A Phase 2, Double-blind, Randomized, Placebo-controlled Study Assessing Efficacy and Safety of SAR441344, a CD40L-antagonist Monoclonal Antibody, in Participants With Relapsing Multiple Sclerosis
Phase: PHASE2
Conditions: Multiple Sclerosis
Sponsor: Sanofi

 
 
 
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According to Template: Sanofi OneDocument Version 4.0, dated 27-JUL-2020 
Page 1 
 
AMENDED CLINICAL TRIAL PROTOCOL 04 
Protocol title: 
A Phase 2, double-blind, randomized, placebo-
controlled study assessing efficacy and safety of 
SAR441344, a CD40L-antagonist monoclonal antibody, 
in participants with relapsing multiple sclerosis 
Protocol number: 
ACT16877 
Amendment number: 
04 
Compound number 
(INN/Trademark): 
SAR441344 
frexalimab  
Brief title: 
Proof-of-concept study for SAR441344 in relapsing 
multiple sclerosis 
LAMPETIA 
Study phase: 
Phase 2 
Sponsor name: 
Sanofi-Aventis Recherche & Développement 
Legal registered 
address:  
82 Avenue Raspail, 94250 Gentilly, FRANCE 
Manufacturer: Sanofi-Aventis Recherche 
& Développement 
Monitoring team’s 
representative name 
and contact information 
The study centers and the Investigators at each center 
are listed in a separate document 
Regulatory agency identifier number(s): 
IND: 
138742 
EU trial number: 
2024-513527-17 
NCT: 
NCT04879628 
WHO: 
U1111-1260-3962 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Pediatric investigational plan number: Not applicable 
 
 
 
Date: 
18-Nov-2024 
Total number of pages: 153 
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PROTOCOL AMENDMENT SUMMARY OF CHANGES  
DOCUMENT HISTORY 
 
Document 
Country/countries 
impacted by 
amendment 
Date, version 
Amended Clinical Trial Protocol 04 All 
18 November 2024, version 1 (electronic 4.0) 
Amended Clinical Trial Protocol 03 All 
16 November 2023, version 1 (electronic 3.0) 
Amended Clinical Trial Protocol 02 All 
21 February 2023, version 1 (electronic 2.0) 
Amended Clinical Trial Protocol 01 All 
20 May 2021, version 1 (electronic 1.0) 
Original protocol 
 
26 November 2020, version 1 (electronic 1.0) 
Amended protocol 04 (18 November 2024) 
This amended protocol 04 (amendment 04) is considered to be non-substantial based on 
the criteria set forth 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 
This amendment is subsequent to European Union (EU) clinical trials regulation (CTR) request to 
update the protocol in line with their requirements. The study intervention in the Part B extension 
is now clarified to be limited to 40 months, as requested by the Health Authority (HA). 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
Title page 
The Legal registered address updated. 
EU trial number was added. 
Change in new address. 
EU trial number was added. 
1.1 Synopsis 
6 Study intervention(s) and concomitant 
therapy 
6.1 Study intervention(s) administered 
6.1.3 Auxiliary medicinal product(s) 
6.7 Treatment of overdose 
6.8 Prior and Concomitant Therapy 
7.2 Participant discontinuation/ 
Withdrawal from the Study 
7.3 Lost to Follow Up 
8.3.4 Regulatory reporting requirements 
for SAEs and other safety reporting 
8.3.7 Adverse events of special interest 
8.3.9 Medication errors, or misuses of 
medicinal product 
Multiple sections updated to align the protocol with 
EU CTR requirements. 
To comply with EU CTR.  
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Section # and Name 
Description of Change 
Brief Rationale 
8.3.10 Guidelines for reporting product 
complains 
8.5.1 Deoxyribonucleic acid (DNA) 
8.5.2 Ribonucleic acid (RNA) 
8.6 Biomarkers 
8.7 Immunogenicity assessments 
8.9 Use of biological samples and data 
for future research 
10.1.1 Regulatory and ethical 
considerations 
10.1.4 Data protection  
10.1.6 Dissemination of clinical study 
data and results 
10.1.7 Data quality assurance 
10.2 Appendix 2: Clinical Laboratory 
tests 
10.3.1 Definition of AE 
10.3.2 Definition of SAE 
10.5 Appendix 5: Genetics 
10.7 Appendix 7 Country specific/region 
requirements 
10.7.1 Germany 
10.7.2 European Union: Safety reporting 
to the agency 
10.8 Appendix 8: Contingency measures 
for a regional or national emergency that 
is declared by a governmental agency 
10.11 Appendix 11: Collection, storage, 
and future use of data and human 
biological samples 
1.1 Synopsis 
4.1 Overall Design 
4.4 End of Study Definition  
Multiple sections updated to reflect the maximum 
Part B duration of 280 weeks (and not exceeding 
296 weeks.) 
To limit the extension of Part 
B to 40 months according to 
Health Authority request. 
1.1 Synopsis 
4.1 Overall Design 
The sentence “The participant must be followed-up 
for 24 weeks after the completion of common 
EOS.” was added to the “overall design” 
subsection. 
To provide better 
explanation regarding 
24-week follow up period. 
1.3.2 Schedule of activities for Part B 
The clarification “every 12 weeks” was added to 
the column “Early EOT (Follow up visits planned 
through EOS)”. 
Quartely safety visits instead 
of monthly. 
 
Phone calls to evaluate potential severe acute 
respiratory syndrome coronavirus 2 (SARS-CoV-2) 
infection was removed. 
Given the COVID-19 
pandemic evolution and 
previous experience with 
frexalimab. 
 
Assessment of immunoglobulin (Ig) levels moved 
under the Safety procedures. 
The assessments MSIS-29 and PROMIS-Fatigue-
MS-8 were updated. 
Clarification. 
 
To allow long term 
assessments. 
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Section # and Name 
Description of Change 
Brief Rationale 
The footnotes of the table were updated. 
2.3.1 Risk assessment 
Statement “There is no signal of increased risk of 
thromboembolism in frexalimab clinical program.” 
added to the Table 2. 
Clarification. 
3 Objectives and endpoints 
Additional timepoints added to exploratory 
endpoints in Table 4 (study Part B). 
To allow long-term 
assessment for these 
exploratory endpoints. 
8.3.7 Adverse events of special interest 
The title was renamed to “Adverse events of 
special interest”. 
 
Clarification. 
10.13 Appendix 13: Protocol 
amendment history 
The Section 10.13 is updated with subsection and 
Overall rationale and summary of changes for 
protocol amendment 03 is included in this section 
in the current amendment. 
To be aligned with 
the current amendment. 
Throughout 
Minor corrections, template update, clarification. 
Minor, therefore, have not 
been summarized. 
 
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TABLE OF CONTENTS 
AMENDED CLINICAL TRIAL PROTOCOL 04 .............................................................................................. 1 
PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................................................................... 2 
TABLE OF CONTENTS .................................................................................................................................. 5 
LIST OF TABLES ......................................................................................................................................... 11 
LIST OF FIGURES ........................................................................................................................................ 11 
1 
PROTOCOL SUMMARY ............................................................................................................... 12 
1.1 
SYNOPSIS ..................................................................................................................................... 12 
1.2 
SCHEMA ........................................................................................................................................ 18 
1.3 
SCHEDULE OF ACTIVITIES (SOA) .............................................................................................. 19 
1.3.1 
Schedule of activities for Part A ..................................................................................................... 19 
1.3.2 
Schedule of activities for Part B ..................................................................................................... 25 
1.3.3 
Schedule of activities for the initial 12 weeks of Part B2 ............................................................... 30 
2 
INTRODUCTION ............................................................................................................................ 31 
2.1 
STUDY RATIONALE...................................................................................................................... 31 
2.2 
BACKGROUND ............................................................................................................................. 32 
2.3 
BENEFIT/RISK ASSESSMENT ..................................................................................................... 36 
2.3.1 
Risk assessment ............................................................................................................................ 36 
2.3.2 
Benefit assessment ........................................................................................................................ 42 
2.3.3 
Overall benefit: risk conclusion ...................................................................................................... 42 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................. 44 
3.1 
APPROPRIATENESS OF MEASUREMENTS .............................................................................. 46 
4 
STUDY DESIGN ............................................................................................................................ 48 
4.1 
OVERALL DESIGN ........................................................................................................................ 48 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN ......................................................................... 49 
4.3 
JUSTIFICATION FOR DOSE ........................................................................................................ 50 
4.4 
END OF STUDY DEFINITION ....................................................................................................... 52 
5 
STUDY POPULATION .................................................................................................................. 53 
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5.1 
INCLUSION CRITERIA .................................................................................................................. 53 
5.2 
EXCLUSION CRITERIA  ............................................................................................................... 54 
5.3 
LIFESTYLE CONSIDERATIONS ................................................................................................... 58 
5.3.1 
Meals and dietary restrictions ........................................................................................................ 58 
5.3.2 
Caffeine, alcohol, and tobacco ....................................................................................................... 58 
5.3.3 
Activity ............................................................................................................................................ 59 
5.4 
SCREEN FAILURES...................................................................................................................... 59 
5.5 
CRITERIA FOR TEMPORARILY DELAYING RANDOMIZATION/ADMINISTRATION OF 
STUDY INTERVENTION ............................................................................................................... 59 
6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY ................................................... 60 
6.1 
STUDY INTERVENTION(S) ADMINISTERED .............................................................................. 61 
6.1.1 
Frexalimab ..................................................................................................................................... 63 
6.1.2 
Placebo .......................................................................................................................................... 64 
6.1.3 
Auxiliary medicinal product(s) ........................................................................................................ 64 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY....................................................... 64 
6.2.1 
Intravenous preparation and handlings.......................................................................................... 65 
6.2.2 
Subcutaneous preparation and handlings ..................................................................................... 65 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING ....................................... 66 
6.4 
STUDY INTERVENTION COMPLIANCE ...................................................................................... 67 
6.5 
DOSE MODIFICATION .................................................................................................................. 68 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY....................... 68 
6.7 
TREATMENT OF OVERDOSE ...................................................................................................... 68 
6.8 
PRIOR AND CONCOMITANT THERAPY ..................................................................................... 69 
6.8.1 
Prohibited medication..................................................................................................................... 69 
6.8.2 
Rescue medicine ............................................................................................................................ 69 
7 
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................................... 70 
7.1 
DISCONTINUATION OF STUDY INTERVENTION  ..................................................................... 70 
7.1.1 
Permanent discontinuation ............................................................................................................ 70 
7.1.2 
Liver chemistry stopping criteria .................................................................................................... 71 
7.1.3 
Temporary discontinuation ............................................................................................................. 71 
7.1.4 
Rechallenge ................................................................................................................................... 72 
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7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY .................................. 72 
7.3 
LOST TO FOLLOW UP ................................................................................................................. 73 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................... 74 
8.1 
EFFICACY ASSESSMENTS ......................................................................................................... 74 
8.1.1 
Magnetic resonance imaging assessments ................................................................................... 74 
8.1.2 
Multiple sclerosis relapse assessment ........................................................................................... 76 
8.1.2.1 
Definition of multiple sclerosis relapse ........................................................................................... 76 
8.1.2.2 
Unscheduled assessment visits ..................................................................................................... 76 
8.1.3 
Expanded disability status scale .................................................................................................... 77 
8.1.4 
Patient-reported outcome and health-related quality-of-life parameters ....................................... 77 
8.1.4.1 
Multiple sclerosis impact scale (MSIS)-29 ..................................................................................... 78 
8.1.4.2 
Patient reported outcome measurement information system (PROMIS)-Fatigue-MS-8 ............... 78 
8.1.4.3 
Patient’s qualitative assessment of treatment version 3 (PQATv3) ............................................... 78 
8.1.4.4 
Patient global impression of change and severity scale (PGIC-Fatigue and PGIS-Fatigue 
measures) ...................................................................................................................................... 78 
8.2 
SAFETY ASSESSMENTS  ............................................................................................................ 79 
8.2.1 
Physical examinations ................................................................................................................... 79 
8.2.2 
Vital signs ....................................................................................................................................... 79 
8.2.3 
Electrocardiograms ........................................................................................................................ 79 
8.2.4 
Clinical safety laboratory assessments .......................................................................................... 80 
8.2.5 
Local tolerability ............................................................................................................................. 80 
8.2.6 
Pregnancy testing .......................................................................................................................... 81 
8.2.7 
Suicidal ideation and behavior risk monitoring .............................................................................. 81 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING ................................................................................................................... 81 
8.3.1 
Time period and frequency for collecting AE and SAE information ............................................... 82 
8.3.2 
Method of detecting AEs and SAEs ............................................................................................... 82 
8.3.3 
Follow-up of AEs and SAEs ........................................................................................................... 82 
8.3.4 
Regulatory reporting requirements for SAEs and other safety reporting ....................................... 82 
8.3.5 
Pregnancy ...................................................................................................................................... 83 
8.3.6 
Disease-related events and/or disease-related outcomes not qualifying as AEs or SAEs ........... 84 
8.3.7 
Adverse events of special interest ................................................................................................. 84 
8.3.8 
Reporting of safety findings from magnetic resonance imaging .................................................... 85 
8.3.9 
Medication errors, or misuses of medicinal product ...................................................................... 85 
8.3.10 
Guidelines for reporting product complaints .................................................................................. 86 
8.4 
PHARMACOKINETICS .................................................................................................................. 86 
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8.5 
GENETICS AND PHARMACOGENOMICS .................................................................................. 86 
8.5.1 
Deoxyribonucleic acid (DNA) ......................................................................................................... 86 
8.5.2 
Ribonucleic acid (RNA) .................................................................................................................. 87 
8.6 
BIOMARKERS ............................................................................................................................... 88 
8.7 
IMMUNOGENICITY ASSESSMENTS ........................................................................................... 89 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS ................................................................................................................................. 89 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH ................................ 89 
9 
STATISTICAL CONSIDERATIONS .............................................................................................. 91 
9.1 
SAMPLE SIZE DETERMINATION ................................................................................................. 91 
9.2 
POPULATIONS FOR ANALYSES ................................................................................................. 92 
9.3 
STATISTICAL ANALYSES ............................................................................................................ 92 
9.3.1 
General considerations .................................................................................................................. 93 
9.3.2 
Primary endpoint (Part A) .............................................................................................................. 94 
9.3.3 
Secondary endpoint(s) ................................................................................................................... 96 
9.3.4 
Safety analysis ............................................................................................................................... 96 
9.3.4.1 
Adverse events .............................................................................................................................. 97 
9.3.4.2 
Laboratory variables, vital signs and electrocardiograms (ECGs) ................................................. 98 
9.3.5 
Tertiary/exploratory endpoint(s) ..................................................................................................... 99 
9.3.6 
Other analysis ................................................................................................................................ 99 
9.3.6.1 
Pharmacokinetics ........................................................................................................................... 99 
9.3.6.2 
Responder population identification and characterization with biomarker data (Part A) ............... 99 
9.3.6.3 
Other biomarkers ......................................................................................................................... 100 
9.4 
INTERIM ANALYSES  ................................................................................................................. 100 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................... 101 
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ..... 101 
10.1.1 
Regulatory and ethical considerations ......................................................................................... 101 
10.1.2 
Financial disclosure...................................................................................................................... 103 
10.1.3 
Informed consent process ............................................................................................................ 103 
10.1.4 
Data protection ............................................................................................................................. 104 
10.1.5 
Committees structure ................................................................................................................... 106 
10.1.6 
Dissemination of clinical study data and results .......................................................................... 106 
10.1.7 
Data quality assurance ................................................................................................................ 107 
10.1.8 
Source documents ....................................................................................................................... 108 
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10.1.9 
Study and site start and closure ................................................................................................... 108 
10.1.10 Publication policy ......................................................................................................................... 109 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS ....................................................................... 109 
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING ....................................................................... 111 
10.3.1 
Definition of AE ............................................................................................................................ 111 
10.3.2 
Definition of SAE .......................................................................................................................... 113 
10.3.3 
Recording and follow-up of AE and/or SAE ................................................................................. 114 
10.3.4 
Reporting of SAEs........................................................................................................................ 116 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE ................................................. 116 
10.4.1 
Definitions .................................................................................................................................... 116 
10.4.2 
Contraception guidance ............................................................................................................... 117 
10.5 
APPENDIX 5: GENETICS ........................................................................................................... 118 
10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-UP 
ASSESSMENTS  ......................................................................................................................... 119 
10.7 
APPENDIX 7: COUNTRY-SPECIFIC/REGION REQUIREMENTS ............................................. 126 
10.7.1 
Germany ...................................................................................................................................... 126 
10.7.2 
European Union: Safety reporting to the Agency ........................................................................ 126 
10.8 
APPENDIX 8: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY ................................. 126 
10.9 
APPENDIX 9: LOCAL TOLERABILITY........................................................................................ 127 
10.9.1 
Assessment of local injection site reaction .................................................................................. 127 
10.9.2 
Local tolerability questionnaire ..................................................................................................... 128 
10.10 
APPENDIX 10: PATIENT-REPORTED OUTCOME .................................................................... 129 
10.10.1 Multiple sclerosis impact scale (MSIS)-29 ................................................................................... 129 
10.10.2 Patient reported outcome measurement information system (PROMIS)-Fatigue-MS-8 ............. 131 
10.10.3 Patient’s qualitative assessment of treatment version 3 (PQATv3) ............................................. 132 
10.10.4 Patient global impression of change scale (PGIC-Fatigue) ......................................................... 135 
10.10.5 Patient global impression of severity scale (PGIS-Fatigue)......................................................... 136 
10.11 
APPENDIX 11: COLLECTION, STORAGE, AND FUTURE USE OF DATA AND HUMAN 
BIOLOGICAL SAMPLES ............................................................................................................. 137 
10.11.1 Compliance with Member State applicable rules for the collection, storage and future use 
of human biological samples (Article 7.1h) .................................................................................. 137 
10.11.2 Compliance with Member State applicable rules for the collection, storage and future use 
of (personal) data (article 7 (1 d) of EU Regulation 536/2014) .................................................... 137 
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10.12 
APPENDIX 12: LIST OF ABBREVIATIONS ................................................................................ 138 
10.13 
APPENDIX 13: PROTOCOL AMENDMENT HISTORY .............................................................. 139 
10.13.1 Amended protocol 03 (16 November 2023) ................................................................................. 139 
10.13.2 Amended protocol 02 (21 February 2023) ................................................................................... 142 
10.13.3 Amended protocol 01 (20 May 2021)........................................................................................... 146 
11 
REFERENCES ............................................................................................................................. 150 
 
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LIST OF TABLES  
Table 1 - Additional activities for the first 12 weeks of Part B2 (if not already planned in the Part B SOA) . 30 
Table 2 - Risk assessment ............................................................................................................................ 36 
Table 3 - Part A objectives and endpoints .................................................................................................... 44 
Table 4 - Part B objectives and endpoints .................................................................................................... 45 
Table 5 - Investigational medicinal product(s) administered ......................................................................... 61 
Table 6 - Arms and associated interventions ................................................................................................ 62 
Table 7 - IMP administration by visit 
 ....................................................... 63 
Table 8 - 
 ............................................. 63 
Table 9 - Populations for analyses ................................................................................................................ 92 
Table 10 - Primary endpoint analysis ............................................................................................................ 94 
Table 11 - Conclusion rules ........................................................................................................................... 94 
Table 12 - Key secondary endpoints analyses ............................................................................................. 96 
Table 13 - Safety analyses ............................................................................................................................ 98 
Table 14 - Protocol-required laboratory tests .............................................................................................. 110 
Table 15 - Clinical and MRI features suggestive of PML ............................................................................ 125 
Table 16 - Assessment of local injection site reactions ............................................................................... 127 
 
LIST OF FIGURES  
Figure 1 - Graphical study design ................................................................................................................. 18 
 
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1 
PROTOCOL SUMMARY  
1.1 
SYNOPSIS  
Protocol title:  
A Phase 2, double-blind, randomized, placebo-controlled study assessing efficacy and safety of 
SAR441344, a CD40L-antagonist monoclonal antibody, in participants with relapsing multiple 
sclerosis. 
Brief title: 
 
Proof-of-concept study for SAR441344 in relapsing multiple sclerosis 
 
Regulatory agency identifier number(s): 
IND: 
138742 
EU trial number 
2024-513527-17 
NCT: 
NCT04879628 
WHO: 
U1111-1260-3962 
EUDAMED: 
Not applicable 
Other: 
Not applicable 
Rationale: 
The goal of this Phase 2 study is to assess efficacy and safety of frexalimab, also know as 
SAR441344 in people with relapsing multiple sclerosis (RMS). Frexalimab is an antagonist 
monoclonal antibody (mAb) which binds to human cluster of differentiation 40 ligand (CD40L) 
and blocks the cluster of differentiation 40 (CD40)/CD40L signaling pathway. This pathway is 
critical for humoral immune response, as well as for proinflammatory cytokines secretion by 
macrophages and reciprocal costimulation between T lymphocytes (T-cells) and antigen 
presenting cells. As such, it is relevant to autoimmune diseases in which pathogenic B lymphocyte 
(B-cells) play a key role, such as multiple sclerosis (MS) (1). 
The proposed mechanism of action is that frexalimab should inhibit the formation of new active 
brain lesions in MS as measured by magnetic resonance imaging (MRI) and is expected to 
demonstrate efficacy by other clinical endpoints in longer trials to follow. This study will assess 
frexalimab efficacy by measuring changes in the number of gadolinium (Gd)-enhancing 
T1-hyperintense (GdE T1) lesions during treatment. This radiographic outcome has been 
established as a highly reliable predictive biomarker for clinical efficacy in pivotal studies in MS 
and has been demonstrated to be a predictive biomarker for clinical efficacy (reduction in 
annualized relapse rate [ARR]) in studies with other MS treatments (2, 3). 
Frexalimab efficacy relative to placebo will be assessed at Week 12 by evaluating inhibition of 
the formation of new active brain lesions (new GdE T1 lesions) as measured by MRI. The study 
will also characterize safety and tolerability of frexalimab in participants with RMS. 
The ACT16877 study will employ secondary MRI endpoints in an effort to collect supportive data 
on the potential benefit of frexalimab in neuroinflammation. 
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Exploratory assessments, such as analysis of neurofilament light chain (NfL) in plasma and 
advanced MRI methods, are expected to build evidence for frexalimab activity on 
neuroinflammation and neurodegeneration as well as potential effects on remyelination and tissue 
preservation.  
Additional exploratory biomarkers will be assessed with the aim of:  
1. Characterizing activation of the CD40/CD40L signaling pathway by analysis of 
the mRNA “signature” (levels of expression of genes) in whole blood or in subsets of 
PBMC in order to study treatment effects (MS CD40/CD40L signature score). 
2. Investigating a potential differential response to treatment in patients utilizing biomarker 
results. This could allow segmentation of the patient population with a potentially higher 
efficacy of frexalimab in a subpopulation. 
Objectives and endpoints  
 
 
Part A  
Objectives 
 
Endpoints 
Primary 
• 
To determine the efficacy of frexalimab as 
measured by reduction of the number of 
new active brain lesions. 
• 
Number of new gadolinium (Gd)-enhancing T1-hyperintense 
(GdE T1) lesions at Week 12 as measured by brain 
magnetic resonance imaging (MRI). 
Secondary 
• 
To evaluate efficacy of frexalimab on 
disease activity as assessed by other MRI 
measures. 
• 
Number of new or enlarging T2 lesions at Week 12. 
• 
Total number of GdE T1 lesions at Week 12. 
• 
To evaluate the safety and tolerability of 
frexalimab. 
• 
Adverse events (AEs), serious adverse events (SAEs), 
potentially clinically significant abnormalities (PCSAs) in 
laboratory tests, electrocardiogram (ECG), and vital signs 
during Part A. 
• 
Anti-drug antibodies (ADAs). 
• 
To evaluate pharmacokinetics of 
frexalimab. 
• 
frexalimab plasma concentrations over time. 
Pharmacokinetic (PK) parameters (maximum concentration 
[Cmax], time to Cmax [tmax], area under the curve over the 
dosing interval [AUC0-tau], and elimination half-life [t1/2]). 
 
 
Part B  
Objectives 
 
Endpoints 
Secondary 
• 
To evaluate the long-term safety and 
tolerability of frexalimab. 
 
 
• 
To evaluate the safety of the 1800 mg SC 
q4w dose regimen. 
• 
Adverse events (AEs), serious adverse events (SAEs), 
potentially clinically significant abnormalities (PCSAs) in 
laboratory tests, electrocardiogram (ECG), and vital signs 
during Part B. 
• 
Adverse events (AEs), serious adverse events (SAEs), 
potentially clinically significant abnormalities (PCSAs) in 
laboratory tests, electrocardiogram (ECG), and vital signs in 
the 1800 mg SC q4w dose regimen group (Part B2). 
 
• 
Anti-drug antibodies (ADAs). 
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Part B  
Objectives 
 
Endpoints 
• 
To evaluate pharmacokinetics of frexalimab 
beyond 12 weeks of study intervention for 
SC and IV regimen, including after switch 
to 1800 mg SC q4w. 
• 
frexalimab plasma concentrations over time. 
Pharmacokinetic (PK) parameters (maximum concentration 
[Cmax], time to Cmax [tmax], area under the curve over 
the dosing interval [AUC0-tau], and elimination half-life [t1/2]). 
Overall design: 
ACT16877 is a Phase 2, multicenter, randomized, parallel-group, double-blind, 
placebo-controlled study to assess the efficacy, safety, and tolerability of 2 doses/routes of 
administration of frexalimab in participants with RMS (relapsing-remitting MS and 
secondary progressive MS participants with relapses as per inclusion criteria). The study is 
open-label for route of administration and dose group and double-blinded for treatment 
assignment. Independent raters of MRI results will be blinded for study treatment and dose and 
other participants data. 
The study consists of 2 parts:  
Part A is a 12-week, double-blind, placebo-controlled part, preceded by a screening period 
starting not earlier than 4 weeks before Day 1. 
At the beginning of Part A, participants will be randomly assigned in a 4:4:1:1 ratio to the 
frexalimab intravenous (IV) every 4 weeks (q4w) or frexalimab subcutaneous (SC) every 2 weeks 
(q2w) or IV placebo q4w or SC placebo q2w. Interactive response technology (IRT) will be used 
to assign treatment to participants. All participants will switch to Part B after the Week 12 visit. 
Once the last participant has entered Part B, analysis of Part A data will be performed as the main 
analysis of the study. 
Part B comprises open-label frexalimab treatment of 212 to approximately 280 weeks 
(approximately 53 to 70 months and not exceeding 296 weeks [74 months]) expected duration for 
individual participants, in order to allow further analysis of safety and efficacy. Participants from 
frexalimab treatment arms in Part A will continue their previous IV or SC treatment. Participants 
from the placebo treatment IV or SC arms in Part A will switch to IV q4w or SC q2w frexalimab 
treatment, respectively, starting from Week 12 visit. This design will allow reduction of exposure 
to placebo and allow continuation of assessment of safety and efficacy of frexalimab for a longer 
period. Treatment will be administered in an open-label fashion from Week 14 until the Common 
end of study (EOS). Further to Part A results, there will be no dose regimen change for 
the IV arm. In the SC arm, dose regimen will be modified to 1800 mg q4w (via syringe infusion 
material). Both regimens will continue until the Common EOS. 
For the SC group, Part B will be divided in 2 subparts: Part B1 until individual participant 
switches to the modified dose regimen and Part B2 after this switch. 
Based on the duration of recruitment of Part A and time needed for primary data analysis, it is 
expected that participants will be treated for a total duration of 292 weeks (73 months) of study 
intervention (and will not exceed 308 weeks [77 months]) in both parts of ACT16877. 
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A Common EOS will be planned when the first participant randomized has reached 
approximately 292 weeks (73 months) of study intervention administration. The participant must 
be followed-up for 24 weeks after the completion of common EOS (see Section 4.4 for details of 
common EOS). Upon completion of both Parts A and B of ACT16877, any decision to switch 
a participant to a locally available RMS treatment (disease-modifying therapy) will be taken by 
the treating physician, generally after the follow-up period. 
Overall, maximum duration of study participation comprising screening period (4 weeks), Part A 
(12 weeks), Part B (up to 280 weeks and not exceeding 296 weeks), and safety follow-up 
(24 weeks) is 320 weeks (80 months) and will not exceed 336 weeks (84 months). 
Brief summary:  
This is a parallel, treatment, Phase 2, double-blind, 4 arms study to assess frexalimab injection 
compared with placebo injection for efficacy and safety in participants with relapsing multiple 
sclerosis.  
Number of participants: 
Approximately 160 participants will be screened to achieve 120 participants randomly assigned to 
the study intervention (based on a 25% screening failure rate) and 100 evaluable participants 
(based on an approximately 15% dropout). 
Intervention groups and duration: 
Part A of the study will last 12 weeks. Participants will receive q4w IV infusions or q2w SC 
injections of frexalimab or placebo (after a loading dose at Day 1) in a blinded fashion 
(not blinded for route of administration). 
At Week 12, participants in the IV and SC placebo arms will switch to corresponding IV or SC 
frexalimab treatment. 
In Part B, participants will receive study treatment in an open-label fashion: 
• In the IV arm, q4w IV infusions until Common EOS. 
• In the SC arm: 
- 
q2w SC injections of frexalimab until amended protocol 02 is approved and the 
syringe infusion material locally available (Part B1) 
- 
Then switched to q4w SC infusion via syringe infusion material until the Common 
EOS (Part B2). The switch to the new SC dose regimen will occur once amended 
protocol 02 is locally approved and the syringe infusion material is available at site. 
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Study intervention(s) 
Part A:  
IV arms: q4w administration of frexalimab (1800 mg on Day 1 followed by 1200 mg doses at 
Weeks 4 and 8) or matching placebo in a blinded fashion. At Week 12, placebo treatment group 
participants will receive frexalimab treatment loading dose of 1800 mg, while participants of 
frexalimab treatment arm will keep on 1200 mg dose on Week 12 in a blinded fashion. 
SC arms: q2w administration of frexalimab (600 mg IV infusion loading dose on Day 1 followed 
by 300 mg SC injections on Weeks 2, 4, 6, 8 and 10) or matching placebo in a blinded fashion. At 
Week 12 visit, placebo treatment group participants will receive frexalimab treatment loading 
dose as an IV infusion of 600 mg and a placebo SC injection; while participants in the frexalimab 
treatment arm remain on the SC 300 mg dose and will receive a placebo IV infusion in a blinded 
fashion. 
Part B:  
IV arm: q4w administration of 1200 mg frexalimab IV will be performed in an open-label fashion 
to all participants from Week 16 onward. 
SC arm: q2w administration of 300 mg frexalimab SC (Part B1). Then q4w administration by 
syringe infusion material of 1800 mg frexalimab SC (Part B2). All these administrations will be 
performed in an open-label fashion to all participants from Week 14 onward. 
Investigational medicinal product(s) 
• Formulation: frexalimab will be supplied in single use vials containing 300 mg frexalimab 
(150 mg/mL; extractable volume: 2 mL) or vials containing 
. A matching placebo will be prepared using the same 
formulation as frexalimab without the active protein and be supplied in single use vials 
(extractable volume: 2 mL or 
). 
• Route(s) of administration: IV infusion in a 100 mL pre-filled 0.9% saline bag with 
a duration of administration of approximately 1 hour, SC injection (2 mL undiluted in 
Part B1) then SC infusion (12 mL undiluted in Part B2). 
• Dose regimen: 1800 mg frexalimab (or matching placebo) IV on Day 1 followed by 
1200 mg q4w IV for the IV arm; and 600 mg frexalimab (or matching placebo) IV on 
Day 1 followed by 300 mg q2w SC (Part A and Part B1) and then switch to 1800 mg q4w 
with the SC syringe infusion material for the SC arm (Part B2). 
Auxiliary medicinal products 
• Formulation: MRI contrast-enhancing preparations. 
• Route(s) of administration: IV. 
• Dose regimen: as per respective label. 
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Posttrial access to study medication 
After participants have completed Part A, they will remain in Part B until the Common EOS. 
Then, post study access to study medication could be provided based on local/country regulations 
or a decision to switch to a locally available DMT will be made by the treating physician, in 
agreement with the participant. 
Statistical considerations: 
• Primary endpoint: Number of new GdE T1 lesions at Week 12 relative to Week 8 as 
measured by brain MRI. 
•  Main secondary endpoints:  
- 
Number of new or enlarging T2 lesions at Week 12 (relative to Week 8). 
- 
Total number of GdE T1 at Week 12. 
For the primary and main secondary endpoints, the reduction in mean counts for participants 
treated with frexalimab relative to counts in participants receiving placebo (regardless of 
the administration route) will be estimated in the Efficacy Population. 
Data Monitoring/Other committee: No
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1.2 
SCHEMA  
Figure 1 - Graphical study design  
 
Abbreviations: S = screening; R = randomization; N = number of participants; W = week; D = day; IV = intravenous; SC = subcutaneous, MRI = magnetic resonance imaging; EOS = end of study. 
N = 120 (for at least 100 evaluable, randomization 4:1:4:1) 
Blinding: double-blind for treatment group, open for dose and route of administration; participants receive either IV or SC. 
* Further to Part A analysis, to increase its exposure at level similar to the IV arm, the SC arm dose regimen will be modified to 1800 mg q4w (via syringe infusion material). The IV arm will remain unchanged. 
** Upon availability of syringe infusion material for SC infusion on site and local approval of amended protocol 02. 
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Period 
Screening  
(up to 
4 weeks 
before Day 1) 
Baseline/
Start of 
IMP 
Part A 
For participants 
with premature 
study 
discontinuation  
Visit  
W-4 to D-1 
D1/W0 
W2a 
W4 
W6a 
W8 
W10a 
W12b 
From D1 to W12 
 
Unscheduled 
visits 
Early EOT 
(follow all 
visits planned 
through 
Common 
EOSc) 
Follow-up visits 
(4 weeks, 
12 weeks, and 
24 weeks after 
EOT) 
Window allowedcc 
 
 
±2 days ±2 days ±2 days ±2 days 
±2 days ±2 days 
 
±3 days 
±3 days 
Visit number 
1 
2 
3 
4 
5 
6 
7 
8 
 
 
 
Whole blood (PaxGene 
sample) (MS 
CD40/CD40L 
signature)d 
 
X 
 
X 
 
 
 
X 
 
X 
 
Archived blood  
sampled, dd  
 
X 
 
 
 
 
 
 
 
 
 
Archived DNA samplebb  
X 
 
 
 
 
 
 
 
 
 
 
Abbreviations: AE = adverse event; β-HCG = beta Human chorionic gonadotropin; CD40 = cluster of differentiation 40; CD40L = CD40 ligand; CHI3L1 = chitinase 3-like 1; D = day; W = week; DNA = deoxyribonucleic 
acid; ECG = electrocardiogram; EDSS = Expanded Disability Status Scale; EOS = end of study; EOT = end of treatment; FSH = follicle‑stimulating hormone; FU = follow-up; HIV = human immunodeficiency virus; 
Ig = immunoglobulin; IMP = investigational medicinal product; MRI = magnetic resonance imaging; MS = multiple sclerosis; MSIS = multiple sclerosis impact scale; NfL = neurofilaments light chain; PBMC = peripheral 
blood mononuclear cell; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PRO = patient-reported outcome; PROMIS = patient reported outcome measurement information 
system; PQATv3 = patient’s qualitative assessment of treatment version 3; SARS-CovV-2 = severe acute respiratory syndrome coronavirus 2; SC = subcutaneous; sCD40L = soluble cluster of differentiation 40 ligand.  
a For the SC treatment arms only.  
b Week 12 correspond to final assessment for Part A and to beginning of treatment for Part B; all laboratory samples must be collected before any treatment of Week12 (see s for PK sampling). 
c See also Part B schedule for EOS details. Participants who agree, should continue all the visits scheduled until Common EOS even in case of early EOT, see relevant columns for visits schedule. 
d To be performed before administration of IMP. 
e At screening only. 
f 
Participants will be contacted before each visit (latest on the day before the visit), by the Investigator or designee, to evaluate for signs and symptoms of a potential SARS-CoV-2 infection. In case of suspicion of 
such infection, the participant will be asked to not come to the study site and will be referred to a testing facility or his/her primary care physician according to local regulations. If the suspicion of a SARS-CoV-2 
infection is excluded and there is no other reason to pause treatment in the judgment of the investigator, the treatment can continue. If the suspicion of a SARS-CoV-2 infection is confirmed, treatment should be 
stopped. 
g Please refer to the administration of IMP by visit detailed in Table 7. 
h SC injection must be performed after the predose PK sample is taken and before the start of the IV infusion. Participants receiving placebo are switched to frexalimab at Week 12.  
i 
Full physical examination at screening, brief physical examination for the following visits. 
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j 
If suspicion of new cardiovascular event and ECG is needed for monitoring. 
k if anti-HBs negative and Anti-HBc positive: perform hepatitis B virus DNA to confirm; if anti-HC IgG positive: IgG, HCV-RNA PCR will be performed. 
l 
Injection/infusion site examination (until 2 hours following administration). Evaluation of SC injection/IV infusion site reactions following IMP administration will be performed by the Investigator or designee (local 
injection site reaction assessment, see Section 10.9.1) and by participants (pain-verbal descriptor scale, See Section 10.9.2). 
m As needed in female of non childbearing potential only. 
n Blood test at screening, then blood or urine test. Additional tests performed at the judgment of the investigator. 
o Blood testing (eg, QuantiFERON® TB Gold test) is preferred; skin testing (eg, tuberculin skin test) with ancillary testing will be allowed if blood testing is not available and T-SPOT® can also be performed, if 
available. This test may not be suitable if previous treatment(s) have produced significant immunosuppression. 
p Sites must consider assay results availability and perform tests more than 4 days before planned randomization. 
q Please see Section 10.2 for details. 
r 
Fasting is preferred if possible where clinical chemistry will be assessed. 
s On Day 1 and at Week 12, PK sample collection will take place at 0 (predose), 1 hour (or end of infusion for IV arms), and 4 hours (after the beginning of infusion or later if participants stay longer at site for 
this visit) after the start of the IMP administration. Samples will be taken in the contralateral arm of that of the IMP infusion. 
t 
Samples taken before IMP administration at Week 4 and Week 8. 
u SC injection must be performed after the predose PK sample and before the IV infusion start. 
v Magnetic resonance imaging can be performed within a window of ±3 days. If a participant has a confirmed relapse within 7 days prior to the next planned MRI scan, an MRI scan should be performed prior to 
administration of any corticosteroid treatment to the extent possible.  
w Magnetic resonance imaging will be done as close as possible to randomization but not less than 5 days before randomization (considering the minimal duration needed for image submission and QC acceptance). 
MRI should preferably be performed once all other screening assessments are checked and none of them have excluded the patient. 
x If the previous MRI was performed more than 1 month before. 
y Patient-reported outcome (PRO) assessments - MSIS-29, PROMIS-Fatigue-MS-8, PGIC-Fatigue, PGIS-Fatigue, and PQATv3 will be completed by each study participant, prior to any treatment, laboratory work, 
radiological assessments, and discussion with the participant regarding treatment or health status. 
z At selected sites. With single cell PBMC samples. PBMC samples from selected participants will be archived for later stage analysis.  
aa On Day 1, sCD40L sample collection will take place at 0 (predose) and 1 hour (or end of infusion for IV arms). 
bb Optional pharmacogenetic sample. 
cc The reference for visit windows calculation is Day 1. 
dd This sample will be collected and stored for use if any unexpected safety issue, to ensure that a pre-dose baseline value is available for previously not assessed parameters (eg, serology) and for biomarkers 
research, if agreed by the participant. 
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Abbreviations: AE = adverse event; β-HCG = beta Human chorionic gonadotropin; CD40 = cluster of differentiation 40; CD40L = CD40 ligand; CHI3L1 = chitinase 3-Like 1; W = week; ECG = electrocardiogram; 
EDSS = Expanded Disability Status Scale; EOS = end of study; EOT = end of treatment; FU = follow-up; Ig = immunoglobulin; IMP = investigational medicinal product; M = month; MRI = magnetic resonance 
imaging; MS = multiple sclerosis; NfL = neurofilament light chain; PBMC = peripheral blood mononuclear cell; PGIS = Patient Global Impression of Severity; PGIC PRO = patient-reported outcome; 
PROMIS = patient reported outcome measurement information system; MSIS = multiple sclerosis impact scale; PGIC = Patient Global Impression of Change; SARS-CovV-2 = severe acute respiratory syndrome 
coronavirus 2; SC = subcutaneous; sCD40L = soluble cluster of differentiation 40 ligand.  
a For additional injection visits in the SC treatment arm only (Part B1). If, in the judgment of the investigator, no adverse reaction have occurred or is suspected, SC injections of frexalimab (from Week 14 on) can be 
performed at home after appropriate medical training, assessment of the participant’s self-injection or partner/caregiver/home healthcare professional capability and technique are done (please refer to product 
management manual). In the case of any injection site or other adverse reactions, the participant must contact the site as soon as possible to report the injection site reaction or other adverse event. The 
Investigator must monitor any worsening of events and schedule an on-site visit for evaluation and treatment, if needed. The Investigator will also proactively contact the participant on the day of injection to ensure 
the best management of injection site reaction or other adverse event, should this occur. Additional SC visit for 300 mg q2w SC regimen continued until switch to 1800 mg q4w SC via syringe infusion material 
(upon local approval of amended protocol 02 and availability of the syringe infusion material on site). Depending on the switch visit: W98, W102, W106, W110, W114, W118, W122, W126, W130, W134, W138, 
W142, W146. 
b  To be performed before administration of IMP. 
c Participants should continue with scheduled visits until the Common EOS even in case of EOT. See relevant columns for visits schedule. 
d From Week 12 on, participants treated with placebo during Part A will be treated with frexalimab. Please refer to the administration of IMP by visit as detailed in Table 7. 
e Brief physical examination. 
f 
Semi-annual visits after Week 24 until Week 144 (W48/M12, W72/M18, W96/M24, W120/M30, W144/M36), then W192/M48 and W240/M60). 
g Injection/infusion site examination (2 hours after administration; can be reduced to 1 hour after Week 12 if the Investigator judges this adequate). Evaluation of SC injection/IV infusion site reactions following IMP 
administration will be performed by the Investigator or designee (local injection site reaction assessment, see Section 10.9.1) and by participants (pain-verbal descriptor scale, See Section 10.9.2). 
h Blood or urine tests; additional test if indicated in the judgment of the Investigator. 
i 
Please see Section 10.2 for details. 
j 
Quarterly visits after Week 24 to EOS (W36/M9, W48/M12, W60/M15, W72/M18, W84/M21, W96/M24, W108/M27, W120/M30, W132/M33, W144/M36, W156/M39, W168/M42, W180/M45, W192/M48, W204/M51, 
W216/M54, W228/M57, W240/M60, W252/M63, W264/M66, W276/M69, W288/M72). 
k Fasting is preferred if possible where clinical chemistry will be assessed. 
l 
Samples are to be taken before IMP administration. 
m Magnetic resonance imaging can be performed within a window of ±3 days. If a participant has a confirmed relapse prior to 7 days before the next planned MRI scan, an MRI scan should be performed at the time 
of the relapse confirmation and prior to administration of any corticosteroid treatment, whenever possible. 
n If the previous MRI was performed more than 1 month prior. 
o If EOT earlier than Week 24. 
p At selected sites. With single cell PBMC samples. PBMC samples from selected participants will be archived for later stage analysis. 
q The reference for visit windows calculation is Day 1. 
r 
The switch should occur at a q4w visit (not at an additional q2w visit). 
s Part B IV and Part B2 SC arm after switch from 300 mg q2w SC to 1800 mg q4w SC via syringe infusion material (upon local approval of amended protocol 02 and availability of the syringe infusion material on 
site).  
t 
For SC arm in part B2 (after switch from 300 mg q2w SC to 1800 mg q4w SC upon local approval of amended protocol 02 and availability of the syringe infusion material on site), monthly assessments of 
hematology/biochemistry and PK/ADA for the first 12 weeks. Then resume Part B periodicity of the q4w arm. See Table 1.  
u W28/M7, W32/M8, W36/M9, W40/M10, W44/M11, W48/M12, W52/M13, W56/M14, W60/M15, W64/M16, W68/M17, W72/M18, W76/M19, W80/M20, W84/M21, W88/M22, W92/M23, W96/M24, W100/M25, 
W104/M26, W108/M27, W112/M28, W116/M29, W120/M30, W124/M31, W128/M32, W132/M33, W136/M34, W140/M35, W144/M36, W148/M37, W152/M38, W156/M39, W160/M40, W164/M41, W168/M42, 
W172/M43, W176/M44, W180/M45, W184/M46, W188/M47, W192/M48, W196/M49, W200/50, W204/M51, W208/M52, W212/M53, W216/M54, W220/M55, W224/M56, W228/M57, W232/M58, W236/M59, 
W240/M60, W244/M61, W248/M62, W252/M63, W256/M64, W260/M65, W264/M66, W268/M67, W272/M68, W276/M69, W280/M70, W284/M71, W288/M72, W292/M73 
v All participants should sign the updated Inform consent form after amended protocol 02 local approval. 
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w  Quarterly visits after Week 24 to Week 144 (W36/M9, W48/M12, W60/M15, W72/M18, W84/M21, W96/M24, W108/M27, W120/M30, W132/M33, and W144/M36) then every 6 months (W192/M48, W216/M54, 
W240/M60, W264/M66, W288/M72) 
x 
 and in Part B2 (from 12 weeks after switch) for SC arm, optional home administration may be considered for interim visits between 2 quarterly onsite visits (those with physical examination and 
laboratory sampling). In this case, home nurse intervention after appropriate medical training and assessment of practical conditions will be required (please refer to product management manual). 
y This sample will be collected and stored for use if any unexpected safety issue, to ensure that a post-baseline value is available for previously not assessed parameters (eg, serology) and for biomarkers research, 
if agreed by the participant. 
z In case of low value, retest is allowed within the screening period. 
aa For individual participant, the maximum duration of Part B is limited to 296 weeks (74 months). 
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1.3.3 Schedule of activities for the initial 12 weeks of Part B2  
In the SC arm, additional procedures will be done, as described in Table 1. 
Table 1 - Additional activities for the first 12 weeks of Part B2 (if not already planned in the Part B 
SOA)  
Period 
Part B2 
Visit  
First 4 q4w visits: 
• 
Switch visit, 
• 
Switch visit +4 weeks,  
• 
Switch visit +8 weeks, 
• 
Switch visit +12 weeks. 
Following visits 
Window allowed 
+/-5 days 
+/-5 days 
Hematology and biochemistry 
X 
As planned per Part B 
SoA 
Antidrug antibodies 
X 
Plasma sample  
collection (frexalimab concentration) 
X 
Other assessments 
As previously planned 
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2 
INTRODUCTION  
2.1 
STUDY RATIONALE  
The goal of this Phase 2 study is to assess the efficacy and safety of frexalimab in people with 
RMS. Frexalimab also know as SAR441344 is an antagonist mAb which binds to human CD40L 
and blocks the CD40/CD40L signaling pathway. This pathway is critical for humoral immune 
response, in particular T-cell-dependent antibody response (TDAR), as well as for reciprocal 
costimulation between T-cells and antigen-presenting cells, and related proinflammatory 
cytokines secretion by macrophages. As such, frexalimab may be relevant to autoimmune diseases 
in which pathogenic B-cells play a key role, such as MS (1). 
The proposed mechanism of action for frexalimab is inhibition of T-cells interaction with B-cells 
and antigen-presenting cells and suppression of autoimmune pathologic processes such as 
formation of new active focal brain lesions in MS as well as diffuse inflammation in brain tissue. 
Focal active brain lesions can be measured by MRI. frexalimab reduction or amelioration of 
these would be predictive of clinical efficacy in MS patients. This study will assess frexalimab 
efficacy by measuring changes in the number of GdE T1 lesions. This radiographic outcome has 
been established as a highly reliable predictive biomarker for clinical efficacy in pivotal studies in 
MS and has been demonstrated to be a predictive biomarker for clinical efficacy (reduction in 
ARR and disability worsening) studies with other MS treatments (2, 3). 
Treatment efficacy for lesion reduction will be assessed at Week 12 comparing frexalimab and 
placebo treatment groups. Frexalimab efficacy relative to placebo will be assessed by evaluating 
inhibition of the formation of new active brain lesions (new GdE T1 lesions) as measured by 
MRI. The study will also characterize safety and tolerability of frexalimab in participants with 
RMS. 
This ACT16877 study will employ secondary MRI endpoints in an effort to collect additional data 
on other potential benefits of frexalimab. 
Important data is expected from the exploratory objective of characterizing activation of 
the CD40/CD40L signaling pathway by analysis of mRNA “signatures” (levels of expression of 
genes) in blood. This will facilitate study of treatment effects, including changes in expression of 
‘signature genes’ (‘MS CD40/CD40L signature’ score) and assessment of correlation of 
the “CD40/CD40L mRNA signature” with efficacy of frexalimab on the primary and other study 
endpoints. Identification of a subpopulation with increased CD40/CD40L signaling might allow 
targeting frexalimab to those who could most benefit. 
Other exploratory assessments, such as quantification of levels of NfL and Chi3L1 in blood and 
advanced MRI methods, are expected to support evidence for frexalimab activity on 
neuroinflammation and neurodegeneration as well as potential effects on tissue preservation. 
Immunophenotyping and other biomarker assessments will allow better understanding of 
frexalimab effects on immune system and on neuroinflammation processes of MS. 
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2.2 
BACKGROUND  
Immunomodulatory drugs are the mainstay of MS therapy. Recently, clinical studies have 
demonstrated very good efficacy of agents that target B-cells, especially B-cell-depleting agents 
like ocrelizumab or ofatumumab (anti-CD20) (4, 5). New treatments that are specific, 
non-depleting, and provide new mechanisms of action are needed to further reduce disease 
progression and improve long-term outcome in MS.  
Beyond the existing strategy of modulating the cellular elements of adaptive immunity, there is 
mounting evidence that innate immunity, mediated by myeloid cell lineages 
(bone-marrow-derived monocytes/macrophages and central nervous system [CNS] -resident 
microglial cells), is responsible for many of the neurodegenerative aspects of MS that persist 
despite the effectiveness of approved disease-modifying therapies in preventing acute relapses 
(6, 7). 
There is still a significant unmet need for therapies that target neuroinflammation in the CNS with 
a goal of halting long-term disability and neurodegeneration in people with RMS a well as in 
those with progressive forms of MS (primary progressive multiple sclerosis [PPMS] and 
secondary progressive multiple sclerosis [SPMS]). Even the most recent high-efficacy 
disease-modifying therapies act mainly on adaptive immunity in the periphery with only modest 
or temporary ability to halt neuroinflammatory and neurodegenerative processes and stop disease 
progression. Therefore, development of MS treatments with new modes of action involving not 
only adaptive but also innate immunity is of interest. 
Through its interactions with CD40, CD40L is best known for its role as an immunologic 
second signal, it is expressed on T-cells and is required for B-cell activation/maturation and 
dendritic cell maturation (8). CD40L loss of function is associated with development of 
hyper-immunoglobulin (Ig) M syndrome characterized by inhibition of B-cell maturation, loss of 
germinal center formation, absence of isotype switching, affinity maturation and somatic 
hypermutation, and inability to form long-lived plasma and memory B-cells (9). In addition to its 
role in B-cell maturation, CD40L is thought to enhance macrophage effector function and aid in 
the development of CD8+ memory T-cells. Disruption of the CD40/CD40L pathway in 
autoimmune diseases, particularly those where pathogenic B-cell responses are a key hallmark of 
disease, as in MS, would be predicted to impact both cellular and humoral responses and have 
therapeutic benefit. 
Importance of CD40/CD40L pathway in immune signaling in MS can indirectly be supported by 
observed increase of soluble CD40L in people with MS (10). Higher levels of soluble CD40L are 
observed in people with RRMS as compared to patients with SPMS (11), suggesting different 
involvement of this pathway activation and which is found related to CD40L expression increase 
on immune cells (12).  
Given the critical role of CD40L in the adaptive immune response, anti-CD40L therapies are 
being developed for the treatment of diseases such as immune thrombocytopenic purpura, and 
systemic lupus erythematosus with some early signs of efficacy. Unfortunately, first generation 
anti-CD40L therapies are associated with increased thromboembolic events in clinical trials and 
ultimately resulted in the discontinuation of their development (“thromboembolic” event or 
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“thromboembolism” are used in this document to denote any arterial or venous thrombotic or 
embolic events). Elevated thromboembolic risk seen with first generation anti-CD40L mAb 
therapies resulted from platelet activation triggered by FcγRIIa activation by higher order immune 
complexes containing the anti-CD40L mAb and CD40L (membrane or soluble forms), expressed 
by platelets (13, 14). 
Understanding fragment crystallizable (Fc)-mediated thromboembolic risk resulted in 
the engineering of second-generation anti-CD40L therapies that either did not contain an Fc or 
contained a modified Fc with low FcγRIIa binding, with the goal of eliminating thromboembolic 
risk. Frexalimab has a modified Fc region. In the first-in-human clinical trial with frexalimab 
(TDU15525/TDR15526) and ongoing Phase 2 clinical trials, no thromboembolic event has 
occurred. 
Frexalimab is derived from the humanized mAb IDEC-131, with 2 major modifications: 
1) affinity maturation of the variable region, and 2) mutations in the Fc region to inhibit binding to 
the FcγRIIa receptor. Similar to the first-generation IDEC-131, frexalimab, binds to CD40L and 
prevents binding to and signaling via CD40. Additional information on frexalimab may be found 
in the Investigator’s Brochure (IB). CD40L is a member of the tumor necrosis factor alpha 
superfamily. It is transiently expressed on the surface of cells and platelets as a homotrimer and 
may be released in a biologically active form into circulation (15). CD40L is also expressed on 
a variety of other cell types including T-helper (Th) cells, platelets, endothelial cells, smooth 
muscle cells, macrophages, and antigen presenting cells. 
Nonclinical studies: The frexalimab nonclinical package, as described in the IB, demonstrated 
that thromboembolism is not an identified hazard of the frexalimab toxicology profile. 
The frexalimab toxicology profile is consistent with its pharmacology and includes decreased 
cellularity in germinal centers, moderate decrease in B-cells and decreased TDAR to keyhole 
limpet hemocyanin (KLH) antigen. Effects on immune system and potential opportunistic 
infections are expected hazards of frexalimab. These effects on the immune system are 
monitorable and are expected to resolve after antibody discontinuation. Antidrug antibody (ADA) 
formation was generally observed at lower doses in frexalimab toxicology studies, but 
the frexalimab mechanism of action should reduce the impact of ADA formation at higher doses. 
The no-observed-adverse-effect level (NOAEL) from the 6-month Good Laboratory Practice 
(GLP) toxicity study in cynomolgus monkeys was 100 mg/kg/week IV, with a Day 169 area under 
the curve (AUC) from hour 0 to 168 hours (AUC0-1 week) of 468 000 μg*h/mL. The maximum 
concentration (Cmax) achieved was 5210 µg/mL. For details on the non GLP and GLP toxicity 
studies performed within the nonclinical assessment of frexalimab, please refer to the IB. 
Based on the 6-month GLP toxicology study in the non-human primate, the PK exposure 
(AUC0-4 weeks) of 1 872 000 μg*h/mL and Cmax of 5210 μg/mL are considered safe. The predicted 
exposure of 1800 mg IV loading dose followed by 1200 mg IV q4w dose regimen in clinical trials 
are estimated at 222 000 µg*h/mL for AUC0-4 weeks (at steady state) and 650 μg/mL for Cmax 
(reached after the IV loading dose), leading to a safety margin of 8 compared to the NOAEL. For 
the initial SC treatment, with 600 mg IV loading dose followed by 300 mg SC q2w, predictive 
exposure corresponds to 3-fold less exposure than for the q4w IV treatment (with AUC0-4 weeks at 
steady state and Cmax after IV loading dose of 75 000 µg*h/mL and 217 µg/mL respectively), so 
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its safety margin is even larger. In part B2, with the SC dose regimen 1800 mg SC q4w, 
AUC0-4 weeks (at steady state) are predicted to be similar to those obtained with the 1200 mg q4w 
IV regimen with a lower Cmax estimated as 450 µg/mL versus 650 µg/mL. 
Phase 1 first-in-human study:  
TDU15525 (single ascending dose study) 
TDU15525 study is a Phase 1, double-blind, randomized, parallel design, placebo-controlled 
single ascending dose study conducted to evaluate the safety, tolerability, PK, and PD of IV doses 
of frexalimab in healthy adult participants. Five sequential ascending single doses of frexalimab 
(200, 600, 1200, 2100, or 3000 mg) or matching placebo were diluted to a final volume of 
approximately 100 mL in 0.9% normal saline and administered on Day 1 by IV infusion over 
approximately 1 hour. All participants were immunized with a single dose of KLH on Day 4. 
A total of 40 healthy adult participants, including 22 (55.0%) males and 18 (45.0%) females 
received the investigational medicinal product (IMP). Each cohort consisted of 8 participants, 
6 receiving frexalimab and 2 receiving placebo. 
Overall, a single IV dose of frexalimab between 200 and 3000 mg was safe and well tolerated. 
There were no SAEs or severe treatment-emergent adverse events (TEAEs). No trends in vital 
signs, electrocardiograms (ECGs) or laboratory values were identified, including assays aimed at 
identifying potential increased risks for thromboembolism or infections. 
The tmax for frexalimab was observed between 1 hour (end of infusion) to 2 hours postdose. 
frexalimab exposure increased with no deviation from dose proportionality from 200 to 3000 mg. 
Mean terminal half-lives ranged from 25 to 35 days over the dose range. 
While there were fewer anti-KLH IgG values above the lower limit of quantification in all active 
treatment groups relative to placebo, the anti-KLH IgG response was weak and variable, even in 
participants receiving placebo. A likely explanation is that only 1 dose of KLH was administered 
which induced variable levels of IgG. Therefore, no formal dose-response relationship was 
established in this study. 
TDR15526 (multiple ascending dose study) 
TDR15526 was a Phase 1, double-blind, randomized, parallel design, placebo-controlled multiple 
ascending dose study investigating 5 dose levels of frexalimab or placebo controls in healthy adult 
participants. Five multiple doses (3 injections, q2w) of frexalimab (150 mg [10 participants], 
300 mg [8 participants], 600 mg [9 participants], 1200 mg [9 participants], and 2100 mg 
[8 participants]) or matching placebo (12 participants) were administered via the SC route on 
Days 1, 15, and 29. All participants were immunized with KLH on Days 4 and 32. A total of 
56 healthy adult participants, including 46 (82.1%) males and 10 (17.9%) females received 
the IMP. 
Overall, 5 dose levels of frexalimab between 150 and 2100 mg administered SC as 3 doses q2w in 
healthy male and female adult participants were safe and well tolerated. There were no serious or 
severe TEAEs. Three participants discontinued treatment due to AEs of elevated transaminases 
(alanine aminotransferase [ALT] increase up to approximately 2.5 × ULN) (frexalimab 150 mg), 
pityriasis (placebo), and presyncope (frexalimab 2100 mg).  
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No trends in vital signs, ECGs, or laboratory values were identified, including assays aimed at 
identifying potential increased risks for thromboembolism or infections. Three participants have 
developed a positive ADA during the study (2 from the 150 mg dose cohort and 1 from 
the 2100 mg dose cohort). 
After single and repeated SC administration of frexalimab, median tmax ranged from 3 to 7 days 
postdose. Frexalimab exposure increased with no deviation from dose proportionality from 150 to 
2100 mg. Steady state was not reached after the third administration. Accumulation ratio 
estimates ranged from 1.90 to 2.43 for Cmax and from 2.09 to 3.05 for AUC0-2 weeks. Mean terminal 
half-lives were estimated at 22 days at the lowest dose of 150 mg and between 29 and 33 days for 
doses ranging from 300 mg to 2100 mg.  
In participants receiving placebo, the 2 doses of KLH administered in this multiple ascending 
dose study induced a strong TDAR response, as measured by anti-KLH IgG levels in the majority 
of participants. frexalimab administration resulted in a dose-dependent inhibition of the TDAR 
response, with partial inhibition in the 150 mg and 300 mg cohorts (84% and 92%, respectively), 
and near complete (>97%) inhibition in the 600 mg, 1200 mg, and 2100 mg dose cohorts. 
The extent of inhibition at each dose level at steady state would be anticipated to be more 
extensive than the values observed in this study after 3 administrations. 
ACT16877 Part A  
ACT16877 Part A was a Phase 2, double-blind, randomized, parallel design, placebo-controlled 
study investigating 2 dose levels of frexalimab or placebo controls in participants with relapsing 
MS. Fifty-two participants were exposed to frexalimab 1200 mg IV q4w, 51 to frexalimab 300 mg 
q2w SC, and 26 to placebo.  
The analysis of the Part A of ACT16877 demonstrated a reduction in the number of new active 
GdE T1 lesions after 12 weeks (relative to Week 8) with frexalimab as compared to the placebo 
group. A 89% reduction (95%CI: 62% - 97%) in the adjusted mean monthly count of new GdE T1 
lesions was observed in the frexalimab IV group as compared to the placebo group meeting the 
predefined criteria for positive conclusions (see Section 9.3.2). A 79% reduction 
(95%CI: 44% - 92%) in the adjusted mean monthly count was observed in the frexalimab SC 
group as compared to the placebo group, but it did not meet the predefined criteria.  
Overall, the dose levels of frexalimab (1200 mg IV q4w and 300 mg q2w SC) administered to 
adult participants with RMS were safe and well tolerated. A higher percentage of participants who 
reported at least 1 TEAE was observed in the frexalimab low dose (SC) group versus frexalimab 
high dose (IV) group and placebo groups (23 [45.1%] in the frexalimab SC group versus 
15 [28.8%] in the frexalimab IV group and versus 8 [30.8%] in the placebo groups). This was 
mainly driven by the TEAEs of coronavirus disease 19 (COVID19) (5 [9.8%] in the frexalimab 
low dose group versus 0 in the frexalimab high dose group and versus 0 in the placebo groups). 
There were no TEAEs leading to death nor treatment-emergent SAEs, nor severe TEAEs. 
One participant in the frexalimab low dose group had TEAE of COVID-19 that led to study 
intervention discontinuation, as per protocol procedure. Six participants had treatment emergent 
AESIs: 5 participants had non-serious COVID-19 and 1 participant had non-serious alanine 
aminotransferase (ALT) increase. All AESIs were resolved. There were no participants with 
TEAEs of TE events or severe infection.  
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
• 
In vitro assessment of the Fc gamma 
receptor binding profile of frexalimab. 
• 
Repeat-dose studies (up to 100 mg/kg 
weekly) in monkeys. 
• 
Platelet activation potential assessment 
in vitro in blood of healthy subjects, and 
MS and SLE patients. 
Platelet count and D-dimer were monitored 
throughout the FIH Study (TDU15525, 
TDR15526) and while transient abnormal values 
were occasionally noted, there were no clinically 
significant sustained changes from baseline.  
No frexalimab-related thromboembolic events 
have been observed in the completed Phase 1 
and Phase 2, and ongoing Phase 1 and Phase 2 
clinical studies with frexalimab (PKM17227, 
ACT16877, ACT16618, and ACT17010). 
There is no signal of increased risk of 
thromboembolism in frexalimab clinical program. 
Risk Minimization: 
• 
Removal or modification of the Fc region 
has addressed the thromboembolic risk as 
indicated by second-generation therapies 
showing no elevated risk in nonclinical 
models or clinical studies. 
• 
Exclusion of participants with any history of 
clinically significanta thromboembolic 
events, as well as myocardial infarction, 
stroke, antiphospholipid syndrome, and/or 
participants requiring antithrombotic 
treatment. 
Infection including 
opportunistic 
infections 
Frexalimab inhibits CD40/CD40L interactions 
which plays a key role in the adaptive immune 
response, particularly humoral immunity. 
Based on the findings of the 13-week GLP 
toxicology study and knowledge of the CD40L 
loss of function phenotype in humans, inhibition 
of CD40L may increase the risk of upper and 
lower respiratory infections and gastrointestinal 
infections as well as opportunistic infections.  
In the 13-week GLP toxicology study, a moderate 
decrease in B-cells was noted, without 
a significant decrease in cell numbers and 
recovered after a 10-week recovery period. In 
the 6-month GLP toxicology study without a 
recovery period dose-independent slight to 
moderate decreases in absolute counts of B-cells 
were observed with statistical significance for all 
frexalimab treated groups. Treatment with anti-
CD40L therapies is associated with modest 
reductions in IgG in clinical studies. Both were 
not detected in the completed Phase 1 studies 
(TDU15525, TDR15526).  
Risk assessment: 
• 
Adverse event reporting. Severe infections, 
including opportunistic infections, are 
considered AESI. 
• 
Baseline detection and exclusion of TB, 
HIV, hepatitis tests. To be repeated in case 
of suspicion. 
Risk minimization: 
• 
Exclusion of participants with active or 
latent tuberculosis with TB test, HIV 
infection, chronic viral hepatitis or other 
known opportunistic infection, history of 
severe parasitic infections, as well as 
active infections or chronic ongoing 
infections of any course.  
• 
Clinical vigilance for infections, including 
prompt diagnosis and treatment. 
• 
Temporary treatment discontinuation can 
be considered in participants with any 
acute infections on a case-by-case basis at 
the discretion of investigator after 
evaluation of severity based on clinical and 
laboratory assessments. Decision to 
continue treatment after discontinuation 
can be made if the investigator considers 
from his/her clinical judgment that the 
participant has recovered from infection, 
based on absence of residual symptoms 
and/or available lab results confirming 
infection resolution. 
• 
No live vaccines/live components. 
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Potential risk 
of clinical 
significance 
Summary of data/rationale for risk 
Mitigation strategy 
 
SARS-COV-2 infection/COVID-19: No detailed 
data available on the specific role of CD40L in 
the course of a SARS‑CoV‑2 
infection/COVID-19. Currently, there is no 
evidence that CD40L is relevant for the viral 
infection with SARS-CoV-2. There is evidence 
that the development of viral clearance and 
a potential protective immunity follow 
the generation of an adaptive immune response, 
including the production of neutralizing 
antibodies, in which the CD40/CD40L interaction 
plays a key role. Therefore, blocking CD40L may 
prevent antibody formation and immune response 
in case of an acute SARS-CoV-2 infection and 
might prevent long-term immunity. No serious 
TEAEs of COVID-19 were reported in 
the ongoing Phase 1 and Phase 2 clinical studies 
(PKM17227, ACT16877, ACT16618, and 
ACT17010) that were conducted during or after 
the start of the pandemic. 
Risk assessment: 
• 
All diagnosed and biologically proven 
SARS-CoV-2 infections are considered 
AESI. 
• 
Monitoring the local, regional, national and 
global situation of COVID-19 spread. 
Risk minimization: 
• 
Exclusion of high risk populations for 
COVID‑19 due to the general selection of 
study participants for the current studies. 
• 
Exclusion of participants who live in long-
term care facilities and nursing homes. 
• 
Exclusion of patients with significant 
lymphopenia and significant neutropenia. 
• 
The IMP may permanently be discontinued 
if according to the Investigator 
a permanent IMP discontinuation is 
necessary in the best interest of 
the participant. 
• 
Temporary study intervention 
discontinuation can be considered in case 
of SARS-CoV-2 suspicion and/or 
biologically confirmed SARS-CoV-2 
infection (positive antigen and/or PCR 
test). Decision to resume treatment after 
discontinuation can be made if the 
investigator considers from his/her clinical 
judgment that the participant has 
recovered from the Covid-19 infection, 
based on absence of residual symptoms 
and available negative PCR test results. 
• 
Study sites need to apply protective 
measures according to local guidance. 
Immunogenicity/ 
hypersensitivity 
Due to its mechanism of action, frexalimab may 
reduce the risk of ADA formation in humans. 
Nevertheless, ADA may result in alterations in 
frexalimab exposure and in extreme cases could 
result in a Type III hypersensitivity reaction. In 
total, only 4 subjects developed ADA (TDU15525: 
One participant after 200 mg IV single infusion; 
TDR15526: 2 participants after 150 mg SC 
3 × q2w, 1 participant in the 2100 mg SC 3 × q2w 
group only at EoS). There were no SAEs relevant 
to this risk in the ongoing Phase 2 studies. 
Risk assessment:  
• 
Antidrug antibodies detection during 
the study through 4 elimination half-lives.  
• 
Hypersensitivity reactions will be 
systematically monitored (eg, chills, rash, 
urticaria, hypotension).  
• 
Anaphylactic reaction/acute allergic as well 
as infusion related reaction to be reported 
as an AESI. 
Risk minimization:  
• 
Intravenous administration of 1 hour 
minimum with a monitoring period of 
3 hours at the study site afterwards. 
• 
Symptomatic treatment of any 
immunogenicity related AEs. 
• 
Antidrug antibodies will be checked if there 
is a safety concern. 
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Although CD40/CD40L interaction is important for B-cell differentiation, there is currently 
no evidence, based on nonclinical and clinical data from the FIH study, that frexalimab is B-cell 
depleting. A slight decrease in B-cells was noted in the 13-week GLP toxicology study, which 
reversed in the recovery period. The same was seen in a 6-month GLP study, which was run 
without a recovery period (GLP studies described in Section 2.2). Throughout the FIH, 
no decrease in B-cells was observed. Therefore, comparison with B-cell-depleting drugs, such as 
rituximab and ocrelizumab, in terms of infectious risk, is limited. However, it is important to note 
that, although viral and respiratory tract infections are very common during treatment with 
these compounds, severe infections are limited.  
Although the general role of CD40L in immune response is well established, there are no detailed 
data available on the specific role of CD40L in SARS-CoV-2 infection/COVID-19. Currently, 
there is no evidence that CD40L is relevant for SARS-CoV-2 infection. There is evidence that 
the development of viral clearance and a potential protective immunity follow the adaptive 
immune response, including the production of neutralizing antibodies, in which the CD40/CD40L 
interaction plays a key role (16, 17, 18, 19, 20, 21). Therefore, blocking CD40L may prevent 
antibody formation and immune response in case of acute SARS-CoV-2 infection and may 
prevent long-term immunity. 
Considering the potential risk of increased infection rates based on the mode of action of 
frexalimab and knowledge of similar and related compounds, and the potential role of CD40L for 
adaptive immune response to a SARS-CoV-2 infection, an increased risk for study participants in 
the context of the COVID-19 pandemic can be assumed; hence appropriate risk mitigation is 
being implemented. 
Risk mitigation  
One potential risk of frexalimab is increased rate of infections. During pandemic, this risk is 
additionally increased. Because of this, risk mitigation actions have been established to address 
the risk of infection for participants in this clinical trial. 
Clear protective measures to mitigate the SARS-CoV-2 spread and reduce the risk of infection are 
given by global health agencies such as the World Health Organization (22), as well as on 
national and local levels. Study sites should ensure that, before study start and throughout, 
the study local guidance is applied to the conduct of the study at the site level. 
Stopping rules are implemented to provide guidance for Investigators: 
• In case of suspicion of COVID-19 (eg, fever, cough, shortness of breath in a context of 
possible contact with an infected person), temporary discontinuation of the IMP will be 
considered by the Investigator in accordance with Section 7.1.3, considering the following 
to evaluate individual benefit-risk of continuation or stop of IMP: the probability of 
COVID-19, the possibility of rapid diagnosis, the severity of symptoms, and risk factors. 
• In case of investigational site closure or complete regional or national lock down due to 
a local epidemic or international pandemic, the study may be suspended by the Sponsor 
completely or at selected sites or in selected regions. Every effort will be made to continue 
to follow up already recruited participants as close to the SoA as possible.  
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Temporary treatment discontinuations and adaptions of the follow-up period may be considered in 
exceptional cases as described in Section 7.1.3. 
Participants will be contacted before each visit by an Investigator or designee, for evaluation of 
signs and symptoms of a potential SARS-CoV-2 infection. In case of suspicion of infection, 
the participant will be asked to not come to the study site and will be referred to a testing facility 
or his/her primary care physician according to local regulations.  
If the suspicion of SARS-CoV-2 infection is excluded, and there is no other reason to pause 
treatment according to the Investigator’s judgment, treatment can continue. 
If suspicion of SARS-CoV-2 infection is confirmed, temporary treatment discontinuation can be 
considered. Decision to resume treatment after discontinuation can be made if the investigator 
considers from his/her clinical judgment that the participant has recovered from the COVID-19 
infection, based on absence of residual symptoms and available negative PCR test results. The 
IMP may permanently be discontinued if according to the Investigator a permanent IMP 
discontinuation is necessary in the best interest of the participant. 
Severe illnesses can occur in otherwise healthy individuals at any age, but it predominantly occurs 
in adults with underlying medical comorbidities including: chronic lung disease, cardiovascular 
disease, diabetes mellitus, hypertension, obesity, and cancer (22, 23, 24, 25, 26, 27, 28). High risk 
populations for COVID-19 are excluded in the general selection of study participants for 
this proof-of-concept study, according to the inclusion/exclusion criteria, eg, I01: excluding 
participants >55 years, I04: partly limiting morbid obesity, E03, E10, E12, and E13: excluding 
certain concomitant pathologies, such as recent malignancies, active infections, history of 
opportunistic infections, human immunodeficiency virus (HIV) infection. (Section 5.1 and 
Section 5.2).  
According to exclusion criteria E 03 (Section 5.2), participants with acute infection or having 
a high risk for an asymptomatic SARS-CoV-2 infection (eg, living with a person that is currently 
infected) should not be included in the study.  
Taking into account the potential increased infectious risk due to lymphopenia and potential 
relevance in SARS-CoV-2 infection (29), people with a significant lymphopenia or neutropenia 
will be excluded from this study (see E 10 in Section 5.2).  
Extensive assessment of the risk of the COVID-19 pandemic has been performed. This has led to 
a risk mitigation plan including stopping rules, which take into account the current knowledge and 
also potential uncertainties, including plans for lock-down situations. Participant selection that 
limits the inclusion of the population at risk of severe COVID-19 should reduce the risk for 
participants included in this study. 
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2.3.2 Benefit assessment  
Dysregulation of cellular and humoral immune responses and benefits of immunotherapies have 
been clearly demonstrated in MS (30). Due to the role of the CD40/CD40L signaling pathway’s 
role in modulating adaptive and innate immune response, as evidenced by the frexalimab 
pharmacodynamic effect on TDAR in the Phase 1 clinical trial, frexalimab is anticipated to reduce 
brain inflammation, which will be monitored by evaluating formation and count of new GdE T1 
lesions and volume and count of new or enlarging T2 lesions.  
Risk of MS relapse, the clinical manifestation of neuroinflammation, is expected to be decreased 
due to the anti-inflammatory activity of frexalimab. Due to the short duration of the treatment 
period in Part A and general low frequency of MS relapses, no significant differences in relapse 
count between groups or compared to the placebo period is expected. Nevertheless, MS relapse 
and Expanded Disability Status Scale (EDSS) data to monitor disability due to MS will be 
collected in Parts A and B to detect any possible changes. This will be used as a baseline for 
long-term observations in this study, open to all participants in ACT16877. 
Magnetic resonance imaging brain volume data acquired during Part B as well as serum 
biomarker such as NfL data, and additional biomarkers (including analysis of the mRNA 
signature of the CD40/CD40L pathway, PBMC immunophenotyping, Chi3L1 and soluble 
CD40L) will also allow evaluation of any effect on neuroinflammation underlying CNS damages. 
The analysis of the Part A of ACT16877 demonstrated a reduction in the number of new active 
GdE T1 lesions after 12 weeks (relative to Week 8) with frexalimab as compared to the placebo 
group. A 89% reduction (95%CI: 62% - 97%) in the adjusted mean monthly count of new GdE T1 
lesions was observed in the frexalimab IV group as compared to the placebo group meeting the 
predefined criteria for positive conclusions (see Section 9.3.2). A 79% reduction  
(95%CI: 44% - 92%) in the adjusted mean monthly count was observed in the frexalimab SC 
group as compared to the placebo group, which did not meet the predefined criteria. 
Both frexalimab groups showed reduction in new/enlarging T2-lesions and total gadolinium-
enhancing T1-lesions, with larger effect of the high dose. Frexalimab was well tolerated. 
The most common adverse events (≥4% in any frexalimab group) were COVID-19 and headache. 
No serious adverse events were reported. 
2.3.3 Overall benefit: risk conclusion  
No safety or tolerability concerns have been identified in the completed Phase 1 FIH clinical 
study and in the Phase 2 experience so far. Phase 1 results indicate that frexalimab treatment with 
the dose chosen for the study can lead up to more than 95% inhibition of TDAR, which supports 
the potential for clinical efficacy. More detailed information on the known and expected benefits 
and risks and reasonably expected AEs of frexalimab may be found in the IB. 
In the single ascending dose study (TDU15525), the Cmax after the highest IV dose (3000 mg) was 
1120 μg/mL and AUCinf was 22 800 μg*day/mL. Overall, a single IV dose of frexalimab between 
200 to 3000 mg was safe and well tolerated.  
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In the multiple ascending dose study (TDR15526), at Day 29, the Cmax after the highest SC dose 
(2100 mg) was 531 μg/mL and AUC0-2 weeks was 5940 μg*day/mL. Overall, 5 dose levels of 
frexalimab between 150 and 2100 mg administered as 3 SC doses q2w were safe and well 
tolerated. 
Estimated exposures for ACT16877 are similar to those observed in the Phase 1 study and are 
well below the NOAEL observed in the non-human primate study. 
The results from Part A of ACT16877 demonstrated a reduction in the number of new 
Gd-enhancing T1-hyperintense brain lesions detected by brain MRI after 12 weeks of treatment. 
There was an 89% relative reduction in lesions at 12 weeks in the IV 1200 mg dose group as 
compared with placebo. Potential benefits include the following: 
• Decrease of annualized relapse rate (ARR). 
• Reduction in the accumulation of confirmed disability worsening. 
• Reduction of disease activity as assessed by MRI. 
Taking into account the measures taken to minimize risk to participants in Study ACT16877, 
the potential risks identified in association with frexalimab are justified by the anticipated benefits 
that may be afforded to participants with MS. The continuation of Part B is confirmed and 
its prolongation is justified by the positive results of Part A. 
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3 
OBJECTIVES AND ENDPOINTS  
Table 3 - Part A objectives and endpoints  
Objectives 
Endpoints 
Primary 
• 
To determine the efficacy of 
frexalimab as measured by 
reduction of the number of 
new active brain lesions. 
• 
Number of new gadolinium (Gd)-enhancing T1-hyperintense (GdE T1) 
lesions at Week 12 as measured by brain magnetic resonance imaging 
(MRI). 
Secondary 
• 
To evaluate efficacy of 
frexalimab on disease activity 
as assessed by other MRI 
measures. 
• 
Number of new or enlarging T2 lesions at Week 12. 
• 
Total number of GdE T1 lesions at Week 12. 
• 
To evaluate the safety and 
tolerability of frexalimab. 
• 
Adverse events (AEs), serious adverse events (SAEs), potentially clinically 
significant abnormalities (PCSAs) in laboratory tests, electrocardiogram 
(ECG), and vital signs during Part A. 
• 
Anti-drug antibodies (ADAs).  
• 
To evaluate 
pharmacokinetics of 
frexalimab. 
• 
frexalimab plasma concentrations over time. Pharmacokinetic (PK) 
parameters (maximum concentration [Cmax], time to Cmax [tmax], area under 
the curve over the dosing interval [AUC0-tau], and elimination half-life [t1/2]). 
Exploratory 
• 
To evaluate efficacy of 
frexalimab on disease 
activity, assessed by clinical, 
imaging measures, and 
patient-reported outcomes. 
• 
Change from baseline to Week 12 in volume, number, and intensity (T1) of 
slowly evolving lesions (SEL).  
• 
Change in number of phase rim lesions in susceptibility weighted imaging 
(SWI) MRI from baseline to Week 8 and Week 12 (subset of centers with 
capacity of 3 Tesla MRI). 
• 
Change in total number of T1-hypointense lesions from baseline to 
Week 8 and Week 12. 
• 
Proportion of participants with no new MRI disease activity at the end of 
12 weeks of treatment. 
• 
Number of new or enlarging T2 lesions at Week 12. 
• 
Number of relapses (annualized relapse rate) over 12 weeks of treatment. 
• 
Proportion of relapse-free participants at the end of 12 weeks of treatment  
Change in EDSS from baseline to Week 12. 
• 
Change in MSIS-29 physical and psychological domains scoring from 
baseline to Week 12. 
• 
Change in PROMIS-Fatigue-MS-8 scoring from baseline to Week 12. 
• 
Descriptive summaries of PQATv3 scores by treatment arm at Week 12. 
• 
PGIC-Fatigue value at Week 12. 
• 
Change in PGIS-Fatigue from baseline to Week 12. 
• 
To explore genetic and 
plasma-based biochemical 
biomarkers that correlate 
with disease 
pathophysiology. 
• 
Analysis of messenger ribonucleic acid (mRNA) signature of cluster of 
differentiation 40/cluster of differentiation-40 ligand (CD40/CD40L) 
pathway activation in blood. 
• 
Change in immune cell at Week 12 compared to baseline. 
• 
Change in plasma neurofilament light chain (NfL) at Week 12 compared to 
baseline. 
• 
Change in serum chitinase-3-like 1 (CHI3L1) at Week 12 compared to 
baseline. 
• 
Change in sTREM2 at Week 12 compared to baseline.  
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Objectives 
Endpoints 
 
• 
Change in CXCL13 at Week 12 compared to baseline. 
• 
Change in IgG, IgM at Week 12 compared to baseline. 
• 
Soluble CD40L (sCD40L) in plasma (at baseline, Week 12, and during 
24 weeks of follow-up after EOT). 
• 
Presence of SNPs in genes related to CD40/CD40L signaling pathway or 
MS disease. 
 
Table 4 - Part B objectives and endpoints  
Objectives 
Endpoints 
Secondary 
• 
To evaluate the long-term 
safety and tolerability of 
frexalimab. 
 
 
• 
To evaluate the safety of the 
1800 mg SC q4w dose 
regimen. 
• 
Adverse events (AEs), serious adverse events (SAEs), potentially 
clinically significant abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG), and vital signs during Part B. 
• 
Adverse events (AEs), serious adverse events (SAEs), potentially 
clinically significant abnormalities (PCSAs) in laboratory tests, 
electrocardiogram (ECG), and vital signs in the 1800 mg SC q4w dose 
regimen group (Part B2). 
• 
Anti-drug antibodies (ADAs). 
• 
To evaluate pharmacokinetics 
of frexalimab beyond 12 weeks 
of study intervention for SC and 
IV regimen, including after 
switch to 1800 mg SC q4w. 
• 
Frexalimab plasma concentrations over time. Pharmacokinetic (PK) 
parameters (maximum concentration [Cmax], time to Cmax [tmax], area 
under the curve over the dosing interval [AUC0-tau], and elimination 
half-life [t1/2]). 
 
Exploratory 
• 
To evaluate efficacy of 
frexalimab on disease activity, 
assessed by clinical, imaging 
measures, and patient-reported 
outcomes. 
• 
Number of new GdE T1 lesions at Week 24, Week 48, and over time.  
• 
Number of new or enlarging T2 lesions at Week 24, Week 48, and over 
time. 
• 
Change in volume, number, and intensity (T1) of slowly evolving lesions 
(SEL) from baseline to Week 12 and Week 48, from Week 48 to Week 
96, from Week 96 to Week 192.  
• 
Change in number of phase rim lesions in susceptibility weighted 
imaging (SWI) MRI from baseline over time (subset of centers with 
capacity of 3 Tesla MRI). 
• 
Change in magnetization transfer imaging (MTR) of GdE T1 lesions 
from Week 8 and Week 12 to Week 24, from Week 20 and Week 24 to 
Week 96, from Week 120, Week 144, and Week 192 to Week 240 
(selected centers).  
• 
Change in volume of T2 lesions from baseline over time. 
• 
Change in brain volume, including regional changes, from baseline to 
EOS. 
• 
Change in total number of T1-hypointense lesions from baseline over 
time. 
• 
Proportion of participants with no new MRI disease activity over time. 
• 
Number of relapses (annualized relapse rate) over time. 
• 
Proportion of relapse-free participants over time. 
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Objectives 
Endpoints 
 
• 
Change in EDSS from baseline over time. 
• 
Change in MSIS-29 physical and psychological domains scoring from 
baseline at Week 24, Week 192, Week 240, Week 288, and at EOS. 
• 
Change in PROMIS-Fatigue-MS-8 scoring from baseline at Week 24, 
Week 192, Week 240, Week 288, and at EOS. 
• 
PGIC-Fatigue value at Week 24. 
• 
Change in PGIS-Fatigue from baseline at Week 24. 
• 
To explore genetic and plasma-
based biochemical biomarkers 
that correlate with disease 
pathophysiology. 
• 
Analysis of messenger ribonucleic acid (mRNA) signature of cluster of 
differentiation 40/cluster of differentiation-40 ligand (CD40/CD40L) 
pathway activation in blood at Week 24. 
• 
Change in immune cell over time compared to baseline. 
• 
Change in plasma neurofilament light chain (NfL) over time compared to 
baseline. 
• 
Change in serum chitinase-3-like 1 (CHI3L1) over time compared to 
baseline. 
• 
Change in sTREM2 over time compared to baseline. 
• 
Change in CXCL13 over time compared to baseline. 
• 
Change in IgG, IgM over time compared to baseline. 
• 
Soluble CD40L (sCD40L) in plasma during 24 weeks of follow-up after 
EOT and Common EOS. 
3.1 
APPROPRIATENESS OF MEASUREMENTS  
Because MS results in a leaky blood-brain barrier, accumulation of Gd contrast agent in brain 
tissue is related to inflammatory activity in MS patients. This radiographic outcome has been 
established as a highly-reliable predictive biomarker for clinical efficacy in pivotal studies in MS. 
The number of new GdE T1 lesions at Week 12 as measured by brain MRI (primary endpoint) is 
a validated and established outcome measurement for therapeutic efficacy in RMS.  
Central review will be used to identify new GdE T1 lesions not present at the previous MRI scans. 
The total count of GdE T1 lesions will also be used as a secondary endpoint to detect any effect 
on pre-existing inflammatory foci. The number of new and enlarging T2-hyperintense lesions, 
another MRI marker of disease activity in MS, will also be evaluated as secondary endpoint to 
collect additional efficacy data.  
In terms of safety, TEAEs, SAEs, adverse events of special interest (AESIs), ECG, vital signs, 
and laboratory analyses will be reported, and local tolerability will be examined. Frexalimab will 
be administered SC or IV after an initial IV loading dose. Measurement of local tolerability will 
be done with a verbal descriptor scale (VDS) and Investigator rating, described in Section 8.2.5. 
Antidrug antibodies will be measured as well, although the mechanism of action of frexalimab 
(prevention of CD40/CD40L interaction) is expected to decrease the risk of ADA formation 
(see Section 2.2). 
Due to the short duration of the study Part A, ARR and changes in EDSS score will be assessed as 
tertiary endpoints. 
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In addition, exploratory assessments, such as analysis of genetic and plasma-based biochemical 
biomarkers and advanced imaging methods are expected to build evidence for frexalimab activity 
on neuroinflammation and neurodegeneration as well as potential effects on remyelination and 
tissue preservation. 
Each of the clinical outcome assessments selected for inclusion in this study is considered relevant 
and fit for purpose in the target populations for the context of use. The multiple sclerosis impact 
scale-29 items (MSIS-29) measure is an established and relevant MS Impact Scale used to 
measure the physical and the psychological impact of MS from the patient’s perspective. 
The patient reported outcome measurement information system-Fatigue-MS-8 (PROMIS-Fatigue-
MS-8) measure is a patient-reported outcome (PRO) questionnaire being qualified by the Food 
and Drug Administration (FDA) in the target population in order to support a label claim for 
fatigue; the Patient Global Impression of Severity-Fatigue (PGIS-Fatigue) and Patient Global 
Impression of Change-Fatigue (PGIC-Fatigue) are each single-item whose measures are used as 
anchors for validating the PROMIS-Fatigue-MS-8. The patient’s qualitative assessment of 
treatment version 3 (PQATv3) is a generic measure developed to provide early patient insights on 
benefits and disadvantages of drugs received within a clinical trial and patient preferences for 
route of administration (ie, SC versus IV). 
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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN  
ACT16877 is a Phase 2, multicenter, randomized, parallel-group, double-blind, 
placebo-controlled study to assess the efficacy, safety, and tolerability of 2 doses/routes of 
administration of frexalimab in participants with RMS (relapsing-remitting MS and 
secondary progressive MS participants with relapses as per inclusion criteria). The study is 
open-label for route of administration and dose group, double-blinded for treatment assignment. 
Independent MRI raters will be blinded for study treatment and dose and other participant data. 
The study consists of 2 parts:  
Part A is a 12-week, double-blind, placebo-controlled part, preceded by a screening period 
starting not earlier than 4 weeks before Day 1. 
At the beginning of Part A, participants will be randomly assigned in a 4:4:1:1 ratio to 
the frexalimab IV q4w or frexalimab SC q2w or IV placebo q4w or SC placebo q2w. Interactive 
response technology will be used to assign treatments to participants. All participants will switch 
to Part B after the Week 12 visit.  
Once the last participant has entered Part B, analysis of Part A data will be performed as the main 
analysis of the study. 
Part B is an open-label frexalimab treatment part of 212 to approximately 280 weeks 
(approximately 53 to 70 months, and not exceeding 296 weeks [74 months]) expected duration for 
individual participants to allow further safety and efficacy analysis. Frexalimab treatment arms 
from Part A will continue the participant’s previous IV or SC treatment routes. Participants from 
the placebo treatment IV or SC arms in Part A will transition to IV q4w or SC q2w frexalimab 
treatment respectively, at Week 12. Further to Part A analysis results, there will be no change of 
dose regimen for the IV arm. In the SC arm, dose regimen will be modified to 1800 mg q4w 
(via syringe infusion material) (for rationale, see Section 4.3). Both treatment arms (IV and SC) 
will be continued until the Common end of study (Common EOS). This design will allow for 
reduction of exposure to placebo and continuation of the evaluation of safety and efficacy of 
frexalimab for a longer period. Treatment will be administered in an open-label fashion from 
Week 14 till the Common EOS. 
For the SC group, Part B is divided in 2 subparts: Part B1 until individual participant switch to 
the modified dose regimen and Part B2 after this switch. 
Based on the expected duration of recruitment of Part A, time needed for primary data analysis, it 
is expected that individual participant treatment duration in both parts of Study ACT16877 will be 
up to 292 weeks (73 months) of study intervention (and will not exceed 308 weeks [77 months]). 
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Investigational medicinal product administration will be performed on-site in Part A. In 
the judgment of the Investigator, if no injections site reactions or adverse events has occurred or is 
suspected, SC injections of frexalimab (from Week 14 onward in Part B1, up to switch to Part B2) 
could be performed at home after appropriate medical training, evaluation of participant’s 
self-injection (or partner/caregiver/home healthcare professional) capability and technique are 
done (please refer to product management manual).  
 and in Part B2 (from 12 weeks after switch) for SC arm, optional home 
administration may be considered for interim visits between 2 quarterly onsite visits (those with 
physical examination and laboratory sampling). In this case, home nurse intervention after 
appropriate medical training and assessment of practical conditions will be required (please refer 
to product management manual). 
In case of any injection site reactions or other adverse events, the participant must contact the site 
as soon as possible for reporting, timely monitoring of any worsening of the events, and decision 
for best evaluation/treatment by the Investigator (including on-site visit if needed). Investigator 
will also proactively contact the participant the day of injection to assure absence of any events or 
to assure their best management if such occur. 
In case of travelling restrictions impacting IMP administration on-site, an in-home Investigator 
visit (or a visit by a qualified physician in communication with the Investigator) may be 
performed in Part B after the agreement of the Sponsor with each concerned site and with 
the establishment of all technical means for such visits. 
A Common EOS will be planned when the first participant randomized has reached 
approximately 292 weeks (73 months) of study intervention administration. The participant must 
be followed-up for 24 weeks after the completion of common EOS (see Section 4.4 for details of 
common EOS). Upon completion of both Parts A and B of this study, post study access to study 
medication could be provided based on local/country regulations or participants will be managed 
individually by their regular caregiver for their future MS therapy, generally after the follow-up 
period. These participants would need to take appropriate RMS treatment (disease-modifying 
therapy) available in their countries per decision of their treating physicians. 
Overall, maximum duration of study participation comprising screening period (4 weeks), Part A 
(12 weeks), Part B (up to 280 weeks and not exceeding 296 weeks), and safety follow-up 
(24 weeks) is 320 weeks (80 months) and will not exceed 336 weeks (84 months). 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN  
A Parallel group design was chosen for this study, providing comparable arms with data collected 
in the same time period for evaluation of efficacy and safety. Randomization of 4:4:1:1 to high 
IV dose, low SC dose, placebo IV, and placebo SC arms was chosen to collect information on 
2 different doses as well as 2 different routes of administration, while keeping the placebo group 
small to minimize participant exposure to placebo. The study is not blinded for route of 
administration and dose group, but is double blinded within each of the SC and IV groups for 
frexalimab or placebo assignment. This allows simplification of the study design while avoiding 
double-dummy additional IMP administration, but maintains the blind for treatment, allowing 
adequate frexalimab evaluation.  
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Duration of the main assessment period of 3 months is expected to be sufficient for efficacy signal 
detection based on the primary endpoint (new T1 GdE lesions in MRI). Duration of 3 months has 
proved to be sufficient to show a meaningful efficacy signal of potent MS treatments (5, 31). 
Choice of the short duration of the placebo comparator is driven by consideration of sample size 
and attempting to minimize participant exposure to the placebo. It is known that treatment effect 
size related to that of placebo can be demonstrated with smaller participant numbers that is 
required for an active comparator. In an attempt to decrease the number of participants receiving 
placebo to a minimum, a randomization ratio of 4:1 was chosen, meaning a participant has only 
a 20% chance to be assigned to a placebo arm. For the same reason, placebo data from the SC and 
IV arms will be pooled for all main analyses, allowing sufficient study power with a small 
placebo group. A main study period of 3 months is rather short and carries a limited risk of 
disease advancement for participants in the placebo arms, keeping in mind the chronic nature of 
RMS and somewhat rare frequency of clinical relapses and generally slow progression. 
This study will assess frexalimab efficacy by measuring number of new GdE T1 lesions, which 
are associated with inflammation. This radiographic outcome has been established as a highly 
reliable predictive biomarker for clinical efficacy in pivotal studies in MS and has been 
demonstrated to be a predictive biomarker for clinical efficacy (reduction in ARR and disability 
worsening) in studies with other MS treatments (2, 3). 
Two secondary efficacy endpoints have been chosen: number of new or enlarging T2 lesions at 
the end of 12 weeks of frexalimab treatment and the number of GdE T1 lesions at the end of 
12 weeks of frexalimab treatment.  
The number of new or enlarging T2 lesions is a recognized to reflect MS inflammatory activity 
and resulting brain tissue lesions. It will provide supportive objective data for efficacy evaluation 
through MRI imaging. The total number of T1 lesions, widely used assessment of inflammatory 
activity in MS trials, will also provide additional support for the primary endpoint. 
Safety and tolerability endpoints including AEs, vital signs, ECG and clinical laboratory 
evaluation are elected as secondary endpoints and will be assessed as per standard practice in 
clinical trials.  
4.3 
JUSTIFICATION FOR DOSE  
The selected doses for Part A and Part B until analysis of Part A are 1200 mg q4w (with 
an IV loading dose of 1800 mg on Day 1) for the IV arm and 300 mg q2w (with an IV loading 
dose of 600 mg) for the SC arm. 
In healthy participants, administration of a single IV dose of frexalimab up to 3000 mg 
(TDU15525) and repeated SC doses (q2w, 3 administrations) of frexalimab up to 2100 mg 
(TDR15526) were safe and well tolerated. Of note, a maximal tolerated dose was not reached in 
either of these clinical studies. There were no serious or severe TEAEs. No trends in vital signs, 
ECGs or laboratory values were identified, including assays aimed at identifying potential 
increased risks for thromboembolism or infections. 
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In the multiple ascending dose study in healthy participants (TDR15526), 150, 300, 600, 1200, 
and 2100 mg doses administered as 3 SC injections q2w were tested. frexalimab inhibited 
KLH-TDAR in a dose dependent manner after 3 doses SC q2w and the sequential administration 
of 2 doses of KLH (Days 4 and 32). Frexalimab administration resulted in a dose-dependent 
inhibition of the TDAR response, with partial inhibition after 3 SC doses of 150 mg and 300 mg 
cohorts (84% and 92%, respectively), and near complete (>97%) inhibition after 3 doses of 
600 mg, 1200 mg, and 2100 mg. After 3 doses, the steady state was not reached. At steady state, 
complete TDAR suppression is to be expected with a dose of 300 mg SC q2w. Thus, a high 
probability of clinical efficacy for this dose is expected. 
A high dose of 1200 mg IV q4w was chosen to assure good target engagement in peripheral 
compartment, but also targeting brain tissue, where drug penetration due to the altered blood-brain 
barrier in MS cannot be ruled out.  
For the dose of 1200 mg IV q4w, expected exposures (AUC0-4 weeks) is equivalent to a dose of 
900 mg SC q2w at steady state, 3-times higher than that of the low dose of 300 mg q2w SC 
planned in the study.  
At the high dose the predicted exposure at steady state, in terms of AUC0-4 weeks (222 000 µg*h/mL), 
will not reach the exposure observed at the highest dose in the TDR15526 repeat dose study 
(SC q2w dose of 2100 mg, estimated AUC0-4 weeks approximately 250 000 µg*h/mL). 
The predicted Cmax of 650 μg/mL (after the loading dose) is approximatively 2-fold lower than 
the Cmax observed in healthy participants after a single dose of 3000 mg IV. Based on preliminary 
PK analysis of the Part A , after the 3rd and last dose, approximatively 90 % of the steady state 
was achieved and AUC0-4weeks was estimated as 190 000 µg*h/mL. 
The rationale of utilizing a loading dose is that, in its absence, steady state is predicted to be 
reached only after 12 weeks. An IV loading dose of double the SC maintenance dose or 1.5-fold 
higher than the IV maintenance dose on Day 1 would assure a plasma concentration close to 
steady state would be reached after the second administration. 
Predicted exposure at steady state in the high dose arm of frexalimab 1200 mg IV q4w has 
a safety margin of 8 relative to the exposure at NOAEL in the chronic toxicology non-human 
primate study. 
The analysis of Part A supports a dose-exposure-response effect. It shows that the efficacy of 
the IV 1200 mg dose is superior to the efficacy of the SC 300 mg dose, with a larger effect size on 
the primary endpoint, new Gd-enhancing T1 lesions (respectively 89% and 79% reduction), and 
secondary endpoints (data on file). The two doses were safe and well tolerated, with no increase in 
frequency or intensity of adverse events. The data therefore support a higher benefit/risk ratio for 
a high dose. Furthermore, it is important to maximize effect in MS when possible.  
In consequence, the open-label period, on the basis of amendment 2, will continue with 
administration of a dose having shown better benefit/risk. Therefore, the starting route of 
administration in each group, IV or SC, will be kept in order to maintain the same route of 
administration for the participants, and PK and safety information will be collected with 
the administration of higher SC doses in participants with RMS.  
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In the IV group, the dose will therefore be unchanged, ie 1200 mg q4W. In the SC group, 
the frequency of administration is reduced (from q2w to q4w) for better convenience to 
the participants, and the change in dose from 300 mg to 1800 mg will allow to reach the exposure 
of the IV arm. The volume to be administered, 12 mL, necessitates an infusion, which will be 
done using a syringe infusion material. Details on the administration will be provided in 
the pharmaceutical manual. Such administration has been performed in Phase 1, with 
administration up to 2100 mg per SC syringe infusion/pump infusion (maximum 0.67 mL/min), 
with good tolerability (more information can be found in the IB). PK sampling and laboratory 
tests will be done every 4 weeks in the 12 weeks following the dose modification (see Table 1).  
With the new proposed SC regimen, 1800 mg q4w, the predicted AUC0-4weeks are similar to 
those at 1200 mg q4w IV (222 000 µg*h/mL compared at steady state), the Cmax is predicted to be 
lower (450 µg/mL versus 650 µg/mL) and Ctrough slightly higher (250 µg/mL versus 220 µg/mL). 
The simulations were conducted using a population PK model (POH0693) developed with 
frexalimab plasma concentration data from 73 healthy subjects included in Phase 1 who received 
either single IV doses (TDU15525) or multiple SC doses (TDR15526). This model is 
a 2 compartmental model and with a linear elimination, the bioavailability after SC administration 
is estimated as 0.7. The preliminary PK data of the Part A of the two arms (SC and IV) showed 
that the predictions in RMS patient population using this model are accurate. 
4.4 
END OF STUDY DEFINITION  
The end of the study is defined as the date of the last visit/last contact of the last participant in 
the study or the last scheduled procedure shown in the Schedule of Activities for the last 
participant in the trial globally.  
Should a participant not consent to transition to the Part B2 modified SC dose regimen, then 
the participant would be withdrawn from the study. 
A Common EOS will be planned when the first participant randomized in the study has reached 
a total duration of approximately 292 weeks (73 months) of study intervention (and will not 
exceed 308 weeks [77 months]). The participant must be followed-up for 24 weeks after 
the completion of Common EOS. 
Routine q4w visits falling into this period will be performed as EOS visits. 
The EOS visit must be performed for every participant as per the SoA (Section 1.3) and must be 
performed for any participant withdrawing consent to continue in the study.  
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit/last contact. 
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5 
STUDY POPULATION  
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
INCLUSION CRITERIA  
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
I 01. Participant must be 18 to 55 years of age inclusive, at the time of signing the informed 
consent.  
Type of participant and disease characteristics 
I 02. The participant must have been diagnosed with RMS (relapsing-remitting MS or 
secondary progressive MS participants with relapses) according to the 2017 revision of 
the McDonald diagnostic criteria (32).  
I 03. The participant must have at least 1 documented relapse within the previous year, or 
≥2 documented relapses within the previous 2 years, or ≥1 active Gd-enhancing brain 
lesion on an MRI scan in the past 6 months and prior to screening. 
Weight 
I 04. Body weight within 45 to 120 kg (inclusive) and body mass index (BMI) within the range 
18.0 to 35.0 kg/m2 (inclusive) at Screening. 
Sex, contraceptive/barrier method and pregnancy testing requirements 
I 05. All 
Contraceptive use by men and women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies.  
a) Male participants: 
Male participants are eligible to participate if they agree to the following during the study 
intervention period and for at least 24 weeks after the last administration of study 
intervention:  
- 
Refrain from donating sperm 
PLUS, either: 
- 
Be abstinent from heterosexual intercourse as their preferred and usual lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent  
OR 
- 
Must agree to use contraception/barrier as detailed below  
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- 
A male condom and an additional highly effective contraceptive method as 
described in Section 10.4.2 when having sexual intercourse with a woman of 
childbearing potential (WOCBP) who is not currently pregnant. 
b) Female participants 
- 
A female participant is eligible to participate if she is not pregnant or breastfeeding, 
and one of the following conditions applies: 
- 
Is a woman of non-childbearing potential (WONCBP) as defined in 
Section 10.4.1. 
OR 
- 
Is a woman of childbearing potential (WOCBP) and agrees to use a contraceptive 
method that is highly effective (with a failure rate of <1% per year), preferably 
with low user dependency, as described in Section 10.4.2 during the study 
intervention period and for at least 24 weeks after the last administration of study 
intervention and agrees not to donate eggs (ova, oocytes) for the purpose of 
reproduction during this period. 
- 
A WOCBP must have a negative highly sensitive pregnancy test (urine or serum 
as required by local regulations) within 24 hours before the first administration of 
study intervention, see Section 8.2.6 Pregnancy testing. If a urine test cannot be 
confirmed as negative (eg, an ambiguous result), a serum pregnancy test is 
required. In such cases, the participant must be excluded from participation if 
the serum pregnancy result is positive. 
Informed Consent 
I 06. Capable of giving signed informed consent as described in Section 10.1 of the protocol 
which includes compliance with the requirements and restrictions listed in the informed 
consent form (ICF) and in this protocol. In countries where legal age of majority is above 
18 years, a specific ICF must also be signed by the participant’s legally authorized 
representative. 
Other inclusions 
Not applicable. 
5.2 
EXCLUSION CRITERIA   
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
E 01. The participant has been diagnosed with PPMS according to the 2017 revision of 
the McDonald diagnostic criteria (32) or with non-relapsing SPMS (33). 
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E 02. The participant has conditions or situations that would adversely affect participation in 
this study, including but not limited to: 
- 
A short life expectancy due to preexisting health condition(s) as determined by 
judgment of investigator or their treating physician. 
- 
Medical condition(s) or concomitant disease(s) making them nonevaluable for 
the primary efficacy endpoint or that would adversely affect participation in this study, 
as judged by the Investigator. 
- 
A requirement for concomitant treatment that could bias the primary evaluation by 
judgment of investigator. 
- 
Contraindication for MRI, ie, presence of pacemaker, metallic implants in high-risk 
areas (ie, artificial heart valves, aneurysm/vessel clips), presence of metallic material 
(eg, shrapnel) in high-risk areas, known history of allergy to any contrast medium, or 
history of claustrophobia that would prevent completion of all protocol scheduled 
MRI. 
- 
Contraindications to use MRI Gd contrast-enhancing preparations. 
E 03. The participant has a history of or currently has concomitant medical or clinical conditions 
that would adversely affect participation in this study, including but not limited to: 
- 
A history of T-lymphocyte or T-lymphocyte-receptor vaccination, transplantation 
(including solid organ, stem cell, and bone marrow transplantation) and/or 
antirejection therapy. 
- 
A history of diagnosis of progressive multifocal leukoencephalopathy (PML) or 
evidence of findings suggestive of PML on the baseline MRI. 
- 
Serious systemic viral, bacterial, or fungal infection (eg, pneumonia, pyelonephritis), 
infection requiring hospitalization or IV antibiotics or significant chronic viral, 
bacterial, or fungal infection (eg, osteomyelitis) 30 days before and during screening. 
- 
Participants with a history of invasive opportunistic infections, such as, but not limited 
to histoplasmosis, listeriosis, coccidioidomycosis, candidiasis, pneumocystis jirovecii, 
and aspergillosis, regardless of resolution. 
- 
Symptomatic herpes zoster within 3 months prior to screening. 
- 
Evidence of active or latent tuberculosis (TB) as documented by medical history and 
examination, chest X-rays (posterior anterior and lateral), and TB testing: either 
a positive tuberculin skin test (TST; defined as a skin induration <5 mm at 48 to 
72 hours, regardless of Bacillus Calmette-Guerin [BCG] or other vaccination history) 
or a positive (not indeterminate) QuantiFERON®-TB Gold test. NOTE: The choice to 
perform a TST or a QuantiFERON-TB Gold test will be made by the investigator 
according to local licensing and standard of care. The QuantiFERON-TB Gold test can 
only be used in countries where it is licensed, and the use of this test is dependent on 
previous treatment(s). This test may not be suitable if previous treatment(s) produced 
significant immunosuppression. 
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- 
Any other active infections that would adversely affect participation or IMP 
administration in this study, as judged by the Investigator. 
- 
A history of malignancy within 10 years prior to the first screening visit, except 
effectively treated carcinoma in situ of the cervix or adequately treated nonmetastatic 
squamous or basal cell carcinoma of the skin. 
- 
A history of alcohol or drug abuse within 1 year prior to the first screening visit. 
- 
A history of any psychiatric disease, behavioral condition, or depression requiring 
hospitalization within 2 years prior to the first screening visit. 
- 
Presence of any screening laboratory or ECG values outside normal limits that are 
considered in the Investigator’s judgment to be clinically significant. 
- 
Current or chronic history of liver disease, or known hepatic or biliary abnormalities 
(with the exception of Gilbert's syndrome or asymptomatic gallstones). 
E 04.  History, clinical evidence, suspicion, or significant risk for thromboembolic events, as 
well as myocardial infarction, stroke and/or antiphospholipid syndrome and any 
participants requiring antithrombotic treatment. 
E 05. Allergies to humanized monoclonal antibodies or severe post-treatment hypersensitivity 
reactions other than localized injection site reaction, to any biological molecule (including, 
but not limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal 
necrolysis, and exfoliative dermatitis). 
Prior/concomitant therapy 
E 06.  The participant has received any of the following medications/treatments within 
the specified time frame before any baseline assessment (no wash-out is required for 
interferons beta or glatiramer acetate treatments): 
 
Medication 
Exclusionary if used/used within 
required wash-out period 
Systemic corticosteroids, adrenocorticotropic hormone 
1 month prior to screening MRI scan 
Dimethyl fumarate 
1 month prior to randomization 
Intravenous (IV) immunoglobulin, plasmapheresis, fingolimod, 
natalizumab (participants who have discontinued natalizumab in 
the 6 months prior to randomization should be evaluated to rule out PML) 
2 months prior to randomization 
Teriflunomide 
3 months prior to randomization. No time restriction 
if accelerated elimination procedure is donea 
B-cell-depleting therapies such as ocrelizumab and rituximab 
6 months prior to randomization or until return of 
B-cell counts to normal levels, whichever is longer 
Mildly to moderately immunosuppressive/chemotherapeutic medications 
such azathioprine and methotrexate 
6 months prior to randomization 
Highly immunosuppressive/chemotherapeutic medications: mitoxantrone 
up to 120 mg/m2 body surface area, cyclophosphamide, cladribine 
2 years prior to randomization 
Alemtuzumab 
4 years prior to randomization 
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Medication 
Exclusionary if used/used within 
required wash-out period 
Other MS-disease modifying treatments 
5 half-lives or until end of pharmacodynamics 
activity, whichever is longer 
Lymphoid irradiation, bone marrow transplantation, mitoxantrone (with 
evidence of cardiotoxicity following treatment, or cumulative lifetime dose 
>120 mg/m2), other strongly immunosuppressive treatments with very 
long-lasting effects 
Any time (not eligible for enrollment) 
Any live (attenuated) vaccine (including but not limited to varicella zoster, 
oral polio, and nasal influenza)  
3 months prior to randomization 
Abbreviations: MRI = magnetic resonance imaging; MS = multiple sclerosis; PML = progressive multifocal leukoencephalopathy; 
IV = intravenous.  
a Teriflunomide accelerated elimination procedure must be followed per locally approved product information. 
 
Prior/concurrent clinical study experience 
E 07. The participant has taken other investigational drug within 3 months or 5-half-lives, 
whichever is longer, before the screening visit. 
Diagnostic assessments 
E 08. The participant has an EDSS score >5.5 at the first screening visit. 
E 09.  The participant has had a relapse in the 30 days prior to randomization. 
E 10. Positive human immunodeficiency virus (HIV) serology (anti HIV1 and anti HIV2 
antibodies) or a known history of HIV infection, active or in remission. 
E 11. Abnormal laboratory test(s) at Screening: 
- 
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.0 × ULN. 
- 
Bilirubin >1.5 × ULN; unless the participant has documented Gilbert syndrome 
(isolated bilirubin >1.5 × ULN is acceptable if bilirubin is fractionated and direct 
bilirubin <35%). 
- 
Hemoglobin <11 g/100 mL for males and <10 g/100 mL for females. 
- 
Lymphocytes <1000/mm3. 
- 
Neutrophils <1500/mm3 (except <1000/mm3 for participants of African descent) . 
- 
Platelets <140 000/mm3. 
- 
Estimated Glomerular filtration rate <60 mL/min/1.73 m2 (Modification of Diet in 
Renal Disease [MDRD]). 
E 12. Presence of hepatitis B surface antigen (HBsAg) and anti-hepatitis B core antibodies 
(anti-HBc Ab) at screening or within 3 months prior to first dose of study intervention. If 
anti-HBs negative and anti-HBc positive: perform hepatitis B virus DNA test to confirm.  
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Positive hepatitis C antibody test result at screening or within 3 months prior to starting study 
intervention. NOTE: Participants with positive Hepatitis C antibody due to prior resolved disease 
can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. 
Other exclusions 
E 13. Individuals accommodated in an institution because of regulatory or legal order; prisoners 
or participants who are legally institutionalized. 
E 14. Any country-related specific regulation that would prevent the participant from entering 
the study - see Appendix 7 (Section 10.7) of the protocol. 
E 15. Participant not suitable for participation, whatever the reason, as judged by the 
Investigator, including medical or clinical conditions, or participants potentially at risk of 
noncompliance to study procedures. 
E 16. Participants are employees of the clinical study site or other individuals directly involved 
in the conduct of the study, or immediate family members of such individuals 
(in conjunction with Section 1.61 of the international conference of harmonization 
[ICH]-good clinical practice [GCP] Ordinance E6). 
E 17. Any specific situation during study implementation/course that may raise ethics 
considerations. 
E 18. Known hypersensitivity to any of the study interventions, or components thereof, or to 
a drug or other allergy that, in the opinion of the Investigator, contraindicates participation 
in the study. 
E 19. Any participant with a known history of ADA to a monoclonal antibody-based biologic. 
E 20. Any participant who has previously received frexalimab. 
 
5.3 
LIFESTYLE CONSIDERATIONS  
5.3.1 Meals and dietary restrictions  
No specific dietary restrictions are applicable throughout the study. Fasting is preferred if possible 
in those visits where clinical chemistry (laboratory) will be assessed, as per the SoA (Section 1.3). 
Fasting is defined as no food/no drinks beside water without any supplements for at least 
10 hours. Fasting/non-fasting status will be recorded at the time of blood collection.  
5.3.2 Caffeine, alcohol, and tobacco  
During the study, it is recommended that participants should try to abstain from drinking alcohol 
and using tobacco products as much as possible. No recommendations or restrictions apply 
regarding caffeine. 
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5.3.3 Activity  
No restriction is required.  
5.4 
SCREEN FAILURES  
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory 
authorities. Minimal information includes demography, screen failure reasons, eligibility criteria, 
and any serious adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once, if criterion at cause can be expected to change (eg, mild laboratory abnormality). 
There is no requirement for a waiting period between the screen failure date and the rescreen date. 
Participants who are rescreened must sign a new informed consent and all Screening visit 
procedures must be repeated, if they were performed more than 4 weeks prior to the new Day 1 
(except DNA test and previously positive serology tests for infectious diseases). 
If participant was not eligible due to abnormal parameter(s) which was(were) retested during 
screening period and eligibility was confirmed, participant may be randomized and will not be 
considered as screen failure. 
5.5 
CRITERIA FOR TEMPORARILY DELAYING RANDOMIZATION/ADMINISTRATION OF 
STUDY INTERVENTION  
During a regional or national emergency declared by a governmental agency, if the site is unable 
to adequately follow protocol mandated procedures, contingency measures are proposed in 
Section 10.8. 
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6 
STUDY INTERVENTION(S) AND CONCOMITANT THERAPY  
Study interventions are all pre-specified IMPs, AxMPs, and medical devices and other 
interventions (eg, surgical and behavioral) intended to be administered to the study participants 
during the study conduct.  
Home administration will not be considered in the Part A of this clinical trial, particularly as 
this is a first study in people with MS. In Part B1, for additional SC injection visits only (from 
Week 14 onward) if, in the judgment of the Investigator, no injection site reactions or adverse 
events have occurred, participants may perform SC injections of frexalimab at home after 
appropriate medical training, evaluation of participant’s self-injection or partner/caregiver/home 
healthcare professional capability and technique are done (please refer to product management 
manual). Visiting nurse may be also solicited for at home injection.  
 and in Part B2 (from 12 weeks after switch) for SC arm, optional home 
administration may be considered for interim visits between 2 quarterly onsite visits (those with 
physical examination and laboratory sampling). In this case, home nurse intervention after 
appropriate medical training and assessment of practical conditions will be required (please refer 
to product management manual). 
In case of any injection site reaction or other adverse event, participant must contact the site as 
soon as possible for reporting, timely monitoring of any worsening of the events and decision for 
best evaluation/treatment by the Investigator (including on-site visit if needed). Investigator or 
designee will also proactively contact the participant the day of injection to assure absence of any 
events or to assure their best management if such occur. 
In case of direct to patient (DTP) IMP delivery, it will be performed directly to the participant’s 
home. The IMP may be supplied from the site to the participant via a Sponsor-approved courier 
company where allowed by local regulations and approved by the participant. Under no other 
circumstances will the Investigator supply the IMP to a third party, allow the IMP to be used other 
than as directed by this clinical study protocol, or dispose of IMP in any other manner.
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6.1 
STUDY INTERVENTION(S) ADMINISTERED  
Table 5 - Investigational medicinal product(s) administered  
Intervention label 
frexalimab IV 
Placebo IV 
frexalimab SC 
Placebo SC 
Intervention name 
frexalimab 
placebo 
frexalimab 
placebo 
Type 
Drug 
Drug 
Drug 
Drug 
Dose formulation 
: frexalimab solution 
for injection 150 mg/mL: 
 
Same as active without 
frexalimab protein 
: frexalimab solution 
for injection 150 mg/mL: 
 
Same as active without 
frexalimab protein 
Unit dose strength(s) 
300 mg/2 mL 
 
2 mL 
300 mg/2 mL 
 
2 mL 
Dosage level(s) 
IV arm: 1800 mg loading dose; then 
1200 mg q4w 
SC arm: 600 mg loading dose 
Not applicable 
Part B1a: 300 mg every 2 weeks after 
600 mg IV loading dose 
Part B2: 1800 mg every 4 weeks  
Not applicable 
Route of administration 
IV infusion 
IV infusion 
Part B1a: SC injection after IV infusion 
Part B2a: SC infusion  
SC injection 
Use 
Experimental active 
placebo 
Experimental active 
placebo 
Packaging and labeling 
Study Intervention will be provided in 
1 vial treatment box (ie, 1 vial per 
treatment box). Each vial and box will be 
labeled as required per country 
requirement 
Study Intervention will be 
provided in 1 vial treatment box 
(ie, 1 vial per treatment box). 
Each vial and box will be labeled 
as required per country 
requirement 
Study Intervention will be provided in 
1 vial treatment box (ie, 1 vials per 
treatment box). Each vial and box will 
be labeled as required per country 
requirement 
Study Intervention will be 
provided in 1 vial treatment 
box (ie, 1 vials per treatment 
box). Each vial and box will 
be labeled as required per 
country requirement 
[Current/Former name(s) 
or alias(es)] 
Not applicable 
Not applicable 
Not applicable 
Not applicable 
Abbreviations: IV = intravenous; SC = subcutaneous. 
a Part B1 until switch from 300 mg q2w SC to 1800 mg q4w SC, Part B2 after switch. Switch will occur after amended protocol 02 is approved and syringe infusion material is available on site 
b 
 
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Table 6 - Arms and associated interventions  
Arm name 
IV frexalimab - frexalimab arm 
IV placebo- frexalimab arm 
SC frexalimab - frexalimab arm 
SC placebo- frexalimab arm 
Associated interventions 
(intervention label[s]) 
frexalimab IV, placebo IV 
frexalimab IV, placebo IV 
frexalimab IV, frexalimab SC, 
placebo IV 
frexalimab IV, frexalimab SC, 
placebo IV, placebo SC 
Abbreviations: IV = intravenous; SC = subcutaneous.
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The administration of IMP by visit is detailed in Table 7. 
Table 7 - IMP administration by visit 
  
Arm  
Day 1  
other Part A visits 
Week 12  
Part B visits 
IV frexalimab - frexalimab  6 vials frexalimab IV 
4 vials frexalimab IV 
every 4 weeks 
4 vials frexalimab IV 
 +2 vials placebo IV 
4 vials frexalimab IV 
every 4 weeks 
IV Placebo- frexalimab 
6 vials placebo IV 
4 vials placebo IV 
 every 4 weeks 
6 vials frexalimab IV 
4 vials frexalimab IV 
every 4 weeks 
SC frexalimab - frexalimab 2 vials frexalimab IV 
1 vial frexalimab SC 
 every 2 weeks 
1 vial frexalimab SC 
and 
 +2 vials placebo IVa 
1 vial frexalimab SC 
every 2 weeks (Part B1b) 
6 vials frexalimab SC 
every 4 weeks (Part B2b) 
SC Placebo- frexalimab 
2 vials placebo IV 
1 vial placebo SC 
every 2 weeks  
1 vial placebo SC  
and  
2 vials frexalimab IVa 
1 vial frexalimab SC 
every 2 weeks (Part B1b) 
6 vials frexalimab SC 
every 4 weeks (Part B2b) 
Abbreviations: IMP = investigational medicinal product; IV = intravenous; SC = subcutaneous. 
Frexalimab vials contain 300 mg/2 mL of frexalimab. 
Placebo vials contain 2mL of matching placebo. 
a Subcutaneous injections should be done after PK sampling and before IV infusion start. 
b Part B1 until switch from 300 mg q2w SC to 1800 mg q4w SC, Part B2 after switch. Switch will occur after amended protocol 02 is approved 
and once syringe infusion material is available on site. 
Table 8 - 
  
 
Abbreviations: IMP = investigational medicinal product; IV = intravenous; SC = subcutaneous. 
 
6.1.1 Frexalimab  
Frexalimab is a humanized mouse monoclonal IgG1 antagonist antibody against CD40L, with 
a modification to the Fc region to prevent binding to FcγRIIa and associated platelet activation. 
 drug product is a sterile, non pyrogenic, clear to opalescent solution for 
injection essentially free of visible particles. It is packaged in an ISO 2R USP/Ph. Eur. Type I 
borosilicate glass vial, stoppered with a 13 mm USP/Ph. Eur. elastomeric stopper and sealed with 
an aluminum seal. Each frexalimab product single use vial contains a nominal volume of 2 mL of 
150 mg/mL frexalimab solution. An overfill volume of 0.35 mL is included to allow for 
withdrawal of 2 mL of solution (300 mg frexalimab). The composition of frexalimab 
 drug product solution includes frexalimab, 
. The pH of the formulated solution is 
. 
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6.1.2 Placebo  
Each matching placebo is packaged as described for frexalimab and is of the same composition as 
the active drug without the monoclonal antibody as described in Section 6.1.2. 
There is no apparent differences between frexalimab and placebo, so they cannot be distinguished 
by the site staff and participant. 
6.1.3 Auxiliary medicinal product(s)  
• Formulation: MRI contrast-enhancing preparations 
• Route(s) of administration: IV 
• Dose regimen: as per respective label. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY  
A complete description of IMP preparation for IV and SC administration will be provided in 
the product management manual available to the clinical site. 
The product must be stored at 2°C to 8°C (36°F to 46°F) and protected from light prior to 
preparation with limited shaking (no vortex). The IMP should not be frozen. Light exposure is 
permitted during preparation and administration. Sites are requested to maintain a temperature log 
to ensure storage temperature remains within acceptable limits.  
1. The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants randomized in the study may receive the study intervention, and only 
authorized site staff may supply or administer the study intervention. All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the Investigator and authorized site staff. 
3. The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
Any quality issue noticed with the receipt or use of an IMP (deficiency in condition, appearance, 
pertaining documentation, labeling, expiration date, etc) must be promptly notified to the Sponsor. 
Some deficiencies may be recorded through a complaint procedure (see Section 8.3.10). 
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A potential defect in the quality of IMP may be subject to initiation of a recall procedure by 
the Sponsor. In this case, the Investigator will be responsible for promptly addressing any request 
made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
Under no circumstances will the Investigator supply the IMP to a third party (except for direct to 
patient [DTP] shipment, for which a courier company has been approved by the Sponsor), allow 
the IMP to be used other than as directed by this clinical trial protocol, or dispose of IMP in any 
other manner. 
6.2.1 Intravenous preparation and handlings  
The IMP will be administered by IV infusion over a minimum of 60 minutes. The necessary 
number of vials of IMP will be diluted in a pre-filled 0.9% saline bag to constitute approximately 
100 mL per single infusion. A system flush needs to be performed after the end of infusion to 
assure that complete dose is administered. A complete and detailed description can be found in 
the product management manual.  
6.2.2 Subcutaneous preparation and handlings  
The IMP should be prepared in an appropriate syringe (details are provided in the product 
management manual).  
In Part B1, each SC dose will require 1 injection with 2 mL IMP per injection. All SC IMP 
injections should be administered in the abdomen. At Week 12 visit SC injection must be 
performed after the predose PK sample and before the start of IV infusion. For additional injection 
visits in the SC treatment arm only (Part B1). If, in the judgment of the investigator, no adverse 
reaction have occurred or is suspected, SC injections of frexalimab (from Week 14 on) can be 
performed at home after appropriate medical training, assessment of the participant’s 
self-injection or partner/caregiver/home healthcare professional capability and technique are done 
(please refer to product management manual). 
For the q4w SC infusion in Part B2, a syringe infusion material will be used (details are provided 
in the product management manual). To administer the 1800 mg dose, 6 vials of 
 will be used. 
The infusion rate for the first infusion should be in line with the TDR15526 study (maximum rate 
0.67 mL/min, ie, approximately 18 min for 12 mL). Then the flow rate can be adjusted depending 
on tolerability. The first SC infusion must be performed at site, under staff supervision. Then, 
after 12 weeks under modified SC dose regimen, home administration may be considered if 
deemed appropriate by the investigator. In this case, home nurse intervention after appropriate 
medical training and assessment of practical conditions will be required (please refer to product 
management manual).  
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It is recommended that SC injection sites are alternated between the 4 quadrants of the abdomen 
with the injection sites at least 2 cm from the umbilicus. 
A complete and detailed description can be found in the product management manual. 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING  
A randomized treatment kit number list will be generated centrally by Sanofi for the IMPs. 
The IMPs (frexalimab or matching placebo) will be packaged in accordance with the list. 
The Sponsor’s Clinical Supply Chain team will provide the randomized treatment kit number list 
to the centralized treatment allocation system (IRT). This centralized treatment allocation system 
will generate the participant randomization list according to which it will allocate the IMP to 
the participants. The Investigator or designee will obtain the treatment kit number(s) and route of 
administration at randomization (Day 1, baseline) and subsequent scheduled dosing visits via 
an IRT that will be available 24 hours/day. Although the kit number(s) will vary for the individual 
participant, the treatment group assignment and randomization will not change throughout 
the study. 
Randomization will take place at baseline (on Day 1) with no stratification factor. 
A participant who has been allocated to a randomized study intervention will be considered 
a randomized participant, regardless of whether the treatment kit was used (ie, the participant was 
registered by the IRT). A participant cannot be randomized more than once in the study. 
Unblinding 
The IRT will be programmed with blind-breaking instructions. In the case of an emergency, 
the Investigator has the sole responsibility for determining if the unblinding of a participant’s 
intervention assignment is warranted (eg, in case of an AE, the code must only be broken in 
circumstances when the knowledge of the IMP is required for treating the participant). Participant 
safety must always be the first consideration when making such a decision. If the Investigator 
decides that the unblinding is warranted, the Investigator, at his/her discretion, may contact 
the Sponsor to discuss the situation prior to unblinding a participant’s intervention assignment, 
unless this could delay emergency treatment of the participant. Code breaking can be performed at 
any time by using the proper module of the IRT. If a participant’s intervention assignment is 
unblinded, the Sponsor must be notified within 24 hours after breaking the blind. The date, time 
of the day, and reason that the blind was broken must be recorded in the source documentation 
and electronic case report form (e-CRF), as applicable. If the code is broken by the Investigator, 
the participant must be withdrawn from the study treatment.  
Methods of blinding 
This study is blinded for treatment allocation (frexalimab or placebo). Vials of frexalimab and 
placebo will be identical. Due to ethical considerations, placebo duration is restricted to 12 weeks, 
which will allow more objective evaluation of safety events at the beginning of the study period 
and will also add to objectivity of evaluation of clinical endpoints. 
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There are no apparent differences between frexalimab and placebo, so they cannot be 
distinguished by the site staff and participant. 
Blinded IMPs will be supplied for treatment in Part A. Participants will receive frexalimab or 
matching placebo IV or SC as per random assignment. At Week 12, a switch of IV and SC 
placebo groups to IV and SC frexalimab groups, respectively, will take place. Participants will 
receive frexalimab with placebo double-dummy masking as needed in a double-blind fashion as 
specified in Table 7. 
The bioanalyst and the pharmacokineticist responsible for sample analysis and PK evaluation will 
be unblinded. However, they will agree not to disclose the randomization schedule or the 
individual unblinded analytical results before the official opening of the randomization schedule. 
Preliminary PK data, if needed and available during the study, will refer to means with descriptive 
statistics, and individual data will not be associated to any individual randomization numbers or 
participant numbers. 
Laboratory assessments of the Part A for biomarkers in the SoA (see Section 1.3), as well as of 
ADA and PK data, will be blinded to study teams, Investigators, and participants from 
baseline/Day 1 throughout the study. In case of a safety concern, unblinding can be performed by 
the Investigator and/or Sponsor for biomarkers. Dedicated Sponsor's team members will be also 
unblinded for technical integration of laboratory data into the database before the database lock of 
Part A. 
Investigators will not have access to MRI data except for any safety-related findings, which will 
be communicated in order to evaluate the safety of the participant. The local radiology service for 
the site will be in charge of timely reporting of any safety-related findings on MRI scans to 
the Investigator. In addition, in accordance with standard clinical practice, the Investigator may 
access full report of MRI performed from Week 24 through the local radiologist. 
Independent raters of MRI will be blinded for study treatment and dose and other participant data. 
6.4 
STUDY INTERVENTION COMPLIANCE  
When participants are treated at the site, they will receive the study intervention directly from 
the Investigator or designee, under medical supervision. The date and time of each dose 
administered in the clinic will be recorded in the source documents. The dose and route of 
administration of the study intervention and study participant identification will be confirmed at 
the time of treatment by a member of the study site staff other than the person administering 
the study intervention. Details on administration of the IMP and recording of the IMP 
administration can be found in the product management manual.  
The same verifications will be performed before dispensing IMP for SC at-home administration 
(see Section 4.1 for detail) at the site or by an authorized third party.  
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6.5 
DOSE MODIFICATION  
Dose reduction is not foreseen in this study. Participants, Investigators, and the Sponsor’s team 
will be blinded with respect to assigned treatments (frexalimab or placebo), but not blinded for 
administration route and dose group. Treatment may need to be interrupted or permanently 
discontinued if deemed necessary due to an AE (Section 7 and Section 8.3). 
A participant may switch to the other arm after evaluation of results of Part A, if it is decided to 
close one arm. This may occur at a different time in the Part B for an individual participant, 
depending on the time of recruitment to the study. 
6.6 
CONTINUED ACCESS TO INTERVENTION AFTER THE END OF THE STUDY  
Upon completion of Parts A and B of this study, post study access to study medication could be 
provided based on local/country regulations or participants will be managed by their treating 
physician who will decide the best DMT appropriate for the participant.  
6.7 
TREATMENT OF OVERDOSE  
An overdose (accidental or intentional) with the IMP is an event suspected by the Investigator or 
spontaneously notified by the participant (not based on systematic pills count) and defined as: 
• Intravenous doses:  
- 
Increase of at least 30% of the dose to be administered or the dose is administered in 
less than 30 minutes. 
- 
At least twice the intended dose within 20 days. 
• Subcutaneous doses:  
- 
q2w regimen: at least twice the intended dose within 8 days. 
- 
q4w regimen: at least twice the intended dose within 20 days. 
Of note, asymptomatic overdose has to be reported as a standard AE. 
The Sponsor does not recommend a specific treatment for an overdose. 
In the event of an overdose, the Investigator/treating physician should: 
1. Contact the Sponsor immediately. 
2. Evaluate the participant to determine, in consultation with the Sponsor, whether study 
intervention should be interrupted or dosing schedule modified. 
3. Closely monitor the participant for any AE/SAE and laboratory abnormalities at least for 
3 months. 
4. Obtain a plasma sample for PK analysis if requested by the Sponsor (determined on 
a case-by-case basis). 
5. Document appropriately in the e-CRF. 
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6.8 
PRIOR AND CONCOMITANT THERAPY  
Any medication or vaccine (including over-the-counter or prescription medicines, recreational 
drugs, vitamins, and/or herbal supplements) or other specific categories of interest that 
the participant is receiving at the time of enrollment or receives during the study must be recorded 
along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency. 
The same data will be collected for all prior medications received during the 4 weeks before 
enrollment, also for all prior MS treatments and treatments considered clinically important to 
assess MS or concomitant disease. 
Multiple sclerosis relapses should be treated as per local practices: eg, with high-dose 
IV methylprednisolone for 3 to 5 days, or other equivalent treatment, per local guidance or 
routine. 
Non-essential systemic corticosteroid use should be avoided, especially in Part A, if other 
equivalent treatments can be used without additional risk for the participant. 
6.8.1 Prohibited medication  
In addition to the medicines excluded in Section 5.2, the following medications are prohibited 
throughout the study: 
• Other MS disease-modifying treatments.  
6.8.2 Rescue medicine  
Not applicable. 
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7 
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL  
  
7.1 
DISCONTINUATION OF STUDY INTERVENTION   
  
7.1.1 Permanent discontinuation  
The study intervention should be continued whenever possible. 
In rare instances, it may be necessary for a participant to permanently discontinue the study 
intervention. If the study intervention is permanently discontinued, the participant will remain in 
the study to be followed until the Common EOS. During this extended participation in the study 
without study intervention, the participant can be treated for RMS according to local clinical 
practices and the best judgment of the investigator, generally after the follow-up period. 
The participant must be followed-up for 24 weeks and shall be asked to perform the key efficacy 
visits until the Common EOS (that may occur after the 24 weeks follow-up period). 
If the participant does not agree to continue until the Common EOS, the 3 additional follow-up 
visits must be performed for 24 weeks after the last administration of the IMP (see SoA, 
Section 1.3) for 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. 
Prescription of subsequent disease-modifying therapy for RMS should generally be made after 
the 24-week follow-up period, depending on individual circumstances. 
In case of the following events, a definitive discontinuation of the IMP is mandatory. This list is 
not intended to be exhaustive: 
• At the request of the participant: ie, withdrawal of consent for the study. 
• Pregnancy of a female participant. 
• Thromboembolic events including, but not limited to, deep vein thrombosis, pulmonary 
embolism, myocardial infarction, and stroke. 
• Any serious opportunistic infections (eg, PML [see Section 10.6]). 
• Occurrence of any malignancy. 
• Severe hypersensitivity or anaphylactic reaction. 
• Severe injection site reaction. 
• Any AE, per Investigator judgment, that may jeopardize the safety of the participant, or if 
discontinuation of the study intervention is considered necessary by the Investigator and/or 
participant.  
• Continuous need for chronic use of prohibited medication (ie, other disease-modifying 
treatments). 
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• Any code breaking performed by the Investigator.  
• At the specific request of the Sponsor.  
• The participant is no longer deriving a therapeutic/clinical benefit in the opinion of 
the Investigator 
Discontinuation of the IMP for laboratory abnormalities should be considered by the Investigator 
when a participant meets one of the conditions outlined in Appendix 6 (Section 10.6) or if 
the Investigator believes that it is in the best interest of the participant.  
Any abnormal laboratory value or ECG parameter will be immediately rechecked for 
confirmation before making a decision regarding possible definitive IMP discontinuation for 
the concerned participant. All efforts should be made to reassess, in a clinically relevant 
timeframe (using either a local or central laboratory), the clinical significance of laboratory 
abnormalities and corrective actions before making a decision of definitive discontinuation of 
the IMP for the concerned participant. 
Handling of participants after permanent intervention discontinuation 
Participants will be followed-up according to the study procedures specified in this protocol up to 
the scheduled date of study completion, or up to recovery or stabilization of any AE to be 
followed-up as specified in this protocol, whichever comes last. 
If possible, and after the permanent discontinuation of intervention, participants will be assessed 
using the procedure normally planned for the last day of treatment with the IMP including PK and 
ADA samples. MRI should be performed as early as possible after discontinuation of the IMP if 
the last MRI was performed earlier than 1 month before. Afterwards, the participant will be asked 
to attend all planned visits until the Common EOS, if possible. The Investigators should 
encourage the participant to attend primarily visits with efficacy assessments until Common EoS. 
If the participant does not agree to continue until the Common EOS, he/she will be followed-up 
for 24 weeks after the last administration of the IMP. 
All cases of permanent intervention discontinuation must be recorded by the Investigator in 
the appropriate pages of the e-CRF when considered as confirmed. 
7.1.2 Liver chemistry stopping criteria  
Discontinuation of study intervention for abnormal liver tests is required by the Investigator when 
a participant meets one of the conditions outlined in the algorithm in Section 10.6 or in 
the presence of abnormal liver chemistry not meeting protocol-specified stopping rules, if 
the Investigator believes that it is in the best interest of the participant. 
7.1.3 Temporary discontinuation  
Temporary intervention discontinuation may be considered by the Investigator because of 
suspected AEs. The Investigator should record the duration of all temporary intervention 
discontinuations, duration should be recorded by the Investigator in the appropriate pages of 
the e-CRF. Planned visits should take place as scheduled, if possible, during this period of 
discontinuation. 
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In case of suspected COVID-19 (eg, fever, cough, shortness of breath in the context of possibly 
infected contact), temporary discontinuation of the IMP can be considered. The following should 
be considered to evaluate individual benefit-risk assessment for resuming or stopping of the IMP: 
probability of COVID-19 disease, possibility of rapid diagnosis, severity of symptoms, and risk 
factors. If the COVID-19 diagnosis is confirmed, the IMP will be suspended until the participant 
recovers (ie, becomes asymptomatic), and presents a negative PCR test, after which IMP can be 
continued (or resumed if a dose was skipped) (Section 7.1.1). 
A discontinuation of the IMP of greater than 45 days during Part A will be considered definitive 
and relevant e-CRF sections should be populated. If this occurs in Part B, the Sponsor must be 
contacted to decide mutually on further treatment continuation. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8. 
7.1.4 Rechallenge  
Reinitiation of intervention with the IMP will be done under close and appropriate clinical and/or 
laboratory monitoring once the Investigator has considered, according to his/her best medical 
judgment that the responsibility of the IMP(s) for the occurrence of the concerned AE was 
unlikely and if the selection criteria for the study are still met (see Section 5.1 and Section 5.2). 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8. 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY  
• A participant may withdraw from the study at any time at the participant’s own request for 
any reason (or without providing any reason), or may be withdrawn at any time at 
the discretion of the Investigator for safety, behavioral or compliance reasons. 
• A participant not willing consenting to switch to Part B2 modified SC dose regimen would 
also be withdrawn. 
• At the time of discontinuing from the study, if possible, an early discontinuation visit 
should be conducted, as shown in the SoA (Section 1.3). See the SoA for data to be 
collected at the time of study discontinuation and follow-up and for any further 
evaluations that need to be completed. 
• If the participant withdraws consent from the study, the Sponsor will retain and continue 
to use any data collected before such a withdrawal of consent as per applicable clinical 
regulation(s). 
• If a participant withdraws from the study, the participant may request destruction of any 
samples taken and not tested, and the Investigator must document this in the site study 
records. 
If participants no longer wish to take the IMP, they will be encouraged to remain in the study. 
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The Investigators should discuss with them key visits to attend, which are all visits with efficacy 
assessments until Common EOS. The value of all their study data collected during their continued 
involvement will be emphasized as important to the public health value of the study. 
Participants who withdraw from the study intervention should be explicitly asked about 
the contribution of possible AEs to their decision, and any AE information elicited must be 
documented. 
All study withdrawals should be recorded by the Investigator in the appropriate screens of 
the e-CRF and in the participant’s medical records. In the medical record, at least the date of 
the withdrawal and the reason should be documented. 
In addition, a participant may withdraw his/her consent to stop participating in the study. 
Withdrawal of consent for intervention should be distinguished from withdrawal of consent for 
follow-up visits and from withdrawal of consent for non-participant contact follow-up, 
eg, medical record checks. The site should document any case of withdrawal of consent. 
Participants who have withdrawn from the study cannot be rerandomized/reallocated (treated) in 
the study. Their inclusion and intervention numbers must not be reused. 
7.3 
LOST TO FOLLOW UP  
A participant will be considered lost to follow-up if the participant 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 and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/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 (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, the participant will be considered to 
have withdrawn from the study. 
Discontinuation of specific sites of the study as a whole are handled as part of Appendix 1 
(Section 10.1.9). 
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8 
STUDY ASSESSMENTS AND PROCEDURES  
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• 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 and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management 
(eg, serology tests) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
• Safety/laboratory/analyte results that could unblind the study will not be reported to 
investigative sites or to other blinded personnel until the final database lock. 
• The maximum amount of blood collected from each participant over the duration of 
the study, including any extra assessments that may be required, will not exceed 
approximately 890 mL, in case of longest possible participation in the study of 73 months. 
Maximum amount of blood collected during 12 weeks in Part A will not exceed 
approximately 225 mL.  
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8. 
8.1 
EFFICACY ASSESSMENTS  
Planned time points for all assessments are provided in the SoA (Section 1.3). 
8.1.1 Magnetic resonance imaging assessments  
Cranial (brain) MRI before and after administration of Gd contrast agent will be performed. 
• The basic MRI will be performed at all sites and will consist of the following sequences: 
T2- and T1-weighted sequences before and after administration of Gd contrast agent 
(if there is no contraindication). 
• An expanded MRI protocol will be conducted using additional MRI sequences such as 
magnetization transfer ratio (MTR) (all centers) and susceptibility-weighted imaging 
(SWI) (subset of centers with capacity of 3T MRI). 
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• Basic MRI sequences will be used to evaluate MRI-related endpoints of change in 
T2-hyperintense lesion volume, new and enlarging T2-hyperintense lesion count, number 
and volume of T1-hypointense lesions, brain volume loss rate, volume, number, and 
intensity (T1) of slowly evolving lesions, and GdE T1 lesion count (see Section 3). 
The expanded MRI protocol will be used to evaluate Gd enhancement recovery (MTR) 
and phase rim lesions (SWI). Additional details about MRI assessments will be provided 
in a separate manual.  
Due to a potential safety risk related to deposition of certain IV Gd contrast agents in the brain, 
these agents should be used in accordance with local recommendations/regulations (34). 
As the use of systemic corticosteroids for treatment of MS relapse or any other medical reasons 
could interfere with the MRI findings, performing of MRI on or close to such treatment needs to 
be avoided. If a study MRI is planned within 7 days of the initiation of treatment, it should be 
rescheduled to be performed prior to the initiation of corticosteroid treatment when possible. 
A separate manual, containing instructions for brain MRI standard image acquisition 
requirements, MRI acquisition validation, data transfer to the central review center, archiving and 
shipping, and the image approval process, will be provided to all participating sites. Study site 
personnel will undergo training regarding MRI acquisition and data handling procedures. Training 
will be documented, and adherence to the manual will be monitored throughout the study with 
retraining performed as necessary. 
Unless specified otherwise, the screening brain MRI scan will be used as the reference to assess 
all MRI-derived endpoints. Standardized endpoint evaluation is assured by central review of brain 
MRI scans. A blinded MRI central review will be performed for all MRI-derived endpoints. 
All MRI reviewers will be blinded to treatment assignments and to other participant data. Details 
of MRI scanning and central review will be described in the manual. 
Magnetic resonance imaging scans need to be reviewed by a local radiologist for any non-MS 
pathology to assure safety reporting as per Section 8.3.8. In the event of the identification of MRI 
findings relevant to participant safety, the local radiologist will provide a report to 
the Investigator. Expected MS findings on MRI scans, not reflecting an acute safety concern for 
the participant, should not be disclosed to the Investigator or to the site team if not relevant to 
any safety concern. Any safety concern noted on MRI, whether related to MS or not, shall be 
provided to the Investigator. In addition, in accordance with standard clinical practice, 
the Investigator may access reports of MRI performed as from Week 24 through the local 
radiologist. 
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8.1.2 Multiple sclerosis relapse assessment  
8.1.2.1 Definition of multiple sclerosis relapse  
For the purposes of this study, MS relapse is defined as a monophasic, acute or subacute onset of, 
new neurological symptoms or worsening of previous neurological symptoms with an objective 
change on neurological examination. Symptoms must: 
• Be attributable to MS. 
• Last for ≥24 hours, with or without recovery. 
• Be present at normal body temperature (ie, no infection, excessive exercise, or excessively 
high ambient temperature), and 
• Be preceded by ≥30 days of clinical stability (including no previous MS relapse). 
Note: An exacerbation or recurrence of symptoms and signs in a participant with MS that can be 
reasonably attributed to transient impairment of conduction in previously demyelinated pathways 
due to drugs (such as rarely occurs a few hours after injections of interferon beta), or raised core 
body temperature (the Uhthoff phenomenon) will not be considered to be a relapse. 
Confirmation of MS relapse will be based on the EDSS score (see Section 8.1.3), based on 
the following definition: 
• A confirmed MS relapse is one accompanied by a clinically relevant change in the EDSS 
score performed by the Investigator, ie, an increase of at least 0.5 points in the EDSS 
score, an increase of 1 point on 2 functional scores, or an increase of 2 points on 
1 functional score, excluding changes involving bowel/bladder and cerebral functional 
score compared to the previously available rating (the last EDSS rating that did not occur 
during a relapse). 
Refer to Section 8.3.6 for details regarding MS relapse reporting. 
8.1.2.2 Unscheduled assessment visits  
Participants must be instructed to immediately report new neurological symptoms and recurring or 
worsening of previous symptoms to the Investigator. Any reported symptoms will be recorded. If 
a participant reports symptoms that may be consistent with relapse, an unscheduled assessment 
visit with the Investigator must be scheduled as soon as possible (whenever possible within 7 days 
after onset of symptoms). The assessment, management, and reporting of MS relapse is performed 
by the Investigator. 
Diagnosing MS relapses during the study: The Investigator will assess whether the reported 
episode is consistent with the definition of MS relapse, per protocol. If it is consistent with 
the definition of MS relapse or if there is any doubt and the possibility of relapse cannot be ruled 
out, the standard neurological examination (for the EDSS score) will be performed. If an EDSS 
rating is not performed, this will be documented with an explanation of the reason. Whenever 
possible, the EDSS rating should be performed the same day of unscheduled visit. 
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All MS relapses are to be reported on the MS relapse e-CRF page. Multiple sclerosis relapse 
should not be reported as an AE unless, in the judgment of the Investigator, it is unusually severe, 
medically unexpected, or matches the definition of a SAE. 
Safety laboratory tests are optional for the unscheduled assessment visit if no intercurrent disease 
is suspected. If any intercurrent disease is diagnosed, it will be reported as an AE as per the safety 
reporting rules. 
The participant will be also asked to report possible relapse symptoms during scheduled quarterly 
visits. If relapse is suspected, the above decision-making and reporting rules apply. 
8.1.3 Expanded disability status scale  
The Investigator/rater will perform the EDSS evaluation (35). All Investigators/raters must be 
qualified to perform neurological assessment as per local requirement. In addition they must be 
trained and certified to perform the EDSS in a consistent manner (Neurostatus® training 
version 04/10.2). 
The EDSS score will be captured. Quality control measures will be put in place to ensure scoring 
error detection and thus minimize the impact of any scoring and calculation errors. Details will be 
included in training materials.  
The Investigator/rater will rate functional systems in the context of a standard neurological 
examination and will report these ratings as per the EDSS score reporting instructions together 
with information on the participant’s mobility, gait, and use of assistive devices. Standard EDSS 
assessments of 7 functional domains (visual, brainstem, pyramidal [motor], cerebellar 
[coordination], sensory, cerebral, and bowel/bladder) will be performed by assessing neurological 
symptoms in each of these domains. Ambulation will be scored to conclude the evaluation. 
The fatigue evaluation may be optionally recorded, but it will not contribute to assignment of 
the EDSS score. The total EDSS score will be assigned according to EDSS scoring rules. 
A screening EDSS assessment must be completed to confirm eligibility, and the EDSS assessment 
must be repeated at the randomization visit. 
Participants will not be informed of their EDSS scores. 
Additional details on EDSS assessment and EDSS score reporting will be provided in training 
materials. 
8.1.4 Patient-reported outcome and health-related quality-of-life parameters  
Patient-reported outcome assessments will be performed in this study in line with the SoA 
(see Section 1.3). These outcome assessments are to be administered prior to treatment and prior 
to discussion of a participant’s health status. It is important that participants complete the outcome 
assessments after ICF is signed and prior to any treatment- or study-related activities, including 
administration of study treatment, laboratory work, radiological assessments, discussion with 
the participant regarding their treatment or health status, and similar activities. This ensures 
the objectivity of the data. Detailed site training on the outcome assessments will be provided. 
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8.1.4.1 Multiple sclerosis impact scale (MSIS)-29  
The Multiple Sclerosis Impact Scale with 29 items (MSIS-29) was developed to evaluate 
the specific physical and the psychological impact of MS from a patient's perspective (36). 
The MSIS-29 has two subscales; 1/ a physical impact score (20 items) and 2/ a psychological 
impact score (9 items). The physical and psychological impact subscales of the MSIS-29 range 
from 0 to 100, with higher scores indicating greater physical or psychological impact. 
8.1.4.2 Patient reported outcome measurement information system (PROMIS)-Fatigue-
MS-8  
The PROMIS-Fatigue-MS-8 is an 8-item short form derived from the Patient-Reported Outcomes 
Measurement Information System® (PROMIS®) Fatigue Item Bank (37). PROMIS measures were 
developed for use with both the general population and individuals living with chronic conditions 
(38). The measures are based on calibrated item banks from which short forms can be derived. 
The PROMIS-Fatigue-MS-8 is scored on a T score metric, with a mean of 50 and a SD of 10. 
A higher PROMIS T-score represents more fatigue.  
8.1.4.3 Patient’s qualitative assessment of treatment version 3 (PQATv3)  
The PQAT is a new patient-reported outcome measure designed to evaluate patient-perceived 
benefits and disadvantages of treatment and their willingness to continue/discontinue treatment 
based on their experience. The PQATv2 collects qualitative and quantitative data on the benefits 
and disadvantages of treatment (39). A modified version of the PQATv2; the PQATv3 will be 
utilized in the study. The PQATv3 has 4 additional questions that assess past IV and SC patient 
experience, and patient preferences for IV or SC depending on IV/SC past experience. 
8.1.4.4 Patient global impression of change and severity scale (PGIC-Fatigue and 
PGIS-Fatigue measures)  
The Patient Global Impression scale (PGI), also known as Subject Global Impression (SGI), is 
the PRO counterpart to the Clinical Global Impressions scale, (CGI), which was published in 
1976 by the National Institute of Mental Health (US). It consists of one item based on the CGI 
and adapted to the patient. It mainly measures change in clinical status (PGI-C) but can also 
measure disease severity (PGI-S). Over the years, PGI scales were used in a broad range of 
diseases and have been modified for clinical settings (item label, number of response options and 
response options) (40). Two global measures, the PGIC, specific to fatigue (PGIC-Fatigue), and 
the PGIS, specific to fatigue (PGIS-Fatigue) will be utilized as an anchors to assess changes in 
fatigue status and in fatigue severity, in order to establish the measurement properties (scoring, 
clinically meaningful change scores) of the PROMIS-Fatigue-MS-8. 
The PGIC-Fatigue and PGIS-Fatigue will be used as anchors to validate the PROMIS-Fatigue-
MS-8 questionnaire. Additional details on scoring will be provided in the SAP. 
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8.2 
SAFETY ASSESSMENTS   
This section presents safety assessments other than adverse events, which are presented in 
Section 8.3. 
Planned time points for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1 Physical examinations  
• A complete physical examination will include, at a minimum, assessments of the skin, oral 
cavities, eyes and cardiovascular, respiratory, gastrointestinal, musculoskeletal, lymphoid, 
and neurological systems. Height and weight will also be measured and recorded. 
• A brief physical symptom-based physical examination will include organ systems, which 
are deemed, at the discretion of the Investigator, necessary to be evaluated. Neurological 
examination will be also to be performed, if EDSS full assessment is not done or needs 
additional testing (adapted as needed). 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses and thromboembolic events. 
• Any new finding or worsening of a previous finding should be reported as a new AE. 
Height and weight 
• Height (in cm) will be measured only at Screening. 
• Weight (in kg) should be taken with the participant wearing light clothing and no shoes. 
The same scale should be used throughout the study. 
• Body mass index will be calculated automatically at each visit when weight is measured as 
per the SoA (Section 1.3). 
8.2.2 Vital signs  
• Vital signs will be measured in a sitting position after 5 minutes of rest and will include 
tympanic temperature, respiratory rate, systolic and diastolic blood pressure, and pulse. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
8.2.3 Electrocardiograms  
• A single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3). 
• Electrocardiogram parameters will be based upon the automatic reading of the device. 
These ECG parameters and morphology need to be reviewed by the Investigator. If 
the device does not provide automatic reading, then the ECG parameters will need to be 
determined and interpreted by the Investigator.  
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• At post randomization visits, ECGs will be performed prior to IMP administration. 
All ECGs will be performed with the participant in a reclining position. Electrocardiogram 
parameters include heart rate, QRS duration, PR, QT, and QTc interval. 
8.2.4 Clinical safety laboratory assessments  
• See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and 
to the SoA (Section 1.3) for the timing and frequency. 
• The Investigator must review the laboratory report, document this review, and record any 
clinically significant changes occurring during the study in the AE section of the e-CRF. 
The laboratory reports must be filed with the source documents. Abnormal laboratory 
findings associated with the underlying disease are not considered clinically significant, 
unless judged by the Investigator to be more severe than expected for the participant’s 
condition. 
• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 24 weeks after the last dose of study intervention 
should be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the Investigator or Medical Monitor. 
- 
If such values do not return to normal/baseline within a period of time judged 
reasonable by the Investigator, the etiology should be identified and the Sponsor 
notified. 
- 
All protocol-required laboratory tests, as defined in Appendix 2 (Section 10.2), must 
be conducted in accordance with the laboratory manual and the SoA (Section 1.3). 
- 
If laboratory values from non-protocol specified laboratory tests performed at the 
institution’s local laboratory require a change in participant management or are 
considered clinically significant by the Investigator (eg, SAE or AE or dose 
modification), then the results must be recorded in the e-CRF.  
8.2.5 Local tolerability  
The evaluation of SC injection/IV infusion site reactions following IMP administration will be 
performed by the Investigator or designee and the participant. 
On-site injections/infusions 
Local tolerability will be assessed by both Investigator or designee and participant. 
Findings at the local injection/infusion site such as, but not limited to tenderness, erythema, and 
swelling will be recorded in the e-CRF in 4 different grades (mild/moderate/severe/very severe) 
based on instructions in Section 10.9.1. Participants will be asked to report sensations at 
the administration site, which will then be evaluated by the Investigator or a designee (and 
reported as AE if criteria of a local administration site reaction are met, at the discretion of 
the Investigator or designee).  
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In addition, self-evaluation of pain will use a pain- verbal descriptor scale before IMP 
administration, after completion of the IMP administration, and 2 hours post-administration 
(see Section 10.9.2). 
Home injections 
The local tolerability will be assessed by participant using the same pain-verbal descriptor scale 
described above.  
In the case of any injection site or other adverse reactions, the participant must contact the site as 
soon as possible to report the injection site reaction or other adverse event. The Investigator must 
monitor any worsening of events and schedule an on-site visit for evaluation and treatment, if 
needed. The Investigator will also proactively contact the participant on the day of injection to 
ensure the best management of injection site reaction or other adverse event, should this occur. 
8.2.6 Pregnancy testing  
• Refer to Section 5.1 Inclusion criteria for pregnancy testing entry criteria; the Investigator 
is responsible for review of medical history, menstrual history, and recent sexual activity 
to decrease the risk for inclusion of a woman with an early undetected pregnancy. 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted at 
q4w visits during intervention (additional tests, if needed). 
• Pregnancy testing (urine or serum as required by local regulations) should be conducted 
corresponding with the time frame for female participant contraception in Section 5.1. 
• Additional serum or urine pregnancy tests may be performed, as deemed necessary by 
the Investigator or required by local regulation, to establish the absence of pregnancy at 
any time during the participant’s participation in the study. 
8.2.7 Suicidal ideation and behavior risk monitoring  
Not applicable. 
8.3 
ADVERSE EVENTS (AES), SERIOUS ADVERSE EVENTS (SAES) AND OTHER 
SAFETY REPORTING  
The definitions of AEs and SAEs can be found in Appendix 3 (Section 10.3). The definition of 
AESI is provided in Section 8.3.7. 
Adverse events will be reported by the participant or, when appropriate, by a caregiver, surrogate, 
or the participant’s legally authorized representative.  
The Investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study (see Section 7). 
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The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.1 Time period and frequency for collecting AE and SAE information  
All AEs (serious or nonserious) will be collected from the signing of the ICF until the EOS at 
the time points specified in the SoA (Section 1.3). 
All SAEs and AESIs (defined in Section 8.3.7) will be recorded and reported to the Sponsor or 
designee immediately. Under no circumstance should the time lag exceed 24 hours, as indicated in 
Appendix 3 (Section 10.3). The Investigator will submit any updated SAE data to the Sponsor 
within 24 hours of it being available. 
Investigators are not obligated to actively seek information on AEs or SAEs after conclusion of 
the study participation. However, if the Investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the Investigator must promptly 
notify the Sponsor. 
8.3.2 Method of detecting AEs and SAEs  
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3 Follow-up of AEs and SAEs  
After the initial AE/AESI/SAE report, the Investigator is required to proactively follow each 
participant at subsequent visits/contacts. At the pre-specified study end-date, all SAEs and AESIs, 
will be followed until resolution, stabilization, the event is otherwise explained, or the participant 
is lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is 
provided in Appendix 3 (Section 10.3). 
8.3.4 Regulatory reporting requirements for SAEs and other safety reporting  
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and Investigators. 
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• Serious adverse events that are considered expected will be specified in the reference 
safety information (see the IB).  
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and Sponsor policy and 
forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing an SAE, SUSAR or 
any other specific safety information (eg, summary or listing of SAEs) from the Sponsor 
will review and then file it along with the IB and will notify the IRB/IEC, if appropriate 
according to local requirements. It is the responsibility of the Sponsor to assess whether 
an event meets the criteria for a SUSAR, and therefore, is expedited to regulatory 
authorities. 
• For the European Union, safety reporting to the agency is described in Section 10.7.2. 
8.3.5 Pregnancy  
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and until the EOS visit. 
• If a pregnancy is reported, the Investigator will record pregnancy information on 
the appropriate form and submit it to the Sponsor within 24 hours of learning of the female 
participant or female partner of male participant (after obtaining the necessary signed 
informed consent from the female partner) pregnancy. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
• The participant/pregnant female partner will be followed to determine the outcome of 
the pregnancy. The Investigator will collect follow-up information on 
the participant/pregnant female partner and the neonate and the information will be 
forwarded to the Sponsor. 
• Any post-study pregnancy-related SAE considered reasonably related to the study 
intervention by the Investigator will be reported to the Sponsor as described in 
Section 8.3.4. While the Investigator is not obligated to actively seek this information in 
former study participants/pregnant female partner, he or she may learn of an SAE through 
spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue the study intervention or be withdrawn from the study. 
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8.3.6 Disease-related events and/or disease-related outcomes not qualifying as AEs or 
SAEs  
Multiple sclerosis relapses, determined from the evaluations described in Section 8.1.2, as with all 
efficacy endpoints, will be exempt from being reported as AEs except when they meet the 
definition of a SAE or are unusually severe or medically unexpected. Hospitalization for MS 
relapse, if done routinely at the site (eg, for high dose IV methylprednisolone administration), will 
not be considered as a seriousness criterion for this study. Data for MS relapses will be collected 
on the e-CRF and be analyzed as part of the efficacy analysis. Other worsening of neurological 
symptoms that do not meet the definition of MS relapse will be reported as AEs according to 
general safety reporting rules. 
8.3.7 Adverse events of special interest  
Adverse events of special interest 
An adverse event of special interest (AESI) is an AE (serious or nonserious) of scientific and 
medical concern specific to the Sponsor’s product or program, for which ongoing monitoring and 
immediate notification by the Investigator to the Sponsor is required. Such events may require 
further investigation in order to characterize and understand them. Adverse events of special 
interest may be added, modified or removed by protocol amendment during a study. 
For AESIs, the Sponsor is to be informed immediately (ie, within 24 hours), as per SAE notification 
guidelines described in Appendix 3 (Section 10.3), even if a seriousness criterion is not met, using 
the corresponding pages of the case report form (to be sent) or screens in the e-CRF: 
• Pregnancy of a female participant entered in a study as well as pregnancy occurring in 
a female partner of a male participant entered in a study with IMP:  
- 
Pregnancy occurring in a female participant entered in the clinical trial or in a female 
partner of a male participant entered in the clinical trial. It will be qualified as an SAE 
only if it fulfills one of the seriousness criteria (see Appendix 3 [Section 10.3]). 
- 
In the event of pregnancy in a female participant, study intervention should be 
discontinued.  
- 
Follow-up of the pregnancy in a female participant or in a female partner of a male 
participant is mandatory until the outcome has been determined (see Section 8.3.5). 
• Symptomatic overdose (serious or nonserious) with IMP (see definition of overdose in 
Section 6.7): 
• Increase in alanine transaminase (ALT) : If increase in ALT >3 × ULN, see the “Increase 
in ALT” flow chart in Appendix 6 (Section 10.6) 
- 
However, if the increase in ALT is ≥2 × the baseline value (with baseline ALT ≥ULN) 
but ≤3 × ULN, then ALT should be retested within 72 hours of initial sample to 
determine if the retest value meets the AESI criterion of ALT > 3 × ULN. If so, 
proceed as above and follow the guidelines of Appendix 6 (Section 10.6). If not, 
monitoring of the laboratory findings will be up to the medical judgment of 
the Investigator. 
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• Other project specific AESI(s) 
- 
Confirmed diagnosis of an arterial and/or venous thrombotic or embolic event. 
All signs and symptoms, clinical or biological, suggestive of a thromboembolic event 
should be investigated immediately (eg, D-dimer, venous ultrasound and other 
radiological investigations) as needed, as per Investigator clinical judgment and/or 
local regulation. Only confirmed thromboembolic events should be reported as 
an AESI. 
- 
Anaphylaxis.  
- 
Severe infusion related reactions. 
- 
Severe IMP injection or infusion site reaction.  
- 
Severe infections including opportunistic infections. 
- 
Tuberculosis or suspected tuberculosis leading to initiation of medications. 
- 
Diagnosed and biologically proven SARS-CoV-2 infection. 
8.3.8 Reporting of safety findings from magnetic resonance imaging  
Magnetic resonance imaging scans need to be reviewed locally for any pathology. In case of 
clinically significant findings, the MRI report needs to be provided to the Investigator for 
appropriate safety reporting. When available, a diagnosis of pathology at cause of such MRI 
findings or the findings themselves will be reported as an AE until the diagnosis is clear. Multiple 
sclerosis findings from MRI scans do not need to be reported unless they are deemed unusual and 
thus a distinct safety finding. 
8.3.9 Medication errors, or misuses of medicinal product  
All reports of medication error, or misuse in relation to the IMP with or without an AE must be 
recorded on the corresponding page(s) of the CRF and transmitted to the Sponsor’s representative 
following standard processes.  
A medication error is an unintended failure in the drug treatment process (ie, mistake in 
the process of prescribing, storing, dispensing, preparing, or administering medicinal products in 
clinical practice) that leads to, or has the potential to lead to harm to the participant.  
This includes situations in which a participant was involved or not (eg, even if the error was 
recognized and intercepted before the participant received or used the product), and whether it 
resulted in harm to the participant or not. 
A misuse refers to situations where the medicinal product is intentionally and inappropriately 
used, ie, not in accordance with the terms of the marketing authorization or outside what is 
foreseen in the protocol, by the participant for a therapeutic purpose.  
Of note, if a medication error or misuse meets the protocol definition of an overdose, it will be 
recorded in the overdose page of the CRF. 
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8.3.10 Guidelines for reporting product complaints  
Any defect in the IMP must be reported as soon as possible by the Investigator to the monitoring 
team that will complete a product complaint form within required timelines. 
Appropriate information (eg, samples, labels or documents like pictures or photocopies) related to 
product identification and to the potential deficiencies may need to be gathered. The Investigator 
will assess whether or not the quality issue has to be reported together with an AE or SAE. 
8.4 
PHARMACOKINETICS  
Frexalimab concentrations at selected time points will be reported using descriptive statistics. 
Additional PK parameters such as Cmax, tmax, t1/2z, and AUC0-tau will be estimated using 
a population PK approach. These parameters will be presented in a separate standalone report. 
• Blood samples will be collected for measurement of plasma concentrations of frexalimab 
as specified in the SoA Section 1.3. Detailed procedures of sample preparation, storage, 
and shipment will be described in the specific laboratory manual. 
• A maximum of 5 samples may be collected at additional time points during the study if 
warranted and agreed upon between the Investigator and the Sponsor. The timing of sampling 
may be altered during the course of the study based on newly available data (eg, to obtain data 
closer to the time of peak plasma concentrations) to ensure appropriate monitoring. 
• Instructions for the collection and handling of biological samples will be provided by 
the Sponsor. The actual date and time (24-hour clock time) of each sample will be 
recorded. 
• Samples will be used to evaluate the PK of frexalimab. Each plasma sample will be 
divided into 2 aliquots. Samples collected for analyses of frexalimab plasma concentration 
may also be used to evaluate safety or efficacy aspects related to concerns arising during 
or after the study. 
• Genetic analyses will not be performed on these plasma samples unless consent for 
this was signed by the participant. Participant confidentiality will be maintained. 
Pharmacokinetic samples may be used for testing analytical method performance such as 
comparability and incurred sample reproducibility. 
Drug concentration information that would unblind the study will not be reported to investigative 
sites or blinded personnel until the final database lock. 
8.5 
GENETICS AND PHARMACOGENOMICS  
8.5.1 Deoxyribonucleic acid (DNA)  
Whole blood sample for DNA isolation will be collected from participants who have consented to 
participate in the genetic analysis component of the study at Baseline. The DNA isolated from 
this sample will be stored from consenting participants. 
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A targeted analysis for genetic polymorphisms in specific loci in CD40 and components of 
downstream signaling pathways known to be associated with increased risk of MS as potential 
predictive markers of response to frexalimab is planned. Further, this sample and the DNA 
isolated from this sample may be used to determine possible relationships between other genes 
and response to treatment with frexalimab, how the body processes frexalimab, possible side 
effects to frexalimab, and/or genes that may potentially be involved in MS or other autoimmune 
diseases. The DNA, and any remaining whole blood, will be stored for up to 25 years from 
the completion of the clinical study report (CSR) of the present study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in 
the study. 
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the participant. Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent. 
Details on processes for collection and shipment and destruction of these samples can be found in 
the laboratory manual. 
Participation is optional. Participants who do not wish to participate in the genetic research may 
still participate in the study. 
8.5.2 Ribonucleic acid (RNA)  
At the study visits specified in the SoA (Section 1.3), RNA blood samples will be collected and 
stored from all participants for isolation of RNA. In selected sites additional peripheral blood 
mononuclear cells (PBMCs) will be collected. The samples and any RNA isolated from 
the samples will be used to study expression levels of genetic transcripts by methods such as 
NanoString and RNA sequencing. 
An analysis of RNA isolated from whole blood for expression of a CD40/CD40L gene signature 
to evaluate correlation between CD40L activation scores and response to frexalimab is planned. 
Additionally, RNA isolated from PBMCs will be used to measure the cell type-specific activation 
state of CD40/CD40L signaling pathway to characterize the CD40/CD40L pathway activation in 
adaptive and innate immune cells and confirm the treatment effect on innate immunity. Further, 
the samples may be used to determine possible relationships between RNA transcripts and 
response to treatment with frexalimab, how the body processes frexalimab, possible side effects of 
frexalimab, and/or transcripts that may potentially be involved in MS and other autoimmune 
diseases. The PBMC sample and/or isolated RNA samples from blood or PBMCs may be stored 
for up to 25 years from the completion of the CSR of the present study. 
Details on processes for collection and shipment and destruction of these samples can be found in 
the laboratory manual. See Appendix 5 (Section 10.5) for information regarding genetic research.  
Details on processes for collection and shipment and destruction of these samples will be provided 
to sites. 
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8.6 
BIOMARKERS  
Collection of biological samples for biomarker research is also part of this study. The following 
samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SoA: 
• Whole blood samples for assessing expression of a CD40/CD40L gene signature by bulk 
RNA sequencing analysis as indicated in Section 8.5.2. Expression levels of a panel of 
genes associated with CD40 pathway activation will be measured to assess 
their association with the observed clinical responses to frexalimab treatment. Collection is 
specified in the SoA (Section 1.3). 
• Serum samples will be tested for IgG and IgM as potential biomarkers. 
• Soluble CD40L in plasma: 
- 
To be evaluated as a potential marker of inflammatory activity in MS patients at 
baseline measurements and for a potential relationship with CD40/CD40L mRNA 
signature expression. 
- 
Increase is expected after frexalimab administration based on previous studies. To be 
used to assess frexalimab target occupancy. 
• Plasma samples will be tested for C-X-C chemokine ligand 13 (CXCL13): 
- 
Biomarker to evaluate germinal center activity in response to frexalimab. 
- 
CXCL-13 protein levels are expected to show a decrease with frexalimab treatment, 
indicative of reduced B-cell activity and activation. 
• Plasma samples will be tested for NfL: 
- 
Biomarker to assess changes in the level of neuroaxonal damage in response to 
frexalimab. 
- 
NfL protein levels are expected to show a decrease with frexalimab treatment, 
indicative of reduced disease activity. 
• Plasma samples will be tested for chitinase-3-like protein 1 (CHI3L1): 
- 
Biomarker to assess changes in neuroinflammation activity in response to frexalimab. 
- 
Chitinase-3-like protein 1 levels are expected to show a decrease with frexalimab 
treatment, indicative of reduced disease activity. 
• Plasma samples will be tested for soluble Triggering receptor expressed on myeloid 
cells 2 (sTREM2): 
- 
Biomarker to assess changes in microglial activation and neuroinflammation activity in 
response to frexalimab. 
- 
sTREM2 protein levels are expected to show a decrease with frexalimab treatment, 
indicative of reduced disease activity. 
• Analysis of mRNA isolated from PBMCs for assessing expression of a CD40/CD40L gene 
signature from selected participants (to be chosen based on bulk RNA sequencing results). 
To be performed on participants from selected sites capable of rapid PBMC isolation.  
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• Immunophenotyping of subpopulations of interest (such as naïve, effector, helper, 
regulatory cell subsets among B and T-cells, pro-inflammatory and regulatory monocyte, 
DC1, and DC2 cell subtypes) from PBMCs collected from participants at selected sites 
capable of rapid PBMC isolation. 
• Biomarkers will be tested to evaluate disease-specific changes and their association with 
the observed responses to frexalimab as judged by the primary MRI endpoint. 
• In addition, optional archival DNA samples for future analysis (see SoA [Section 1.3]) 
will be collected and stored for up to 25 years from the completion of the CSR of 
the present study. Analysis of DNA isolated from whole blood may be performed to assess 
presence of gene variants involved in the CD40/CD40L signaling pathway, as well as 
those thought to play a role in the pathogenesis and treatment of MS and related 
autoimmune disease (see Section 8.5.1). 
• Remaining samples from the study may be used for additional research of biomarkers 
related to MS or to the CD40/CD40L signaling or to frexalimab effects or prognosis of 
its efficacy. 
• Samples collected for biomarker analyses and their derivatives will be stored for a period 
of up to 25 years after last participant’s last visit for potential re-analyses. 
8.7 
IMMUNOGENICITY ASSESSMENTS  
Antibodies to frexalimab will be evaluated in serum samples collected from all participants 
according to the SoA (see Section 1.3). Additionally, serum samples should also be collected at 
the final visit from participants who discontinued study intervention or were withdrawn from 
the study. These samples will be tested by the Sponsor or Sponsor’s designee. 
Serum samples will be screened for antibodies binding to frexalimab and the titer of confirmed 
positive samples will be reported. Other analyses may be performed to verify the stability of 
antibodies to frexalimab and/or further characterize the immunogenicity of frexalimab. 
The detection and characterization of antibodies to frexalimab will be performed using a validated 
assay method by or under the supervision of the Sponsor. All samples collected for detection of 
antibodies to frexalimab will also be evaluated for frexalimab serum concentration to enable 
interpretation of the antibody data. Antibodies may be further characterized and/or evaluated for 
their ability to neutralize the activity of the study intervention(s). Samples may be stored for 
a maximum of 5 years (or according to local regulations) following the last participant’s last visit 
for the study at a facility selected by the Sponsor to enable further analysis of immune responses 
to frexalimab. 
8.8 
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION AND HEALTH 
ECONOMICS  
Not applicable. 
8.9 
USE OF BIOLOGICAL SAMPLES AND DATA FOR FUTURE RESEARCH  
Future research may help further the understanding of disease and the development of medicines. 
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Reuse of coded data and biological samples (leftover and additional) will be limited to future 
scientific research conducted under a research plan for the purpose of diagnosing, preventing or 
treating diseases. The future research projects will be conducted under the Sponsor’s and/or its 
affiliates’ and/or, if applicable, the partner of the Sponsor which has licensed the study drug to 
the Sponsor or which is co-developing the study drug with the Sponsor’s control, acting alone or 
in collaboration with research partners such as universities, research institutions or industrial 
partners with whom the coded data may be shared. 
Coded study data and biological samples will be stored and used for future research only when 
consented to by participants (see Section 10.1.3) and when applicable, further information on 
the future research has been provided to the study participant, unless prohibited by local laws or 
IRBs/IECs (in such case, consent for future use of data/sample will not be included in the local 
ICF). The conditions for reuse will be adapted locally with the appropriate language in the ICF. 
A specific consent will be collected for the performance of genetic analyses on leftover and/or 
additional samples. 
Data protection – Processing of coded clinical data 
The study participant will be provided with all mandatory details of the data processing in 
Section 2 of the core ICF. The Sponsor adopts safeguards for protecting participant confidentiality 
and personal data (see Section 10.1.4). 
Use of leftover samples and additional samples for future research 
Leftover biological samples (eg, remaining and backup PK and biomarker samples) and additional 
samples (eg, optional DNA samples) will be collected as defined in the SoA (see Section 1.3) and 
can be used for future research during the study conduct or at the end of the study if consent 
provided in Part 3 of the Core ICF. 
Biological samples for future use will be stored for up to 25 years after the end of the study. Any 
samples remaining at the end of the retention period will be destroyed. If a participant requests 
destruction of his/her samples before the end of the retention period, the Investigator must notify 
the Sponsor (or its contract organization) in writing. In such cases, samples will be destroyed and 
related coded data will be anonymized, unless otherwise required by applicable laws. 
Study participant coded data will be stored for future research for up to 25 years after the end of 
the study. If data are still considered of important scientific value after this period, coded data 
already available will be anonymized unless otherwise required by applicable laws (the same will 
apply to the data of a study participant who has requested the destruction of his/her samples). 
Participant’s coded data sets provided to researchers for a specific research project will be 
available to the researchers for a maximum of 2 years after the end of their specific project (end of 
project is defined by publication of the results or finalization of the future research project report). 
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9 
STATISTICAL CONSIDERATIONS  
9.1 
SAMPLE SIZE DETERMINATION  
The sample size was derived by applying the frequentist approach of the Quantitative Decision 
Making method described by Quan et al (41). This approach is based on the comparison of 
the lower (LL) and upper limits (UL) of an asymmetric confidence interval of the treatment 
difference, with target (TV) and lower reference (LRV) values. 
Using the following features: 
• TV: 90% reduction 
• LRV: 70% reduction 
• Significance criterion: 86% (P(Non-negative conclusion| LRV)≈14%) 
• Relevance criterion: 15% (P(Negative conclusion| TV)≈15%). 
And, assuming the following: 
• The number of new GdE T1 lesions by month follows a negative binomial distribution 
with a mean of 0.1 in the frexalimab group and a mean of 1 in the placebo group (that is, 
90% reduction of mean lesions count in the frexalimab group relative to that of 
the placebo group).  
• The dispersion parameter of the negative binomial distributions equals 2 (estimated from 
Week 12 placebo data from the vatelizumab [SAR339658] DRI13839 study). 
Then, with 40 evaluable participants in the frexalimab group, and 20 evaluable participants in 
the placebo group, the probability for the asymmetric confidence interval of the relative reduction 
in mean new GdE T1 lesions count at Week 12 in participants receiving frexalimab compared to 
that of those receiving placebo to be located in the “Positive” conclusion area is approximately 
71%, and the probability to be located in the “Negative” conclusion area is approximately 15%. 
Conclusion rules are detailed in Table 11. 
Assuming that IV and SC placebo arms can be pooled for comparison with either frexalimab 
1200 mg IV q4w arm or frexalimab 300 mg SC every 2 weeks arm, and as no adjustment for 
multiplicity of doses is planned, approximately 160 people will be screened to achieve 
120 participants randomly assigned to study intervention and 100 evaluable participants for 
an estimated total of 40 and 10 evaluable participants per frexalimab and placebo intervention in 
each of the dose groups respectively. 
It is planned to perform subgroup analysis according to CD40/CD40L pathway activation as 
measured by mRNA signature in peripheral blood cells. With this sample size and assuming 
40% of participants classified as participants with the activated pathway at baseline 
(CD40/CD40L+) and assuming the absence of effect on primary endpoint in the placebo group, 
the comparison of 16 participants CD40/CD40 + treated with frexalimab versus 20 participants 
receiving placebo will results in an overall probability for a positive conclusion of approximately 
53% and a negative conclusion of less than 15%. Assuming a 95% reduction of mean lesion 
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counts versus placebo in this sub-population, the probability of positive conclusion increases to 
64% and negative conclusion decreases to 5% with 31 % probability of intermediate outcome. 
9.2 
POPULATIONS FOR ANALYSES  
The following populations for analyses are defined:  
Table 9 - Populations for analyses  
Population 
Description 
Screened 
All participants who signed the ICF.  
Randomized 
All participants from screened population who have been allocated to a randomized 
intervention by IRT regardless of whether the intervention was received. 
Intent-to-treat (ITT) 
All randomized participants. Participants will be analyzed according to the intervention 
allocated by randomization.  
Efficacy 
All participants from the ITT population who take all Part A doses of study intervention 
(one SC dose skipped is allowed) and with an evaluable primary endpoint. 
The primary endpoint is evaluable when the following conditions are met: 
• 
Availability of the blinded MRI central assessment of the primary endpoint. 
• 
No systemic corticosteroids administration 30 days before baseline MRI and during 
Part A period. 
Participants will be analyzed according to the intervention they actually received. 
Safety 
All randomized participants who take at least 1 dose (regardless of the amount) of study 
intervention. Participants will be analyzed according to the intervention they actually received. 
Pharmacokinetic (PK) 
All randomized and treated participants (safety population) with at least one post-baseline PK 
sample with adequate documentation of dosing and sampling dates and times. Participants 
will be analyzed according to the intervention they actually received. 
Open-Label Extension (OLE) 
All participants who received at least one dose of intervention during the open-label extension 
phase. 
Participants exposed to study intervention before or without being randomized will not be 
considered randomized and will not be included in any analysis population. The safety experience 
of these participants will be reported separately. 
Randomized participants for whom it is unclear if they took the study intervention will be 
considered to be exposed and will be included in the safety population as randomized. 
For any participant randomized more than once, only the data associated with 
the first randomization will be used in any analysis population. The safety experience associated 
with any later randomization will be reported separately. 
9.3 
STATISTICAL ANALYSES  
This section is a summary of the planned statistical analyses of the most important endpoints 
including primary and key secondary endpoints. A statistical analysis plan (SAP) will be finalized 
prior to the database lock and will include a more technical and detailed description of 
the statistical analyses described in this section. 
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9.3.1 General considerations  
A statistical analysis plan (SAP) will be finalized prior to the database lock and it will include 
a more technical and detailed description of the statistical analyses described in this section. 
Continuous data will be summarized using the number of available data, mean, standard 
deviation (SD), median, minimum, Q1, Q3 and maximum for each treatment group. Categorical 
and ordinal data will be summarized using the number and percentage of participants in 
each treatment group.  
The baseline value is defined as the last available value before the first dose of double-blind IMP. 
For participants randomized but not treated, the baseline value is defined as the last available 
value before randomization. 
Unless otherwise specified, Part A analyses will be performed by initial intervention group, 
ie, placebo, frexalimab 1200 mg IV q4w, frexalimab 300 mg SC every 2 weeks (and overall for 
baseline and demographics characteristics).  
The observation period will be divided into 4 segments:  
• The pre-treatment period is defined as the period up to the first IMP administration. 
• The treatment-emergent period is defined as the period from the first IMP 
administration to the last IMP administration +180 days. The treatment-emergent period 
includes the following 2 periods:  
- 
The on-treatment period is defined as the period from the first IMP administration to 
the last administration of the IMP +24 days (maximal administration interval allowed 
by the protocol) for the SC group or 38 days for the IV group. 
- 
The residual treatment period is defined as the period from the end of 
the on-treatment period to the end of the treatment-emergent period.  
The post-treatment period is defined as the period from the end of the treatment-emergent 
period. 
Unless otherwise specified, Part B analyses will be performed by initial intervention group, 
ie, Placebo 1200 mg IV q4w, Placebo 300 mg SC q2w, frexalimab 1200 mg IV q4w, frexalimab 
300 mg SC q2w. 
Analyses specific to Part B2 will be performed by the initial intervention group, in participants 
treated with frexalimab 1800 mg SC q4w in Part B2. 
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9.3.2 Primary endpoint (Part A)  
Primary analysis: 
Table 10 - Primary endpoint analysis  
Primary Endpoint 
Statistical Analysis Methods 
Number of newa GdE T1 lesions at 
Week 12 as measured by brain MRI. 
The number of new GdE T1 lesions will be analyzed by a negative binomial 
regression model including terms for between treatment and baseline lesion activity 
(presence/absence). The relative reduction in each frexalimab group compared to 
placebo will be estimated, with a 95% confidence interval. 
Abbreviations: GdE T1 = gadolinium-enhancing T1-hyperintense; MRI = magnetic resonance imaging. 
a “new” lesions compared with Week 8 MRI 
The primary analysis of the number of new GdE T1 lesions at Week 12 will be performed in 
the Efficacy Population through a negative binomial regression model. 
This model will include natural (base e) logarithm of the baseline GdE T1 lesion activity 
(presence/absence) as a covariate and treatment as factor. The duration (in months) between 
the Week 12 MRI and the previous MRI will be also taken into account as an offset variable after 
natural logarithm transformation.  
The mean number of new GdE T1 lesions at Week 12 in each treatment group, as well as 
the relative reduction under treatment with frexalimab when compared to placebo will be 
estimated (estimates and 95% confidence intervals) respectively through exponentiated least 
squared means and exponentiated least squared means differences.  
For Quantitative Decision Making methodology, the asymmetric confidence interval of 
the relative reduction in each frexalimab group compared to placebo will be also obtained through 
exponentiated least squared means differences. Using a significance criterion of 86% 
(P [Non-negative conclusion| LRV]≈14%), upper limits of these asymmetric confidence intervals 
will correspond to upper limits of one-sided 86% confidence intervals. Using a relevance criterion 
of 15% (P [Negative conclusion|TV]≈15%), the lower limits of the asymmetric confidence 
intervals will correspond to lower limits of one-sided 85% confidence intervals. The evaluation 
will be based on cut-offs described in Table 11. 
Table 11 - Conclusion rules  
Lower limit of the asymmetric 
confidence interval 
Upper limit of the asymmetric 
confidence interval 
Outcome 
< TV 
< LRV 
Positive 
< TV 
≥ LRV 
Intermediate 
≥ TV 
< LRV 
Intermediate 
≥ TV 
≥ LRV 
Negative 
TV=0.1 (ie, 90% relative reduction to placebo) – LRV=0.3 (ie, 70% relative reduction to placebo) and additionally LRV=0.25 (ie, 75% relative 
reduction to placebo) 
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Supportive analyses: 
As a sensitivity analysis, the primary analysis model will be rerun on Efficacy Population but 
adjusting for the continuous covariate baseline GdE T1 lesion count instead of the categorical 
covariate baseline GdE T1 lesion activity. 
The imbalance between treatment groups in term of participants without new GdE T1 lesions at 
Week 12 will be analysed in the ITT population through a logistic regression model considering 
participants without the primary endpoint or with ≥1 new lesions at Week 12 as failures. 
This model will include the same factors as that included in the primary analysis model. Odds 
ratios of success (success = “no new GdE T1 lesions at Week 12”) versus placebo will be 
provided for each frexalimab group (estimates and 95% confidence intervals). 
Besides, a negative binomial regression including the baseline GdE T1 activity (presence/absence) 
and the baseline score of activation of CD40/CD40L pathway as covariates, and treatment as 
factor will be done on the Efficacy Population. 
In addition, the number of new GdE T1 lesions at Week 12 will be summarized in the ITT 
Population as categorical data (number of participants with a specific lesion count), adding 
categories for main reasons for non-available primary endpoint. 
Exploratory analysis: 
It is hypothesized that the efficacy of frexalimab may depend on the activation of CD40/CD40L 
pathway. A pre-defined threshold will be determined based on the baseline activation score 
distribution (percentile). In addition, exploratory analyses detailed Section 9.3.6.2 will aim to 
determine a refined threshold for the activation score above which participants could better 
benefit from frexalimab treatment. Once determined, the frexalimab effect on the primary 
endpoint in this subgroups of participants will be estimated in the Efficacy Population using 
a similar model and population as that utilized for the primary analysis, but including additionally 
the categorized CD40/CD40L pathway activation score (score above predefined threshold Y/N) 
and categorized CD40/CD40L pathway activation score by treatment interaction. Frexalimab 
effect will be estimated through the categorized CD40/CD40L pathway activation score by 
treatment interaction. The mean number of new lesions at Week 12 in frexalimab treatment 
groups in each subgroup, as well as the relative reduction compared to placebo group (whatever 
the score) will be estimated (estimates and 95% confidence intervals) using linear function of the 
least squares means obtained through this model and exponential transformation.  
In the subset of participants from the Efficacy Population including frexalimab participants with 
CD40/CD40L pathway activation scores greater than the pre-defined threshold, and all placebo 
participants: frexalimab effect on the primary endpoint will be estimated using a negative 
binomial regression including the baseline GdE T1 activity (presence/absence) and treatment as 
factors. Same asymmetric confidence intervals as above will be also provided for Quantitative 
Decision Making methodology. The frexalimab effect in this subgroup of participants will be also 
estimated in the ITT Population using the same logistic regression model described above but 
only included the baseline GdE T1 activity (presence/absence) as a covariate. 
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9.3.3 Secondary endpoint(s)  
Part A 
For the MRI secondary endpoints (number of new or enlarging T2 lesions at Week 12; total 
number of GdE T1 lesions at Week 12) similar analyses as for the primary endpoint will be 
provided (Quantitative Decision Making methodology excepted). 
Table 12 - Key secondary endpoints analyses  
Secondary endpoint 
Statistical analysis methods 
Number of new or enlarginga T2 lesions at Week 12. 
(See primary endpoint analysis) 
Total number of Gd-enhancing T1-hyperintense lesions (GdE T1) at Week 12. 
(See primary endpoint analysis) 
a “new or enlarging” lesions compared with Week 8 MRI. 
Part B 
Secondary endpoints are safety related. Details are provided in Section 9.3.4. 
9.3.4 Safety analysis  
All the safety analyses will be performed using the Safety Population, unless otherwise specified, 
using the following common rules: 
• Safety data in participants who do not belong to the Safety Population (eg, exposed but not 
randomized) will be listed separately. 
• The baseline value is defined as the last measurement collected on or before 
the randomization visit (Day 1) prior to initiation of the first dose of the study intervention.  
• Potentially clinically significant abnormality (PCSA) values are defined as abnormal 
values considered medically important by the Sponsor according to predefined 
criteria/thresholds based on literature review and defined by the Sponsor for clinical 
laboratory tests, vital signs, and ECG (PCSA analyses will be performed based on 
the PCSA list in effect at Sanofi at the time of the database lock). 
• PCSA criteria will determine which participants had at least 1 PCSA during the TEAE 
period, taking into account all evaluations performed during the TEAE period, including 
nonscheduled or repeated evaluations. The number of all such participants will be 
the numerator for the on-treatment PCSA percentage. 
• The treatment-emergent PCSA denominator by group for a given parameter will be based 
on the number of participants assessed for that given parameter in the TEAE period by 
treatment group on the safety population. 
• For quantitative safety parameters based on central laboratory/reading measurements, 
descriptive statistics will be used to summarize results and change from baseline values by 
visit and treatment group. 
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The analysis of safety variables will be essentially descriptive. No systematic analysis is planned. 
The summary of safety results will be presented by initial treatment group separately for Part A, 
Part B (including B1 and B2) and B2 (only in participants treated with frexalimab SC in Part B). 
9.3.4.1 Adverse events  
General common rules for adverse events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA; 
version in use by the Sponsor at the time of database lock). 
The AEs will be analyzed in the following 3 categories: 
• Pre-treatment AEs: AEs that developed, worsened or became serious during 
the pre-treatment period. 
• TEAEs: AEs that developed, worsened or became serious during the treatment-emergent 
period. 
• Post-treatment AEs: AEs that developed, worsened or became serious during 
the post-treatment period. 
Similarly, deaths will be analyzed in the pre-treatment, treatment-emergent, and post-treatment 
periods.  
Treatment-emergent AEs will be assigned to the treatment received as per the Safety Population.  
If the onset date (or time) of an AE (occurrence, worsening, or becoming serious) is incomplete or 
missing, the AE will be considered as a TEAE unless a partial date (or time) shows it as a pre- or 
post-treatment event. 
Analysis of all adverse events 
Adverse event incidence tables will be provided by treatment group for all types of TEAEs: 
all TEAEs, all treatment-emergent AESIs (defined with a PT or a prespecified grouping), 
all treatment-emergent SAEs, and all TEAEs leading to permanent treatment discontinuation. 
Adverse event summaries will be generated with number (%) of participants experiencing at least 
one event.  
Deaths will also be analyzed. 
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Table 13 - Safety analyses  
Safety measures 
Statistical analysis methods 
Adverse events  
• 
AEs  
• 
SAEs  
• 
AEs leading to IMP or study discontinuation  
• 
AEs leading to death  
• 
AESIs  
• 
PCSAs 
Treatment-emergent adverse event incidence tables will be presented 
by system organ class and preferred term for each treatment group 
and overall, showing the number (n) and percentage (%) of 
participants experiencing a TEAE.  
Proportion of participants with at least 1 TEAE, treatment emergent 
SAEs, TEAE leading to death, and TEAEs leading to definitive 
treatment discontinuation will be tabulated by treatment group and 
overall.  
The incidence of PCSAs occurring during the TEAE period will be 
summarized by treatment group overall and by baseline status. 
Abbreviations: AE = adverse event; AESI = adverse event of special interest; IMP = investigational medicinal product; PCSA = potentially 
clinically significant abnormality; SAE = serious adverse event; TEAE = treatment-emergent adverse event. 
Immunogenicity 
Antidrug antibodies to frexalimab will be summarized by visit. 
9.3.4.2 Laboratory variables, vital signs and electrocardiograms (ECGs)  
Quantitative analyses 
For laboratory variables, vital signs and ECG variables, descriptive statistics for results and 
changes from baseline will be provided for each planned visit, the last value and the worst value 
(minimum and/or maximum value depending on the parameter) during the on-treatment period. 
These analyses will be performed using central measurements only for laboratory variables and 
ECG variables. 
Analyses according to PCSA 
PCSA analyses will be performed based on the PCSA list currently in effect at Sanofi at the time 
of the database lock. 
Analyses according to PCSA will be performed based on the worst value during 
the treatment-emergent period, using all measurements (either local or central and either 
scheduled, nonscheduled or repeated). 
For laboratory variables, vital signs, and ECG variables, the incidence of participants with at least 
one PCSA during the treatment-emergent period will be summarized regardless of the baseline 
level and according to the following baseline status categories: 
• Normal/missing. 
• Abnormal according to PCSA criterion or criteria. 
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For ECG, the incidence of participants with at least one abnormal ECG during 
the treatment-emergent period will be summarized regardless of the baseline level and according 
to the following baseline status categories:  
• Normal/missing. 
• Abnormal. 
9.3.5 Tertiary/exploratory endpoint(s)  
Part A 
In addition to exploratory analysis described in Section 9.3.2, other tertiary/exploratory endpoint 
will be presented as descriptive data. Additional analysis may be done and will be detailed in 
the SAP. 
Part B 
Exploratory endpoints will be summarized using descriptive statistics. Further details will be 
provided in the Statistical Analysis Plan. 
9.3.6 Other analysis  
9.3.6.1 Pharmacokinetics  
Summaries will be provided separately for Part A, Part B (including Part B1 and Part B2) and 
Part B2 (only in participants treated with frexalimab SC in Part B). 
For each above period, plasma concentration over time will be summarized by time window using 
the number of available data, mean, geometric mean, standard deviation (SD), median, minimum 
and maximum for each frexalimab dose group. 
Other analyses performed, as specified in Section 8.4, to estimate PK parameters and other PK/PD 
analyses with the main efficacy parameters, will be presented in a separate report. 
9.3.6.2 Responder population identification and characterization with biomarker data 
(Part A) 
It is hypothesized that the efficacy of frexalimab may depend on the activation of CD40/CD40L 
pathway. In consequence, below exploratory analyses will be performed to identify threshold of 
the activation score of the CD40/CD40L pathway above which participants would better benefit 
from frexalimab treatment. 
The expected number of new GdE T1 lesions at Week 12 will be modeled through a negative 
binomial regression with the baseline GdE T1 activity (presence/absence) and treatment as effects 
and score by treatment interaction, in the Efficacy Population. The non-responder patients are 
assumed to have a non-substantial relative reduction of new GdE T1 lesions count per month in 
the intervention group compared to the placebo group. The relative reduction for 
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the non-responders is assumed to be less than 70% (and 90% as a second approach). A threshold 
in the activation score can be calculated by solving the following equation: E[ GdE T1 lesion 
count|treatment, covariates]/E[GdE T1 lesion count| placebo, covariates]<0.3 (0.1 in the second 
approach). Bootstrap 95% CI will be provided with the threshold estimation. 
9.3.6.3 Other biomarkers  
Other biomarker analyses will be reported separately. 
9.4 
INTERIM ANALYSES   
No interim analysis is planned. 
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10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
10.1 
APPENDIX 1: REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS  
10.1.1 Regulatory and ethical considerations  
• This study will be conducted in accordance with the protocol and with the following: 
- 
Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and the applicable amendments and Council for 
International Organizations of Medical Sciences (CIOMS) International Ethical 
Guidelines. 
- 
Applicable ICH Good Clinical Practice (GCP) Guidelines. 
- 
The Regulation (EU) No 536/2014 of the European Parliament and the Council of 
16 April 2014 on clinical trials on medicinal products for human use, as applicable. 
- 
The General Data Protection Regulation (GDPR) and any other applicable data 
protection laws. 
- 
Any other applicable laws and regulations. 
• The protocol, protocol amendments, ICF, Investigator Brochure, [IDFU] and other 
relevant documents (eg, advertisements) must be submitted to an IRB/IEC by 
the Investigator and reviewed and approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• Protocols and any substantial amendments to the protocol will require health authority 
approval prior to initiation except for changes necessary to eliminate an immediate hazard 
to study participants. 
• The Investigator will be responsible for the following, as applicable: 
- 
Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC.  
- 
Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
- 
Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, Regulation No 536/2014 of 
the European Parliament and the Council of the European Union for clinical studies, 
European Medical Device Regulation 2017/745 for clinical device research, and 
all other applicable local regulations. 
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- 
Determining whether an incidental finding (as per Sanofi policy) should be returned to 
a participant and, if it meets the appropriate criteria, to ensure the finding is returned 
(an incidental finding is a previously undiagnosed medical condition that is discovered 
unintentionally and is unrelated to the aims of the study for which the tests are being 
performed). The following should be considered when determining the return of 
an incidental finding: 
- 
The return of such information to the study participant (and/or his/her designated 
healthcare professional, if so designated by the participant) is consistent with 
all applicable national, state, or regional laws and regulations in the country where 
the study is being conducted, and 
- 
The finding reveals a substantial risk of a serious health condition or has 
reproductive importance, AND has analytical validity, AND has clinical validity.  
- 
The participant in a clinical study has the right to opt out of being notified by 
the Investigator of such incidental findings. In the event that the participant has 
opted out of being notified and the finding has consequences for other individuals, 
eg, the finding relates to a communicable disease, Investigators should seek 
independent ethical advice before determining next steps. 
- 
In case the participant has decided to opt out, the Investigator must record in 
the site medical files that she/he does not want to know about such findings. 
As applicable, according to requirements of the Regulation No 536/2014 of the European 
Parliament and the Council of the European Union, the Sponsor will be responsible for obtaining 
approval from the Competent Authorities of the EU Member States and/or Ethics Committees, as 
appropriate, for any amendments to the clinical trial that are deemed as “substantial” (ie, changes 
which are likely to have a significant impact on the safety or physical or mental integrity of 
the clinical trial participants or on the scientific value of the trial) prior to their implementation. 
According to the Regulation No 536/2014 of the European Parliament and the Council of the 
European Union and as specified by the applicable regulatory requirements in non-EU/EEA 
countries, Sanofi, as the clinical trial Sponsor, needs to report to the concerned regulatory 
agency/ies serious breaches without undue delay but not later than 7 calendar days of becoming 
aware of that breach. A serious breach is defined as a deviation of the version of the protocol 
applicable at the time of the breach or the applicable clinical trial regulation that is likely to affect 
to a significant degree the safety and rights of a subject or the reliability and robustness of the data 
generated in the clinical trial. 
The Sponsor shall ensure that all parties involved in the conduct of the clinical trial promptly 
report any events that might meet the definition of a serious breach. 
Therefore, Investigators shall within 48h after being aware of a deviation that might meet 
the definition of a serious breach, report to the Sponsor any suspected serious breach to enable 
the Sponsor to carry out the required assessment and notify the regulatory agency/ies in the event 
of a confirmed serious breach. To that extent, the principal Investigator must have a process in 
place to ensure that the site staff or service providers engaged by the principal 
Investigator/institution are able to identify the occurrence of a (suspected) serious breach and that 
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a (suspected) serious breach is promptly reported to the Sponsor through the contacts 
(email address or telephone number) provided by the Sponsor. 
10.1.2 Financial disclosure  
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3 Informed consent process  
For the ICF and the optional future use of sample ICF, the following applies: 
• The Investigator or his/her representative will explain the nature of the study to 
the participants or their legally authorized representative, and answer all questions 
regarding the study, including what happens to the participant when his/her participation 
ends (post-trial access strategy for the study).  
• Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Privacy and 
Data Protection requirements including those of the Global Data Protection Regulation 
(GDPR) and of the French law, 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. 
• In case of ICF amendment while the participants are still included in the study, they must 
be re-consented to the most current version of the ICF(s).Where participants are not in 
the study anymore, teams in charge of the amendment must define if those participants 
must or not re-consent or be informed of the amendment (eg, if the processing of personal 
data is modified, if the Sponsor changes, etc). 
• A copy of the ICF(s) must be provided to the participants or their legally authorized 
representative, where applicable.  
Participants who are rescreened must sign a new ICF. 
The ICF contains 2 separate sections that addresses the use for research of participants’ data 
and/or samples (remaining mandatory ones or new extra samples collected for optional research). 
Optional exploratory research must be detailed in the section “Optional tests/procedures” and 
future research is to be defined in Core Study Informed Consent Form (CSICF) Part 2. Each 
option is subject to an independent consent and must be confirmed by ticking a checkbox in 
CSICF Part 3. The Investigator or authorized designee will explain to each participant the 
objectives of the exploratory research and why data and samples are important for future research. 
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Participants will be told that they are free to refuse to participate and may withdraw their consent 
at any time and for any reason during the storage period. 
For a regional or national emergency declared by a governmental agency, contingency measures 
are included in Section 10.8.  
10.1.4 Data protection  
All personal data collected and/or processed in relation to this study will be handled in 
compliance with all applicable Privacy & Data Protection laws and regulations, including 
the GDPR (General Data Protection Regulation). The study Sponsor is the Sanofi company 
responsible for ensuring compliance with this matter, when processing data from any individual 
who may be included in the Sanofi databases, including Investigators, nurses, experts, service 
providers, Ethics Committee members, etc. 
When archiving or processing personal data pertaining to the Investigator and/or to 
the participants, the Sponsor takes all appropriate measures to safeguard and prevent access to 
this data by any unauthorized third party. 
Protection of participant data 
Data collected must be adequate, relevant and not excessive, in relation to the purposes for which 
they are collected. Each category of data must be properly justified and in line with the study 
objective. 
Participant race and ethnicity will be collected in this study because they are expected to modify 
the drug response/because they are required by regulatory agencies (eg, on African American 
population for the FDA or on Japanese population for the Pharmaceuticals and Medical Devices 
Agency in Japan)”. They will not be collected in the countries where this is prohibited by local 
regulation. 
• Participants will be assigned a unique identifier by the Sponsor. Any participant records or 
datasets that are transferred to the Sponsor or its service providers, when applicable, will 
be identifiable only by the unique identifier; participant names or any information which 
would make the participant identifiable will not be transferred to the Sponsor.  
• Participants must be informed that their personal study-related data will be used by 
the Sponsor in accordance with applicable data protection laws. The level of disclosure 
must also be explained to the participant as described in the informed consent.  
• Participants must be informed that their medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the Sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
• The contract between Sponsor, Investigators, and study sites specifies responsibilities of 
the parties related data protection, including handling of data security breaches and 
respective communication and cooperation of the parties. Accordingly, the Investigator 
and the institution will promptly notify the Sponsor about any data security breaches and 
detail in the notification the nature of the breach, the categories (eg, Sponsor’s personnel, 
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study participants or their relatives, healthcare professionals, etc), the approximate number 
of subjects concerned, the type and approximate number of data records concerned and the 
likely consequences of the breach. The institution and/or Investigator will investigate the 
causes of the data security breach and take actions to minimize the effects of said breach. 
The institution and/or Investigator will record all information relating to the breach, 
including the results of their own investigations and investigations by authorities, as 
applicable, and will take all measures as necessary to prevent future data security 
breaches. 
• Information technology systems used to collect, process, and store study-related data are 
secured by technical and organizational security measures designed to protect such data 
against accidental or unlawful loss, alteration, or unauthorized disclosure or access. 
• Participants must be informed that their study-related data will be used for the whole 
“drug development program”, ie, for this trial as well as for the following steps necessary 
for the development of the investigational product, including to support negotiations with 
payers and publication of results. 
Protection of personal data related to professionals involved in the study  
• Personal data (eg, contact details, affiliation(s) details, job title and related professional 
information, role in the study, professional resume, training records) are necessary to 
allow Sanofi to manage involvement in the study and/or the related contractual or 
pre-contractual relationship. They may be communicated to any company of the Sanofi 
group (“Sanofi”) or to Sanofi service providers, where needed. 
• Personal data can be processed for other studies and projects. At any time, objection to 
processing can be made by contacting the Sanofi Data Protection Officer (link available at 
Sanofi.com).  
• In case of refusal to the processing of personal data by or on behalf of Sanofi, it will be 
impossible to involve the professionals in any Sanofi study. In case the professionals have 
already been involved in a Sanofi study, they will not be able to object to the processing of 
their personal data as long as they are required to be processed by applicable regulations. 
The same rule applies in case the professionals are listed on a regulatory agencies 
disqualification list. 
• Personal data can be communicated to the following recipients:  
- 
Personnel within Sanofi or partners or service providers involved in the study.  
- 
Judicial, administrative and regulatory authorities, in order to comply with legal or 
regulatory requirements and/or to respond to specific requests or orders in 
the framework of judicial or administrative procedures. Contact details and identity 
may also be published on public websites in the interest of scientific research 
transparency. 
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• Personal data may be transferred towards entities located outside the Economic European 
Area, in countries where the legislation does not necessarily offer the same level of data 
protection or in countries not recognized by the European Commission as offering 
an adequate level of protection. Those transfers are safeguarded by Sanofi in accordance 
with the requirement of European law including, notably:  
- 
The standard contractual clauses of the European Commission for transfers towards 
our partners and service providers. 
- 
Sanofi’s Binding Corporate Rules for intra-group transfers.  
• Professionals have the possibility to lodge a complaint with Sanofi leading Supervisory 
Authority, the “Commission Nationale de l’Informatique et des Libertés” (CNIL) or with 
any competent local regulatory authority. 
• Personal data of professionals will be retained by Sanofi for up to thirty (30) years, unless 
further retention is required by applicable regulations. 
• In order to facilitate the maintenance of Investigators personal data, especially if they 
contribute to studies sponsored by several pharmaceuticals companies, Sanofi participates 
in the Shared Investigator Platform (SIP) and in the TransCelerate Investigator Registry 
(IR) project (https://transceleratebiopharmainc.com/initiatives/investigator-registry/). 
Therefore, personal data will be securely shared by Sanofi with other pharmaceutical 
company members of the TransCelerate project. This sharing allows Investigators to keep 
their data up-to-date once for all across pharmaceutical companies participating in 
the project, with the right to object to the transfer of the data to the TransCelerate project.  
• Professionals have the right to request the access to and the rectification of their personal 
data, as well as their erasure (where applicable) by contacting the Sanofi Data Protection 
Officer: Sanofi DPO – 46 avenue de la Grande Armée - 75017 PARIS - France (to contact 
Sanofi by email, visit https://www.sanofi.com/en/our-responsibility/sanofi-global-privacy-
policy/contact). 
10.1.5 Committees structure  
Not applicable. 
10.1.6 Dissemination of clinical study data and results  
Study participants 
After the end of the double-blind Part A of the clinical study, the Sponsor may publish 
the intermediate study results in scientific journal(s) and/or at scientific conference(s). As part of 
the review for publication, independent scientists may need to use “coded” data of all the study 
participants to independently verify the study’s results. 
Sanofi shares information about clinical trials and results on publicly accessible websites, based 
on company commitments, international and local legal and regulatory requirements, and other 
clinical trial disclosure commitments established by pharmaceutical industry associations. 
These websites include clinicaltrials.gov, EU clinicaltrialregister (euclinicaltrials.eu), and 
sanofi.com, as well as some national registries. For adult trials, the results will generally be 
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submitted/released 6 and 12 months respectively, after the end of the clinical trial worldwide 
(ie, the last active, participating country). 
In addition, results from clinical trials in patients are required to be submitted to peer-reviewed 
journals following internal company review for accuracy, fair balance and intellectual property. 
For those journals that request sharing of the analyzable data sets that are reported in the publication, 
interested researchers are directed to submit their request to vivli.org. 
Individual participant data and supporting clinical documents are available for request at vivli.org. 
While making information available we continue to protect the privacy of participants in our 
clinical trials. Details on data sharing criteria and process for requesting access can be found at 
this web address: vivli.org. 
Professionals involved in the study or in the drug development program 
Sanofi may publicly disclose, and communicate to relevant authorities/institutions, the funding, 
including payments and transfers of value, direct or indirect, made to healthcare organizations and 
professionals and/or any direct or indirect advantages and/or any related information or document 
if required by applicable law, by regulation or by a code of conduct such as the “EFPIA Code on 
Disclosure of Transfers of Value from Pharmaceutical Companies to Healthcare Professionals and 
Healthcare Organisations”. 
10.1.7 Data quality assurance  
• All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the Sponsor or designee electronically (eg, laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 
• Guidance on completion of CRFs will be provided in the CRF completion guideline. 
• The Investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• The Sponsor or designee is responsible for the data management of this study including 
quality check of the data. 
• Monitoring details describing strategy (eg, 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 provided in separate study documents. 
• The Sponsor assumes accountability for actions delegated to other individuals 
(eg, Contract Research Organizations). 
• Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator for 25 years after the signature of the final study 
report unless local regulations or institutional policies require a different retention period. 
No records may be destroyed during the retention period without the written approval of 
the Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor. 
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10.1.8 Source documents  
• Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the Investigator’s site. 
• Data reported on the CRF or entered in the eCRF 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. 
• Definition of what constitutes source data can be found in trainings materials or study 
manuals. 
• The Investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. 
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements. 
10.1.9 Study and site start and closure  
First act of recruitment 
The study start date is the date on which the clinical study will be open for recruitment of participants. 
The first act of recruitment is the first participant screened and will be the study start date. 
Study/Site termination 
The Sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the Sponsor. 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 study-site closure visit has been performed. 
In case of investigational site closure or complete regional or national lock-down due to a local 
epidemic or international pandemic, the study may be suspended regionally or nationally at 
the affected sites. Every effort will be kept to continue the follow-up of already recruited 
participants as close to the SoA as possible. 
The Investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for study termination by the Sponsor, as well as reasons for the early closure of a study 
site by the Sponsor or Investigator may include but are not limited to: 
• For study termination: 
- 
Information on the product leads to doubt as to the benefit/risk ratio. 
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- 
Discontinuation of further study intervention development. 
• For site termination: 
- 
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 or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
- 
Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the Sponsor shall 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 shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
10.1.10 Publication policy  
• 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 the Sponsor to protect proprietary information and to 
provide comments. 
• The Sponsor will comply with the requirements for publication of study results. In 
accordance with 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 mutual agreement. 
• Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements. 
10.2 
APPENDIX 2: CLINICAL LABORATORY TESTS  
• The tests detailed in Table 14 will be performed by the central laboratory, if feasible, 
unless local laboratory use is specified, per laboratory manual.  
• Local laboratory results are required for some tests listed in Table 14. Local laboratories 
may also be used in the event that the central laboratory results are not available or are not 
feasible to result in time for either study intervention administration and/or response 
evaluation. Additionally, if the local laboratory results are used to make either a study 
intervention decision or response evaluation, the results must be recorded in the e-CRF.  
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary 
by the Investigator or required by local regulations (eg, D-dimer, in case of suspicion of 
thromboembolic event). 
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• Pregnancy testing: For Screening, a HCG blood test which will be obtained from all 
female participants, must be deemed negative (see Section 5). During the study, blood or 
urine HCG testing will be performed for women of childbearing potential (WOCBP), if 
the urine test is positive or non conclusive, a blood test will be taken and sent to the central 
laboratory, if feasible, per laboratory manual. 
Table 14 - Protocol-required laboratory tests  
 
Laboratory tests 
Parameters 
Hematology 
 
 
Platelet count 
 
Red blood cell (RBC) count 
 
Hemoglobin 
 
Hematocrit 
 
RBC indices: 
 
MCV 
 
MCH 
 
%Reticulocytes 
 
White blood cell (WBC) count with differential: 
 
Neutrophils 
 
Lymphocytes 
 
Monocytes 
 
Eosinophils 
 
Basophils 
Coagulation 
 
 
International normalized ratio (INR), activated partial thromboplastin time (aPTT). 
Clinical chemistrya 
 
 
Blood urea nitrogen (BUN) 
 
Creatinine (for estimated glomerular filtration rate calculation, according to Modification of 
Diet in Renal Disease [MDRD]) 
 
Serum glucoseb 
 
Potassium 
 
Sodium 
 
Calcium  
Chloride 
Bicarbonate 
Phosphorous  
 
Aspartate aminotransferase (AST)/Serum glutamic-oxaloacetic transaminase (SGOT) 
 
Alanine aminotransferase (ALT)/Serum glutamic-pyruvic transaminase (SGPT) 
 
Alkaline phosphatase 
Creatine phosphokinase 
 
Total and direct bilirubin 
Albumin 
 
Total protein 
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Laboratory tests 
Parameters 
Routine urinalysis 
• 
Specific gravity 
• 
pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte 
esterase (performed by dipstick locally at the site), quantitative measurement for 
glucose, protein, erythrocytes, and leukocytes count will be required if the urine 
sample test is positive for any of the above parameters by urine dipstick and rated 
clinically significant by the Investigator (sample will be sent to central laboratory)  
• 
Microscopic examination (if blood or protein is abnormal) 
Urine pregnancy testing 
• 
β-human chorionic gonadotropin (HCG) for women of childbearing potential 
(performed locally at the site)c 
Other screening tests 
• 
Follicle-stimulating hormone (as needed in postmenopausal women) 
• 
Highly sensitive serum β-HCG pregnancy test  
• 
Serology: human immunodeficiency virus 1 and 2 antibodies, hepatitis B surface 
antigen (HBsAg), hepatitis B core antibody, (HBc Ab), and hepatitis C antibody 
(HCV-Ab); if anti-HBs negative and anti-HBc positive: perform hepatitis B virus 
DNA to confirm; if anti-HC IgG positive: IgG, HCV-RNA PCR will be performed 
• 
Tuberculosis test (local or central by country)d 
PD/Genetics/Biomarkerse 
• 
IgM, IgG 
• 
Anti-drug antibodies 
• 
Plasma sampling for proteinic exploratory biomarkers 
• 
Whole blood for mRNA sequencing 
• 
(Subset of sites) whole blood for PBMC isolation 
• 
Whole blood for DNA analysis 
NOTES : 
a Details of liver chemistry stopping criteria and required actions and follow-up are given in Section 7.1.2 and Appendix 6 (Section 10.6). 
b Fasting glucose is preferred. Fasting/non fasting status will be recorded at the time of blood collection for glucose assessment. 
c Local urine testing is accepted after screening for the protocol unless serum testing is required by local regulation or IRB/IEC. 
d Blood testing (eg, QuantiFERON TB Gold test) is preferred; skin testing (eg, tuberculin skin test) with ancillary testing will be allowed if 
blood testing is not available, T-SPOT can also be performed, if available. 
e The Investigator and study site will be blinded for these parameters. Unblinding is appropriate in case of a safety issue. 
Investigators must document their review of each laboratory safety report. 
Laboratory/analyte results that could unblind the study will not be reported to investigative sites 
or other blinded personnel until the final database lock (see Section 6.3).  
Unblinding is appropriate in case of a safety issue and deemed necessary by the Investigator.  
10.3 
APPENDIX 3: AES AND SAES: DEFINITIONS AND PROCEDURES FOR RECORDING, 
EVALUATING, FOLLOW-UP, AND REPORTING  
10.3.1 Definition of AE  
AE definition 
• An AE is any untoward medical occurrence in a participant or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered related 
to the study intervention. 
NOTE: An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of study intervention. 
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Events meeting the AE definition 
• Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or 
other safety assessments (eg, ECG, radiological scans, vital signs measurements), 
including those that worsen from baseline, considered clinically significant in the medical 
and scientific judgment of the Investigator (ie, not related to progression of underlying 
disease, or more severe than expected for the participant’s condition), eg: 
- 
Symptomatic and/or 
- 
Requiring either corrective treatment or consultation, and/or  
- 
Leading to IMP discontinuation or modification of dosing, and/or  
- 
Fulfilling a seriousness criterion, and/or  
- 
Defined as an AESI. 
• Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study intervention administration even though 
it may have been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
intervention or a concomitant medication. 
• Signs, symptoms, or the clinical sequelae of any medication errors, misuse and abuse with 
the IMP. 
• “Lack of efficacy” or “failure of expected pharmacological action” per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy assessments. 
However, the signs, symptoms, and/or clinical sequelae resulting from lack of efficacy 
will be reported as AE or SAE if they fulfill the definition of an AE or SAE. 
• The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be 
reported as AE or SAE if they fulfill the definition of an AE or SAE. Also, “lack of 
efficacy” or “failure of expected pharmacological action” also constitutes an AE or SAE. 
Events NOT meeting the AE definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the Investigator to be more severe than expected for the participant’s condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the participant’s 
condition. 
• Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to 
the procedure is the AE. 
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• Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
10.3.2 Definition of SAE  
An SAE is defined as any untoward medical occurrence that, at any dose, meets one or more 
of the criteria listed: 
A) Results in death 
B) Is life-threatening 
The term “life-threatening” in the definition of “serious” refers to an event in which 
the participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
C) Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been admitted (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If 
a complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE. 
D) Results in persistent or significant disability/incapacity 
- 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
- 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
E) Is a congenital anomaly/birth defect 
F) Other situations: 
- 
Medical or scientific judgment should be exercised by the Investigator in deciding 
whether SAE reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or hospitalization 
but may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition. These events should 
usually be considered serious. 
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- 
Note: The following list of medically important events is intended to serve as 
a guideline for determining which condition has to be considered as a medically 
important event. The list is not intended to be exhaustive:  
- 
Intensive treatment in an emergency room or at home for:  
- 
Allergic bronchospasm. 
- 
Blood dyscrasias (ie, agranulocytosis, aplastic anemia, bone marrow 
aplasia, myelodysplasia, pancytopenia, etc). 
- 
Convulsions (seizures, epilepsy, epileptic fit, absence, etc).  
- 
Development of drug dependence or drug abuse.  
- 
ALT >3 × ULN + total bilirubin >2 × ULN or asymptomatic ALT increase 
>10 × ULN.  
- 
Suicide attempt or any event suggestive of suicidality.  
- 
Syncope, loss of consciousness (except if documented as a consequence of 
blood sampling).  
- 
Bullous cutaneous eruptions.  
10.3.3 Recording and follow-up of AE and/or SAE  
AE and SAE recording 
• When an AE/SAE occurs, it is the responsibility of the Investigator to review 
all documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) 
related to the event. 
• The Investigator will then record all relevant AE/SAE information. 
• It is not acceptable for the Investigator to send photocopies of the participant’s medical 
records to the Sponsor’s representative in lieu of completion of the required form. 
• There may be instances when copies of medical records for certain cases are requested by 
the Sponsor’s representative. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to the Sponsor’s representative. 
• The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE. 
Assessment of intensity 
The Investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: 
• Mild: An event that is easily tolerated by the participant, causing minimal discomfort and 
not interfering with everyday activities. 
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• Moderate: An event that causes sufficient discomfort to interfere with normal everyday 
activities. 
• Severe: An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with an SAE. “Severe” is a category used for rating 
the intensity of an event; and both AEs and SAEs can be assessed as severe. 
An event is defined as “serious” when it meets at least 1 of the predefined outcomes as described 
in the definition of an SAE, NOT when it is rated as severe. 
Assessment of causality 
• The Investigator is obligated to assess the relationship between study intervention and 
each occurrence of each AE/SAE. 
• A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than that a relationship cannot be ruled 
out. 
• The Investigator will use clinical judgment to determine the relationship. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk 
factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• The Investigator will also consult the IB and/or Product Information, for marketed 
products, in his/her assessment. 
• For each AE/SAE, the Investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report to the Sponsor. However, it is very important 
that the Investigator always make an assessment of causality for every event before 
the initial transmission of the SAE data to the Sponsor. 
• The Investigator may change his/her opinion of causality in light of follow-up information 
and send an SAE follow-up report with the updated causality assessment. 
• The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• The Investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the Sponsor’s 
representative to elucidate the nature and/or causality of the AE or SAE as fully as 
possible. This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals. 
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• If a participant dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide the Sponsor with a copy of any post-mortem findings 
including histopathology. 
• New or updated information will be recorded in the originally submitted documents. 
• The Investigator will submit any updated SAE data to the Sponsor within 24 hours of 
receipt of the information. 
10.3.4 Reporting of SAEs  
SAE reporting to the Sponsor via an electronic data collection tool 
• The primary mechanism for reporting an SAE to the Sponsor’s representative will be 
the electronic data collection tool. 
• If the electronic system is unavailable, then the site will use the paper SAE data collection 
tool (see next section) to report the event within 24 hours. 
• The site will enter the SAE data into the electronic system as soon as it becomes available. 
• After the study is completed at a given site, the electronic data collection tool will be taken 
off-line to prevent the entry of new data or changes to existing data. 
• If a site receives a report of a new SAE from a study participant or receives updated data 
on a previously reported SAE after the electronic data collection tool has been taken 
off-line, then the site can report this information on a paper SAE form (see next section) or 
to the Sponsor’s representative by telephone. 
• Contacts for SAE reporting can be found in the investigator site file. 
SAE reporting to the Sponsor via paper data collection tool 
• Facsimile transmission of the SAE paper data collection tool is the preferred method to 
transmit this information to the Sponsor’s representative. 
• In rare circumstances and in the absence of facsimile equipment, notification by telephone 
is acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE data collection tool within the designated reporting time frames. 
• Contacts for SAE reporting can be found in the Investigator site file. 
10.4 
APPENDIX 4: CONTRACEPTIVE AND BARRIER GUIDANCE  
10.4.1 Definitions  
A woman is considered WOCBP (fertile) from the time of menarche until becoming 
postmenopausal (see below) unless permanently sterile (see below). 
• A postmenopausal state is defined as the period of time after a woman has experienced 
no menses for 12 consecutive months without an alternative medical cause. 
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• A high follicle-stimulating hormone (FSH) level in the postmenopausal range must be 
used to confirm a postmenopausal state in women not using hormonal contraception or 
hormonal replacement therapy (HRT).  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the non-estrogen hormonal highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Permanent sterilization methods include: 
• Documented hysterectomy. 
• Documented bilateral salpingectomy. 
• Documented bilateral oophorectomy. 
• For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, Mullerian agenesis, androgen insensitivity, gonadal dysgenesis), 
investigator discretion should be applied to determining study entry eligibility. 
Note: Documentation can come from the site personnel’s review of the participant’s medical 
records, medical examination, or medical history interview. 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first administration of study intervention, additional evaluation should be 
considered. 
10.4.2 Contraception guidance  
• If locally required, acceptable contraceptive methods are limited to those which inhibit 
ovulation as the primary mode of action. 
CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
Highly effective methodsb that have low user dependency Failure rate of <1% per year when used consistently and correctly. 
• 
Implantable progestogen-only hormone contraception associated with inhibition of ovulationc 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system (IUS)c 
• 
Bilateral tubal occlusion 
• 
Azoospermic partner (vasectomized or due to a medical cause) 
Azoospermia is a highly effective contraceptive method provided that the partner is the sole sexual partner of the woman 
of childbearing potential and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used.  
Note: documentation of azoospermia for a male participant can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
Highly effective methodsb that are user dependent Failure rate of <1% per year when used consistently and correctly. 
• 
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationc 
- 
oral 
- 
Intravaginal 
- 
Transdermal 
- 
Injectable 
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CONTRACEPTIVESa ALLOWED DURING THE STUDY INCLUDE: 
• 
Progestogen-only hormone contraception associated with inhibition of ovulationc 
- 
Oral 
- 
Injectable 
• 
Sexual abstinence 
Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual 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 and the preferred and usual lifestyle of the participant. 
a Contraceptive use by men or women should be consistent with local regulations regarding the use of contraceptive methods for 
those participating in clinical studies. 
b Failure rate of <1% per year when used consistently and correctly. Typical use failure rates differ from those when used consistently and 
correctly. 
c Male condoms must be used in addition to hormonal contraception. 
Note: Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and 
lactational amenorrhea method (LAM) are not acceptable methods of contraception for this study. Male condom and female condom should 
not be used together (due to risk of failure from friction). 
 
10.5 
APPENDIX 5: GENETICS  
Use/Analysis of DNA 
• Genetic variation may impact a participant’s response to study intervention, susceptibility 
to, and severity and progression of disease. Variable response to study intervention may be 
due to genetic determinants that impact drug absorption, distribution, metabolism, and 
excretion; mechanism of action of the drug; disease etiology; and/or molecular subtype of 
the disease being treated. Therefore, where local regulations and IRB/IEC allow, a blood 
sample will be collected for DNA analysis from consenting participants. 
• DNA samples will be used for research related to frexalimab or multiple sclerosis and 
related diseases. They may also be used to develop tests/assays including diagnostic tests 
related to frexalimab and/or interventions of this drug class and frexalimab. Genetic 
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). 
• DNA samples will be analyzed for genetic polymorphisms such as relevant to MS. 
Analysis of polymorphisms in CD40 and CD40L and associated genes may be conducted 
if it is hypothesized that this may help further understand the clinical data. 
• The samples may be analyzed as part of a multi-study assessment of genetic factors 
involved in the response to frexalimab or study interventions of this class to understand 
MS or related conditions. 
• The results of genetic analyses may be reported in the CSR or in a separate study 
summary. 
• The Sponsor will store the DNA samples in a secure storage space with adequate measures 
to protect confidentiality. 
• The samples will be retained while research on frexalimab or study interventions of 
this class or indication continues but no longer than 25 years or other period as per local 
requirements. 
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10.6 
APPENDIX 6: LIVER AND OTHER SAFETY: SUGGESTED ACTIONS AND FOLLOW-
UP ASSESSMENTS   
 
Neutropenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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Thrombocytopenia is to be recorded as an AE only if at least 1 of the criteria listed in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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*If unable to retest in 72 hours, use original lab results to decide on further reporting/monitoring/discontinuation. 
** Unless a protocol-defined criterion for permanent discontinuation is met. 
*** See box below. 
Note: 
“Baseline” refers to ALT sampled at baseline visit; or if baseline value unavailable, to the latest ALT sampled before the baseline 
visit. The algorithm does not apply to the instances of increase in ALT during screening. 
See Section 10.3 for guidance on safety reporting.  
Normalization is defined as ≤ULN or baseline value if baseline value is >ULN. 
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Increase in serum creatinine is to be recorded as an AE only if at least 1 of the criteria listed in 
the general guidelines for reporting adverse events in Section 10.3 is met. 
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Increase in CPK is to be recorded as an AE only if at least 1 of the criteria in the general 
guidelines for reporting adverse events in Section 10.3 is met. 
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SUSPECTED PML 
If either the clinical presentation or MRI features of a participant are suggestive of PML, 
the following diagnostic and action algorithm is recommended. 
 
Clinical manifestations or MRI lesions features suspicious for PML are proposed in Table 15. 
Table 15 - Clinical and MRI features suggestive of PML  
Clinical 
history  
Subacute onset of weakness, paresthesias, cognitive or behavioral changes, gait dysfunction, speech/language 
difficulties or any other signs of cortical dysfunction, retrochiasmal visual defects or seizure  
Brain 
MRI  
≥1 T2/FLAIR hyperintense and T1 hypointense lesions involving the subcortical and juxtacortical white matter, 
sparing the cortex, with no mass effect, with a continuous progression; new lesions with no enhancement (even when 
large) or with faint rim enhancement  
• The detection of JCV DNA in the cerebrospinal fluid of a participant with clinical and 
MRI features suggestive of PML establishes the diagnosis of PML.  
• If JCV DNA is not detected in cerebrospinal fluid and if clinical suspicion of PML 
remains high, another 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. 
Clinical or MRI features suggestive of PML should be recorded as an AE/AESI/SAE following 
the definitions and procedures in Appendix 3 (Section 10.3).  
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10.7 
APPENDIX 7: COUNTRY-SPECIFIC/REGION REQUIREMENTS  
10.7.1 Germany  
For Germany Only: Acceptable forms of effective contraception include: 
• Established use of oral, injectable, or implantable progestogen-only hormonal 
contraception associated with inhibition of ovulation. 
• Placement of an intrauterine device (IUD) or intrauterine hormone-releasing system (IUS). 
• Bilateral tubal occlusion. 
• Male sterilization (provided that the partner is the sole sexual partner of the WOCBP study 
participant and that the sterilized partner has received medical assessment of the surgical 
success). 
• True abstinence: When this is in line with the preferred and usual lifestyle of the subject. 
(Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulationmethods] and 
withdrawal are not acceptable methods of contraception). 
• All references to "legally authorized representative" are not applicable in Germany; only 
participants who can give written consent themselves are included in the study. References 
to "legally authorized representative" are found in Section 5.1, Section 8.3, and 
Section 10.1.3. 
10.7.2 European Union: Safety reporting to the Agency  
In the European Union, the Sponsor will comply with safety reporting requirements and 
procedures as described in the European Clinical Trials Regulation (EU) No 536/2014. 
All SUSARs to IMP will be reported to the EudraVigilance database within the required 
regulatory timelines. 
Safety reporting with regard to authorized AxMPs shall be made in accordance with Chapter 3 of 
Title IX of Directive 2001/83/EC, irrespective if they are used in accordance with the terms of the 
marketing authorizations of these products. The Investigator is requested to report any suspected 
adverse reactions assessed as solely related to an authorized AxMP to the National Competent 
Authority via the national reporting system. 
10.8 
APPENDIX 8: CONTINGENCY MEASURES FOR A REGIONAL OR NATIONAL 
EMERGENCY THAT IS DECLARED BY A GOVERNMENTAL AGENCY  
Temporary IMP discontinuation may apply in exceptional cases, under regional or national 
emergencies (eg, natural disaster, epidemic diseases, terrorist attack) due to which a visit at 
the clinical study site is no longer feasible. In the case of an exceptional temporary treatment 
discontinuation, the discontinuation should be approved by the Sponsor.  
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The Sponsor should also be notified to determine if treatment should be resumed. If deemed safe, 
the treatment can be resumed at the next scheduled visit. During the discontinuation period, 
remote checks (eg, telephone calls) will take the place of on-site visits per the SoA (Section 1.3). 
• If the above emergency scenario occurs during the follow-up period, one or more follow 
up visits can be performed remotely (eg, via telephone call), but at least one follow-up 
visit should be performed on site (EOS visit), even if the visit window needs to be 
extended (to a maximum of 8 weeks). Remote follow up should be done according to local 
regulations and approved by the Sponsor. 
• If the above emergency scenario leads to site closure or complete regional or national 
lock-down, the study may be suspended for the affected sites (Section 10.1.9). 
For Germany, contingency measures are currently only applicable for the COVID-19 pandemic. 
A discontinuation of IMP in Part A of greater than 45 days will be considered definitive and 
relevant e-CRF sections should be populated. If this occurs in Part B, the Sponsor must be 
contacted to decide mutually on further treatment continuation. 
 
10.9 
APPENDIX 9: LOCAL TOLERABILITY  
10.9.1 Assessment of local injection site reaction  
Local injection site reactions, if appeared, should be characterized and assessed by 
the investigator or a trained designee/sub-investigator according to Table 16. If such a local 
injection site reaction appears, this needs to be recorded in addition as an adverse event. 
Table 16 - Assessment of local injection site reactions  
Reaction to 
injectable product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Very Severe 
(Grade 4) 
Pain 
Does not interfere 
with activity 
Interferes with activity or 
repeated 
use of non-narcotic pain 
reliever 
Prevents daily activity or 
repeated use of narcotic 
pain reliever 
Emergency Room 
(ER) visit or 
hospitalization 
Tenderness 
Mild pain to touch 
Pain with movement 
Significant pain at rest 
ER visit or 
hospitalization 
Erythema/Rednessa  
2.5-5 cm 
5.1-10 cm 
>10 cm 
Necrosis or 
exfoliative 
 dermatitis 
Swellingb 
2.5-5 cm and does 
not interfere with 
activity 
5.1-10 cm or interferes 
with activity 
>10 cm or prevents daily 
activity 
Necrosis 
Itching 
Does not interfere 
with activity 
Interferes with activity or 
repeated 
use of topical or systemic 
treatment 
Prevents daily activity or 
leads to other significant 
dermatologic conditions 
(such as infection, 
scarring, etc) 
ER visit or 
hospitalization 
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Reaction to 
injectable product 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Very Severe 
(Grade 4) 
Other (Please specify)c No modification of 
daily activities and/or 
does not require 
symptomatic 
treatment 
Hinders normal daily 
activities and/or requires 
symptomatic treatment 
Prevents daily activities 
and requires 
symptomatic treatment 
ER visit or 
hospitalization 
a In addition to grading the measured local reaction at the greatest single diameter, the measurement should be recorded as a continuous 
variable. 
b Swelling should be evaluated and graded using the functional scale as well as the actual measurement. 
c Please specify the other signs or symptoms (for example, hematoma, discoloration, re activation, etc). 
ADAPTED from the toxicity grading scale table from the FDA Draft Guidance for Industry: Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials April 2005. 
10.9.2 Local tolerability questionnaire  
Participants will be asked to fill out a local tolerability questionnaire before IMP administration, 
after the completion of the SC or IV administration until 2-hours post administration. 
The local tolerability questionnaire is a verbal descriptor scale (VDS) to record pain at 
the injection site. It is part of the participant booklet with participant questionnaires and is 
presented below. 
 
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10.10 APPENDIX 10: PATIENT-REPORTED OUTCOME  
10.10.1 Multiple sclerosis impact scale (MSIS)-29  
 
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10.10.2 Patient reported outcome measurement information system (PROMIS)-Fatigue-
MS-8  
 
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10.10.3 Patient’s qualitative assessment of treatment version 3 (PQATv3)  
 
 
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10.10.4 Patient global impression of change scale (PGIC-Fatigue)  
 
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10.10.5 Patient global impression of severity scale (PGIS-Fatigue)  
 
 
 
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10.11 APPENDIX 11: Collection, storage, and future use of data and human biological 
samples  
10.11.1 Compliance with Member State applicable rules for the collection, storage and 
future use of human biological samples (Article 7.1h)  
This appendix is provided separately. 
10.11.2 Compliance with Member State applicable rules for the collection, storage and 
future use of (personal) data (article 7 (1 d) of EU Regulation 536/2014)  
This appendix is provided separately. 
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10.12 APPENDIX 12: LIST OF ABBREVIATIONS  
 
ADA: 
antidrug antibodies 
AESI: 
adverse event of special interest 
ALT: 
alanine aminotransferase 
ARR: 
annualized relapse rate 
AUC: 
area under the curve 
AxMP: 
auxiliary medicinal product 
B-cell: 
lymphocyte B 
CD40: 
cluster of differentiation 40 
CD40L: 
cluster of differentiation 40 ligand 
Cmax: 
maximum concentration 
CNS: 
central nervous system 
COVID-19: 
coronavirus disease 2019 
CSR: 
clinical study report 
DMT: 
disease-modifying therapy 
DNA: 
deoxyribonucleic acid 
ECG: 
electrocardiogram 
e-CRF: 
electronic case report form 
EDSS: 
expanded disability status scale 
EOS: 
end of study 
Fc: 
fragment crystallizable 
FDA: 
Food and Drug Administration 
FIH: 
first-in-human 
GCP: 
good clinical practice 
Gd: 
gadolinium 
GdE T1: 
gadolinium-enhancing T1-hyperintense  
GLP: 
good laboratory practice 
HCG: 
human chorionic gonadotropin 
HIV: 
human immunodeficiency virus 
HRT: 
hormonal replacement therapy 
IB: 
investigator’s brochure 
ICF: 
informed consent form 
ICH: 
international conference of harmonization  
Ig: 
immunoglobulin 
IMP: 
investigational medicinal product 
IRT: 
interactive response technology 
IV: 
intravenous 
KLH: 
keyhole limpet hemocyanin 
mAb: 
monoclonal antibody 
MRI: 
magnetic resonance imaging 
MS: 
multiple sclerosis 
MSIS: 
multiple sclerosis impact scale 
NfL: 
neurofilament light chain 
NOAEL: 
no observed adverse effect level 
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PGIC: 
patient global impression of change 
PGIS: 
patient global impression of severity 
PML: 
progressive multifocal leukoencephalopathy 
PPMS: 
primary progressive multiple sclerosis 
PQATv3: 
patient’s qualitative assessment of treatment version 3 
PRO: 
patient-reported outcome 
PROMIS: 
patient reported outcome measurement information system 
q2w: 
every 2 weeks 
q4w: 
every 4 weeks 
RMS: 
relapsing multiple sclerosis 
RNA: 
ribonucleic acid 
SAE: 
serious adverse event 
SARS-CoV-2: 
severe acute respiratory syndrome coronavirus-2 
SC: 
subcutaneous 
SPMS: 
secondary progressive multiple sclerosis 
SUSAR: 
suspected unexpected serious adverse reaction 
TB: 
tuberculosis 
T-cell: 
lymphocyte T 
TDAR: 
T-cell-dependent antibody response 
TEAE: 
treatment-emergent adverse event 
VDS: 
verbal descriptor scale 
 
10.13 APPENDIX 13: PROTOCOL AMENDMENT HISTORY  
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents (TOC). 
10.13.1 Amended protocol 03 (16 November 2023)  
This amended protocol 03 (amendment 03) is considered to be substantial based on the criteria set 
forth 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 main purpose of this amendment is to further extend the duration of Part B (open-label 
period) by approximately 36 months.  
This will allow collecting additional long-term safety and exploratory efficacy data. 
 
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Protocol amendment summary of changes table 
Section # and 
Name 
Description of Change 
Brief Rationale 
Throughout 
the document 
SAR441344 replaced by frexalimab. 
INN available. 
1.1 Synopsis 
Duration of Part B extended up to 280 weeks (study 
intervention duration extended up to approximately 
292 weeks, ie, approximately 73 months). 
To collect additional long-term safety and 
exploratory efficacy data and to make 
frexalimab available. 
 
 
 
 
Addition of possibility of a post trial access option. 
To allow participants to continue 
frexalimab after the study (if applicable). 
1.2 Schema 
Duration of Part B updated. 
To harmonize. 
1.3.1 Schedule of 
activities for Part A 
Footnote added for archived bood sample. 
To clarify the future use. 
1.3.2 Schedule of 
activities for Part B 
Addition of visits up to Week 292/M73. 
To harmonize. 
 
12-lead ECG assessment every 6 months and at 
follow-up visits modified from mandatory to “if needed”. 
To decrease the burden for 
the participants as there is no safety 
issue for these parameters. 
These assessments will be done if 
deemed necessary by the Investigator. 
 
Hematology and biochemistry assessment and 
coagulation assessment removed for all follow-up 
visits. 
 
Antidrug antibodies and frexalimab concentration 
assessment frequency modified to every 6 months from 
W168 (at W192, W216, W240, W264, and W288). 
To decrease the burden for the 
participants that were on steady state 
after the last dose modification per 
amended protocol 02, 
 
 
Addition of PROMIS-Fatigue-MS-8 at EOS. 
 
 
IgG/IgM schedule revised from every 6 months to 
yearly from W120 (ie, W120, W168, W216, and W264). 
Biomarkers assessment reduced to NfL and CXCL13 
after W120 (W144, W240, and early EOT). 
Immunophenotyping assessment added at W144, 
W240, and early EOT. 
Whole blood (PaxGene sample) added at W144, 
W240, early EOT, and common EOS. 
To decrease the burden for 
the participants and to focus on important 
biomarkers and timepoints during study 
intervention. 
 
Archived blood sample added at W144, W240, and at 
early EOT and common EOS. 
In case of unexpected safety issue, to 
ensure that a post baseline value is 
available for previously not assessed 
parameters and for biomarkers research, 
if agreed by the participant. 
 
Footnotes updated or added accordingly. 
 
 
Footnote “n” corrected to -3 days to ±3 days. 
Typo correction. 
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Section # and 
Name 
Description of Change 
Brief Rationale 
1.3.3 Schedule of 
activities for the initial 
12 weeks in Part B2 
Following visits corrected from “as previously planned” 
to as planned per Part B SoA” 
To clarify, since the Part B SoA is being 
modified by amended protocol 03. 
2.3.1 Risk assessment 
Updated information, no major change. 
Alignment with Investigator’s brochure. 
4.1 Overall design 
 
Duration of Part B extended up to 280 weeks (study 
intervention duration extended up to approximately 
292 weeks, ie, approximately 73 months). 
To collect additional long-term safety and 
exploratory efficacy data. 
 
Addition of the option for 
 and 
for SC arm (Part B2) between 2 quarterly onsite visits. 
To decrease the burden for 
the participants 
 
Addition of possibility of a post trial access. 
To allow participants to continue 
frexalimab after the study (if applicable) 
4.4 End of study 
definition 
Duration of Part B extended up to 292 weeks. 
To collect additional long-term safety and 
exploratory efficacy data 
6. Study intervention(s) 
and concomitant 
therapy 
Addition of the option for 
 and 
for SC arm (Part B2) between 2 quarterly onsite visits. 
To decrease the burden for 
the participants 
 
Pharmacy manual updated to product management 
manual also updated throughout the document). 
At the time of the implementation of this 
amended protocol 03, a new version of 
the pharmacy manual newly named 
product management manual will be in 
force 
6.1 Study 
intervention(s) 
administered 
6.1.1 Frexalimab 
 
 
 
. 
6.2.1 Intravenous 
preparation and 
handlings 
Addition of the option for 
 
between 2 quarterly onsite visits. 
To decrease the burden for 
the participants. 
6.2.2 Subcutaneous 
preparation and 
handlings 
. 
 
Addition of the option for home infusion for Part B1 SC 
arm between 2 quarterly onsite visits. 
Harmonization with the Part B SoA for Part B1. 
To decrease the burden for 
the participants. 
Correction/clarification. 
6.6 Continued access to 
intervention after the 
end of the study 
Addition of possibility of a post trial access option. 
To allow participants to continue 
frexalimab after the study (if applicable). 
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Section # and 
Name 
Description of Change 
Brief Rationale 
8 Study assessment 
and procedures 
Maximum amount of blood collected from each 
participant over the duration of the study updated to 
approximately 620 mL to approximately 890 mL for 
the longest participation in the study (updated from 
37 months to 73 months). 
Extension of duration of the study. 
8 Study assessment 
and procedures 
8.4 Pharmacokinetics 
10.2 Appendix 2: 
Clinical laboratory tests 
“Laboratory/analyte results that could unblind the study 
will not be reported to investigative sites or other 
blinded personnel until” updated from “study has been 
unblinded” to “final database lock” 
Although results of Part A were unblinded, 
the investigative sites and other blinded 
personnel will remain blinded for study 
intervention taken during Part A until 
the final database lock. 
 
10.13.2 Amended protocol 02 (21 February 2023)  
This amended protocol 02 (amendment 02) is considered to be substantial based on the criteria set 
forth 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 
This amendment is subsequent to the efficacy and safety analysis of Part A (double-blind period). 
In ACT16877 Part A, frexalimab led to a significant reduction of new T1 gadolinium-enhancing 
lesions and was well-tolerated; high-dose being most efficacious (see Section 2.3.2). 
Consequently, the main purpose of this amendment is to modify the dose regimen of the 
participants in the SC arm from 300 mg q2w to SC 1800 mg q4w (via syringe infusion material) 
to increase their exposure, thus achieving similar exposure to that of the most efficacious dose 
regimen of 1200 mg q4w IV in Part A, while proposing a more convenient dosing schedule.  
In addition, the Part B (open-label period) is extended by 15 months to collect additional long-
term safety and exploratory efficacy data.  
Also, alignment with Part A SAP, minor clarification, template updates, editorial, and document 
formatting revisions were done. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1 Protocol summary 
 
 
1.1 Synopsis 
Update of the duration of Part B (extended by 
15 months). Increase the dose regimen of SC 
group to SC 1800 mg q4w via syringe infusion 
material.  
See overall rationale 
Syringe infusion material is to be used to 
administer the required volume (12 mL).  
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Section # and Name 
Description of Change 
Brief Rationale 
 
Update process for continuation of treatment and 
assessment through study extension rather than 
new long-term study.  
For the SC group, Part B will be divided in 
2 subparts: Part B1 until individual participant 
switch to the modified dose regimen and Part B2 
after this switch. 
For this long-term assessment, extending 
the duration of Part B rather than setting up 
a separate long-term safety study will 
simplify operational aspects. 
 
Objectives and endpoints table splited into Part A 
and Part B and addition of safety objective and 
endpoint for the modified SC dose regimen in 
Part B2. 
Clarification, alignment with Part A SAP, 
assessment of the modified SC dose 
regimen (Part B2). 
1.2 Schema 
Updated to reflect the changes in Part B of 
the study. 
 
1.3.2 Schedule of 
activities for Part B 
Updated to reflect the changes. 
Add Inform consent and corresponding footnote 
 
Participants have to be informed of 
the modified SC dose regimen and 
the extension of Part B duration. 
 
Lighten some safety assessments: quarterly 
physical examination, body temperature and vital 
signs after W24 in Part B. 
No more need for a close safety 
assessment after 24 weeks in the study. 
 
Change the periodicity of plasma sample for NfL, 
CHI3L1, and other biomarkers from every 6 months 
to yearly from W72 and added a check mark for 
sample for PBMC substudy and a check mark for 
MSIS-29 at EOS  
No more need for every 6 months plasma 
sample for NfL, CHI3L1, and other 
biomarkers. PBMC sample at EOS will 
allow to have immune profiling to 
determine chronic treatment effect on 
immune cells. 
1.3.3 Schedule of 
activities for the initial 
12 weeks of Part B2 
Subsection added to include additional 
assessments at the time of switching to 1800 mg 
q4w SC regimen and up to 12 weeks after the 
switch. 
Participants have to be informed and safety 
and PK assessment have to be initially 
reinforced due to the increased dose 
regimen. 
2.2 Background 
Update of thromboembolic statement. 
Available safety data from frexalimab 
Phase 2 clinical program: no TEAE of 
thromboembolism reported. 
 
Update of predicted exposure for the 1800 mg SC 
q4w dose regimen in Part B2. 
To support the proposed 1800 mg SC q4w 
regimen. 
 
Update with Part A results. 
Available data from Part A. 
2.3.1 Risk assessment 
Update of exposure and safety assessment in 
frexalimab clinical trials. 
Available safety data from frexalimab 
Phase 2 clinical program. 
 
Update of management of COVID-19 infection. 
As different variants of COVID-19 emerge 
and worldwide vaccination continues 
the need for systematic permanent IMP 
discontinuation due to COVID-19 is no 
longer justified and can be assessed on 
a case-by-case basis. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Added that for administration of high SC doses 
(1800 mg in 12 mL), SC infusions will be 
administered via syringe infusion material to allow 
slow delivery. 
To support SC infusion of 12 mL. 
2.3.2 Benefit assessment 
Update with efficacy results from ACT16877 
Part A. 
Efficacy analysis of ACT16877 Part A 
available. 
2.3.3 Overall benefit:risk 
conclusion 
Update with efficacy and safety results from 
ACT16877 Part A. 
Efficacy and safety analysis of ACT16877 
Part A available. 
3 Objective and endpoints 
Objectives and endpoints splited into Part A and 
Part B and updated. 
Addition of safety objectives and endpoints for 
the modified SC dose regimen (Part B2). 
Clarification. Alignment with Part A SAP. 
Assessment of the modified SC dose 
regimen. 
4.1 Overall design 
Update of the duration of Part B (extended by 
approximately 15 months). Increase the dose 
regimen of SC group to SC 1800 mg q4w via 
syringe infusion material. 
See overall rationale 
SC injections are limited to 2 mL volume. 
Syringe infusion material is to be used to 
administer the required large volume 
(12 mL). 
 
Update process for continuation of treatment and 
assessment through study extension rather than 
new long-term study. 
For the SC group, Part B will be divided in 
2 subparts: Part B1 until individual participant 
switch to the modified dose regimen and Part B2 
after this switch. 
For this long-term assessment it was 
decided to extend the duration of Part B 
rather than setting up a separate long-term 
safety study to simplify operational 
aspects. 
4.3 Justification for dose 
Update to justify the dose of 1800 mg q4w via 
syringe infusion material. 
See overall rationale. 
SC injections are limited to 2 mL volume. 
Syringe infusion material is to be used to 
administer the required large volume 
(12 mL). 
4.4 End of study definition 
Added text specifying the criteria for participants 
not consenting to transition to Part B2 and also 
updated the total duration of Part B (extended by 
approximately 15 months) 
See overall rationale. 
 
Update process for continuation of treatment and 
assessment through study extension rather than 
new long-term study. 
For this long-term assessment, extending 
the duration of Part B rather than setting up 
a separate long-term safety study will 
simplify operational aspects. 
 
If individual participant does not consent to 
continue with the modified dose regimen, 
the individual participation to the study will end. 
See overall rationale. 
6.1 Study intervention(s) 
administered 
Table 5 and Table 7 updated to include the 
1800 mg q4w SC regimen. 
See overall rationale. 
6.2.2 Subcutaneous 
preparation and handlings 
Add details for syringe infusion material. 
SC injections are limited to 2 mL volume. 
Syringe infusion material is to be used to 
administer the required large volume 
(12 mL). 
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Section # and Name 
Description of Change 
Brief Rationale 
6.6 Continued access to 
intervention after the end 
of the study 
Update process for continuation of treatment and 
assessment through study extension rather than 
new long-term study. 
For this long-term assessment, extending 
the duration of Part B rather than setting up 
a separate long-term safety study will 
simplify operational aspects. 
7.1.1 Permanent 
discontinuation 
Update process for continuation of treatment and 
assessment through study extension rather than 
new long-term study. 
For this long-term assessment, extending 
the duration of Part B rather than setting up 
a separate long-term safety study will 
simplify operational aspects. 
 
Removal of permanent discontinuation in case of 
COVID-19 infection. 
As different variants of COVID-19 emerge 
and worldwide vaccination continues, the 
need for systematic permanent IMP 
discontinuation due to COVID-19 is no 
longer justified and can be and can be 
assessed on a case-by-case basis. 
7.1.3 Temporary 
discontinuation 
Update of management of discontinuation in case 
of COVID-19 infection. 
As different variants of COVID-19 emerge 
and worldwide vaccination continues 
the need for systematic permanent IMP 
discontinuation due to COVID-19 is no 
longer justified and can be assessed on 
a case-by-case basis.  
7.2 Participant 
discontinuation/withdrawal 
from the study 
If individual participant do not consent to continue 
with the modified dose regimen, the individual’s 
participation in the study will end. 
See overall rationale. 
8 Study assessments and 
procedures 
Update of approximate maximum amount of blood 
collected from each participant (620 ml) and 
approximate total duration of the study 
(37 months). 
See overall rationale. 
8.3.7 Adverse event of 
special interest 
Clarification of definition of overdose for IV 
1200 mg q4w arm. 
Add definition of overdose for the SC 1800 mg q4w 
arm. 
Clarification and update for new dose 
regimen for overdose definition. 
9.3.2 Primary endpoint 
(Part A)  
In the primary analysis, baseline score of activation 
of CD40/CD40L pathway and baseline score of 
activation of CD40/CD40L pathway by treatment 
interaction will not be included as covariates. 
Baseline GdE T1 lesion count by treatment 
interaction will be deleted as well. They will be 
included as covariates in a supplementary analysis. 
Due to missing data and lack of evidence 
for the prognostic value of 
baseline score of activation of 
CD40/CD40L pathway. Interactions not 
included in the scope of the primary 
analysis. 
 
In the primary analysis and other similar analysis, 
baseline GdE T1 lesion count will be included as 
a categorical covariate instead of continuous. 
A sensitivity analysis based on baseline GdE T1 
lesion count as a continuous covariate will be done. 
Account for the outliers in the distribution of 
baseline Gde T1 count. 
 
A statistical model has been added to include 
additionally baseline score of activation of 
CD40/CD40L pathway as covariate. 
To assess the prognostic effect of baseline 
score of activation of CD40/CD40L 
pathway. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Frexalimab will be assessed additionally in 
a subgroup of participants with baseline 
CD40/CD40L pathway activation score above 
a pre-defined threshold. 
A threshold will be determined based on 
the baseline activation score distribution 
(percentile). 
 
Exploratory subgroup analyses will be done using 
the same model and population as that utilized for 
the primary analysis within each subgroup and not 
in a model including CD40/CD40L pathway 
activation score entered as an effect (score above 
threshold Y/N). 
To assess the treatment effect within 
each subgroup separately. 
 
An additional cut-off of 0.25 will be used for LRV 
(ie, 75% relative reduction to placebo). 
To check the outcome of the decision using 
a smaller LRV. 
9.3.1 General 
considerations/ 
9.3.3 Secondary 
endpoint(s)/  
9.3.4 Safety analysis/ 
9.3.5 Tertiary/exploratory 
endpoint(s)/ 
9.3.6.1 Pharmacokinetics 
Add the handling of participants under the new 
frexalimab 1800mg SC regimen in the descriptive 
statistics. 
See overall rationale. 
9.3.6.2 Responder 
population identification 
and characterization with 
biomarker data (Part A) 
Update of the responder population analysis.  
Analysis based on a negative binomial 
model which is used for the primary 
analysis. 
10.1.6 Dissemination of 
clinical study data 
Website for requests updated to vivli.org. 
Update. 
10.1.9 Study and site start 
and closure 
First act of recruitment updated from first site open 
to first participant screened. 
Template update. 
10.6 Appendix 6: Liver 
and other safety: 
suggested actions and 
follow-up assessments 
Update of algorithm. 
Template update to comply with new DILI 
group recommendation. 
10.12 Appendix 12: 
protocol amendment 
history 
Amended protocol 01 overall rationale and 
summary of change moved to the history section. 
 
10.13.3 Amended protocol 01 (20 May 2021)  
The amended protocol 01 (amendment 01) is considered to be substantial based on the criteria set 
forth in Article 10(a) of Directive 2001/20/EC of the European Parliament and the Council of 
the European Union. 
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OVERALL RATIONALE FOR THE AMENDMENT 
The purpose of the amendment is mainly to extend the follow-up period from 12 weeks to 
24 weeks (including contraceptive methods and pregnancy testing requirements) to address 
comments raised by Health Authorities. In addition, minor clarification of discrepancies, template 
updates, editorial and document formatting revisions were done. 
Protocol amendment summary of changes table 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.3 Schedule of activities 
Follow-up duration after EOT increased from 12 weeks to 
24 weeks. Three follow-up visits are planned (4 weeks, 
12 weeks, and 24 weeks after EOT, instead of 4 weeks, 
8 weeks, and 12 weeks after EOT). 
Health authority request. 
3 Objectives and 
Endpoints 
Endpoints Soluble CD40L in plasma “at baseline, 
Week 12, and during 3 months of follow-up after EOT” 
changed to plasma “at baseline, Week 12, and during 
24 weeks of follow-up after EOT “ 
 
4.1 Overall design 
Additional follow-up after the stop of study treatment 
increased from 3 months to 24 weeks. 
 
7.1.1 Permanent 
discontinuation 
Follow-up visits duration extended from 3 months to 
24 weeks. 
 
8.2.4 Clinical safety 
laboratory assessment 
Follow-up of abnormal laboratory test extended from 
12 weeks to 24 weeks.  
 
9.3.1 General 
considerations 
Treatment-emergent period extended from 90 to 
180 days. 
To better align with the study intervention half-life at the 
highest doses from results of previous studies. 
 
1.1 Synopsis 
4.1 Overall design 
7.1.1 Permanent 
discontinuation 
Clarified that the participants who early stopped 
intervention can be prescribed disease-modifying therapy 
for RMS, generally after the 24-week follow-up period. 
To allow RMS treatment during the extended 
participation without intervention, generally after the 
24 weeks follow-up period. 
Health Authority request. 
1.1 Synopsis 
6.2.1 Intravenous 
preparation and handling 
Clarified that the IV infusion is prepared in a 100 mL 
pre-filled 0.9% saline bag. 
Clarification. 
1.3 Schedule of activities 
 
Visit window increased from +/-2 days to +/-5 days after 
Week 24. 
To allow more flexibility for visits after 
12 weeks in the open-label Part B. 
 
ADA and PK samples collection during follow-up was 
changed from “last” to “2nd and 3rd visit” in Part A and 
Part B schedules. 
To adapt to the new 24 weeks 
follow-up duration. 
 
Plasma sample collection for soluble CD40L during 
follow-up was changed from every months to “2nd and 
3rd visit” in Part A and Part B schedules. 
To adapt to the new 24 weeks 
follow-up duration. 
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Section # and Name 
Description of Change 
Brief Rationale 
 
Footnotes “cc” and “r” were added in Part A and Part B 
schedules, respectively, to specify that the reference to 
calculate visit windows is Day 1. 
Clarification. 
 
Footnotes “l” of Part A and “h” of Part B schedules were 
clarified with the applicable local tolerability assessment 
by Investigator/designee (see Section 10.9.1) and the 
participant (pain-verbal descriptor scale, 
see Section 10.9.2). 
Clarification. 
1.3.1 Schedule of 
activities for Part A 
Footnote “d” referring to all MRI (to be performed before 
IMP administration) in Part A was modified to be 
applicable to Week 8 and Week 12. 
Footnote “w” in Part A schedule was updated to clarify 
that the MRI should be done not less than 5 days before 
randomization and that MRI should preferably be 
performed once all other screening assessments are 
checked and none of them have excluded the patient. 
Clarification. 
1.3.2 Schedule of 
activities for Part B 
(footnote “a”) 
4.1 Overall design 
6 Study intervention(s) 
and concomitant therapy 
Possibility for the partner/caregiver/home healthcare 
professional to manage the subcutaneous injection at 
home and reference to pharmacy manual were added. 
Clarification. 
5.1 Inclusion criteria 
In Inclusion criteria I05, contraceptive/barrier method and 
pregnancy testing requirements extended from 12 weeks 
to 24 weeks. 
To better align with the study intervention half-life at 
the highest doses from results of previous studies. 
Health Authority request. 
5.2 Exclusion criteria 
10.2 Clinical laboratory 
tests 
In Exclusion criteria E11, method of calculation of 
glomerular filtration rate was changed from Cockroft and 
Gault formula to Modification of Diet in Renal Disease. 
Correction. 
6.3 Measures to minimize 
bias: randomization and 
blinding 
Unblinding 
Statement about unblinding updated in compliance with 
international guidelines, the Sponsor cannot require or 
insist on being involved in the decision to unblind, stall or 
delay in anyway the unblinding of trial participant 
treatment in emergency situations. 
Health Authority request. 
 
6.3 Measures to minimize 
bias: randomization and 
blinding 
Methods of blinding 
8.1.1 Magnetic resonance 
imaging assessments 
Availability of MRI report was changed from “once a year 
starting at Week 48” to “full report of MRI performed from 
Week 24”. 
To make MRI results available earlier to Investigators. 
Health Authority request. 
 
6.6 Continued access to 
intervention after the end 
of the study 
Clarification that the entry in the LTS study will occur 
after the end of the study for participants who completed 
the study and are still taking the study intervention. 
Clarification. 
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Section # and Name 
Description of Change 
Brief Rationale 
7.1.1 Permanent 
discontinuation 
Clarified that during extended participation in the study 
without study intervention, the participant can be treated 
for RMS according to local clinical practices and the best 
judgment of the investigator, generally after the follow-up 
period. 
Addition of reasons for mandatory definitive 
discontinuation (considered necessary by Investigator 
and/or participant, need for use of prohibited medication, 
no longer deriving therapeutic/clinical benefit for the 
participant in the opinion of the investigator). 
Health Authority request. 
7.1.1 Permanent 
discontinuation 
7.2 Participant 
discontinuation/withdrawal 
from the study 
Addition of definition of key visits until Common EOS for 
participants with early EOT: primarily visits with efficacy 
assessment. 
Clarification. 
8.1.3 Expanded disability 
status scale 
Clarified that all Investigators/raters should be qualified to 
perform neurological assessments as per local 
requirement and that they must be trained and certified to 
perform the EDSS in a consistent manner (Neurostatus® 
training version 04/10.2). 
Clarification. 
 
Clarification that investigator and rater can be the same 
person by removing an ambiguous sentence. 
Correction. 
8.2.5 Local tolerability 
Clarification of assessment of local tolerability by 
investigator/designee and participant at site and home 
visits. 
Clarification. 
8.3.4 Regulatory reporting 
requirements for SAEs 
Specific rules for SUSARs reporting were replaced by 
a more general reporting statement to comply with local 
regulatory requirements and Sponsor policy. 
Clarification. 
8.3.7 Adverse event of 
special interest 
Specification of exploratory assessments to be 
performed in case of suspicion of thromboembolic event 
(eg, D-dimer, venous ultrasound and other radiological 
investigations) as needed, as per Investigator clinical 
judgment and/or local regulation.  
Health Authority request. 
9.3.1 General 
considerations 
The on-treatment period was updated from +18 to 
+24 days for SC group and from 32 to 38 days for the 
IV group.  
To comply with the updated visit 
window in the late Part B 
(from +/-2 days to +/-5 days). 
Appendix 2: Clinical 
laboratory tests 
Specification of laboratory assessments to be performed 
in case of suspicion of thromboembolic event (D-dimer). 
Addition of CPK, chloride, bicarbonates, phosphorous, 
and albumin. 
Omission in the initial protocol. 
Appendix 10 Patient-
reported outcome  
Correction of PQATv3 (10.10.3) and PGIC-Fatigue 
(10.10.4). 
Correction. 
 
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11 
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SAR441344-ACT16877 - frexalimab 
18-Nov-2024 
Version number: 1 
 
Property of the Sanofi group - strictly confidential 
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