is tra nsf or me d t o a 0-1 0 0 scale sc ore usi n g 
t he f oll o wi n g f or m ula: 
 
𝐷𝑢𝑟𝑎𝑡 𝑖𝑜𝑛 𝑜𝑓𝐸𝑣𝑜= 1 0 0  ×  (R a w  sc or e –  L o w est  p ossi bl e  r a w sc or e)
P ossi bl e  r a w sc or e r a n g e
 
T a ble 2 2  
S F -3 6 –  V al ues use d i n T r a nsf or mi n g S F-3 6 v 2 He alt h S ur ve y He alt h 
D o m ai n Sc ale T ot al R a w Sc ores o n t he 0 -1 0 0 Sc ale   
S c al e  
S u m of Fi n al R e s p o n s e V al u e s  
L o w e st a n d hi g h e st 
p o s si bl e t ot al r a w 
s c or e s  
P o s si bl e t ot al r a w 
s c or e r a n g e  
P F  
3 a + 3 b + 3 c + 3 d + 3 e + 3f + 3 g + 3 h + 3i + 3j  
1 0, 3 0  
2 0  
R P  
4 a + 4 b + 4 c + 4 d  
4, 2 0  
1 6  
B P  
7 + 8  
2, 1 2  
1 0  
G H  
1 + 1 1 a + 1 1 b + 1 1 c + 1 1 d  
5, 2 5  
2 0  
V T  
9 a + 9 e + 9 g + 9i  
4, 2 0  
1 6  
S F  
6 + 1 0  
2, 1 0  
8  
R E  
5 a + 5 b + 5 c  
3, 1 5  
1 2  
M H  
9 b + 9 c + 9 d + 9f + 9 h  
5, 2 5  
2 0  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 0 /1 5 9  
 
 
 
Ra w a n d tra nsf or me d scale sc ores are n ot cal c ulate d f or t h e Re p ort e d Healt h Tra nsiti o n ( H T) ite m.  
As rec o m me n de d b y t he de vel o pers of t he q uesti o n naire, missi n g ite m res p o nses will be treate d 
usi n g t he “ Half -s cale r ul e”, w hic h states t hat a s c ore ca n b e calc ulat e d if t he res p o n de nt a ns wers 
at least 5 0 % of t he ite ms i n a m ulti -ite m scale. I n s uc h cas es, t he missi n g ite m data will be re place d 
b y t he mea n of t he a ns were d ite ms of its scale. If m or e t ha n 5 0 % of t he ite ms are missi n g wit hi n a 
scale, t he scale sc ore will be missi n g. 
Ste p 3: C alc ul ati n g N or m alize d He alt h D o m ai n Sc ores  
T he n or malize d scale s c ores will t he n be calc ulate d usi n g t he f oll o wi n g f or m ulas:  
𝐷𝑢𝑟𝑎𝑡ℎ 𝑖𝑜𝑛𝑜𝑓𝐸 𝑣s c o r e =  (𝑜𝑏𝑟𝑢𝑡ℎ 𝑖𝑛𝑖𝑏𝑜𝑟0 −1 0 0  𝑇𝑒𝑟𝑖𝑓  –  𝑙)
𝑢⁄  
𝑛𝑜𝑚𝑖𝑑𝑒𝑑𝑎𝑡𝑒 𝑜𝑓𝑙𝑎𝑠ℎ 𝑡𝑑𝑜𝑠𝑒𝑑 𝑎𝑡𝑒𝑜𝑓= 5 0 + (𝑓𝑖𝑟𝑠𝑡ℎ 𝑑𝑜𝑠𝑒𝑑𝑎 𝑦s c o r e × 1 0 ) 
w here a a n d b are t he Mea n a n d Sta n dar d De viati o n of t he Healt h D o mai n scale i n t he 1 9 9 8 U. S. 
ge n eral p o p ula ti o n as s h o w n i n Ta ble 2 3 . 
T a ble 2 3  
S F -3 6 –  1 9 9 8 Ge ner al U S P o p ul ati o n Me a ns a n d St a n d ar d De vi ati o ns 
use d t o C alc ul ate N or m alize d He alt h D o m ai n Sc ores   
H e alt h D o m ai n S c al e s  
M e a n  
St a n d ar d D e vi ati o n  
P F  
8 3. 2 9 0 9 4  
2 3. 7 5 8 8 3  
R P  
8 2. 5 0 9 6 4  
2 5. 5 2 0 2 8  
B P  
7 1. 3 2 5 2 7  
2 3. 6 6 2 2 4  
G H  
7 0. 8 4 5 7 0  
2 0. 9 7 8 2 1  
V T  
5 8. 3 1 4 1 1  
2 0. 0 1 9 2 3  
S F  
8 4. 3 0 2 5 0  
2 2. 9 1 9 2 1  
R E  
8 7. 3 9 7 3 3  
2 1. 4 3 7 7 8  
M H  
7 4. 9 8 6 8 5  
1 7. 7 5 6 0 4  
T he a d va nta ges of t he n or malizati o n of t he 8 healt h d o mai n scales are t hat res ults f or o ne healt h 
d o mai n scale ca n be me a ni n gf ull y c o m pare d wit h t h ose fr o m t he ot her s cales a n d t hat d o mai n 
sc ores ha v e a direct i nter pretati o n i n relati o n t o t h e distri b uti o n of sc ores i n t he 1 9 9 8 U. S. ge neral 
p o p ulati o n.  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 1 /1 5 9  
 
 
 
Ste p 4: Sc ori n g t he P h ysic al a n d Me nt al C o m p o ne nt S u m m ar y Me as u res  
T he P C S a n d M C S meas ures are sc ore d usi n g a 3 -ste p pr oce d ure:  
1.  First, t he 8 healt h d o mai n scale sc ores are sta n dar dize d usi n g mea ns a n d st a n dar ds d e viati o ns 
fr o m t he 1 9 9 8 U. S. ge neral p o p ulati o n (see Ta bl e 2 3 ).  
 
2.  Se c o n d, t hese Z -sc ores are a g gre gat e d usi n g wei g hts (fact or sc ore c o effici e nt) fr o m t he 1 9 9 0 
U. S ge n eral p o p ulati o n.  
 
3.  T hir d, a g gre gate P C S a n d M C S sc ores are sta n dar dize d b y m ulti pl yi n g t he sta n dar dize d scale 
b y 1 0 a n d a d di n g 5 0.  
U. S. ge n eral p o p ul ati o n st atistics use d i n t he sta n dar dizati o n a n d i n t he a g gre gati o n of S F -3 6 v 2 
Healt h S ur ve y healt h d o mai n scale sc ores are prese nte d i n  Ta ble 2 4 . 
T a ble 2 4  
S F -3 6 –  F act or Sc ore C oefficie nts use d t o C alc ul ate P C S a n d 
M C S 
Sc ores f or t he S F -3 6 v 2   
 
S u m m ar y c o m p o n e nt m e a s ur e f a ct or s c or e c o effi ci e nt s  
S c al e s  
P C S  
M C S  
P F  
0. 4 2 4 0 2  
-0. 2 2 9 9 9  
R P  
0. 3 5 1 1 9  
-0. 1 2 3 2 9  
B P  
0. 3 1 7 5 4  
-0. 0 9 7 3 1  
G H  
0. 2 4 9 5 4  
-0. 0 1 5 7 1  
V T  
0. 0 2 8 8 7 7  
0. 2 3 5 3 4  
S F  
-0. 0 0 7 5 3  
0. 2 6 8 7 6  
R E  
-0. 1 9 2 0 6  
0. 4 3 4 0 7  
M H  
-0. 2 2 0 6 9  
0. 4 8 5 8 1  
E x a m ple:  
Let’s c o nsi der t he f oll o wi n g a ns w ers fr o m a partici pa nt :  
T a ble 2 5  
S F -3 6 –  N u meric al E x a m ple –  R a w D at a   
#  
It e m d e s cri pti o n 
A n s w er  
1  
I n g e n er al, w o ul d y o u s a y y o ur h e alt h i s: 
1 –  E x c ell e nt  
2  
C o m p ar e d t o o n e y e ar a g o, h o w w o ul d y o u r at e y o ur h e alt h i n g e n er al n o w ?  
2 –  S o m e w h at b ett er 
n o w t h a n o n e y e ar a g o  
3  
Vi g or o u s a cti viti e s, s u c h a s r u n ni n g, lifti n g h e a v y o bj e ct s, p arti ci p ati n g i n 
str e n u o u s s p ort s  
2 –  Y e s, li mit e d a littl e  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 2 /1 5 9  
 
 
 
#  
It e m d e s cri pti o n 
A n s w er  
4  
M o d er at e a cti viti e s, s u c h a s m o vi n g  a t a bl e, p u s hi n g a v a c u u m cl e a n er, 
b o wli n g, or pl a yi n g g olf  
2 –  Y e s, li mit e d a littl e  
5  
Lifti n g or c arr yi n g gr o c eri e s  
2 –  Y e s, li mit e d a littl e  
6  
Cli m bi n g s e v er al fli g ht s of st air s  
2 –  Y e s, li mit e d a littl e  
7  
Cli m bi n g o n e fli g ht of st air s  
2 –  Y e s, li mit e d a littl e 
8  
B e n di n g, k n e eli n g or st o o pi n g  
1 –  Y e s, li mit e d a l ot  
9  
W al ki n g m or e t h a n a mil e  
2 –  Y e s, li mit e d a littl e  
1 0  
W al ki n g s e v er al h u n dr e d y ar d s  
2 –  Y e s, li mit e d a littl e  
1 1  
W al ki n g o n e h u n dr e d y ar d s  
2 –  Y e s, li mit e d a littl e  
1 2  
B at hi n g or dr e s si n g y o ur s elf  
2 –  Y e s, li mit e d a littl e  
1 3  
C ut d o w n o n t h e a m o u nt of ti m e y o u s p e nt o n w or k or ot h er a cti viti e s  
2 –  M o st of t h e ti m e  
1 4  
A c c o m pli s h e d l e s s t h a n y o u w o ul d li k e  
3 –  S o m e of t h e ti m e  
1 5  
W er e li mit e d i n t h e ki n d of w or k or ot h er a cti viti e s  
2 –  M o st of t h e ti m e  
1 6  
H a d diffi c ult y p erf or mi n g t h e w or k or ot h er a cti viti e s (f or e x a m pl e, it t o o k e xtr a 
eff ort)  
3 –  S o m e of t h e ti m e  
1 7  
C ut d o w n o n t h e a m o u nt of ti m e y o u s p e nt o n w or k or ot h er a cti viti e s  
2 –  M o st of t h e ti m e  
1 8  
A c c o m pli s h e d l e s s t h a n y o u w o ul d li k e  
3 –  S o m e of t h e ti m e  
1 9  
D o n’t d o w or k or ot h er a cti viti e s a s c ar ef ull y a s u s u al  
2 –  M o st of t h e ti m e  
2 0  
D uri n g t h e p a st 4 w e e k s, t o w h at e xt e nt h a s y o ur p h y si c al h e alt h or e m oti o n al 
pr o bl e m s i nt erf er e d wit h y o ur n or m al s o ci al a cti viti e s wit h f a mil y, fri e n d s, 
n ei g h b o ur s, or gr o u p s ?  
2 –  Sli g htl y  
2 1  
H o w m u c h b o dil y p ai n h a v e y o u h a d d uri n g t h e p a st 4 w e e k s ?  
3 –  Mil d  
2 2  
D uri n g t h e p a st 4 w e e k s, h o w m u c h di d p ai n i nt erf er e wit h y o ur n or m al w or k 
(i n cl u di n g b ot h w or k o ut si d e t h e h o m e a n d h o u s e w or k) ?  
2 –  A littl e bit  
2 3  
Di d y o u f e el f ull of lif e ?  
4 –  A littl e of t h e ti m e  
2 4  
H a v e y o u b e e n a v er y n er v o u s p er s o n ?  
3 –  S o m e of t h e ti m e  
2 5  
H a v e y o u f elt s o d o w n i n t h e d u m p s t h at n ot hi n g c o ul d c h e er y o u u p ?  
2 –  M o st of t h e  ti m e 
2 6  
H a v e y o u f elt c al m a n d p e a c ef ul ?  
4 –  A littl e of t h e ti m e  
2 7  
Di d y o u h a v e a l ot of e n er g y ?  
3 –  S o m e of t h e ti m e  
2 8  
H a v e y o u f elt d o w n h e art e d a n d l o w ?  
2 –  M o st of t h e ti m e  
2 9  
Di d y o u f e el w or n o ut ?  
4 –  A littl e of t h e ti m e  
3 0  
H a v e y o u b e e n a h a p p y p er s o n ?  
3 –  S o m e of t h e ti m e  
3 1  
Di d y o u f e el tir e d ?  
2 –  M o st of t h e ti m e  
3 2  
D uri n g t h e p a st 4 w e e k s, h o w m u c h of t h e ti m e h a s y o ur p h y si c al h e alt h or 
e m oti o n al pr o bl e m s i nt erf er e d wit h y o ur s o ci al a cti viti e s (li k e vi siti n g wit h 
fri e n d s, r el ati v e s, et c.) ?  
4 –  A littl e of t h e ti m e  
3 3  
I s e e m t o g et ill m or e e a sil y t h a n ot h er p e o pl e 
3 –  D o n’t k n o w  
3 4  
I a m a s h e alt h y a s a n y b o d y I k n o w 
2 –  M o stl y tr u e  
3 5  
I e x p e ct m y h e alt h t o g et w or s e 
3 –  D o n’t k n o w  
3 6  
M y h e alt h i s e x c ell e nt  
2 –  M o stl y tr u e  
After ha vi n g rec o d e d t he a ns wers, t he 8 d o m ai n sc ores are e q ual t o:  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 3 /1 5 9  
 
 
 
T a ble 2 6  
S F -3 6 –  N u meric al E x a m ple –  D o m ai n Sc ores   
 
R a w 
S c or e  
R a w S c or e 0 -1 0 0  
H e alt h D o m ai n Z -S c or e  
N or m ali z e d H e alt h 
D o m ai n Z -S c or e  
P F  
1 9  
1 0 0 x ( 1 9 -1 0) / 2 0 = 4 5  
4 5 - 8 3. 2 9 0 9 4 / 2 3. 7 5 8 8 3 = -1. 6 1  
-1. 6 1 x 1 0 + 5 0 = 3 3. 9  
R P  
1 0  
1 0 0 x ( 1 0-4) / 1 6 = 3 7. 5  
3 7. 5 - 8 2. 5 0 9 6 4 / 2 5. 5 2 0 2 8 = -1. 7 6  
-1. 7 6 x 1 0 + 5 0 = 3 2. 4  
B P  
8. 2  
1 0 0 x ( 8. 2-2) / 1 0 = 6 2  
6 2 - 7 1. 3 2 5 2 7 / 2 3. 6 6 2 2 4 = -0. 3 9  
-0. 3 9 x 1 0 + 5 0 = 4 6. 1  
G H  
1 9  
1 0 0 x ( 1 9-5) / 2 0 = 7 0  
7 0 - 7 0. 8 4 5 7 0 / 2 0. 9 7 8 2 1 = -0. 0 4  
-0. 0 4 x 1 0 + 5 0 = 4 9. 6  
V T  
1 1  
1 0 0 x ( 1 1-4) / 1 6 = 4 3. 7 5  
4 3. 7 5 - 5 8. 3 1 4 1 1 / 2 0. 0 1 9 2 3 = -0. 7 3  
-0. 7 3 x 1 0 + 5 0 = 4 2. 7  
S F  
8  
1 0 0 x ( 8-2) / 8 = 7 5  
7 5  - 8 4. 3 0 2 5 0 / 2 2. 9 1 9 2 1 = -0. 4 1  
-0. 4 1 x 1 0 + 5 0 = 4 5. 9  
R E  
7  
1 0 0 x ( 7-3) / 1 5 = 2 7  
2 7 - 8 7. 3 9 7 3 3 / 2 1. 4 3 7 7 8 = -2. 8 2  
-2. 8 2 x 1 0 + 5 0 = 2 1. 8  
M H  
1 2  
1 0 0 x ( 1 2-5) / 2 0 = 3 5  
3 5 - 7 4. 9 8 6 8 5 / 1 7. 7 5 6 0 4 = -2. 2 5  
-2. 2 5 x 1 0 + 5 0 = 2 7. 5  
Fi nall y, P C S a n d M C S are pr o vi de d bel o w usi n g T a ble 2 4 :  
•  P C S = -1. 6 1 x 0. 4 2 4 0 2 + … + -2. 2 5 x -0. 2 2 0 6 9 = -0. 4 1  
•  N or malize d P C S = 1 0 x P C S + 5 0 = 4 5. 9  
•  M C S =  -1. 6 1 x -0. 2 2 9 9 9 + … + -2. 2 5 x 0. 4 8 5 8 1 = -2. 6 2  
•  N or malize d M C S = 1 0 x M C S + 5 0 = 2 3. 8  
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


Evobrutinib
EVOLUTION RMS 1
MS200527_0080
20 November 2023/ Version 8.0
C O N F I D E N T I A L
I N F O R M A T I O N
144/159
18.3
EQ-5D-5L
The EQ-5D questionnaire comprises 5 questions (items) relating to current problems in the 
dimensions mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. 
Responses in each dimension are divided into 5 ordinal levels coded: (1) no problems, (2) slight 
problems, (3) moderate problems, (4) severe problems, (5) extreme problems. This part, called the 
EQ-5D descriptive system, provides a 5-dimensional description of health status. 
A unique health state is defined by combining one level from each of the 5 dimensions. A total of 
3125 possible health states is defined in this way. Each state is referred to in terms of a 5-digits 
code. For example, state 11111 indicates no problems on any of the 5 dimensions, while state 
12345 indicates no problems with mobility, slight problems with self-care, moderate problems 
with doing usual activities, severe pain or discomfort, and extreme anxiety or depression.
The EQ-5D-5L descriptive system is followed by a VAS (EQ VAS), similar to a thermometer, 
ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The EQ VAS 
records the respondent’s self-rated valuation of health state, i.e. a value which is based on the 
respondent's preferences (EQ VAS score).
Based on the EQ-5D-5L, the numeric EQ-5D-5L index can be derived, using validated translations 
provided by EuroQoL presented in the following XLS file. The EQ-5D-5L index is frequently 
used in economic evaluations: it represents societal preference values for the full set of EQ-5D-5L 
health states with the best state (perfect health) and “death” being assigned values of 1 and 0, 
respectively.
The United Kingdom value set of this questionnaire will be used for all participants regardless of 
their country.
EQ-5D-5L_Crosswalk_
Index_Value_Calculato
Example: 
Let’s consider a French participant who answered the questionnaire according to Table 27.
Table 27
EQ-5D-5L – Example
Item #
Description
Answer
1
MOBILITY
1 – I have no problems in walking about
2
SELF-CARE
3 – I have moderate problems washing or dressing 
myself
3
USUAL ACTIVITIES
4 – I have severe problems doing my usual activities
4
PAIN / DISCOMFORT
2 – I have slight pain or discomfort
5
ANXIETY / DEPRESSION
2 – I am slightly anxious or depressed
The health state is then defined as 13422, and the Index value as 0.403.
Global Version ID: 78691_1358828_6645561
PPD
PPD


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 5 /1 5 9  
 
 
 
1 8. 4  
A n al ysis Visit  Wi n d o ws   
See Secti o n  9. 5  f or t he d efi niti o n of st u d y d a y 1, w hic h is use d t o deter mi ne t he a n al ysis visit da y 
i n t he ta bles bel o w. 
T a ble 2 8  
A n al ysis visit wi n d o ws f or  Ne ur ol o gic al E v al u ati o n  E D S S , T 2 5-F W, 9 -
H P T, S D M T , 
C-S S R S , P R O MI S, 
E Q -5 D -5 L a n d 
H R U t hr o u g h 
Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 1 2  
8 5  
[ 2, 1 2 7 ) 
W e e k 2 4  
1 6 9  
[1 2 7 , 2 1 1 ) 
W e e k 3 6  
2 5 3  
[2 1 1 , 29 5 ) 
W e e k 4 8  
3 3 7  
[ 29 5, 3 7 9 ) 
W e e k 6 0  
4 2 1  
[ 37 9 , 46 3 ) 
W e e k 7 2  
5 0 5  
[ 46 3 , 54 7 )  
W e e k 8 4  
5 8 9  
[ 54 7 , 6 3 1 ) 
W e e k 9 6  
6 7 3  
[6 3 1 , 7 1 5 ) 
W e e k 1 0 8  
7 5 7  
[ 7 1 5, 7 9 9 ) 
W e e k 1 2 0  
8 4 1  
[ 7 9 9, 8 8 3) 
W e e k 1 3 2  
9 2 5  
[ 8 8 3, 9 6 7) 
W e e k 1 4 4  
1 0 0 9  
[ 9 6 7, 1 0 5 1) 
W e e k 1 5 6  
1 0 9 3  
[ 1 0 5 1, 1 1 0 0) 
T a ble 2 9  
A n al ysis visit wi n d o ws f or Vit al Si g ns a n d Wei g ht t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 1 2  
8 5  
[ 2, 1 2 7) 
W e e k 2 4  
1 6 9  
[ 1 2 7, 2 1 1) 
W e e k 3 6  
2 5 3  
[ 2 1 1, 2 9 5) 
W e e k 4 8  
3 3 7  
[ 2 9 5, 3 7 9) 
W e e k 6 0  
4 2 1  
[ 3 7 9, 4 6 3) 
W e e k 7 2  
5 0 5  
[ 4 6 3, 5 4 7)  
W e e k 8 4  
5 8 9  
[ 5 4 7, 6 3 1) 
W e e k 9 6  
6 7 3  
[ 6 3 1, 8 8 3 ) 
W e e k 1 5 6  
1 0 9 3  
[ 8 8 3, 1 1 0 0) 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 6 /1 5 9  
 
 
 
T a ble 3 0  
A n al ysis visit wi n d o ws f or M RI t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
S cr e e ni n g/ B a s eli n e  
-2 8 t o 1  
≤1  
W e e k 2 4  
1 6 9  
[ 2, 2 5 3 ) 
W e e k 4 8  
3 3 7  
[2 5 3 , 5 0 5 ) 
W e e k 9 6  
6 7 3  
[5 0 5 , 8 8 3 ) 
W e e k 1 5 6  
1 0 9 3  
[ 8 8 3, 1 1 0 0) 
T a ble 3 1  
A n al ysis visit wi n d o ws f or S F -3 6 v 2 t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 2 4  
1 6 9  
[ 2, 2 5 3) 
W e e k 4 8  
3 3 7  
[ 2 5 3, 4 2 1) 
W e e k 7 2  
5 0 5  
[ 4 2 1, 5 8 9) 
W e e k 9 6  
6 7 3  
[ 5 8 9,7 5 7 ) 
W e e k 1 2 0  
8 4 1  
[ 7 5 7, 9 2 5) 
W e e k 1 4 4  
1 0 0 9  
[ 9 2 5, 1 0 5 1) 
W e e k 1 5 6  
1 0 9 3  
[ 1 0 5 1, 1 1 0 0) 
T a ble 3 2  
A n al ysis visit wi n d o ws f or 1 2 -le a d E C G t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
[ 1, d o s e ti m e) 
D a y 1 P o st d o s e  
1  
[ d o s e ti m e, 1] 
W e e k 4  
2 9  
[ 2, 1 4 9 ) 
W e e k 2 4  
2 6 9  
[1 4 9 , 47 1)  
W e e k 9 6  
6 7 3  
[4 7 1 , 8 8 3 ) 
W e e k 1 5 6  
1 0 9 3  
[ 8 8 3, 1 1 0 0) 
T a ble 3 3  
A n al ysis visit 
wi n d o ws f or 
Bi oc he mistr y 
(e xce pt tests n ote d as 
S u p ple me nt L F Ts) a n d He m at ol o g y  t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 1 2  
8 5  
[ 2, 1 2 7) 
W e e k 2 4  
1 6 9  
[ 1 2 7, 2 5 3) 
W e e k 4 8  
3 3 7  
[ 2 5 3, 4 2 1)  
W e e k 7 2  
5 0 5  
[ 4 2 1, 5 8 9)  
W e e k 9 6  
6 7 3  
[ 5 8 9, 7 1 5) 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 7 /1 5 9  
 
 
 
W e e k 1 0 8  
7 5 7  
[ 7 1 5, 8 4 1 ) 
W e e k 1 3 2  
9 2 5  
[ 8 4 1, 1 0 0 9) 
W e e k 1 5 6  
1 0 9 3  
[ 1 0 0 9, 1 1 0 0) 
T a ble 3 4  
A n al ysis visit wi n d o ws f or Bi oc he mist r y tests n ote d as S u p ple me nt L F Ts 
t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 2  
1 5  
[ 2, 2 2 ) 
W e e k 4  
2 9  
[2 2 , 36 ) 
W e e k 6  
4 3  
[ 36 , 5 0 ) 
W e e k 8  
5 7  
[5 0 , 6 4 )  
W e e k 1 0  
7 1  
[6 4 , 7 8 ) 
W e e k 1 2  
8 5  
[ 7 8, 9 2) 
W e e k 1 4  
9 9  
[ 9 2, 1 0 6) 
W e e k 1 6  
1 1 3  
[ 1 0 6, 1 2 0) 
W e e k 1 8  
1 2 7  
[ 1 2 0, 1 3 4) 
W e e k 2 0  
1 4 1  
[ 1 3 4, 1 4 8) 
W e e k 2 2  
1 5 5  
[ 1 4 8, 1 6 2) 
W e e k 2 4  
1 6 9  
[ 1 6 2, 1 8 3)  
W e e k 2 8  
1 9 7  
[ 1 8 3, 2 1 1) 
W e e k 3 2  
2 2 5  
[ 2 1 1, 2 3 9) 
W e e k 3 6  
2 5 3  
[ 2 3 9, 2 6 7) 
W e e k 4 0  
2 8 1  
[ 2 6 7, 2 9 5) 
W e e k 4 4  
3 0 9  
[ 2 9 5, 3 2 3) 
W e e k 4 8  
3 3 7  
[ 3 2 3, 3 7 9) 
W e e k 6 0  
4 2 1  
[ 3 7 9, 4 6 3) 
W e e k 7 2  
5 0 5  
[ 4 6 3, 5 4 7) 
W e e k 8 4  
5 8 9  
[ 5 4 7, 6 3 1) 
W e e k 9 6  
6 7 3  
[ 6 3 1, 7 1 5) 
W e e k 1 0 8  
7 5 7  
[ 7 1 5, 7 9 9 ) 
W e e k 1 2 0  
8 4 1  
[ 7 9 9, 8 8 3) 
W e e k 1 3 2  
9 2 5  
[ 8 8 3, 9 6 7) 
W e e k 1 4 4  
1 0 0 9  
[ 9 6 7, 1 0 5 1)  
W e e k 1 5 6  
1 0 9 3  
[ 1 0 5 1, 1 1 0 0) 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 8 /1 5 9  
 
 
 
T a ble 3 5  
A n al ysis visit wi n d o ws f or Uri n al ysis t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi si t wi n d o w ( d a y s) 
B a s eli n e  
1  
≤1  
W e e k 2 4  
1 6 9  
[ 2, 2 5 3) 
W e e k 4 8  
3 3 7  
[ 2 5 3, 4 2 1) 
W e e k 7 2  
5 0 5  
[ 4 2 1, 5 8 9)  
W e e k 9 6  
6 7 3  
[ 5 8 9, 8 8 3 ) 
W e e k 1 5 6  
1 0 9 3  
[ 8 8 3, 1 1 0 0) 
T a ble 3 6  
A n al ysis visit wi n d o ws f or Bi o m ar kers (i ncl u di n g Nf L  a n d I g le vels ) 
t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 1 2  
8 5  
[ 2, 1 2 7) 
W e e k 2 4  
1 6 9  
[ 1 2 7, 2 5 3) 
W e e k 4 8  
3 3 7  
[ 2 5 3, 4 2 1) 
W e e k 7 2  
5 0 5  
[ 4 2 1, 5 8 9)  
W e e k 9 6  
6 7 3  
[ 5 8 9, 7 5 7) 
W e e k 1 2 0  
8 4 1  
[ 7 5 7, 9 2 5) 
W e e k 1 4 4  
1 0 0 9  
[ 9 2 5, 1 0 5 1) 
W e e k 1 5 6  
1 0 9 3  
[ 1 0 5 1, 1 1 0 0) 
T a ble 3 7  
A n al ysis visit wi n d o ws f or P D/ Bi o m a r kers me as ure d as p art of t he P D 
s u bst u d y ( B T K O, cell ul ar f u ncti o n a n d c yt o ki nes) t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 2  
1 5  
[ 2, 2 2 ) 
W e e k 4  
2 9  
[2 2 , 4 3 ) 
W e e k 8  
5 7  
[ 4 3, 7 1) 
W e e k 1 2  
8 5  
[ 7 1, 1 2 7) 
W e e k 2 4  
1 6 9  
[ 1 2 7, 1 7 2) 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 4 9 /1 5 9  
 
 
 
T a ble 3 8  
A n al ysis visit wi n d o ws f or H B V D N A t hr o u g h Wee k  1 5 6   
A n al y si s vi sit  
N o mi n al a n al y si s vi sit d a y  
A n al y si s vi sit wi n d o w ( d a y s)  
B a s eli n e  
1  
≤1  
W e e k 4  
2 9  
[ 2, 4 3) 
W e e k 8  
5 7  
[ 4 3, 7 1) 
W e e k 1 2  
8 5  
[7 1 , 1 2 7) 
W e e k 2 4  
1 6 9  
[ 1 2 7, 2 1 1 ) 
W e e k 3 6  
2 5 3  
[ 2 1 1, 2 9 5) 
W e e k 4 8  
3 3 7  
[2 9 5, 3 7 9 ) 
W e e k 6 0  
4 2 1  
[ 3 7 9, 4 6 3) 
W e e k 7 2  
5 0 5  
[ 46 3 , 5 4 7 )  
W e e k 8 4  
5 8 9  
[ 5 4 7, 6 3 1) 
W e e k 9 6  
6 7 3  
[6 3 1 , 7 5 7)  
W e e k 1 2 0  
8 4 1  
[ 7 5 7, 9 6 7 ) 
W e e k 1 5 6  
1 0 9 3  
[9 6 7 , 1 1 0 0)  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 0 /1 5 9  
 
 
 
1 8. 5  
Tier 1 A Es a n d A E SI s  
A refere n ce s prea ds heet c o ntai ni n g t he list of A E ter ms t o pr o gra m maticall y fla g p artici pa nt s wit h 
Tier 1 A Es a n d A E SI s will be  s hare d b y t he Safet y T ea m  a n d re g ul arl y u p date d  as p er M e d D R A 
versi o n u p date s. 
T he latest versi o n of t he file at ti me of a nal ysis will be use d.  
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 1 /1 5 9  
 
 
 
1 8. 6  
L a b or at or y P ar a meters t o be S u m m arize d i n t he T L Fs   
T a ble 3 9  
L a b or at or y P ar a meters t o be S u m m a rize d i n t he T L Fs   
 
N a m e s of Cli ni c al S af et y 
L a b or at or y E v al u ati o n s i n 
Pr ot o c ol  
If gr a d a bl e p ar a m et er, 
c orr e s p o n di n g e v al u ati o n 
n a m e s i n N CI -C T C A E 5 . 0 
W or st o n 
tr e at m e nt 
v al u e b a s e d 
o n n or m al 
r a n g e  
Bi o c h e mi str y  
Al b u mi n  
H y p o al b u mi n e mi a  
L O W  
A s p art at e a mi n otr a n sf er a s e  
A s p art at e a mi n otr a n sf er a s e 
i n cr e a s e d 
HI G H  
Al a ni n e a mi n otr a n sf er a s e  
Al a ni n e a mi n otr a n sf er a s e 
i n cr e a s e d 
HI G H  
Al k ali n e p h o s p h at a s e  
Al k ali n e p h o s p h at a s e i n cr e a s e d  
HI G H  
G a m m a -Gl ut a m yl -tr a n sf er a s e 
G G T i n cr e a s e d  
HI G H  
L a ct at e d e h y dr o g e n a s e  
Bl o o d l a ct at e d e h y dr o g e n a s e 
i n cr e a s e d 
HI G H  
Bilir u bi n (t ot al)  
Bl o o d bilir u bi n i n cr e a s e d  
HI G H  
Pr ot ei n (t ot al)  
 
L O W  
Cr e ati ni n e  
Cr e ati ni n e i n cr e a s e d  
HI G H  
e G F R  
C hr o ni c ki d n e y di s e a s e  
L O W  
A m yl a s e  
S er u m a m yl a s e i n cr e a s e d  
HI G H  
Li p a s e  
Li p a s e i n cr e a s e d  
HI G H  
Bl o o d ur e a nitr o g e n  
 
HI G H  
Gl u c o s e  
H y p o gl y c e mi a  
L O W  
S o di u m  
H y p er n atr e mi a  
HI G H  
S o di u m  
H y p o n atr e mi a  
L O W  
P ot a s si u m  
H y p er k al e mi a  
HI G H  
P ot a s si u m  
H y p o k al e mi a  
L O W  
C hl ori d e  
 
N A  
C al ci u m  
H y p er c al c e mi a * 
HI G H  
C al ci u m  
H y p o c al c e mi a * 
L O W  
M a g n e si u m  
H y p er m a g n e s e mi a  
HI G H  
M a g n e si u m  
H y p o m a g n e s e mi a  
L O W  
P h o s p h at e  
 
L O W  
T ot al C ar b o n Di o xi d e  
Bl o o d bi c ar b o n at e d e cr e a s e d  
L O W  
H e m at ol o g y  
H e m at o crit  
 
L O W/ HI G H  
H e m o gl o bi n  
H e m o gl o bi n i n cr e a s e d  
HI G H  
H e m o gl o bi n  
A n e mi a  
L O W  
M e a n c or p u s c ul ar v ol u m e ( M C V)  
 
N A  
M e a n c or p u s c ul ar h e m o gl o bi n  
( M C H) 
 
N A  
M e a n c or p u s c ul ar h e m o gl o bi n 
c o n c e ntr ati o n  ( M C H C) 
 
N A  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 2 /1 5 9  
 
 
 
 
N a m e s of Cli ni c al S af et y 
L a b or at or y E v al u ati o n s i n 
Pr ot o c ol  
If gr a d a bl e p ar a m et er, 
c orr e s p o n di n g e v al u ati o n 
n a m e s i n N CI -C T C A E 5 . 0 
W or st o n 
tr e at m e nt 
v al u e b a s e d 
o n n or m al 
r a n g e  
R e d bl o o d c ell c o u nt  
 
N A  
R eti c ul o c yt e c o u nt  
 
N A  
Pl at el et c o u nt  
Pl at el et c o u nt d e cr e a s e d  
L O W  
W hit e bl o o d c ell c o u nt  
L e u k o c yt o si s  
HI G H  
W hit e bl o o d c ell c o u nt  
W hit e bl o o d c ell d e cr e a s e d  
L O W  
W hit e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s: B a s o p hil s $  
 
N A  
W hit e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s: E o si n o p hil s $  
E o si n o p hili a  
HI G H  
W hit e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s: L y m p h o c yt e s $  
L y m p h o c yt e c o u nt i n cr e a s e d  
HI G H  
W hit e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s: L y m p h o c yt e s $  
L y m p h o c yt e c o u nt d e cr e a s e d  
L O W  
W hit e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s: M o n o c yt e s $  
 
N A  
W hit e bl o o d c ell diff er e nti al s a n d 
a b s ol ut e c o u nt s: N e utr o p hil s $  
N e utr o p hil c o u nt d e cr e a s e d  
L O W  
Uri n al y si s  
p H  
 
N A  
Nitrit e  
 
N A  
Pr ot ei n  
 
N A  
Bl o o d  
 
N A  
Gl u c o s e  
 
N A  
K et o n e s b o di e s  
 
N A  
Ur o bili n o g e n  
 
N A  
Bilir u bi n  
 
N A  
L e u k o c yt e e st er a s e b y di p sti c k  
 
N A  
S p e cifi c gr a vit y  
 
N A  
Mi cr o s c o pi c e x a mi n ati o n (if bl o o d 
or pr ot ei n i s a b n or m al)  
 
N A  
β h C G ( w o m e n o nl y)  
 
N A  
C o a g ul ati o n  
I nt er n ati o n al n or m ali z e d r ati o 
 
N A  
P arti al t hr o m b o pl a sti n ti m e  
 
N A  
R efl e x T e sti n g f or 
H B V D N A  
H B V D N A  P C R  
 
HI G H  
A nti n u cl e ar a nti b o d y, a nti s m o ot h 
m u s cl e a nti b o d y, a nti b o d y t o li v er 
ki d n e y mi cr o s o m e s  
 
N A  
Al k ali n e p h o s p h at a s e, Al b u mi n  
 
N A  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 3 /1 5 9  
 
 
 
 
N a m e s of Cli ni c al S af et y 
L a b or at or y E v al u ati o n s i n 
Pr ot o c ol  
If gr a d a bl e p ar a m et er, 
c orr e s p o n di n g e v al u ati o n 
n a m e s i n N CI -C T C A E 5 . 0 
W or st o n 
tr e at m e nt 
v al u e b a s e d 
o n n or m al 
r a n g e  
H e p ati c/ A ut oi m m u n e 
P a n el (t o b e 
p erf or m e d i n t h e 
e v e nt of el e v at e d 
L F T s ) 
A nti -H A V I g M, H B s A g, a nti -H B c, 
a nti - H B s A g, a nti -H C V, a nti -H E V 
I g G a n d I g M, a nti-V C A I g G a n d 
I g M, a nti-E A I g G, a nti -E B N A I g G, 
a nti -C M V I g G a n d I g M, E B V P C R, 
a n d C M V P C R  
 
N A  
F erriti n/ Tr a n sf erri n s at ur ati o n  
 
N A  
Fi bri n o g e n, E S R, h s C R P  
 
N A  
F o c u s e d G e n eti c T e sti n g  ( e. g Hi g h 
Ir o n F e) 
 
N A  
* C orr e ct e d c al ci u m ( m m ol/ L) t o b e u s e d i n C T C A E gr a di n g d eri v e d a s ‘ m e a s ur e d t ot al c al ci u m ( m m ol/ L) + 0. 0 2 
( 4 0 –  s er u m al b u mi n [ g/ L]’ . 
$  F or W B C diff er e nti al c o u nt s (t ot al n e utr o p hil [i n cl u di n g b a n d s], l y m p h o c yt e, m o n o c yt e, e o si n o p hil, a n d b a s o p hil 
c o u nt s), t h e a b s ol ut e v al u e will b e u s e d w h e n r e p ort e d.  W h e n o nl y p er c e nt a g e s ar e a v ail a bl e (t hi s i s m ai nl y 
i m p ort a nt f or n e utr o p hil s a n d l y m ph o c yt e s, b e c a u s e t h e C T C A E gr a di n g i s b a s e d o n t h e a b s ol ut e c o u nt s), t h e 
a b s ol ut e v al u e i s d eri v e d a s f oll o w s: D eri v e d diff er e nti al a b s ol ut e c o u nt = ( W B C c o u nt) * ( Diff er e nti al % v al u e / 
1 0 0).  
If t h e r a n g e f or t h e diff er e nti al a b s ol ut e c o u nt i s n ot a v ail a ble ( o nl y r a n g e f or v al u e i n % i s a v ail a bl e) t h e n Gr a d e 1 
will b e attri b ut e d t o a s f oll o w s:  
•  
L y m p h o c yt e c o u nt d e cr e a s e d:   
o  
d eri v e d a b s ol ut e c o u nt d o e s n ot m e et Gr a d e 2 -4 crit eri a, a n d  
o  
% v al u e < % L L N v al u e, a n d  
o  
d eri v e d a b s ol ut e c o u nt ≥ 8 0 0/ m m 3  
•  
N e utr o p hil c o u nt d e cr e a s e d : 
o  
d eri v e d a b s ol ut e c o u nt d o e s n ot m e et Gr a d e 2 -4 crit eri a, a n d  
o  
% v al u e < % L L N v al u e, a n d  
o  
d eri v e d a b s ol ut e c o u nt ≥ 1 5 0 0/ m m 3  
 
I n N CI-C T C A E v 5. 0 t he f oll o wi n g para meters are n ot gra da ble at Baseli ne  as gra di n g i m plies 
de pe n de n cies t o Bas eli ne  (e. g. A L T Gra de  1: > U L N - 3. 0 x U L N if Baseli n e  was n or mal; 1. 5 - 3. 0 
x Baseli ne  if Baseli ne  was a b n or mal):  
•  E osi n o p hilia (a d de d ter m, Gra de  1 d e pe n ds o n Bas eli ne ) 
•  Ala ni ne a mi n otra nsf eras e i ncrease d  
•  Al kali ne p h os p hatase i ncrease d  
•  As partate a mi n otra nsferase  i ncrease d 
•  Bl o o d t otal bilir u bi n i ncrease d  
•  Creati ni ne i ncrease d  
•  G G T i ncrease d  
•  I N R i ncreas e d ( de pe n de nt o n Baseli ne  als o i n v 4. 0 3)  
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 4 /1 5 9  
 
 
 
I n a d diti o n, i n v 5. 0 t he ter m ‘ H y per gl yce mi a’ d oes n ot de pe n d o n gl uc os e la b orat or y 
meas ure me nts a n y m or e a n d is t h us e x cl u de d fr o m la b orat or y a nal yses a n d part of A E re p orti n g 
o nl y.  
F or t h e ter m ‘ He m o gl o bi n i ncreas e d’ t he d e pe n de nc y t o Baseli ne  is re m o ve d i n v 5. 0. ‘I N R 
i ncreas e d’ is de pe n d e nt o n Baseli ne  v al ues a n d i nt a ke of a ntic o a g ula nts i n b ot h versi o ns.  
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 5 /1 5 9  
 
 
 
1 8. 7  
H a n dli n g of l a b or at or y res ults wit h m o difiers   
S o me la b orat or y para met ers res ults are prese nte d wit h m o difiers i n S D T M. L B ( < x x, > x x, < = x x, 
> = x x). I n or der e. g. t o us e t he m i n s u m mar y st atistics o ut p uts, la b orat or y m o difiers will be ha n dle d 
as f oll o ws:  
•  W he n t he m o difier is e q ual t o “ <” t he d eri ve d l a b o rat or y val ue will be e q ual t o t he ori gi n al 
val ue mi n us a q ua ntit y. T he q ua ntit y will be e q ual t o:  
•  1 if t he ori gi n al val ue is a n i nte ger  
•  0. 1 if t he ori gi n al val ue h as o ne si g nifica nt di git after t he deci mal place  
•  0. 0 1 if t he ori gi n al val ue has 2  si g nifica nt di gits after t he deci mal place 
•  Etc …  
As t he deri ve d val u e m ust al wa ys b e p ositi ve, t here is a n e x ce pti o n f or ori gi nal val ues e q ual t o 1, 
0. 1, 0. 0 1, a n d s o o n. F or s uc h cases, t he q ua ntit y will be e q ual t o t he q ua ntit y defi ne d a b o ve di vi de d 
b y 1 0.  
E x a m ple s:  
1.  If t he ori gi nal val ue is e q ual t o “ < 1 5”, t he n t h e c orres p o n di n g n u meric v al ue f or s u m mar y 
statistics will be e q ual t o 1 4 
2.  If t he ori gi nal v al ue is e q ual t o “ < 0. 5 ”, t he n t he c orres p o n di n g n u m eric v al ue f or s u m mar y 
statistics will be e q ual t o 0. 4 
3.  If t he ori gi nal val u e is e q ual t o “ < 0. 0 0 1”, t h e n t he c orres p o n di n g n u meric val ue f or s u m mar y 
statistics will be e q ual t o 0. 0 0 0 9 
•  W he n t he m o difier is e q ual t o “ >” t he d eri ve d l a b orat or y val ue will be e q ual t o t he ori gi n al 
val ue pl us a q ua ntit y. T h e q ua ntit y will be  e q ual t o:  
•  1 if t he ori gi n al val ue is a n i nte ger  
•  0. 1 if t he ori gi n al val ue h as 1  si g nifica nt di git after t he deci mal place 
•  0. 0 1 if t he ori gi n al val ue has 2  si g nifica nt di gits after t he deci mal place 
•  Etc …  
E x a m ples :  
1.  If t he ori gi nal val ue is e q ual t o “ > 2 0”, t he n t h e c orres p o n di n g n u meric v al ue f or s u m mar y 
statistics will be e q ual t o 2 1 
2.  If t he ori gi nal v al ue is e q ual t o “ > 8. 5 ”, t he n t he c orres p o n di n g n u m eric v al ue f or s u m mar y 
statistics will be e q ual t o 8. 6 
3.  If t he ori gi nal val u e is e q ual t o “ > 1. 0 4 5”, t h e n t he c orres p o n di n g n u meric val ue f or s u m mar y 
statistics will be e q ual t o 1. 0 4 6 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 6 /1 5 9  
 
 
 
E xce pti o ns:  
1.  F or C yt o me gal o vir us I g M A nti b o d y, E pstei n -Barr Ca psi d I g M A nti b o d y, E pstei n -Barr Earl y 
D A nti ge n I g G A b, E pstei n -Barr N uclear A nti ge n 1 I g G A b, w he n t he val us is “ < y y” t he n 
c orres p o n di n g n u meric v al ue f or s u m mar y statisti cs will be e q ual t o “ y y/ 2”.  
2.  He patitis B Vir us D N A Q ua nt P C R  : If t h e ori gi nal v al ue is e q ual t o “ < 1 0 ”, t he n t he 
c orres p o n di n g n u meric val ue f or s u m mar y statistics will be e q ual t o 5 (f or ot her ori gi nal 
va l ues, t he ge neral r ule a b o ve a p plies) 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 7 /1 5 9  
 
 
 
1 8. 8  
M ulti plicit y Gr a p h   
 
A R R  =  A n n u ali z e d 
R el a p s e 
R at e, 
C D P  =  C o nfir m e d 
Di s a bilit y 
Pr o gr e s si o n, 
C F B  =  c h a n g e fr o m 
B a s eli n e, 
G d +  =  g a d oli ni u m p o siti v e, Nf L = N e ur ofil a m e nt Li g ht C h ai n, P R O MI S  =  P ati e nt R e p ort e d O ut c o m e s M e a s ur e m e nt 
I nf or m ati o n S y st e m, T 1 a n d T 2 =  t y p e of M a g n eti c R e s o n a n c e I m a g e, w k = W e e k.  
 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 8 /1 5 9  
 
 
 
1 8. 9  
St atistic al Met h o d ol o g y   
T he d oc u me nt d etaili n g statistical met h o d ol o g y a n d pr oce d ures is f o u n d i n ct p-ms 2 0 0 5 2 7 -0 0 8 0 -
-st at-met h o d -v 1 -0. d ocx . 
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


E v o br uti ni b  
E V O L U TI O N  R M S 1
M S 2 0 0 5 2 7 _ 0 0 8 0
2 0  N o ve m ber  2 0 2 3/ Versi o n 8 . 0 
 
 
C O N F I D E N T I A L  
I N F O R M A T I O N 
1 5 9 /1 5 9  
 
 
 
1 8. 1 0  
S A P f or I D M C/ S M C   
T he I D M C S A P is f o u n d i n  ct p-ms 2 0 0 5 2 7 -0 0 8 0 -
-sa p-i d mc-v 7 -0. d oc x.  
B R E E Z E l ocati o n:  
M S 2 0 0 5 2 7 _ 0 0 8 0 -Statistical A nal ysis Pla n -I D M C S A P V 7 . 0/ D oc u me nt I D: V V -C LI N -3 3 3 1 6 4  
M S 2 0 0 5 2 7 _ 0 0 8 0 -Statistical A nal ysis Pla n -I D M C S A P S hells V 7 . 0/ D oc u me nt I D: V V -C LI N -
3 3 3 1 6 5  
 
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D
P P D


Si g nat ure Pa ge f or V V- C LI N- 1 7 1 5 6 9 v 1 1. 0
Si g nat ure Pa ge f or V V- C LI N- 1 7 1 5 6 9 v 1 1. 0
A p pr o val Tas k
N o ncli nical
2 1- N o v- 2 0 2 3 1 5: 2 5: 0 6 G M T + 0 0 0 0
A p pr o val Tas k
Cli nical
2 1- N o v- 2 0 2 3 1 5: 4 4: 3 7 G M T + 0 0 0 0
Gl o bal Versi o n I D: 7 8 6 9 1 _ 1 3 5 8 8 2 8 _ 6 6 4 5 5 6 1
P P D
P P D