A Phase II, Randomized, Double-Blind, Placebo-Controlled Dose-Ranging Study To Evaluate the Safety and Efficacy of M2951 in Subjects With SLE
Phase: PHASE2
Conditions: Systemic Lupus Erythematosus
Sponsor: EMD Serono Research & Development Institute, Inc.

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
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Clinical Trial Protocol
Clinical Trial Protocol Number
MS200527-0018 
Title
A 
Phase II, 
Randomized, 
Double-Blind, 
Placebo-Controlled Dose-Ranging Study To Evaluate
the Safety and Efficacy of M2951 in Subjects with 
Systemic Lupus Erythematosus (SLE)
Phase
II
IND Number
EudraCT Number
2016-002950-19
Coordinating Investigator
Telephone: 
Sponsor
For all countries except the USA, and Japan
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt
Germany 
For Japan only:
Merck Serono Co., Ltd.
(Affiliate of Merck KGaA, Darmstadt, Germany)
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
And
For the USA
EMD Serono Research & Development Institute, Inc. 
45A Middlesex Turnpike
Billerica, MA 01821
USA
Medical Responsible:
EMD Serono Research & Development Institute
45A Middlesex Turnpike
Billerica MA 01821
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
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USA
Telephone: 
Clinical Trial Protocol Version
22 May 2018 / Version 7.0
Replaces Version
05 January 2018 / Version 6.0
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It 
is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2018 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................3
Table of In-Text Tables .......................................................................................................9
Table of In-Text Figures......................................................................................................9
List of Abbreviations .........................................................................................................10
1
Synopsis..............................................................................................14
2
Sponsor, Investigators and Trial Administrative Structure ................38
2.1
Investigational Sites............................................................................38
2.2
Trial Coordination / Monitoring.........................................................38
3
Background Information.....................................................................40
3.1
Benefit and Risk .................................................................................44
4
Trial Objectives ..................................................................................45
4.1
Primary Objectives .............................................................................45
4.2
Secondary Objectives .........................................................................46
4.3
Exploratory Objectives .......................................................................46
4.4
Open-label Long-Term Extension (LTE) Period Objectives..............47
5
Investigational Plan ............................................................................47
5.1
Overall Trial Design and Plan ............................................................47
5.2
Discussion of Trial Design .................................................................52
5.2.1
Scientific Rationale for Study Design ................................................52
5.2.2
Justification for Dose..........................................................................53
5.2.3
Rationale for Endpoints......................................................................55
5.2.4
Inclusion of Special Populations ........................................................55
5.3
Selection of Trial Population..............................................................55
5.3.1
Inclusion Criteria ................................................................................56
5.3.2
Exclusion Criteria...............................................................................58
5.4
Criteria for Randomization/Initiation of Treatment with the 
Investigational Medicinal Product......................................................65
5.5
Criteria for Subject Withdrawal..........................................................65
5.5.1
Withdrawal from the Trial..................................................................65
5.5.2
Withdrawal from the Investigational Medicinal Product ...................66
5.6
Premature Termination of the Trial ....................................................69
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5.7
Definition of End of Trial...................................................................69
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................70
6.1
Description of the Investigational Medicinal Product........................70
6.2
Dosage and Administration ................................................................70
6.3
Assignment to Treatment Groups.......................................................71
6.4
Non Investigational Medicinal Products to be Used ..........................71
6.4.1
Background Systemic Lupus Erythematosus Therapies.....................72
6.4.2
Corticosteroids....................................................................................73
6.4.2.1
Corticosteroid Use as Standard of Care..............................................76
6.4.2.2
Corticosteroid Use as Rescue Medication in Treatment of Flare.......78
6.5
Concomitant Medications and Therapies ...........................................78
6.5.1
Permitted Medicines...........................................................................78
6.5.1.1
Corticosteroids....................................................................................79
6.5.1.2
Non-Systemic Corticosteroids............................................................79
6.5.1.3
Vaccinations .......................................................................................79
6.5.1.4
Additional Permitted Medications......................................................79
6.5.2
Prohibited Medicines..........................................................................81
6.5.3
Other Interventions.............................................................................83
6.5.4
Special Precautions.............................................................................83
6.5.4.1
For M2951 ..........................................................................................83
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................83
6.6
Packaging and Labeling of the Investigational Medicinal Product....84
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................84
6.8
Investigational Medicinal Product Accountability.............................84
6.9
Assessment of Investigational Medicinal Product Compliance .........86
6.10
Blinding ..............................................................................................86
6.11
Emergency Unblinding.......................................................................87
6.11.1
Unblinding for Regulatory Authorities...............................................88
6.12
Treatment of Overdose .......................................................................88
6.13
Medical Care of Subjects after End of Trial.......................................88
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7
Trial Procedures and Assessments......................................................88
7.1
Schedule of Assessments....................................................................89
7.1.1
Screening Visit....................................................................................89
7.1.2
DBPC Treatment Period.....................................................................90
7.1.2.1
DBPC End of Treatment/Early Withdrawal Visit ..............................90
7.1.3
LTE Period..........................................................................................90
7.1.3.1
LTE End of Treatment Visit...............................................................91
7.1.4
Safety Follow-Up/End of Study Visit.................................................91
7.2
Demographic and Other Baseline Characteristics ..............................91
7.2.1
Medical History ..................................................................................92
7.2.2
Diagnosis of Systemic Lupus Erythematosus.....................................92
7.2.3
Other Baseline Assessments...............................................................93
7.3
Efficacy Assessments .........................................................................93
7.3.1
British Isles Lupus Assessment Group 2004......................................93
7.3.2
Physician Global Assessment.............................................................94
7.3.3
Systemic Lupus Erythematosus Disease Activity Index-2000 and 
Systemic Lupus Erythematosus Disease Activity Index Flare 
Index ...................................................................................................95
7.3.4
Cutaneous Lupus Erythematosus Disease Area and Severity Index ..96
7.3.5
Systemic Lupus International Collaborating Clinics / American 
College of Rheumatology Damage Index...........................................96
7.3.6
Health Related Quality of Life Assessments......................................97
7.3.6.1
Medical Outcomes Study 36-item Short Form Health Survey...........97
7.3.6.2
Lupus Quality of Life .........................................................................97
7.3.6.3
Patient Global Impression of Change.................................................98
7.3.6.4
Functional Assessment of Chronic Illness Therapy-Fatigue..............98
7.3.6.5
EuroQoL 5 Dimension 5 Levels.........................................................98
7.4
Assessment of Safety..........................................................................99
7.4.1
Adverse Events ...................................................................................99
7.4.1.1
Adverse Event Definitions..................................................................99
7.4.1.2
Methods of Recording and Assessing Adverse Events ....................101
7.4.1.3
Definition of the Adverse Event Reporting Period...........................102
7.4.1.4
Procedure for Reporting Serious Adverse Events ............................102
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7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators............103
7.4.1.6
Monitoring of Subjects with Adverse Events...................................104
7.4.2
Pregnancy and In Utero Drug Exposure...........................................104
7.4.3
Clinical Laboratory Assessments .....................................................104
7.4.4
Vital Signs, Physical Examinations, and Other Assessments...........107
7.4.4.1
Vital Signs ........................................................................................107
7.4.4.2
Physical Examination .......................................................................107
7.4.4.3
Resting 12-lead Electrocardiogram and Chest X-ray.......................107
7.4.4.4
Review of Concomitant Medications and Procedures......................108
7.4.4.5
Unscheduled Visits ...........................................................................108
7.4.5
Columbia-Suicide Severity Rating Scale..........................................108
7.5
Exploratory Assessments..................................................................109
8
Statistics............................................................................................113
8.1
Sample Size ......................................................................................113
8.2
Randomization..................................................................................114
8.3
Endpoints..........................................................................................114
8.3.1
Primary Endpoints of Efficacy and Safety .......................................114
8.3.2
Secondary Endpoints ........................................................................115
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8.3.3
Exploratory Endpoints......................................................................117
8.3.4
Endpoints for Long-Term Extension Period.....................................118
8.4
Analysis Sets.....................................................................................118
8.4.1
Subgroups .........................................................................................120
8.5
Description of Statistical Analyses...................................................120
8.5.1
General Considerations.....................................................................120
8.5.2
Analysis of Primary Endpoints.........................................................121
8.5.3
Analysis of Secondary Endpoints.....................................................122
8.5.4
Analysis of Safety.............................................................................123
8.5.5
Analysis of Exploratory Endpoints...................................................124
8.5.6
Analysis of LTE Endpoints ..............................................................125
8.6
Interim and Additional Planned Analyses ........................................125
9
Ethical and Regulatory Aspects........................................................126
9.1
Responsibilities of the Investigator ..................................................126
9.2
Subject Information and Informed Consent .....................................127
9.3
Subject Identification and Privacy....................................................128
9.4
Emergency Medical Support and Subject Card................................129
9.5
Clinical Trial Insurance and Compensation to Subjects...................129
9.6
Independent Ethics Committee or Institutional Review Board........130
9.7
Health Authorities.............................................................................130
10
Trial Management.............................................................................130
10.1
Case Report Form Handling.............................................................130
10.2
Source Data and Subject Files..........................................................131
10.3
Investigator Site File and Archiving.................................................132
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10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ........................................................................................132
10.5
Changes to the Clinical Trial Protocol..............................................132
10.6
Clinical Trial Report and Publication Policy....................................133
10.6.1
Clinical Trial Report.........................................................................133
10.6.2
Publication........................................................................................133
11
References Cited in the Text.............................................................134
12
Appendices .......................................................................................138
Appendix I: Contraceptive Guidance and Woman of Childbearing Potential.................139
Appendix II: Systemic Lupus International Collaborating Clinics Criteria for 
Systemic Lupus Erythematosus........................................................141
Appendix III: Revised American College of Rheumatology Criteria for Systemic 
Lupus Erythematosus........................................................................144
Appendix IV:
Signature Pages and Responsible Persons for the Trial....................146
Signature Page – Protocol Lead.......................................................................................147
Signature Page – Coordinating Investigator ....................................................................148
Signature Page – Principal Investigator...........................................................................149
Sponsor Responsible Persons Not Named on the Cover Page ........................................150
Appendix V:
Protocol Amendments and List of Changes .....................................151
Amendment 14
152
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Table of In-Text Tables
Table 1
Schedule of Assessments; Screening and Treatment Period (All 
Subjects), End of Study (Subjects Not Entering LTE Period)............28
Table 2
Schedule of Assessments – Optional Long-Term Extension Period..34
Table 3
Additional Pregnancy Testing for Long-Term Extension ..................37
Table 5
Common Terminology Criteria for Adverse Events Grades for 
Relevant Laboratory Parameters.........................................................69
Table 6
Dosage and Administration of Investigational Medicinal Product.....71
Table 7
Permitted Background Systemic Lupus Erythematosus Therapies....72
Table 8
Prednisone Equivalence Calculation (Total Daily Dose)...................73
Table 9
Oral Corticosteroid Dose (in prednisone-equivalent) and 
Taper Guidance...................................................................................75
Table 11
Clinical Laboratory Evaluations.......................................................105
Table of In-Text Figures
Figure 2
Study Design of MS200527-0018 ......................................................51
Figure 3
Study Design for Long-Term Extension.............................................51
Figure 5
Physician Global Assessment Visual Analog Scale with Anchors ....95
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List of Abbreviations
ACR
American College of Rheumatology
AE(s)
Adverse Event(s)
AIID(s)
Autoimmune And Inflammatory Disorders
ALT
Alanine Aminotransferase
ANA
Antinuclear Antibody(ies)
Anti-La 
An Antinuclear Antibody Associated With Autoimmune Diseases 
Including Sjögren Syndrome
Anti-Ro
An Antinuclear Antibody Associated With Autoimmune Diseases 
Including Sjögren Syndrome and Systemic Lupus Erythematosus
Anti-Sm
Anti-Smith Antibody, an Antinuclear Antibody Associated with 
Autoimmune Diseases Including Systemic Lupus Erythematosus
APRIL
A Proliferation-Inducing Ligand
AST
Aspartate Aminotransferase
β-hCG
Beta-Human Chorionic Gonadotropin
BICLA
BILAG-Based Composite Lupus Assessment
BILAG
British Isles Lupus Assessment Group
BLyS
B Lymphocyte Stimulator (Also Called B Cell Activating Factor or 
BAFF)
BP
Blood pressure
CLASI
Cutaneous Lupus Erythematosus Disease Area and Severity Index
CLASI-A
CLASI Activity
CLASI-D
CLASI Damage
CRA
Clinical Research Associate
CRO
Contract Research Organization
CRP
C-Reactive Protein
CS
Corticosteroid(s)
CSR
Clinical Study Report
C-SSRS
Columbia-Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
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CXR
Chest X-ray
DBPC
Double-Blind, Placebo-Controlled
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eGFR
Estimated Glomerular Filtration Rate
EOT
End of Treatment
ePRO
Electronic Patient-Reported Outcome
EQ-5D-5L
EuroQoL 5 Dimension 5 Levels
FACIT
Functional Assessment of Chronic Illness Therapy
Fc
Fragment Crystallizable
FSH
Follicle-Stimulating Hormone
FWER
Family-Wise Type 1 Error Rate
GCP
Good Clinical Practice
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDA
High Disease Activity
HIV
Human Immunodeficiency Virus
HRQoL
Health Related Quality of Life
HRT
Hormone Replacement Therapy 
HRU
Health Resource Utilization
IA
Interim Analysis
IAP
Integrated Analysis Plan
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
Immunoglobulin
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IMP
Investigational Medicinal Product
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IND
Investigational New Drug
INR
International Normalized Ratio
IPMP
Integrated Project Management Plan
IRB
Institutional Review Board
ITT
Intent-To-Treat
IWRS
Interactive Web Response System
LLN
Lower Limit of Normal
LTBI
Latent TB Infection
LTE
Long-Term Extension
LupusQoL
Lupus Quality of Life
MAD
Multiple Ascending Dose
MCS
Mental Component Summary
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary For Regulatory Activities
mITT
Modified Intent-To-Treat
MMF
Mycophenolate Mofetil
MPS
Mycophenolate Sodium
mRNA
messenger Ribonucleic Acid
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for 
Adverse Events
NK
Natural Killer
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
OCS
Oral Corticosteroids
OR
Odds Ratio
PCR
Polymerase chain reaction
PCS
Physical Component Summary
PGA
Physician’s Global Assessment
PGIC
Patient Global Impression of Change
PI
Principal Investigator
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PP
Per-Protocol
PRO
Patient-Reported Outcome
PTT
Partial Thromboplastin Time
QoL
Quality of Life
RA
Rheumatoid Arthritis
RoW
Rest of the World
SAD
Single Ascending Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SF-36v2®
Medical Outcomes Study 36-Item Short Form Health Survey 
SFI
SLEDAI Flare Index
SLE
Systemic Lupus Erythematosus
SLEDAI-2K
SLE Disease Activity Index-2000
SLICC
Systemic Lupus International Collaborating Clinics
SMC
Safety Monitoring Committee
SOA
Schedule of Assessments
SoC
Standard of Care
SRI
SLE Responder Index
SUSAR
Suspected Unexpected Serious Adverse Reaction
TB
Tuberculosis
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
UPCR
Urine Protein to Creatinine Ratio
VAS
Visual Analog Scale
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1
Synopsis
Clinical Trial Protocol Number
MS200527-0018
Title
A 
Phase II, 
Randomized, 
Double-Blind, 
Placebo-Controlled Dose-Ranging Study To Evaluate
the Safety and Efficacy of M2951 in Subjects with 
Systemic Lupus Erythematosus (SLE)
Trial Phase
II
IND Number
FDA covered trial
yes
no
EudraCT Number
2016-002950-19 
Coordinating Investigator
Telephone: 
Sponsors
For all countries except the USA and Japan
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt
Germany 
For Japan only:
Merck Serono Co., Ltd.
(Affiliate of Merck KGaA, Darmstadt, Germany)
Arco Tower, 1-8-1 Shimomeguro
Meguro-ku, Tokyo 153-8926, Japan
And
For the USA
EMD Serono Research & Development Institute, Inc. 
45A Middlesex Turnpike
Billerica, MA 01821
USA
Trial centers/countries
Approximately 180 sites / 20 countries
Planned Trial Period
(first subject in-last subject out)
First subject in: Q4, 2016
Last subject out: Q3, 2022
Trial Registry
ClinicalTrials.gov, EudraCT, clinicaltrials.jp
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Trial Objectives 
Primary
! To evaluate the efficacy and dose response of evobrutinib (also referred to as M2951)
compared to placebo in reducing disease activity in adult subjects with active, 
autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard of 
care (SoC) therapy based on SLE Responder Index (SRI)-4 response at Week 52 in all 
subjects, or on SRI-6 response at Week 52 in the High Disease Activity (HDA) subgroup, 
defined as SLE Disease Activity Index 2000 (SLEDAI-2K) ≥10
! To evaluate the safety of M2951 in subjects with SLE on SoC therapy.
Key Secondary
! To evaluate the efficacy and dose response of M2951 compared to placebo in delaying time 
to first severe flare during the Treatment Period, in subjects with SLE on SoC therapy, where 
a severe flare is defined as at least one British Isles Lupus Assessment Group (BILAG
2004) A in any organ system due to items that are new or worse, compared to the BILAG 
evaluation at the previous visit.
! To evaluate the efficacy and dose response of M2951 compared to placebo in reducing 
disease activity, based on the SRI-4 response at Week 52, in the serologically active 
subgroup, which is defined as subjects with positive anti-double-stranded deoxyribonucleic 
acid (anti-dsDNA) and/or low complement levels.
Secondary
! To evaluate the efficacy of M2951 compared to placebo on changes in disease activity over 
52 weeks
! To evaluate the efficacy of M2951 compared to placebo on changes in organ-specific 
disease activity over 52 weeks
! To evaluate the effect of M2951 compared to placebo on the annualized flare rate
! To evaluate the impact of M2951 treatment compared to placebo on subject reported health 
related quality of life (HRQoL) over 52 weeks
! To evaluate the effect of M2951 on corticosteroid (CS) usage over 52 weeks.
Exploratory
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Open-label Long-Term Extension (LTE) Period Objectives
The objective of the LTE Period is:
! To evaluate the long-term safety, efficacy, and HRQoL of M2951 at an initial dose of 50 mg 
twice daily or the eventual Phase III dose when decided for an additional two years.
Methodology
This is a Phase II, multicenter, international, randomized, double-blind, placebo-controlled 
(DBPC) parallel-arm study designed to determine the efficacy, dose response, and safety of 
M2951 in subjects with SLE, and to consider a dose to take forward into Phase III development. 
 
 
 
The study is composed of a Screening Period of four weeks, a DBPC Treatment Period of 
52 weeks, an open-label LTE Period of 104 weeks, and a Safety Follow-Up Period of 
four weeks.
Planned number of subjects
Approximately 468 enrolled subjects (approximately 117 enrolled subjects per treatment 
group). To ensure enrollment of an adequate number of subjects with HDA, recruitment of 
subjects without HDA may be capped, depending on enrollment rates observed during the 
study of subjects with and without HDA.
Primary endpoints
! The co-primary efficacy endpoints are SRI-4 response at Week 52 in all subjects and SRI-6 
response at Week 52 in a HDA subgroup.
! The primary safety endpoints are nature, severity, and incidence of adverse events (AEs), 
serious adverse events (SAEs); vital signs, electrocardiograms (ECGs); absolute values of 
and change from Baseline in serum total immunoglobulin (Ig) levels (IgG, IgA, IgM), total 
B cell counts, and clinical laboratory parameters.
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Secondary endpoints
Key Secondary
! Time to first severe flare, where a severe flare is defined as at least one BILAG A score in 
any organ system due to items that are new or worse, compared to the BILAG evaluation at 
the previous visit, during the Treatment Period
! SRI-4 response at Week 52, in the serologically active subgroup, which is defined as 
subjects with positive anti-dsDNA and/or low complement levels.
Other Secondary
! SRI-6 response at Week 52, in the serologically active subgroup, which is defined as 
subjects with positive anti-dsDNA and/or low complement levels.
! SRI-4 Response at Week 52 with a Sustained Reduction of Oral Corticosteroids (OCS) Dose 
to 7.5 milligrams prednisone-equivalent per day or less (≤7.5 mg/day) and less than or equal 
to (≤) Day 1 dose during Week 41 Through Week 52, in all subjects.
! SRI-6 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams 
prednisone-equivalent per day or less (≤7.5 mg/day) and less than or equal to (≤) Day 1 
dose during Week 41 Through Week 52, in the HDA subgroup, defined as SLEDAI-2K 
≥10 at Screening.
! SRI-4 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams 
prednisone-equivalent per day or less (≤7.5 mg/day) and less than or equal to (≤) Day 1 
dose during Week 41 Through Week 52, in the serologically active subgroup, which is 
defined as subjects with positive anti-dsDNA and/or low complement levels.
! Time to first flare, flare-free status at Week 52, and annualized flare rate, during the 
Treatment Period, will be analyzed separately, each assessed with flare defined as:
o
BILAG A Severe flare
o
BILAG A or 2B Moderate to Severe flare
o
SLEDAI Flare Index (SFI) Severe flare
! Disease activity over time, during the Treatment Period, as measured by:
o
Low disease activity status, defined by SLEDAI-2K ≤ 2, at Week 52
o
Low disease activity status, defined by clinical SLEDAI-2K (SLEDAI 2K excluding 
anti-dsDNA and low complement parameters) ≤ 2, at Week 52
o
Lupus low disease activity state (LLDAS), defined as meeting all of the following 
(Franklyn 2016):
-
SLEDAI-2K ≤ 4
-
No activity in any major organ systems (renal, central nervous system, 
cardiopulmonary, vasculitis, fever)
-
No new features of disease activity compared with the previous assessment
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
18/205
-
Prednisone-equivalent ≤7.5 mg/day
-
Unchanged background immunosuppressive therapy
o
Change from Baseline in SLEDAI-2K score by visit
o
Change from Baseline in Cutaneous Lupus Erythematosus Disease Area and 
Severity Index-Activity (CLASI-A) by visit
o
BILAG-based Composite Lupus Assessment (BICLA) response by visit
o
Change from Baseline in BILAG-2004 by visit
o
Change from Baseline in Physician’s Global Assessment (PGA) by visit
! HRQoL over time, during the Treatment Period, as measured by:
o
Change from Baseline in Medical Outcomes Study 36-Item Short Form Health 
Survey (SF-36v2®) Physical Component Summary (PCS) and Mental Component 
Summary (MCS) score (and their components) by visit
o
Change from Baseline in EuroQoL 5 Dimension 5 Levels (EQ-5D-5L) score by
visit
o
Change from Baseline in Lupus Quality of Life (LupusQoL) scores by visit
o
Patient Global Impression of Change (PGIC) score by visit
o
Change from Baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue score by visit
! Corticosteroid usage over time, during the Treatment Period, as measured by:
o
Reduction from Baseline in prednisone-equivalent CS dose by ≥25% to a dose 
of ≤7.5 mg/day, with no BILAG A or 2B flare in disease activity (at that visit)
o
Change from Baseline to Week 52 in prednisone-equivalent CS daily dose
o
Reduction from Baseline to Week 52 in prednisone-equivalent CS daily dose of 
zero to < 25%, 25% to 50%, > 50%, or an increase 
o
Cumulative prednisone-equivalent CS dose from Baseline until completion of the 
Treatment Period
o
Clinically meaningful reduction in CS dose from Baseline, defined by:
-
A reduction of daily prednisone-equivalent CS dose ≥25% to a dose 
of ≤7.5 mg/day by Week 40 and sustained through Week 52
And
-
No new BILAG A organ domain scores and no more than one new BILAG 
B organ domain score during Weeks 40 through 52.
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
19/205
Exploratory Endpoints
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CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
20/205
Endpoints for Long-Term Extension Period
LTE Safety:
! Nature, severity, and incidence of AEs, SAEs, vital signs, ECGs, absolute values and change 
from Baseline in serum total Ig levels (IgG, IgA, IgM) and total B cell counts, and clinical 
laboratory parameters.
LTE Efficacy:
! The following LTE efficacy endpoints will be analyzed at Week 24, Week 52, and 
Week 104:
o
Changes over time in SRI response
o
Changes over time in Low Disease Activity status (LLDAS, SLEDAI-2K ≤2, 
clinical SLEDAI-2K ≤2).
o
Changes over time in CLASI-A, CLASI-D, and SLICC/ACR Damage Index organ 
damage scores
o
Changes over time in disease activity as measured by the BILAG, SLEDAI-2K, and 
PGA
o
Change over time in prednisone-equivalent CS dose
o
Changes over time in HRQoL
o
Changes over time in autoantibodies and complement levels
! Changes in HRU by visit, including but not limited to doctor/home/emergency visits, 
hospitalizations, paid assistance, and missed work
! Time to first flare; flare-free status at Weeks 24, 52, and 104; and annualized flare rate, will 
be analyzed separately, each assessed with flare defined as:
o
BILAG A Severe flare
o
BILAG A or 2B Moderate to Severe flare
o
SLEDAI Flare Index (SFI) Severe flare.
Schedule of visits and assessments
The study will be conducted on an outpatient basis. Subjects will attend clinic visits at regular 
intervals as indicated in the Schedule of Assessments (SOA).
Screening Period
The first visit will be a Screening Visit and will include a review of the inclusion/exclusion 
criteria. Subjects should undergo the Day 1 Visit as soon as possible after eligibility for the 
study has been confirmed. During the Screening Period, there will be no change in OCS dose.
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
21/205
Double-Blind, Placebo-Controlled Treatment Period
Duration of the Treatment Period will be 52 weeks starting at randomization (Day 1). The 
Day 1 Visit will be considered the Baseline for disease activity (e.g., BILAG 2004, 
SLEDAI-2K, PGA, and CLASI). Subject eligibility must be reviewed on Day 1 prior to 
randomization, and the first dose of the Investigational Medicinal Product (IMP) (M2951 or 
placebo) will be given while the subject is still on site for Day 1. Subjects must then return to 
the study site for study visits as indicated in the SOA. Subjects will receive the last dose of 
IMP at Week 52, which is the End of Treatment (EOT) for the study, unless they enter the LTE 
Period.
From Day 1 to the Week 4 Visit, corticosteroids may be increased, decreased, initiated (within 
the first two weeks of the treatment period), or remain unchanged. However, the corticosteroid 
dose must be ≤30 mg/day prednisone-equivalent by the end of Week 4. From Week 4 to the 
Week 8 Study Visit, OCS dose will be reduced to establish a Threshold Dose, the maximum 
dose allowed at any time in the study, other than for treatment of flares. Treatment decisions 
will be made by Investigator assessment for the purpose of subject management. Rescue 
therapy will be allowed for the treatment of flares.
Any subjects permanently withdrawn from IMP will be expected to complete the EOT/Early 
Withdrawal study visit within five days of IMP withdrawal, followed by the Safety 
Follow-Up Visit four weeks post last dose.
Optional Open-Label Long-Term Extension Period
Subjects who completed the 52-week DBPC Treatment period will be offered participation in 
the 104-week open-label, LTE Period of the study. The purpose of the LTE Period is to allow 
all the subjects with the opportunity to receive active treatment with M2951 and to collect long 
term safety and efficacy data. The Investigator should review the optional LTE Period with the 
subject prior to the DBPC Week 52 visit. Signed consent will be obtained prior to participation 
in the LTE Period. The DBPC Week 52/EOT Visit will be considered the LTE Day 1 Visit.  
The Safety Follow-Up Visit will be deferred until treatment is stopped in the LTE Period, due 
to either a subject’s premature withdrawal/early termination from the LTE, termination of the 
study by the Sponsor, or completion of the LTE treatment period. 
In some cases, due to Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval, regulatory-specific, or other administrative delays, a subject may experience a 
treatment gap between the IMP last dose received in the DBPC Period (Week 52/EOT visit) 
and the start of the LTE IMP treatment. Upon Principal Investigator (PI) request, these subjects 
may still be able to enroll in the LTE with approval from Merck/EMD Serono, on a 
case-by-case basis. If the day of rollover to the LTE occurs after the DBPC Week 56/EOS visit, 
all assessments noted at the LTE Day 1 visit will need to be completed. For subjects that 
rollover after the Week 52/EOT visit but prior to their scheduled Week 56/EOS visit, 
concomitant medications and AEs will need to be reviewed and updated, and the PI will need 
to ensure that the subject remains eligible for the study. No other additional assessments other 
than dispensing of IMP will need to be completed.
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CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
22/205
Safety Follow-Up Period
The Safety Follow-Up/End of Study Visit is scheduled four weeks (+ 5 days) after the last 
administration of study treatment. For subjects who do not participate in the LTE Period, the 
Safety Follow-Up Visit is scheduled four weeks (+ 5 days) after the last administration of study 
treatment in the DBPC Period. For subjects who participate in the LTE Period, the Safety 
Follow-Up Visit is delayed until four weeks (+ 5 days) after the last administration of study 
treatment in the LTE Period. Subjects who are approved to rollover into LTE Period after they 
entered, or completed, the DBPC Safety Follow-Up Period, may have two Safety Follow-Up 
Visits. Additional details of the Safety Follow-Up/ End of Study Visit are provided in the SOA.
Assessment of Endpoints
During the study, efficacy endpoints will be evaluated using several disease activity indices, 
such as the BILAG 2004, SLEDAI-2K, PGA, and CLASI-A. As part of the efficacy 
assessment, the effects of treatment on HRQoL will be examined using Patient-Reported 
Outcome (PRO) measures including but not limited to: SF-36v2, EQ-5D-5L, LupusQoL, 
FACIT-Fatigue, and PGIC. Health Resource Utilization will also be collected as part of the 
efficacy assessment. 
Safety will be evaluated through the nature, incidence, severity and outcome of AEs, and 
assessment of physical examination findings, ECGs, hematology and chemical laboratory 
assessments, vital signs, and change from Baseline in serum total Ig levels (IgG, IgA, and IgM)
and total B cell counts.
Treatment decisions will be made by Investigator assessment for the purpose of subject 
management. Rescue therapy will be allowed for the treatment of flares.
Diagnosis and key inclusion and exclusion criteria
Eligible male and female subjects, aged 18 to 75 years (In Japan, if a subject is < 20 years of 
age, the written informed consent from the subject’s parent or guardian will be required in 
addition to the subject’s written consent); must have diagnosis of SLE with either the SLICC 
criteria for SLE, or at least four of the 11 ACR classification criteria for SLE, of at least 
six months duration prior to Screening; SLEDAI-2K total score ≥6 (including clinical 
SLEDAI ≥4) at Screening Visit; and have positive test results for anti-double-stranded DNA
(anti-dsDNA) antibody and/or anti-nuclear antibody (human epithelial cell-2 ANA ≥1:80) at 
the time of Screening. Subjects are not eligible for this study if they have active, clinically 
significant interstitial lung disease or pulmonary arterial hypertension; proteinuria (urine 
protein to creatinine ratio [UPCR] > 4 mg/mg); acutely worsened renal function; central 
nervous system SLE; or within two weeks prior to Screening or during Screening: use of 
OCS > 30 mg daily prednisone-equivalent; use of injectable corticosteroids, or change in dose 
of corticosteroids.
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CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
23/205
Oral CS restrictions during study
Restrictions within two weeks prior to Screening or during Screening: included use of 
OCS > 30 mg daily prednisone-equivalent, use of injectable corticosteroids, or change in dose. 
Restrictions and guidance for the use of OCS during the course of the study include prohibiting 
doses above 30 mg/day after Week 4 of the Treatment Period, prohibiting injectable CSs
(outside limited exceptions), limits on when change in dose of CS may occur, recommendations 
to decrease CS dose within parameters allowed by the study, and limits on the use of CS during 
treatment of SLE flares.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule 
Subjects randomized into the study will receive one of three doses of M2951 (25 mg once daily, 
75 mg once daily, or 50 mg twice daily) or placebo, taken orally for 52 weeks. To maintain 
blinding for placebo and M2951, subjects will self-administer three tablets once daily in the 
morning and two tablets once daily in the evening. Subjects who choose to participate in the 
LTE Period will receive open-label M2951 50 mg twice daily or the eventual Phase III dose 
when decided, taken orally for 104 weeks.
Reference therapy: dose/mode of administration/dosing schedule 
N/A
Planned trial and treatment duration per subject 
Total duration of subject participation is approximately 420 days (60 weeks), which includes:
! Screening: 28 days (up to four weeks)
! DBPC Treatment: 364 days (52 weeks)
! Safety Follow-Up: 28 days (four weeks)
The optional LTE Treatment Period is approximately 104 weeks in duration and will be offered 
to subjects after completion of the DBPC Period.
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CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
24/205
Statistical Methods 
A sample size of 103 evaluable subjects per group provides 80% power at the α = 0.025 
one-sided significance level to detect 
!
an absolute improvement of 20% in Week 52 SRI-4 response proportion for 
M2951-treated subjects relative to placebo-exposed subjects, among subjects with 
SLEDAI-2K total score ≥6 at Screening, assuming a placebo response proportion of 
40%,
or
!
an absolute improvement of 25% in Week 52 SRI-6 response proportion for 
M2951-treated subjects relative to placebo-exposed subjects, among subjects with a 
SLEDAI-2K total score ≥10 at Screening (i.e., HDA), assuming a placebo response 
proportion of 30%,
assuming that each co-primary endpoint is tested via a chi-squared test of the odds ratio (OR)
for treatment effect at the 0.0125 one-sided level, and assuming that approximately 50% of 
randomized subjects are in the HDA group. If the absolute improvement in Week 52 SRI-6
response in HDA subjects is only 20%, the power is 76%. Approximately 108 subjects will be 
randomized per treatment group to protect against a loss of information due to drop-out (for 
reasons other than efficacy/safety) of 5% over 52 weeks. Given the randomization ratio 1:1:1:1, 
the total sample size is planned to be 432 subjects. 
The study includes a Japanese cohort: 32 evaluable Japanese subjects total, increased to 
approximately 36 randomized Japanese subjects total to protect against loss of information. If 
enrollment of Japanese subjects is slow, the entire Japanese cohort may not be part of the 
primary analysis. Therefore, the total enrollment will range from n = 432 to 468, where
468 = 432 + 36 is the number enrolled if none of the 36 Japanese subjects enroll in time to be 
included in the primary analysis.  The number of subjects enrolled per group will range from 
n = 108 to 117.
Eligible subjects will be randomized to treatment with placebo or M2951 (doses 25 mg once 
daily, 75 mg once daily, or 50 mg twice daily), through a central randomization process by an 
Interactive Web Response System (IWRS), stratified according to race (Black versus 
non-Black), region (US and Western Europe, Japan, and the rest of the world [RoW]) and 
disease activity at Screening (SLEDAI-2K total score < 10 versus ≥10) prior to dosing on 
Day 1. Subjects with SLEDAI-2K total score ≥10 at Screening will be considered to have 
HDA.
There will be at least two planned analyses in this study - the primary and final analyses.  There 
may be up to four planned analyses, depending on whether the optional futility interim analysis 
(IA) is conducted, and whether the analysis for treatment effect consistency is coincident with 
the primary analysis, or is conducted after the primary analysis. If the futility IA is conducted, 
it will be based on Week 24 SRI-4 response among all subjects in the primary analysis cohort 
and Week 24 SRI-6 response among HDA subjects in the primary analysis cohort. The IA will 
be conducted when 100% of subjects in the primary analysis cohort reach Week 24 of treatment 
or prematurely discontinue from treatment. If enrollment is slower than expected, consideration 
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
25/205
will be given to conducting the interim futility analysis when the first 50% of the primary 
analysis cohort reach Week 24 of treatment, or prematurely discontinue from treatment. 
The primary analysis cohort consists of the first 432 subjects randomized.  However, if drop-out 
for reasons unrelated to efficacy or safety is higher than expected, effectively reducing the 
power of the study, the Integrated Analysis Plan (IAP) may prespecify that the primary analysis
cohort will include all subjects randomized.  The primary analysis will be based on Week 52 
SRI-4 response among all subjects in the primary analysis cohort, and Week 52 SRI-6 response 
among HDA subjects in the primary analysis cohort. This analysis will be triggered when 100% 
of subjects in the primary analysis cohort.
!
Complete Week 52 of treatment and either enter LTE or complete Safety Follow-Up, 
or
!
Prematurely discontinue from treatment prior to Week 52 and complete Safety 
Follow-Up, or
!
Prematurely discontinue from study without Safety Follow-Up.
The Japanese cohort may be fully, partially, or not included in this primary analysis, depending 
on the enrollment rate. 
The Family-Wise type 1 error rate (FWER) due to the co-primary endpoints and multiple
M2951 dose group comparisons versus placebo will be controlled at the two-sided α = 0.05
level via a tree gatekeeping procedure. The four hypotheses associated with the comparisons 
involving the co-primary endpoints and the two highest dose groups will form the first family 
of hypotheses in the tree.  This family will be tested via the truncated Hochberg procedure, 
with truncation fraction pre-specified in the IAP. The multiple-testing procedure for the 
remainder of the tree, including the hypotheses associated with the comparisons involving the 
co-primary endpoints and the lowest dose group, and the key secondary endpoints and all dose 
groups, will be pre-specified in the IAP.
A treatment effect consistency analysis may be scheduled if the Japanese cohort does not enroll 
in time to be included with the primary analysis cohort.  If the Japanese cohort enrolls in time 
to be included, the evaluation of consistency with respect to ethnicity of Week 52 SRI-4 
response can be performed at the time of the primary analysis.  If the Japanese cohort enrolls 
slowly, then the primary analysis will occur without inclusion of the Japanese cohort, and a 
separate consistency analysis will be triggered when 100% of enrolled Japanese subjects: 
! Complete Week 52 of treatment and either enter LTE or complete Safety Follow-Up, or 
! Prematurely discontinue from treatment prior to Week 52 and complete Safety Follow-Up, 
or 
! Prematurely discontinue from study without Safety Follow-Up.
The final analysis will be triggered when 100% of subjects enrolled: 
! Complete Week 104 of the LTE and the Safety Follow-Up, or
! Complete Week 52 of treatment and the Safety Follow-Up (if they did not rollover into the 
LTE), or
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CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
26/205
! Prematurely discontinue from treatment and complete Safety Follow-Up, or
! Prematurely discontinue from study. 
The final analysis will be performed by 
 staff when the final analysis trigger condition 
has been met, protocol violations determined, and the database is locked for the final analysis.
Analysis of Co-primary Efficacy Endpoints
The primary analysis of SRI-4 response at Week 52 among all subjects in the primary analysis
cohort, and SRI-6 response at Week 52 among HDA subjects in the primary analysis cohort, 
will be an estimate of OR, together with associated two-sided 95% CI and p-value (testing null 
hypothesis H0: OR = 1.0), comparing each M2951 dose group to placebo, based on a logistic 
model for the odds of a given SRI response in the appropriate population, with M2951 dose 
group or placebo group as a factor and adjustment for covariates based on randomization strata. 
The primary analysis of the co-primary efficacy endpoints will be based on the modified intent-
to-treat (mITT) analysis set. 
Descriptive statistics for SRI-4 response, and for SRI-6 response in the HDA subgroup, will be 
provided for each treatment group by time point. 
Analysis of Key Secondary Endpoints
Time to first severe (BILAG A) flare during the Treatment Period in all subjects will be 
compared between M2951 and placebo via a stratified log rank test.  The adjusted hazard ratio 
comparing M2951 to placebo will be estimated (together with 95% CI)  via a Cox regression 
model, with treatment group as a factor, and controlling for covariates defining randomization 
strata. A subject who discontinues treatment or completes treatment without experiencing 
severe flare will have his/her time to flare censored at the last time point at which flare could 
be assessed. 
Kaplan-Meier estimates of probability of surviving free of severe (BILAG A) flare as a function 
of time on treatment will be provided for each treatment group.
The analysis of SRI-4 response at Week 52 among serologically active subjects will be an 
estimate of OR, together with associated 95% CI and p-value, comparing each M2951 dose 
group to placebo, based on a logistic model for the odds of SRI-4 response in the serologically 
active population, with M2951 dose group or placebo group as a factor and adjustment for 
covariates based on randomization strata. A test for trend in dose-response, using the same 
logistic model, will be reported as a supportive analysis.
Descriptive statistics for SRI-4 response in the serologically active subgroup, will be provided 
for each treatment group by time point. 
Analysis of Other Secondary Efficacy Endpoints
Binary endpoints will be modeled via logistic regression, time to event endpoints will be 
modeled via Cox regression and tested via stratified log rank test, continuous endpoints 
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CCI
PPD

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
27/205
measured longitudinally (i.e., HRQoL change from baseline) will be analyzed using 
Mixed-effect Model for Repeated Measures (MMRM), and count endpoints (i.e., annualized 
flare rate) will be modeled via negative binomial regression, with treatment group as a factor, 
and adjusting for covariates defining randomization strata. Analysis of annualized flare rate 
will use the log of observation time (in years) as an offset in the model. Change in a binary 
endpoint between two time points will be analyzed via McNemar’s test. The effect of treatment 
on change in a binary endpoint will be analyzed via logistic regression, with treatment group, 
time point, and interaction as predictors, and adjusting for covariates defining randomization 
strata. All tests of efficacy will be conducted at a two-sided α level of 0.05, with p-values 
considered nominal unless generated as part of the tree gatekeeping multiple testing strategy 
as described in the Integrated Analysis Plan (IAP). P-values and the 95% CIs will be presented 
where applicable.
Analysis of Safety
Safety data for all treatment groups (M2951 dose groups, placebo group) will be listed and 
summarized using descriptive statistics. 
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
28/205
Table 1
Schedule of Assessments; Screening and Treatment Period (All Subjects), End of Study (Subjects Not 
Entering LTE Period)
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
Up/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
Informed consent
X
LTE informed 
consent
X
Inclusion/exclusion 
criteria
X
Xb
Demographics and 
medical historyc
X
Chest X-rayd
X
12-lead ECG
X
X
X
X
X
X
Xe
Physical 
examination
X
Xf
Xg
Xg
Xg
Xg
Xg
Xg
X
Xh
Xh
Xh
Xh
Xh
Xh
X
X g
Vital signs, weight, 
height i
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SFI, SLEDAI-2K, 
PGA, BILAG 2004, 
CLASI
X
Xf
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SLICC/ACR 
Damage Index
Xf
X
C-SSRS
X
X
X
X
X
X
X
X
X
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
29/205
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
Up/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
IMP 
administrationk
Daily administration of IMP
Urinalysis and 
microscopy
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Routine 
hematology, 
chemistrym
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
Supplementary 
LFTsn
X
X
X
Total Ig Levels 
(IgG, IgA, IgM)
X
Xf
X
X
X
X
X
X
X
Coagulation (INR, 
PTT)
X
HIVq, HCV, and 
HBV testing
X
Reflex testing for 
HBV DNAr
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy 
and FSH testings
X
Serum β-D-glucant
X
TSH
X
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CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
30/205
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
Up/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
Tuberculosis 
assessmentl
X
Urine pregnancy 
tests
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
UPCR
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36v2, 
LupusQoL, FACIT-
Fatigue, EQ-5D-
5Lu
X
X
X
X
X
X
X
X
X
X
HRU
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGICu
X
X
X
X
X
X
X
X
X
Dispense IMP 
X
Dispense as needed, using IWRS
Dispense subject 
diary 
X
Dispense as needed.
Concomitant 
medications / 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Evobrutinib (M2951)
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Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
Up/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
Immunological Assessments
Anti-dsDNA, 
Complement 
(C3, C4), CRP
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ANA, anti-Sm
X
Autoantibodies
X
X
X
X
Exploratory Biomarkers
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
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Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
Up/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
+5
ACR = American College of Rheumatology, ALT = alanine aminotransferase, ANA = Antinuclear Antibody(ies), Anti-dsDNA = Anti-Double-Stranded 
Deoxyribonucleic Acid, Anti-Sm = anti-Smith antibody, AST = aspartate aminotransferase, BILAG = British Isles Lupus Assessment Group, BP = blood pressure,
, CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index, CRP = C-Reactive Protein,
C-SSRS = Columbia-Suicide Severity Rating Scale, DNA = deoxyribonucleic acid, ECG = Electrocardiogram, EOT = End of Treatment, EQ-5D-5L = EuroQoL 5 
Dimension 5 Levels, FACIT = Functional Assessment of Chronic Illness Therapy, GGT = γ-Glutamyl-transferase, Ig = Immunoglobulin, IMP = Investigational 
Medicinal Product, IWRS = Interactive Web Response System, HBV = Hepatitis B Virus, HCV = Hepatitis C Virus, HIV = Human Immunodeficiency Virus,
HRQoL = Health Related Quality of Life, HRU = Health Resource Utilization, INR = International Normalized Ratio, LFT = liver function test, LTE = long-term 
extension, LupusQoL = Lupus Quality of Life, mRNA = messenger Ribonucleic Acid,
 PCR = polymerase chain reaction, PGA = Physician’s 
Global Assessment, PGIC = Patient Global Impression of Change,
, PTT = Partial Thromboplastin Time, SF-36v2 = Medical Outcomes 
Study 36-Item Short Form Health Survey, SFI = SLEDAI Flare Index, SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index-2000,
SLICC = Systemic Lupus International Collaborating Clinics, TB = tuberculosis, TSH = Thyroid Stimulating Hormone, UPCR = Urine Protein To Creatinine Ratio,
Wk = Week.
a
Safety Follow-Up Visit will be conducted at four weeks after the last dose of IMP for subjects who have been discontinued from IMP or have completed the 
52-week Treatment Period, unless subjects have entered the LTE period.
b
Subject eligibility to be confirmed on Day 1 prior to randomization.
c
Medical history includes documentation of SLE classification criteria, SLE medical history, medications, and surgery/procedures (see Section 7.2.1).
d
The results of a chest X-ray performed within three months prior to the Screening Visit (if available) are acceptable, provided there is no reason to suspect 
any clinical changes, per Investigator discretion.
e
Only required if change noted at Wk52/EOT, when compared to Baseline ECG.
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Evobrutinib (M2951)
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MS200527-0018
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f
Predose sample/procedure to be collected/performed before the first daily dose.
g
Abbreviated physical examination at these visits (see Section 7.4.4.2).
h
Abbreviated physical examination may be performed at Primary Investigator discretion, as required to fully obtain information needed for the BILAG and/or 
SLEDAI assessments, if scheduled, as well as required to fully evaluate any subject complaints or adverse events. 
i
Vital signs include arterial BP, pulse rate, respiratory rate, and body temperature. Height will be measured at Screening only. Body weight will be measured 
with a balance beam scale, if possible. Pulse rate and BP will be measured after 10 minutes rest in the semisupine position with the subject’s arm 
unconstrained by clothing or other material. The BP should be assessed on the same arm for each subject throughout the study.
j
Only CLASI assessed at Week 2.
k
On Study Visit Days, IMP should be administered during the Study Visit; otherwise, IMP should be self-administered at home at a set time each day (every 
12 hours ± 2 hours). Investigational medicinal product administration at Week 52 will only occur for subjects rolling over into the LTE.
l
A Quantiferon test will be performed centrally. Prior TB testing results must be entered into the eCRF.
m
See Table 11 for list of clinical laboratory evaluations.
n
Supplementary LFTs include AST, ALT, alkaline phosphatase, GGT, and bilirubin.
p
To be collected at Screening only in subjects who have previously received B cell depleting therapy (see Exclusion Criterion 33, in Section 5.3.2).
q
HIV testing will be performed locally.
r
For subjects who are negative for hepatitis B surface antigen (HBsAg) but are anti-hepatitis B surface antibody positive and/or anti-hepatitis B core antibody 
positive, an HBV DNA PCR reflex test is to be completed at screening. If the subject enters the study with positive HBV DNA negative OR has detectable 
HBV DNA < 20 IU/mL only, additional HBV DNA PCR testing must be performed (see Exclusion criteria 20, in Section 5.3.2).
s
For women of childbearing potential or who are postmenopausal see inclusion criterion 7. A follicle-stimulating hormone (FSH) must be drawn at Screening 
if necessary to confirm postmenopausal status. The urine pregnancy test being used at all time points in this study must be a highly sensitive urine 
pregnancy test.
t
For Japan only.
u
HRQoL Questionnaires should be completed before any other procedures are performed.
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Evobrutinib (M2951)
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Table 2
Schedule of Assessments – Optional Long-Term Extension Period
LTE Trial Period
Visit Weeks During LTE Treatment Period
Follow-Up Visit 
4 weeks
Post-Last Dosea
Week
0
2
4
6
8
10
12
14
16
24
40
52
76
Week 104/
LTE
EOT/Early 
Withdrawal
Week 108/
Safety Follow-
Up/LTE End of 
Study
Trial Day
1
15
29
43
57
71
85
99
113
169
281
365
545
745
774
Visit
Day 1b
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
24
Wk
40
Wk
52
Wk
76
Wk
104
Wk
108
Visit window (±day)
-
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
+5
Informed Consent
X
Verify subject remains 
eligible for the study (no 
prohibited medication, etc.)
X
Vital signs, weightc
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Xd
Physical examination
X
Xe
Xe
Xe
Xe
Xe
Xe
X
Xe
X
Xe
Routine hematology, 
urinalysis, chemistry
X
X
X
X
X
X
X
X
X
X
Urine microscopy
X
X
X
X
Supplementary LFT labs
X
X
X
X
X
Total Ig Levels 
(IgG, IgA, IgM)
X
X
X
X
X
X
X
X
X
X
Urine pregnancy testg
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test kit 
dispensationg
X
X
X
X
X
Reflex testing for HBV DNAh
X
X
X
X
X
X
X
X
X
X
X
UPCR
X
X
X
X
IMP dispensationi
X
Dispense as needed, using IWRS and complete compliance documentation
IMP administrationj
Daily Administration of Evobrutinib
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
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LTE Trial Period
Visit Weeks During LTE Treatment Period
Follow-Up Visit 
4 weeks
Post-Last Dosea
Week
0
2
4
6
8
10
12
14
16
24
40
52
76
Week 104/
LTE
EOT/Early 
Withdrawal
Week 108/
Safety Follow-
Up/LTE End of 
Study
Trial Day
1
15
29
43
57
71
85
99
113
169
281
365
545
745
774
Visit
Day 1b
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
24
Wk
40
Wk
52
Wk
76
Wk
104
Wk
108
Visit window (±day)
-
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
+5
C-SSRS
X
X
X
X
X
X
X
SFI, SLEDAI-2K, PGA, 
BILAG 2004, CLASI
X
X
X
X
SLICC/ACR Damage Index
X
X
X
X
SF-36v2, LupusQoL, 
FACIT-Fatigue, EQ-5D-5Lk
X
X
X
X
PGICk
X
X
X
X
HRU
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications / 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunological Assessments
Anti-dsDNA Complement 
(C3, C4), CRP
X
X
X
X
ANA and other 
Autoantibodies
X
X
X
X
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MS200527-0018
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ACR = American College of Rheumatology, ANA = Antinuclear Antibody(ies), Anti-dsDNA = Anti-Double-Stranded Deoxyribonucleic Acid, BILAG 2004 = British 
Isles Lupus Assessment Group 2004, CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index, C-SSRS = Columbia-Suicide Severity Rating 
Scale, D = day, DNA = deoxyribonucleic acid, ECG = Electrocardiogram, EOT = End of Treatment, EQ-5D-5L = EuroQoL 5 Dimension 5 Levels,
FACIT = Functional Assessment of Chronic Illness Therapy, HBsAg = hepatitis B surface antigen, HBV = Hepatitis B Virus, HRU = Health Resource Utilization,
Ig = Immunoglobulin, IMP = Investigational Medicinal Product, LFT = liver function test, LTE = Long-Term Extension, LupusQoL = Lupus Quality of Life,
PGA = Physician’s Global Assessment, PGIC = Patient Global Impression of Change,
, SFI = SLEDAI Flare Index, SLEDAI-2K = Systemic 
Lupus Erythematosus Disease Activity Index-2000, SLICC = Systemic Lupus International Collaborating Clinics, SoA = Schedule of Assessments, UPCR = Urine 
Protein To Creatinine Ratio, Wk = Week, WOCBP = women of childbearing potential.
a
Safety Follow-Up Visits will be conducted at four weeks after the last dose of IMP for subjects who have been discontinued from IMP or have completed the 
LTE Treatment Period.
b
The LTE D1 visit is the EOT/Wk 52 visit from the DBPC Period unless a subject rollsover more than four weeks after the Wk 52/EOT visit. If a subject 
exceeds the four weeks due to unanticipated causes (e.g., regulatory approval delay), prior approval from the Medical Monitor is required and the subject 
will need to complete the LTE D1 visit (see Section 7.1.3).
c
Vital signs including weight, oral temperature, seated blood pressure, pulse rate, and respiratory rate.
d
Only required if change noted at Wk 104/EOT, when compared to Baseline ECG.
e
Abbreviated physical examination may be performed at Primary Investigator discretion, as required to fully obtain information needed for the BILAG and/or 
SLEDAI assessments, if scheduled, as well as required to fully evaluate any subject complaints or adverse events (see Section 7.4.4.2).
g
The urine pregnancy test being used at all time points in this study must be a highly sensitive urine pregnancy test. In-between visit urine pregnancy tests 
will be dispensed and performed at home per SOA (Table 3) for WOCBP. The site staff will confirm completion of the home pregnancy testing and discuss 
results (Section 7.1.3).
h
Additional HBV DNA PCR testing must be performed for subjects who entered the study with negative HBsAg and positive for anti-hepatitis B surface 
antibody and/or anti-hepatitis B core antibody with an HBV DNA negative OR detectable HBV DNA < 20 IU/mL only.
i
The IMP will be dispensed per IWRS and IMP compliance documented using pill counts. All remaining IMP will be collected at Week 104 for all subjects.
j
IMPs will be self-administered at a set time each day (± 2 hours).
k
HRQoL Questionnaires should be completed before any other procedures are performed.
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Evobrutinib (M2951)
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Table 3
Additional Pregnancy Testing for Long-Term Extension
LTE Trial 
Period
Visit Weeks During LTE Treatment Period
Week
20
28
32
36
44
48
56
60
64
68
72
80
84
88
92
96
100
Trial Day
143
200
229
258
315
344
402
430
459
488
516
574
602
631
660
688
717
Visit
8a
9a
9b
9c
10a
10b
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
12f
Visit window 
(±day)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Highly 
sensitive 
urine 
pregnancy 
testa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse events, LTE = Long-Term Extension.
a
In-between visit urine pregnancy test will be performed at home. The site staff will call the subject to confirm completion of the home pregnancy testing and 
discuss results. Any occurrence of pregnancy results in subject withdrawal from IMP and the trial (see Section 5.5.1 and 5.5.2). 
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MS200527-0018
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2
Sponsor, Investigators and Trial Administrative Structure
The Sponsor of this clinical study is EMD Serono Research & Development Institute, Inc. (EMD 
Serono R&D), Billerica, MA, in the USA; Merck Serono Co., Ltd. (Affiliate of Merck KGaA, 
Darmstadt, Germany) in Japan; and Merck KGaA, Darmstadt, Germany, in rest of the world 
(RoW).
Study Organization in Japan:
Refer to the Study Organization in Japan in the supporting documentation for additional 
information.
A contract research organization (CRO), 
, will undertake the 
operational aspects of this study. In Japan, 
, will 
undertake the operational aspects. Details of such structures and associated procedures will be 
defined in a separate Integrated Project Management Plan (IPMP). The IPMP will be prepared by 
the 
Clinical Project Manager in cooperation with other 
Operational Team Leads.
2.1
Investigational Sites
The study will be conducted in multiple centers, at approximately 180 sites, across approximately 
20 countries.
Approximately 40 sites are anticipated to participate in the United States.
Study sites in Japan:
Refer to the Study Sites in Japan in the supporting documentation for additional information.
2.2
Trial Coordination / Monitoring
The study will appear in the following clinical trial registry: clinicaltrials.gov.
The Sponsor will enlist the support of 
, a CRO, to conduct the clinical part of the study
including study set-up, operation of an interactive web response system (IWRS) for randomization, 
coordination, monitoring, medical oversight, data capture, data management, statistical analysis, 
and clinical study reporting. The Sponsor will also make use of the CRO’s central laboratory for 
sample analyses, storage, and shipment to specialized bioanalytical laboratories. The Sponsor will 
supervise all outsourced activities.
Investigational medicinal product (IMP) will be supplied by the Clinical Trial Supply Department 
of the Sponsor, and packaged, labeled and distributed by a designated contract manufacturing 
organization.
The Coordinating Investigator 
represents 
all Investigators for decisions and discussions regarding this study, consistent with the 
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
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International Council for Harmonisation (ICH) Topic E6 Good Clinical Practice (GCP); hereafter 
referred to as ICH GCP. The Coordinating Investigator will provide expert medical input and 
advice relating to study design and execution and is responsible for the review and signoff of the 
clinical study report (CSR). Signature pages for the protocol lead and the Coordinating Investigator 
as well as a list of Sponsor responsible persons are in Appendix IV.
Subject enrollment and randomization will be managed by an IWRS.
Safety laboratory assessments will be performed centrally. Use of local laboratories is optional and 
to be used at the discretion of the Investigator; however, duplicate samples must also be collected 
and sent for central laboratory analysis. Only central laboratory data will be transferred into the 
clinical database. Unless otherwise specified (see Section 7.4.3), local laboratory results will not 
be recorded in the electronic case report forms (eCRFs). Urinalysis will be performed locally;
microscopic analysis and urine protein to creatinine ratio (UPCR) will be performed centrally.
The Global Drug Safety Department, Merck KGaA, Darmstadt, Germany, or their designated 
representatives will supervise drug safety and the timely reporting of adverse events (AEs), and 
serious adverse events (SAEs). Quality assurance of the study conduct will be performed by the 
Development Quality Assurance Department, Merck KGaA, Darmstadt, Germany.
The department of Global Biostatistics, Merck KGaA, Darmstadt, Germany, will supervise the 
statistical analyses, which will be outsourced to a CRO. Pharmacokinetic data analyses will be 
completed by Merck KGaA.
An independent data monitoring committee (IDMC) will be established to assess safety and 
tolerability of IMP during the conduct of the study and review the interim analysis (IA) if 
completed. The IDMC will be composed of a minimum of three members who do not have any 
conflict of interests with the study Sponsor, including two clinicians and a biostatistician. The full 
membership, mandate, and processes of the IDMC will be detailed in the IDMC charter. The 
IDMC will review the data from the interim futility analysis conducted by an independent third 
party statistician. Based on the pre-defined futility criteria, the IDMC will make recommendations 
to the Sponsor. 
The IDMC will monitor the study until the last subject has either entered the LTE or completed 
the Safety Follow-Up Visit following the DBPC Treatment Period for subjects that did not rollover 
into the LTE, whichever occurs last. At that time, study monitoring may transition to an internal 
Safety Monitoring Committee (SMC). The SMC will review all available safety data on a regular 
basis during the open-label LTE. The SMC consists of Sponsor representatives (including, but not 
limited to, the Medical Responsible, the Drug Safety Product Lead, the biostatistician), the Medical 
Monitor from the CRO, and the Coordinating Investigator. The full membership, mandate, and 
processes of the SMC will be detailed in the SMC charter.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
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In addition, the trial will be advised and monitored by a Study Steering Committee.  Details about 
this committee will be provided in a separate charter.
Details of structures and associated procedures will be defined in a separate Manual of Procedures, 
which will be prepared under the supervision of the Clinical Trial Leader.
 
 
 
 
 
 
 
 B cell modulators have shown efficacy in several AIIDs. Belimumab, approved in 2011 
in the US and EU for the treatment of lupus, inhibits B cell survival and differentiation into plasma 
cells (Benlysta® 2015). 
 
 
Rituximab has established efficacy (approved in the 
USA and EU) in RA and granulomatosis with polyangiitis/microscopic polyangiitis (Rituxan®
2016) and reported efficacy in a broad range of AIID disorders, including multiple sclerosis 
(Naismith 2010, Tanasescu 2014) and other autoimmune disorders (Kasperkiewicz 2011, 
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
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Lunardon 2012, Tony 2011, Xin 2013). In addition, other agents targeting B cells are in late stage 
development for systemic lupus erythematosus (SLE) (Furie 2014, Wallace 2014).
Although randomized controlled studies with rituximab in SLE and lupus nephritis have not 
demonstrated significant benefit over placebo (Borba 2014, Merrill 2010, Rovin 2012), this may 
be related in part to study design, as significant changes in background therapy were allowed. 
These results contrast with numerous uncontrolled studies and observational studies that have 
suggested benefit; many in the rheumatology community perceive rituximab to be effective for a 
number of manifestations of SLE, and this off-label use is recommended in SLE treatment 
guidelines as an alternative for the treatment of refractory lupus nephritis (Bertsias 2008, 
Hahn 2012, KDIGO 2012).
 
 
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A Phase II Study of M2951 in SLE
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The present Phase II study (MS200527-0018) is designed to determine the efficacy and safety of 
M2951 in subjects with SLE, and to determine a dose to take forward into Phase III development.
Based on the available nonclinical and clinical data to date, the conduct of the study specified in 
this protocol is considered justifiable.
The available nonclinical and clinical data to date clearly support the pathogenic contribution of 
B cells in SLE. Novel non-depleting B cell therapies may deliver a more favorable benefit-risk 
balance than current B cell directed therapeutic approaches. In addition to silencing B cells, 
M2951 prevents innate immune cell activation which contributes to its efficacy. This is underlined 
by in-house preclinical data demonstrating superior efficacy over B cell depletion in a mouse lupus 
model, as well as efficacy in a mouse arthritis model despite continued presence of 
collagen-specific autoantibodies.
 
 
 
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M2951 is being considered for the treatment of autoimmune diseases, including RA, SLE, and 
multiple sclerosis. To date, no efficacy data are available. However, because its mechanism of 
action directly targets both the production of autoantibodies and cellular effectors of end-organ 
injury, it is reasonable to anticipate that M2951 may represent a significant advance in the 
treatment of SLE and other autoimmune diseases. 
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3.1
Benefit and Risk
No identified risks or new potential risks have emerged from clinical studies thus far. In the first 
in human Study EMR200527-001, M2951 was well tolerated
 
 In the completed Phase Ib study in subjects with SLE 
(Study EMR200527-002) M2951 was well tolerated. There were no SAEs reported during the 
study and no new safety signals were identified. Evidence of clinical benefit was not expected in 
this 4-week safety study. 
 
 
 
 
 
Important potential risks to subjects are based on nonclinical safety data of M2951 and clinical 
data on adverse drug effects associated with compounds of a similar pharmacological class. They 
include infection, leukopenia, thrombocytopenia, hemorrhage, gastrointestinal intolerance, renal 
toxicity, hepatocellular injury, atrial fibrillation, drug-drug interactions, and embryo-fetal toxicity. 
Asymptomatic elevations in amylase and/or lipase have been observed in completed clinical 
studies of M2951. The clinical significance and risk status of these observations are being assessed. 
The Sponsor is also assessing the clinical significance of convulsions observed in dogs at very 
high levels of exposure.
Risk minimization measures inherent to early phase clinical trials are considered adequate for the 
proposed clinical trial in subjects with SLE. An IDMC will continually review available safety and 
tolerability data and will be mandated to make immediate decisions regarding the conduct of the 
trial; no additional risk minimization measures are proposed. During the LTE, an internal SMC 
may review safety data on a regular basis during the LTE in lieu of the IDMC.
 
 
 
 
 
 
 
 
 
 
 
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Taking the above information into account, benefit-risk considerations support conduct of the 
proposed clinical trial MS200527-0018 in subjects with SLE.
 
 
 
 
 
 
 
 
 
 
 
 
Refer to the Investigator's Brochure for more details of each study. This clinical trial will be 
conducted in compliance with the CTP, ICH GCP, and any additional applicable regulatory 
requirements.
4
Trial Objectives
4.1
Primary Objectives
The primary objectives are:
! To evaluate the efficacy and dose response of M2951 compared to placebo in reducing disease 
activity in adult subjects with active, autoantibody-positive SLE who are receiving standard of 
care (SoC) therapy based on SLE Responder Index (SRI)-4 response at Week 52 in all subjects, 
or on SRI-6 response at Week 52 in the High Disease Activity (HDA) subgroup, defined as 
SLE Disease Activity Index 2000 (SLEDAI-2K) ≥10.
! To evaluate the safety of M2951 in subjects with SLE on SoC therapy.
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4.2
Secondary Objectives
The key secondary objectives are:
! To evaluate the efficacy and dose response of M2951 compared to placebo in delaying time to 
first severe flare during the Treatment Period, in subjects with SLE on SoC therapy, where a 
severe flare is defined as at least one British Isles Lupus Assessment Group (BILAG 2004) A 
in any organ system due to items that are new or worse, compared to the BILAG evaluation at 
the previous visit.
! To evaluate the efficacy and dose response of M2951 compared to placebo in reducing disease 
activity, based on the SRI-4 response at Week 52, in the serologically active subgroup, which 
is defined as subjects with positive anti-double-stranded deoxyribonucleic acid (anti-dsDNA)
and/or low complement levels.
Other secondary objectives are:
! To evaluate the efficacy of M2951 compared to placebo on changes in disease activity over 
52 weeks
! To evaluate the efficacy of M2951 compared to placebo on changes in organ-specific disease 
activity over 52 weeks
! To evaluate the effect of M2951 compared to placebo on the annualized flare rate
! To evaluate the impact of M2951 treatment compared to placebo on subject reported health 
related quality of life (HRQoL) over 52 weeks
! To evaluate the effect of M2951 on corticosteroid (CS) usage over 52 weeks.
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4.4
Open-label Long-Term Extension (LTE) Period Objectives
The objective of the LTE Period is:
! To evaluate the long-term safety, efficacy, and HRQoL of M2951 at an initial dose of 50 mg
twice daily or the eventual Phase III dose when decided for an additional two years.
5
Investigational Plan
5.1
Overall Trial Design and Plan
This is a Phase II, multicenter, international, randomized, double-blind, placebo-controlled 
(DBPC) parallel-arm trial, designed to determine the efficacy, dose response, and safety of M2951
in subjects with SLE, and to consider a dose to take forward into Phase III development. 
Approximately 432 subjects are planned to be randomized in a ratio of 1:1:1:1 to receive one of 
three doses of M2951 (doses 25 mg once daily, 75 mg once daily, or 50 mg twice daily) or placebo, 
taken orally for 52 weeks. The study includes a Japanese cohort (approximately 36 Japanese 
subjects). If enrollment of Japanese subjects is slow, the entire Japanese cohort may not be part of 
the primary analysis. Therefore, the total enrollment will range from n = 432 to 468 (n = 108 to 
117 subjects per group). All subjects that choose to enter the LTE Period will be switched to active 
treatment with M2951 
 or to the eventual Phase III dose when 
decided. This trial will be conducted at approximately 180 sites across 20 countries.
The study is composed of a Screening Period of four weeks, a DBPC Treatment Period of 
52 weeks, an open-label LTE Period of 104 weeks, and a Safety Follow-Up Period of four weeks.
The study will be conducted on an outpatient basis. Subjects will attend clinic visits at regular 
intervals as indicated in the Schedule of Assessments (SOA).
Screening Period
The first visit will be a Screening Visit and will include a review of the inclusion/exclusion criteria 
(see Section 5.3). Subjects should undergo the Day 1 Visit as soon as possible after eligibility for 
the study has been confirmed. During the Screening Period, there will be no change in oral 
corticosteroid (OCS) dose (see Section 6.4.2). Subjects who do not meet all inclusion criteria or 
meet an exclusion criterion within the Screening Period and are considered screen failures may 
undergo rescreening once, after approval by the Medical Monitor (see Section 7.1.1).
DBPC Treatment Period
Duration of the Treatment Period will be 52 weeks starting at randomization (Day 1). The 
Day 1 Visit will be considered the Baseline for disease activity (e.g., BILAG 2004, SLE Disease 
Activity Index-2000 [SLEDAI-2K], Physician’s Global Assessment [PGA], and CLASI). Subject 
eligibility must be reviewed on Day 1 prior to randomization, and the first dose of the IMP (M2951
or placebo) will be given while the subject is still on site for Day 1. Subjects must then return to 
the study site for study visits as indicated in the SOA. Subjects will receive the last dose of IMP at
Week 52, which is the EOT for the study, unless they enter the LTE Period.
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From Day 1 to the Week 4 Visit, corticosteroids may be increased, decreased, initiated (within the 
first two weeks of the treatment period), or remain unchanged. However, the daily corticosteroid 
dose must be ≤30 mg/day prednisone-equivalent by the end of Week 4. From Week 4 to the 
Week 8 Study Visit, OCS dose will be reduced to establish a Threshold Dose, the maximum dose 
allowed during the remainder of the study, other than for treatment of flares. Treatment decisions 
will be made by Investigator assessment for the purpose of subject management. Rescue therapy 
will be allowed for the treatment of flares (see Section 6.4.2.2).
Any subjects permanently withdrawn from IMP will be expected to complete the EOT/Early 
Withdrawal study visit within five days of IMP withdrawal, followed by the Safety 
Follow-Up Visit four weeks post last dose.
Optional Open-Label Long-Term Extension Period
Subjects who completed the 52-week DBPC Treatment period will be offered participation in the 
104-week open-label, LTE Period of the study. The purpose of the LTE Period is to allow all the 
subjects with the opportunity to receive active treatment with M2951 and to collect long term 
safety and efficacy data. The Investigator should review the optional LTE Period with the subject 
prior to the DBPC Week 52 visit. Signed consent will be obtained prior to participation in the LTE 
Period. The DBPC Week 52/EOT Visit will be considered the LTE Day 1 Visit. The Safety 
Follow-Up Visit will be deferred until treatment is stopped in the LTE Period, due to either a 
subject’s premature withdrawal/early termination from the LTE, termination of the study by the 
Sponsor, or completion of the LTE treatment period. 
In some cases, due to Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
approval, regulatory-specific, or other administrative delays, a subject may experience a treatment 
gap between the IMP last dose received in the DBPC Period (Week 52/EOT visit) and the start of 
the LTE IMP treatment. Upon Principal Investigator (PI) request, these subjects may still be able 
to enroll in the LTE with approval from Merck/EMD Serono, on a case-by-case basis. If the day 
of rollover to the LTE occurs after the DBPC Week 56/EOS visit, all assessments noted at the LTE 
Day 1 visit will need to be completed. For subjects that rollover after the Week 52/EOT visit but 
prior to their scheduled Week 56/EOS visit, concomitant medications and AEs will need to be 
reviewed and updated, and the PI will need to ensure that the subject remains eligible for the study. 
No other additional assessments other than dispensing of IMP will need to be completed.
Safety Follow-Up Period
The Safety Follow-Up/End of Study Visit is scheduled four weeks (+ 5 days) after the last 
administration of study treatment. For subjects who do not participate in the LTE Period, the Safety 
Follow-Up Visit is scheduled four weeks (+ 5 days) after the last administration of study treatment 
in the DBPC Period. For subjects who participate in the LTE Period, the Safety Follow-Up Visit 
is delayed until four weeks (+ 5 days) after the last administration of study treatment in the LTE 
Period. Subjects who are approved to rollover into LTE Period after they entered, or completed, 
the DBPC Safety Follow-Up Period, may have two Safety Follow-Up Visits. Additional details of 
the Safety Follow-Up/ End of Study Visit are provided in the SOA.
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Assessment of Endpoints
During the study, efficacy endpoints will be evaluated using several activity indices, such as the 
BILAG 2004, SLEDAI-2K, PGA, and Cutaneous Lupus Erythematosus Disease Area and Severity 
Index-Activity (CLASI-A). As part of the efficacy assessment, the effects of treatment on HRQoL
will be examined using Patient-Reported Outcome (PRO) measures including but not limited to:
Medical Outcomes Study 36-item Short Form Health Survey (SF-36v2®), EuroQoL 5 Dimension 
5 Levels (EQ-5D-5L), Lupus Quality of Life (LupusQoL), Functional Assessment of Chronic 
Illness Therapy
(FACIT-Fatigue), and Patient Global Impression of
Change
(PGIC)
(see Section 7.3.5). Health Resource Utilization will also be collected as part of the efficacy 
assessment. 
Safety will be evaluated through the nature, incidence, severity and outcome of AEs, and 
assessment of physical examination findings, ECGs, hematology and chemical laboratory 
assessments, vital signs, and absolute values of and change from Baseline in serum total 
immunoglobulin (Ig) levels (IgG, IgA, and IgM) and total B cell counts.
Treatment decisions will be made by Investigator assessment for the purpose of subject 
management. Rescue therapy will be allowed for the treatment of flares.
Statistical Methods
There will be at least two planned analyses in this study - the primary and final analyses. There 
may be up to four planned analyses, depending on whether the optional futility interim analysis 
(IA) is conducted, and whether the analysis for treatment effect consistency is coincident with the 
primary analysis, or is conducted after the primary analysis.
If the futility IA is conducted, it will be based on Week 24 SRI-4 response among all subjects in 
the primary analysis cohort and Week 24 SRI-6 response among HDA subjects in the primary 
analysis cohort. The IA will be conducted when 100% of subjects in the primary analysis cohort,
reach Week 24 of treatment or prematurely discontinue from treatment prior to Week 24. If the 
response proportion difference for both co-primary endpoints is sufficiently low at Week 24, as 
defined in the Integrated Analysis Plan (IAP), consideration will be given to termination of the 
study. If enrollment is slower than expected, consideration will be given to conducting the interim 
futility analysis when the first 50% of the primary analysis cohort reach Week 24 of treatment, or 
prematurely discontinue from treatment. An IDMC will monitor safety and tolerability as well as 
review the data from the IA. The IA will be prepared by a team independent of the study teams 
(Sponsor and 
).
The primary analysis cohort consists of the first 432 subjects randomized. However, if drop-out 
for reasons unrelated to efficacy or safety is higher than expected, effectively reducing the power 
of the study, the IAP may prespecify that the primary analysis cohort may include all subjects 
randomized. The primary analysis will be based on Week 52 SRI-4 response among all subjects
in the primary analysis cohort, and Week 52 SRI-6 response among HDA subjects in the primary 
analysis cohort. This analysis is triggered when 100% of subjects in the primary analysis cohort:
! Complete Week 52 of treatment and either enter LTE or complete Safety Follow-Up, or
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! Prematurely discontinue from treatment prior to Week 52 and complete Safety Follow-Up, or
! Prematurely discontinue from study without Safety Follow-Up.
The Japanese cohort may be fully, partially, or not included in this primary analysis, depending on 
the enrollment rate. The primary analysis will be performed by 
staff when the primary 
analysis trigger condition has been met, protocol violations determined, and the database is locked
for the primary analysis.
The Family-Wise type 1 error rate (FWER) due to the co-primary endpoints and multiple M2951
dose group comparisons versus placebo will be controlled at the two-sided α = 0.05 level via a tree 
gatekeeping testing procedure. The four hypotheses associated with comparisons involving the 
co-primary endpoints and the two highest dose groups will form the first family of hypotheses in 
the tree. This family will be tested via the truncated Hochberg procedure, with truncation fraction 
pre-specified in the IAP. The multiple-testing procedure for the remainder of the tree, including 
the hypotheses associated with the comparisons involving the co-primary endpoints and the lowest 
dose group, and the key secondary endpoints and all dose groups, will be pre-specified in the IAP.
A treatment effect consistency analysis may be scheduled if the Japanese cohort does not enroll in 
time to be included with the primary analysis cohort.  If the Japanese cohort enrolls in time to be 
included, the evaluation of consistency with respect to ethnicity of Week 52 SRI-4 response can 
be performed at the time of the primary analysis.  If the Japanese cohort enrolls slowly, then the 
primary analysis will occur without inclusion of the Japanese cohort, and a separate consistency 
analysis will be triggered when 100% of enrolled Japanese subjects: 
! Complete Week 52 of treatment and either enter LTE or complete Safety Follow-Up, or 
! Prematurely discontinue from treatment prior to Week 52 and complete Safety Follow-Up, or
! Prematurely discontinue from study without Safety Follow-Up.
If required, the consistency analysis will be performed by 
.
The final analysis is triggered when 100% of subjects enrolled: 
! Complete Week 104 of the LTE and the Safety Follow-Up, or
! Complete Week 52 of treatment and the Safety Follow-Up (if they did not rollover into the 
LTE), or
! Prematurely discontinue from treatment and complete Safety Follow-Up, or
! Prematurely discontinue from study. 
The final analysis will be performed by 
staff when the final analysis trigger condition has 
been met, protocol violations determined, and the database is locked for the final analysis.
A schematic of the trial design is presented in Figure 2 and Figure 3 and the trial SOA is provided 
in Table 1, Table 2 and Table 3.
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Figure 2
Study Design of MS200527-0018
BID = Twice Daily, CS = Corticosteroid, HDA = High Disease Activity, QD = Once Daily, SRI = SLE Responder Index; 
Wk = week.
a
CS dose may increase, decrease, be initiated, or remain unchanged from Day 1 to the Week 4 Visit, and 
reduce as tolerated from Week 4 through the Week 8 Visit (see Section 6.4.2).
b
The Japanese cohort may be fully, partially, or not included in the primary analysis, depending on the 
enrollment rate.
Figure 3
Study Design for Long-Term Extension
BID = twice daily, D = day, LTE = Long-Term Extension, QD = once daily, SFU = Safety Follow-Up, SLE = Systemic 
Lupus Erythematosus, WOCBP = women of child bearing potential.
** = Subjects will receive an initial dose of 50 mg BID. When a Phase 3 dose is determined, all subjects may be 
switched to this dose at the Sponsor’s discretion.
* = For subjects entering the Open Label Extension, the Week 52 visit is considered the Day 1 visit for the Open 
Label LTE Period.
NOTE: For WOCBP, urine pregnancy tests will be performed at home to ensure monthly pregnancy testing.
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5.2
Discussion of Trial Design
5.2.1
Scientific Rationale for Study Design
The present study (MS200527-0018) is designed to determine the efficacy and safety of M2951 in 
subjects with active SLE without severe organ system disease (e.g., central nervous system and 
renal). Subjects will be on standard of care background therapy (e.g., antimalarials, 
immunosuppressants). The primary objective will focus on reduction in disease activity relative to 
placebo over 52 weeks in adult subjects with active, autoantibody-positive SLE who are receiving 
SoC therapy based on SRI-4 response at Week 52, or in reducing disease activity in a HDA 
subgroup (SLEDAI-2K total score ≥10) based on SRI-6 response at Week 52.
The key secondary measures will evaluate reduction in flares relative to placebo and assess SRI-4 
response in the serologically active subgroup, where serologically active is defined as anti-dsDNA 
positive and/or low complement levels.
Both SRI-4 response in the study population as a whole and SRI-6 response in a HDA subgroup
will be evaluated to ensure that a robust signal on disease activity is demonstrated.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Refer to the current Investigator’s Brochure for more detailed results from the completed clinical 
studies, including final data from clinical Study EMR200527-002. Based on the available 
nonclinical and clinical data to date, the conduct of the study specified in this protocol is considered 
justifiable (see Section 3).
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5.2.2
Justification for Dose
Refer to the current Investigator’s Brochure for more detailed results from the completed clinical 
studies.
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5.2.3
Rationale for Endpoints
The primary and key secondary endpoints are standard for SLE studies and are accepted by 
regulators. The co-primary endpoints are SRI-4 response in the entire study population and SRI-6
response in subjects with HDA, both at Week 52. These endpoints provide a measure of a subject’s 
response to disease treatment. The evaluation for greater improvement in subjects with HDA 
reflects the goal of specifically evaluating the ability of M2951 to provide relief in the subjects 
with more severe disease. The key secondary endpoint, time to first severe (BILAG A) flare during 
the Treatment Period, characterizes another aspect of response to treatment, specifically the ability 
of M2951 to improve control of flares. For the other key secondary endpoint, subjects who are 
serologically active (i.e., positive anti-dsDNA and/or low complement) will also be evaluated for 
response to treatment. As shown in other SLE studies, serologically active subjects demonstrated 
higher treatment effect size between the active and placebo groups in the SRI-4 response rates 
compared to the serologically inactive subjects (Stohl 2012).
The secondary HRQoL endpoints are complementary to the disease activity endpoints. The 
SF-36v2 has widely been used to assess physical, psychological and social impact of chronic 
diseases like SLE. The disease specific LupusQoL, and the symptom specific FACIT-Fatigue are 
well validated tools to measure disease specific aspects of HRQoL in SLE studies. The EQ-5D-5L
is the most accepted and often required instrument generating quality of life (QoL) outcomes data 
to be used by Health Technology Assessment bodies.
5.2.4
Inclusion of Special Populations
Not applicable.
5.3
Selection of Trial Population
Subject enrollment will be randomized and managed by an IWRS (see Section 6.3). Only subjects 
meeting all inclusion criteria and no exclusion criteria may be enrolled into the study as subjects
(see Section 5.4). Prior to performing any study assessments not part of the subject’s routine 
medical care, the Investigator will ensure that the subject or the subject’s legal representative has 
provided written informed consent following the procedure described in Section 9.2.
Eligibility will be evaluated and confirmed by the study eligibility team. Sites will be required to 
submit an eligibility packet (consisting of an eligibility checklist and appropriate documentation) 
for potential eligible subjects. The subjects’ eligibility will be assessed at a Screening Visit that 
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will occur up to four weeks prior to the Randomization Visit (Day 1). When a laboratory test must 
be repeated during the Screening Period or an unanticipated event occurs, the Screening Period 
can be extended to 8 weeks after discussion with the Medical Monitor. See Table 1 for a list of 
assessments done at Screening to determine the eligibility of the subject to participate in the study. 
Subjects cannot be randomized into the study until eligibility is confirmed.
Screen failures may be rescreened once (see Section 7.1.1).
5.3.1
Inclusion Criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Signed written informed consent before any study-related procedure is undertaken that is 
not part of the standard subject management and able to comply with requirements of 
protocol. In Japan, if a subject is < 20 years of age, the written informed consent from the 
subject’s parent or guardian will be required in addition to the subject’s written consent. 
2. Male or female subjects, 18 to 75 years of age.
3. Diagnosis of SLE with either the SLICC criteria for SLE (see Appendix II), or at least four 
of the 11 ACR classification criteria for SLE (see Appendix III), of at least six months 
duration prior to Screening.
4. SLEDAI-2K total score ≥6 (including SLEDAI-2K clinical score ≥4) at Screening Visit.
5. Positive test results for anti-dsDNA antibody and/or anti-nuclear antibody (human 
epithelial cell-2 ANA ≥1:80) and/or anti-Smith (anti-Sm) antibody at the time of 
Screening.
6. Due to newly available nonclinical data, previous requirements for male participant 
contraception have been removed (see Section 6.5.3).
7. A female participant is eligible to participate if she is not pregnant (see Appendix I), not
breastfeeding, and at least one of the following conditions applies:
a.
Not a woman of childbearing potential (WOCBP) as defined in Appendix I
OR
b. A WOCBP who agrees to use 2 methods of birth control: a barrier method together 
with a highly effective method (i.e., methods with a failure rate of less than 1% per 
year) as detailed in Appendix I of this protocol for at least 28 days before start of 
first dose of study treatment (as appropriate), during the treatment period and for at 
least 90 days after the last dose of study treatment.
8. History of vaccinations, as per local guidelines:
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a.
Vaccination against Streptococcus pneumoniae with PPSV23 and/or PCV13 or 
local equivalent with repeat administration as necessary to be up to date. If 
vaccination during Screening, there must be at least 2 weeks between vaccination 
and randomization.
b. Vaccination against influenza virus (as seasonally required) or vaccination against 
these pathogens during Screening (as seasonally required for influenza virus). If 
vaccinated during Screening, there must be at least 2 weeks between vaccination 
and randomization. If the subject is screened after the most recent influenza season
and/or the influenza vaccine is no longer available, the influenza vaccine should be 
given during the study once available, as per local guidelines. 
9. Subjects should be on SLE standard of care (SoC) background therapy, consisting of at 
least one protocol permitted therapy (e.g., immunosuppressants, immunomodulators, 
antimalarials, corticosteroids, or nonsteroidal anti-inflammatory drugs [NSAIDs] [see 
Section 6.4.1]). Subjects not on SoC background therapy may be enrolled after approval 
by the Medical Monitor. 
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5.3.2
Exclusion Criteria
Subjects are not eligible for this study if they fulfill any of the following exclusion criteria:
1. Active, clinically significant, interstitial lung disease or pulmonary arterial hypertension, 
defined as follows:
a.
Pulmonary Hypertension (with presence of any of the following):
i. Presence of uncontrolled World Health Organization (WHO) Pulmonary 
Hypertension Functional Class III or IV (Galiè 2016):
1. WHO Class III – Pulmonary hypertension resulting in marked 
limitation of physical activity. Comfortable at rest. Less than 
ordinary activity causes undue dyspnea or fatigue, chest pain or near 
syncope.
2. WHO Class IV – Pulmonary hypertension resulting in inability to 
carry out any physical activity without symptoms. Signs of right 
heart failure are present. Dyspnea and/or fatigue may even be 
present at rest. Discomfort is increased by any physical activity.
ii. Pulmonary hypertension requiring past or current treatment with any of the 
following: supplemental oxygen, endothelin receptor antagonists (e.g.,
ambrisentan, bosentan, macitentan), phosphodiesterase type 5 inhibitors 
(e.g., sildenafil, tadalafil, vardenafil), riociguat, prostacyclin analogues 
(epoprostenol, iloprost, treprostinil, beraprost), selexipag, or any other 
systemic therapies targeting pulmonary hypertension. In addition, subjects 
that would be considered to require initiation of systemic therapy for PHTN 
by the Investigator or evaluating pulmonologist and/or cardiologist would 
also be excluded.
iii. History of transthoracic echocardiography showing any of the following, 
(unless right heart catheterization subsequent to these measures did not 
reveal pulmonary hypertension): 
1. tricuspid regurgitation jet > 2.8 m/sec
2. right atrial enlargement (major dimension > 53 mm)
3. right ventricular enlargement (mid cavity dimension > 35 mm)
4. moderate to severe left ventricular dysfunction.
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b. Interstitial Lung Disease (with presence of any of the following):
iv. Interstitial lung disease requiring treatment with supplemental oxygen or 
cyclophosphamide within the 12 months prior to Screening.
v. Interstitial lung disease diagnosed by lung biopsy and/or high-resolution 
computed tomography with significant respiratory symptoms at Screening
based on the Investigator’s assessment.
c. Further, subjects with either diagnosis may be excluded if the Investigator or 
Sponsor/designee feels that the diagnosis constitutes an inappropriate risk or a 
contraindication for participation in the study or that could interfere with the study 
objectives, conduct or evaluation (see Exclusion Criterion 28).
2. Proteinuria > 4 g/day (spot UPCR > 4 mg/mg), and/or estimated glomerular filtration rate 
(eGFR) < 45 mL/min/1.73 m2 as calculated by the 4-component Modification of Diet in 
Renal Disease (MDRD) equation by the central laboratory):
a.
The four-component Modification of Diet in Renal Disease equation (Levey 2006):
eGFR = 175 × (serum creatinine in mg/dL) –1.154 × (age in years) –0.203 × 0.742 (if 
female) × 1.212 (if race is black)
3. Evidence of recent, acutely worsened renal function (e.g., reduction in eGFR by 
≥30 mL/min to < 60 mL/min/1.73 m2;
or a syndrome of Rapidly Progressive 
Glomerulonephritis, as defined by a 50% decline in glomerular filtration rate in three
months; in the six months prior to Screening).
4. Subjects with any of the following will be excluded:
a.
Active seizures, seizures requiring long-term treatment, or a recent seizure (in the 
past 2 years) with the exception of: remote seizures (e.g., in childhood or 
adolescence with resolution and not on treatment, or a past history of febrile 
seizures) OR a seizure related to a metabolic / physiologic disturbance in the past 
(e.g., related to low electrolytes, low glucose, or secondary to a vasovagal event). 
These subjects would have no greater risk of developing a seizure than a normal 
individual who had not had seizures, and would not need to be excluded.
b. Active central nervous system SLE deemed to be severe or progressive including 
any history of transverse myelitis, seizures as detailed in Exclusion Criterion 4a 
above, and/or associated with significant cognitive impairment leading to inability 
to provide informed consent and/or comply with the protocol.
If the Investigator’s assessment provides for an outcome of exclusion, or a question 
regarding eligibility, a Neurologist may be consulted, but inclusion in the study regarding 
this criterion is at the discretion of the Investigator.
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5. Within two weeks prior to Screening or during Screening: use of OCS > 30 mg daily 
prednisone-equivalent, use of injectable corticosteroids, or change in dose of 
corticosteroids.
6. Within two months prior to Screening or during Screening: initiation of or change in dose 
of antimalarial, methotrexate, 6-mercaptopurine, sulfasalazine, mycophenolate (mofetil
[MMF] or sodium [MPS]*), or azathioprine (*not approved in Japan). 
7. Calcineurin inhibitors (cyclosporine, tacrolimus) and cyclophosphamide are prohibited 
during the study. Calcineurin inhibitors must be washed out one month prior to Screening.
Cyclophosphamide must be washed out three months prior to Screening.
8. A stable dose of leflunomide is not exclusionary; however, subjects having discontinued 
leflunomide must have washed out for three months prior to Screening.
9. Within three months prior to Screening or during Screening, use of abatacept, antitumor 
necrosis factor alpha agents, intravenous Ig, plasmapheresis, or other disease modifying, 
immunosuppressive or immunomodulatory therapies not otherwise specified in protocol.
10. Within six months prior to Screening or during Screening: use of alkylating agents other 
than cyclophosphamide (e.g., chlorambucil).
11. Within one year prior to Screening or during Screening: use of belimumab* or any anti-B 
Lymphocyte Stimulator (BLyS) therapy.
13. Within two weeks prior to Screening, initiation or change in dose of angiotensin-converting 
enzyme inhibitor or angiotensin receptor blocker, or NSAIDs, or use of NSAIDs above 
maximum prescribed dose per local label.
14. On anticoagulation (e.g., vitamin K antagonists) or antiplatelet therapy (e.g., clopidogrel) 
other than daily low-dose aspirin (≤350 mg/day) for cardioprotection. Low-dose aspirin 
therapy for other indications may be permitted after discussion with medical monitor.
15. On fish oil (unless discontinued prior to first dose).
16. Within one month prior to Screening, vaccination with live or live-attenuated virus 
vaccine.
17. Known hypersensitivity to any study treatment, component, or placebo.
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18. Active clinically significant viral, bacterial or fungal infection, or any episode of infection 
requiring hospitalization or treatment with parenteral anti-infectives within four weeks 
prior to Screening, or completion of oral anti-infectives within two weeks before or during 
Screening, or a history of recurrent infections (i.e., three or more of the same type of 
infection in a 12 month rolling period). Vaginal candidiasis, onychomycosis and genital or 
oral herpes simplex virus considered by the Investigator to be sufficiently controlled would 
not be exclusionary.
19. Any of the following:
a.
History of or positive for human immunodeficiency virus (HIV) at Screening
b. History of or positive for hepatitis C antibody and/or hepatitis C RNA by 
polymerase chain reaction (PCR) at Screening
c.
Positive for hepatitis B surface antigen (HBsAg) at Screening
d. For subjects who are negative for HBsAg at Screening but are anti-hepatitis B 
surface antibody positive and/or anti-hepatitis B core antibody positive at 
Screening, reflex testing for hepatitis B virus DNA (HBV DNA) by PCR will be 
performed:
1.
Hepatitis B antibody positive subjects who have detectable HBV DNA 
≥20 IU/mL are excluded.
2.
Hepatitis B antibody positive subjects who are HBV DNA negative OR have 
detectable HBV DNA < 20 IU/mL are not excluded from the study. 
However, these subjects will have HBV DNA measured by PCR at visits 
noted in the SOA.
Note: Subjects who have previously been vaccinated for Hepatitis B will not be 
tested for anti-hepatitis B surface antibody, as they will be positive for anti-hepatitis 
B surface antibody as the protective consequence of vaccination.
20. Any of the following:
a.
History of active tuberculosis (TB)
b. Current diagnosis of active TB
c.
Untreated latent TB infection (LTBI)
d. Undergoing current treatment for LTBI
e.
Subjects with current household contacts with active TB. 
In the absence of a diagnosis of active TB, or clinical features consistent with a diagnosis 
of active TB, LTBI is determined by any of the following:
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o
prior TB skin test with purified protein derivative (PPD) with induration ≥5 mm
(unless vaccinated with Bacille Calmette-Guérin)
o
prior positive T-SPOT.TB (Elispot) test result
o
positive Quantiferon test, either at Screening or with documented past results.
Note: All subjects, except those who have previously completed appropriate and
documented LTBI treatment, are required to undergo Quantiferon testing during Screening.
Individuals with indeterminate or positive Quantiferon test results felt to represent a false 
positive result by the Investigator, with no clinical features consistent with active TB, will 
be evaluated with T-SPOT.TB at the request of the Investigator. In this case, if the 
T-SPOT.TB is negative, the individual may be enrolled after approval by the study 
eligibility team.
Note: Prophylactic use of antituberculous drugs is not permitted during the study, and if 
used must be discontinued prior to the first dose of study medication. If an Investigator 
feels that a subject requires antituberculous prophylaxis while participating in the study, 
this may be allowed after review of the case by the Medical Monitor.
21. History of shingles within 12 months prior to Screening unless vaccinated following onset.
22. History of splenectomy at any time or any major surgery within two months prior to 
Screening. Major elective surgeries such as abdominal, thoracic, or joint replacement 
surgeries should not be planned to occur in the Study Period.
23. Clinically significant cardiovascular events (e.g., acute myocardial infarction, unstable 
angina or peripheral vascular disease symptoms, hospitalization for congestive heart 
failure, cardiac surgery, ischemic or hemorrhagic stroke, or transient ischemic attack)
within six months before the Screening Visit or during Screening, or current active angina 
or untreated hypertension at the Screening Visit.
24. Active cardiac arrhythmia or other ECG abnormality that could constitute a clinical risk 
(including but not limited to): long QT syndrome, Wolff-Parkinson-White syndrome, or an
untreated malignant ventricular arrhythmia (e.g., ventricular fibrillation or tachycardia) at 
the Screening Visit or Day 1.
25. Presence of uncontrolled or New York Heart Association (NYHA) Class 3 or 4 congestive 
heart failure. 
a.
NYHA Class 3: Cardiac disease resulting in marked limitation of physical activity. 
Subjects are comfortable at rest. Less than ordinary activity causes fatigue, 
palpitation, dyspnea, or anginal pain.
b. NYHA Class 4: Cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of heart failure or the anginal syndrome 
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may be present even at rest. If any physical activity is undertaken, discomfort is 
increased.
26. Antiphospholipid antibody syndrome associated with a thromboembolic event in the 
12 months prior to or during Screening. See Exclusion Criterion 14 for discussion of 
anticoagulation or anti-platelet therapy.
27. Any condition, including any uncontrolled disease state other than SLE, that in the 
Investigator’s opinion or Sponsor/designee opinion constitutes an inappropriate risk or a 
contraindication for participation in the study or that could interfere with the study
objectives, conduct or evaluation.
28. History or current systemic autoimmune diagnosis other than SLE, including 
demyelinating diseases (e.g., multiple sclerosis, optic neuritis), or any other condition 
requiring systemic corticosteroid therapy (such as asthma or inflammatory bowel disease) 
with the exception of concomitant Sjögren’s or secondary Sjögren’s syndrome. 
29. History of cancer with the following exceptions:
a.
A history of non-melanoma skin cancer Stage 0 (in situ) or Stage 1, considered 
cured > five years is not exclusionary.
b. A history of in situ cervical cancer, considered cured > five years, is not 
exclusionary.
Any history of cancer not meeting these exceptions is exclusionary.
30. Breastfeeding/lactating or pregnant women. Lactating women are excluded regardless of 
whether or not they are nursing infant(s). 
31. Alanine or aspartate aminotransferase, amylase or lipase > 2 × above upper limit of normal 
(ULN) of laboratory reference range, total bilirubin > 1.5 × ULN, thyroid stimulating 
hormone [TSH] < 0.01 or ≥7.1 mIU/L per central laboratory results) or any other clinically 
significant laboratory abnormality.
32. Participation in any investigational drug study within three months or five half-lives of the 
investigational drug, whichever is longer, prior to Screening. For this protocol, this 
includes JAK inhibitors, therefore JAK inhibitors must have been discontinued for at least 
three months prior to Screening.
33. Total B cell count < 50% of the lower limit of normal (LLN) at the Screening Visit in 
subjects who previously received B cell depleting therapy such as with anti-CD20 agents 
(e.g., rituximab, 
ocrelizumab*, 
ofatumumab, 
obinutuzumab*,
ocaratuzumab*, 
veltuzumab*) (*not approved in Japan).
34. Significant cytopenia, such as neutrophil count < 1,000/mm3, or platelet count
< 75,000/mm3.
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35. Serum IgG below 6 g/L at the Screening Visit.
37. Active infective process or any other clinically significant abnormality on chest X-ray 
(CXR). Chest X-ray must have been taken within three months prior to the Screening Visit, 
or during the Screening Period.
38. History or current alcohol, substance, or drug abuse:
a.
Excessive alcohol use is defined as alcohol and/or substance abuse or dependence 
(as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th
edition, Text revision) in the past year or a history of alcohol or substance abuse, 
as determined by the Investigator.
39. Subjects who have evidence of serious suicide risk including any history of suicidal 
behavior in the last three months and/or any suicidal ideation of type 4 or 5 on the 
Columbia-Suicide Severity Rating Scale (C-SSRS) in the month prior to Screening, 
OR
Are a significant suicide risk, as determined by the Investigator, including any history of 
active suicidal ideation with intent to act in the last three months or any history of suicidal 
behavior in the subject’s lifetime.
40. Legal incapacity or limited legal capacity.
41. History of bleeding disorder and/or drug-induced thrombocytopenia.
42. Any of the following diagnoses are exclusionary due to lactose present in the IMP:
a.
Galactosemia/Galactose intolerance:
i. Classical 
Galactosemia, 
also 
known 
as 
galactose-1-phosphate 
uridyltransferase deficiency or GALT deficiency
ii. Galactosemia type II, also known as galactokinase deficiency or GALK 
deficiency
iii. Galactosemia type III, also known as galactose epimerase deficiency, 
UDP-Galactose-4-epimerase deficiency, or GALE deficiency
b. Fanconi-Bickel syndrome, also known as glycogen storage disease XI, 
Bickel-Fanconi glycogenosis, or glucose transporter 2 (GLUT2) deficiency
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c.
Congenital lactase deficiency, also known as congenital alactasia or disaccharide 
intolerance II
d. Glucose/Galactose malabsorption, also known as monosaccharide malabsorption
e.
Individuals with acquired lactose intolerance are not excluded, but should be aware 
that the IMP contains lactose and should be monitored for gastrointestinal 
symptoms related to the increased consumption of lactose in the IMP, and made 
aware of the risks.
43. For Japan only - Positive serum β-D-glucan test at Screening.
5.4
Criteria for Randomization/Initiation of Treatment with the 
Investigational Medicinal Product
Randomization can occur only after informed consent and confirmation that the Medical Monitor 
has reviewed the Screening Period data including SLE diagnostic criteria, inclusion/exclusion 
criteria, SLEDAI-2K, medical history (including date of SLE diagnosis), concomitant 
medications, ECG and clinical laboratory assessments.
Eligible subjects will be randomized in a 1:1:1:1 ratio to treatment with placebo or M2951 (doses 
25 mg once daily, 75 mg once daily, or 50 mg twice daily), through a central randomization 
process by an IWRS, stratified according to race (Black versus non-Black), region (US and 
Western Europe, Japan, and the RoW) and disease activity (SLEDAI-2K total score < 10 
versus ≥10 at Screening) prior to dosing on Day 1. Subjects with SLEDAI-2K total score ≥10 at 
Screening will be considered to have HDA.
5.5
Criteria for Subject Withdrawal
5.5.1
Withdrawal from the Trial
Subjects may withdraw from the study at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the study. Subjects who withdraw from the study while still 
on the IMP should return for an EOT/Early Withdrawal Visit upon discontinuation of the IMP and 
a Safety Follow-Up Visit as indicated in the SOA. Subjects who withdraw and are no longer on 
the IMP must complete the Safety Follow-Up/End of Study Visit assessments as indicated in the 
SOA provided in Table 1, and in Table 2 (for the LTE). A complete final evaluation at the time of 
the subject's withdrawal should be made, and AEs followed up as per Section 7.4.1.
A subject must be withdrawn if any of the following occur during the study:
! Subject withdrew consent
! Participation in any other clinical study during the duration of this study
! Occurrence of Pregnancy (for further details in case of pregnancy, see Section 7.4.2)
! Any events that endanger the safety of the subject. 
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! Subject lost to follow-up 
! Sponsor decision to end clinical study
! Subject is considered a treatment failure
! IMP is permanently withdrawn (see Section 5.5.2)
If a subject fails to return for the Safety Follow-Up/End of Study Visit, all attempts should be made 
to contact the subject to ensure the reason for not returning is not an AE. Likewise, if a subject 
wishes to discontinue from the study (e.g., for personal reasons), attempts should be made to 
establish the true reason is not an AE (bearing in mind the subject is not obliged to state the 
reasons).
If a subject has failed to attend scheduled study assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible. At least three attempts to 
contact lost to follow-up subjects should be made and documented (two phone calls and one 
authorized organization representative letter).
If IMP is prematurely discontinued, the primary reason for discontinuation must be recorded in the 
appropriate section of the eCRF, and all efforts will be made to complete and report the 
observations as thoroughly as possible. 
Subjects who are withdrawn after randomization due to safety or lack of efficacy will not be 
replaced. Consideration will be given to increasing enrollment to compensate for loss of 
information due to subjects who withdraw for reasons unrelated to safety or lack of efficacy.
Subjects who are withdrawn from the study will not be allowed to re-enroll in the study.
5.5.2
Withdrawal from the Investigational Medicinal Product
Subjects who withdraw from IMP must immediately return for an EOT/Early Withdrawal Visit
followed by the Safety Follow-Up/End of Study Visit as indicated in the SOA provided in Table 1, 
and in Table 2 (for the LTE). Subjects considered a treatment failure, as defined in the protocol, 
must be withdrawn from the study (see Section 5.5.1).
Escape Criteria
If during the study, in the opinion of the Investigator, the subject's SLE disease level is 
unacceptably high requiring therapy not permitted per the protocol, the subject may withdraw from 
the study treatment and initiate therapy recommended per the treating physician. In this case, the 
subject will be considered a treatment failure. See Section 6.4.2.2 for handling of flares.
A subject must be withdrawn from M2951 or placebo if any of the following occur:
! Withdrawal from the study (see Section 5.5.1).
! Enrollment despite violation of an exclusion criterion which, in the Investigator’s and/or 
Sponsor’s opinion, makes discontinuation of the subject necessary. 
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! Occurrence of an AE and if discontinuation of IMP is desired or considered necessary by the 
Investigator and/or the subject.
! Occurrence of pregnancy (for further details in case of pregnancy, see Section 7.4.2).
! Use of a prohibited medication, as defined in Section 6.5.2. However, any medications that are 
considered necessary for the subject’s well-being may be given at the discretion of the 
Investigator. If, in the view of the Investigator, the use of a prohibited medication should not 
impact subject safety or bias efficacy assessments, the Investigator can request the Medical 
Monitor review the case. Such a request must be made as soon as the Investigator is aware of 
the use of prohibited medication, and the Medical Monitor, along with the Sponsor, will 
determine if the subject must be permanently withdrawn from IMP. See Section 6.4.2.2 for 
specifics regarding treatment of flares during the DBPC and LTE treatment periods of the study 
and withdrawal from IMP.
! Occurrence of any other clinical condition for which discontinuation is considered necessary 
by the Investigator and/or the Sponsor/designee.
Criteria for Withdrawal of Investigational Medical Product (Temporary and Permanent)
The IMP should be temporarily withheld or permanently withdrawn if the following laboratory 
abnormalities occur or re-occur, as relevant, and re-initiation following temporarily withholding 
of IMP should be discussed with the Medical Monitor. If a subject’s pre-dose baseline value is 
abnormal and/or falls within any of the below criteria, consult with the Medical Monitor regarding 
potential withdrawal, continued participation in study, and additional monitoring if needed. 
Retesting should be completed within 1 week:
! For a neutrophil count < 1000/mm3 (Grade 3 or 4) or platelet count < 50,000/mm3 (Grade 3 or 
4), temporarily hold the IMP and recheck the value. If the value is still Grade 3 or 4, 
permanently discontinue the IMP; if the value improves to Grade 2, Grade 1 or is within normal 
limits, IMP may be reinitiated after discussion with the Medical Monitor. For a recheck value 
that decreases to Grade 2, perform repeat testing within 1 month.
! For a lymphocyte count < 200/mm3 (Grade 4), temporarily hold the IMP and recheck the value. 
If the value is still Grade 4, permanently discontinue the IMP; if the value improves to a 
Grade 3, discuss with the Medical Monitor; if the value improves to Grade 2, Grade 1 or is 
within normal limits, IMP may be reinitiated after discussion with the Medical Monitor. For a 
recheck value that improves to Grade 2, perform repeat testing within 1 month.
! For an increase in aspartate aminotransferase (AST) or alanine aminotransferase (ALT)
to > 3× ULN (Grade 2 or higher), temporarily hold the IMP and recheck the value. If the value 
is still Grade 2 or higher, the IMP should be permanently withdrawn. The subject should be 
followed with additional testing as needed until a return to ULN or acceptable value as agreed 
upon by the Investigator and Medical Monitor. Consultations with specialists, such as a 
hepatologist, can be considered at the discretion of the Investigator and in conjunction with the 
Medical Monitor.
! For an increase in bilirubin to > 1.5 × ULN (Grade 2 or higher), temporarily hold the IMP and 
recheck the value. If the value is still Grade 2 or higher, the IMP should be permanently 
withdrawn.
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! A comprehensive hepatic panel is requested for any subjects, for whom above AST or ALT 
withdrawal criteria are met and who permanently discontinue dosing due to elevated liver 
function tests. Subjects should be referred to a hepatologist who may recommend testing in 
addition to the following:
o
INR, PTT, fibrinogen, hsCRP
o
Hepatitis serology: anti-HAV IgG, anti-HAV IgM, HBsAg, anti-HBc, anti-HBsAg, anti-
HCV, anti-HEV IgG and IgM, anti-VCA IgG and IgM, anti-EA IgG, anti-EBNA IgG, 
anti-CMV IgG and IgM
o
Antinuclear antibody, anti-smooth muscle antibody, and liver-kidney microsomal 
antibody
o
Albumin
! For an increase in amylase or lipase to > 2× ULN (Grade 3 or 4), temporarily hold the IMP and 
recheck the value. If the value is still Grade 3 or 4, permanently discontinue the IMP; if the 
value improves to Grade 2, Grade 1, or is within normal limits, IMP may be reinitiated after
discussion with the Medical Monitor. For a recheck value that improves to Grade 2, perform 
repeat testing within 1 month.
! For an increase in serum creatinine to > 3× Baseline (Grade 3 or 4), temporarily hold the IMP 
and recheck the value. If the value is still a Grade 3 or 4, permanently discontinue the IMP. 
! For an increase in serum creatinine > 1.5× Baseline to ≤ 3× Baseline (Grade 2), temporarily 
hold the IMP and recheck the value. If the value is still Grade 2, discuss with the Medical 
Monitor; if the value improves to Grade 1 or is within normal limits, IMP may be reinitiated 
after discussion with the Medical Monitor.
! For any serum IgG level < 3 g/L, temporarily hold the IMP and recheck the value. If the value 
is still < 3 g/L, the IMP should be permanently withdrawn.
! For any increase in HBV DNA by PCR from negative/undetectable to detectable, and/or
increase in HBV DNA by PCR from < 20 IU/mL to ≥20 IU/mL, the IMP should be 
permanently withdrawn. The subject should be followed with additional testing and Hepatitis B 
treatment, as indicated per local guidelines, including consultation with a specialist, such as a 
hepatologist, at the discretion of the Investigator and in conjunction with the Medical Monitor.
! For any other laboratory abnormality of Grade 4 severity, temporarily hold the IMP and recheck 
the value. If the value is still a Grade 4, the IMP should be permanently withdrawn. If the retest 
value improves, discuss with the Medical Monitor.
! For any other laboratory increase/decrease (as relevant) from Baseline to Grade 3 (unless 
otherwise indicated in this section of the protocol), temporarily hold the IMP, recheck the value,
and discuss results with Medical Monitor.
All laboratory abnormalities outlined must be followed to resolution. Laboratory values 
corresponding to Common Terminology Criteria for AEs (CTCAE) Grades 1 to 4 are presented 
for selected laboratory parameters in Table 5. For all other laboratory abnormalities, refer to the 
CTCAE, version 4.03 (CTCAE 2009).
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The reason for IMP withdrawal and the nature, duration, and results of any planned follow-up 
observations should be recorded in the appropriate section of the eCRF.
Table 5
Common Terminology Criteria for Adverse Events Grades for Relevant 
Laboratory Parameters
Laboratory Parameter
Grade 1
Grade 2
Grade 3
Grade 4
Neutrophil (/mm3)
< LLN to 1,500
< 1,500 to 1,000
< 1,000 to 500
< 500
Platelets (/mm3)
< LLN to 75,000
< 75,000 to 50,000
< 50,000 to 25,000
< 25,000
AST and ALT
> ULN to 3× ULN
> 3 to 5× ULN
> 5 to 20× ULN
> 20× ULN
Bilirubin
> ULN to 1.5× ULN
> 1.5 to 3× ULN
> 3 to 10× ULN
> 10× ULN
Amylase and lipase
> ULN to 1.5× ULN
> 1.5 to 2× ULN
> 2 to 5× ULN
> 5× ULN
Creatinine
> Baseline to 1.5×
Baseline, or > ULN to 
1.5× ULN
> 1.5 to 3× Baseline 
or > 1.5 to 3× ULN
> 3× Baseline, or 
> 3 to 6× ULN
> 6× ULN
ALT = Alanine Aminotransferase, AST = Aspartate Aminotransferase, LLN = Lower Limit of Normal, ULN = Upper 
Limit of Normal.
5.6
Premature Termination of the Trial
The clinical study may be terminated prematurely or suspended at the request of Health Authorities 
or if new safety or efficacy information leads to an unfavorable risk benefit judgment for any IMP.
The Sponsor may discontinue the study if the IA indicates that the study is unlikely to achieve the 
primary endpoint at the time of the primary analysis, the study becomes unjustifiable for medical 
or ethical reasons, for poor enrollment, or because of discontinuation of clinical development of 
an IMP or withdrawal of an IMP or comparator from the market for safety reasons.
Health Authorities and Independent Ethics Committees (IECs/IRBs) will be informed about the 
discontinuation of the study in accordance with applicable regulations.
5.7
Definition of End of Trial
The end of the study is defined as the last contact date with the last subject who participates in this 
study (i.e., last subject’s last visit).
A CTP may not be considered closed as long as:
!
Any subject is still receiving any IMP,
!
Visits specified by the protocol are still taking place,
!
Procedures or interventions according to the protocol are still being undertaken in any subject, 
!
The post-treatment Safety Follow-Up Period, defined in the clinical study protocol as being 
part of the study, has not yet been completed for any subject.
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6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
6.1
Description of the Investigational Medicinal Product
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference therapy in a clinical study, including products that have a marketing 
authorization but are formulated, packaged, or administered differently from the authorized form, 
used for an unauthorized indication, or used to gain further information about the authorized form.
M2951 will be administered as film-coated tablets (white to off-white, round biconvex with band 
and no embossing) ready for oral administration and containing 25 mg of drug substance (chemical 
name 
1-(4-{[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino]-methyl}-piperidin-1-yl)-
propenone) formulated with excipients. The placebo will be administered as tablets ready for oral 
administration matching the active both in color and in size and shape.
Reference therapy: dose/model of administration/dosing schedule
Not applicable.
Specific rules for treatment modifications
Not applicable.
6.2
Dosage and Administration
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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6.3
Assignment to Treatment Groups
Following informed consent and evaluation of inclusion/exclusion criteria, eligible subjects will 
be randomized in a 1:1:1:1 ratio to treatment with placebo or M2951 (doses 25 mg once daily, 
75 mg once daily, or 50 mg twice daily), through a central randomization process by an IWRS, 
stratified according to race (Black versus non-Black), region (US and Western Europe, Japan, and
RoW) and disease activity (SLEDAI-2K total score < 10 versus ≥10 at Screening) prior to dosing 
on Day 1. Subjects with SLEDAI-2K total score ≥10 at Screening will be considered to have 
HDA.
For the purposes of this study, Black race will be defined as per the US Census definition. 
Specifically, Black race includes individuals who self-identify as Black, African American, Negro, 
and/or have origins in any of the Black racial groups of Africa, including individuals of 
sub-Saharan African origin (e.g., Kenyan, Nigerian) and individuals of Afro-Caribbean origin 
(e.g., Haitian, Jamaican). Individuals of North African origin (e.g., Morocco, Egypt) are classified 
as non-Black, along with individuals from Sudan and Cape Verde due to their complex population 
history. Subjects declining to identify race will be placed in the non-Black stratum.
The study is fully controlled by the IWRS, which assigns treatment individual (unique) kit numbers 
for each subject. The kit number is linked via the Good Manufacturing Practice qualified system 
to the corresponding treatment as well as to the subject.
Subject identifiers will be comprised of three sets of numbers representing the study number, the 
site number, and the subject number, which is allocated sequentially starting with 0001.
6.4
Non Investigational Medicinal Products to be Used
Permitted medications (including rescue medications) are any medications required per the 
medical history and not specifically prohibited by the protocol during the study (i.e., from 
Screening to the end of the 52 week Treatment Period or LTE Period) (see Section 6.5). Any such 
medications used should be recorded in the eCRF.
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Rescue medications are medicines identified in the CTP as those that may be administered to the 
subject when the efficacy of the IMP is not satisfactory, in case of adverse reactions, or to manage 
an emergency situation.
6.4.1
Background Systemic Lupus Erythematosus Therapies
Background SLE therapies include SoC medications prescribed as part of the subject’s previous 
SLE treatment. Not all SoC therapy will be permitted to be continued during this study. The SoC 
therapy that is allowed to be continued during this study for SLE is presented in Section 6.5.1 and 
includes the use of one single immunosuppressant or immunomodulator, and the use of 
antimalarials, CSs, and NSAIDs. Although it is expected subjects will be on SoC medications, not 
all therapies are permitted (e.g.,
cyclophosphamide, thalidomide, and chlorambucil*
[see Section 6.5]) (*not approved in Japan). 
Table 7
Permitted Background Systemic Lupus Erythematosus Therapies
Permitted SoC Therapy
Immunosuppressants / 
Immunomodulators
(use of one is permitted)
Azathioprine
up to 2.5 mg/kg/day
6-Mercaptopurine
up to 1.5 mg/kg/day
Mycophenolate
either as MMF up to 3 g/day or MPSa up to 
2160 mg/day
Methotrexate
up to 25 mg/week
Sulfasalazine
up to 3 g/day
Leflunomide
up to 20 mg/day
Antimalarials
Hydroxycholoroquine
Quinacrinea
Chloroquinea
Corticosteroids
(see Section 6.4.2 and Section 6.5.1)
NSAIDs
(see Section 6.5.1)
Note: Not all SoC medications are permitted. Prohibited SoC therapies include cyclophosphamide, thalidomide, and 
chlorambucil (see Section 6.5)
MMF = mycophenolate mofetil, MPS = mycophenolate sodium, NSAIDs = nonsteroidal anti-inflammatory drugs.
a: not approved in Japan.
All background therapy for SLE given prior to Screening must have been kept stable or 
discontinued according to the specifications in the exclusion criteria for a subject to be eligible for 
the study. These medications (i.e.,
single immunosuppressant/immunomodulator and/or 
antimalarials, if used) must remain stable during the Screening Period as well as the 52 week
Treatment Period, with the exception of CS and NSAIDs which can be adjusted as long as doses 
are consistent with allowed levels as indicated in Section 6.4.2. Background therapy may only be 
changed for documented safety issues. Initiation of any new immunosuppressant or 
immunomodulator therapy would be considered a treatment failure during the DBPC Treatment 
Period and should result in withdrawal of the subject from the IMP and study (see Section 5.5). 
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SoC medications are part of the subject’s previous SLE treatment and thus will not be provided by 
the Sponsor, including CS and NSAIDs. For Peru, Baseline treatments will be provided by the 
Sponsor as required per local regulation.
Additional treatments commonly given to subjects with SLE are permitted during the study
(see Section 6.5.4.1).
Any medications (other than those excluded per exclusion criteria in Section 5.3.2 or prohibited as 
per Section 6.5.2) that are considered necessary for the subjects’ welfare and will not interfere with 
the study medication may be given at the Investigator’s discretion.
6.4.2
Corticosteroids
DBPC Period
Subjects may enter the Screening Period on CS up to 30 mg/day prednisone-equivalent
(see Table 8), and must be no higher than 30 mg/day on Day 1. Corticosteroid doses above 
30 mg/day prednisone-equivalent should be avoided if possible, but may occur between Day 1 and 
Week 4. If a corticosteroid dose of 30 mg/day prednisone-equivalent or less cannot be achieved at 
the end of Week 4, the subject will be withdrawn from the study and will be considered a treatment
failure. After Week 4 of the Treatment Period, doses above 30 mg/day are prohibited. Furthermore, 
injectable corticosteroids (e.g., intramuscular, intravenous, subcutaneous, and intra-articular) are
prohibited during the study with the exception of a single dose of intramuscular steroid, no more 
than 80 mg of prednisolone equivalent, permitted prior to the twelfth week of the DBPC Period. 
Table 8
Prednisone Equivalence Calculation (Total Daily Dose)
Oral CS Medication
Equivalent (mg) to 1 mg of Prednisone
Betamethasone
0.15 mg
Cortisone
5 mg
Dexamethasone
0.15 mg
Hydrocortisone
4 mg
Prednisolone
1 mg
Meprednisonea
0.8 mg
Methylprednisolone
0.8 mg
Triamcinolone
0.8 mg
CS = Corticosteroids.
a: not approved in Japan.
The corticosteroid dose achieved by the end of Week 8 is defined as the Threshold Dose. This is 
the maximum dose allowed at any time in the study other than for treatment of flares as outlined 
below (see Section 6.4.2.2). After treatment for a flare the corticosteroid dose must be reduced 
within seven days to less than or equal to the Threshold Dose. If this is not possible then the subject 
is considered a treatment failure and will be withdrawn from the study.
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Investigators are strongly encouraged to decrease the CS dose of the subject as much as tolerated 
and as soon as possible until after the Week 16 study visit. Between Weeks 17 and 24, no changes 
to the CS dose may be made. After Week 24 assessments are completed, dose may be decreased, 
as tolerated, through the Week 40 study visit. Between Weeks 41 and 52, no changes to the CS 
dose may be made. The rules for CS dose changes during Screening and the DBPC Treatment 
Period are outlined in Table 9. There is no minimum CS dose required during the study.
Guidance regarding the use of oral CS during the study is provided below. Doses given are for a 
total daily dose of prednisone or prednisolone; CS other than prednisone/prednisolone may be used 
instead orally at the equivalent doses (Table 8).
LTE Period
During the LTE Period, CS doses up to 30 mg/day prednisone-equivalent (see Table 8) are 
permitted. Injectable corticosteroids (e.g., intramuscular, intravenous, subcutaneous, and intra-
articular) remain prohibited during the LTE Period, with the exception of a single dose of 
intramuscular steroid, no more than 80 mg of prednisolone equivalent, permitted prior to the 
twelfth week of the LTE Period.
Screening Period, DBPC Period, and LTE Period
There are no restrictions on non-systemic corticosteroid dosage (see Section 6.5.1.2).
The Investigator will record all concomitant medications taken by the subject during the study,
from the date of signature of informed consent, in the appropriate section of the eCRF, after 
recording them in the source documents.
Any additional concomitant therapy that becomes necessary during the study and any change to 
concomitant drugs must be recorded in the corresponding section of the eCRF, noting the name, 
dose, duration and indication of each drug.
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Table 9
Oral 
Corticosteroid 
Dose 
(in 
prednisone-equivalent) 
and 
Taper Guidance
Study Visit
Study 
Period
Maximum 
Allowable Dosea
Target Dose
Action for CS dosing
Screening 
Screening 
Period
30 mg/day
≤30 mg/day
No change in CS doseb
Day 1 Week 1
30 mg/day
≤30 mg/day
After Day 1, may initiate, 
increase, decrease, or have no 
change to dose. Dose must be 
tapered to ≤Day 1 dose by 
Week 4
Week 1 
through 3
30 mg/dayf
≤30 mg/day
Week 4 Visit
Week 4
Day 1 dosec
≤Dose at Day 1 Visit
Begin taper to ≤10 mg/day by 
Week 8, as tolerated
Weeks 5 
through 7
Week 4 
Visit dose 
≤10 mg/day
Continue to taper to 
≤10 mg/day by Week 8, as 
tolerated
Week 8 Visit
Week 8
Week 4
Visit dose
≤10 mg/day
Begin taper to ≤7.5 mg/day by 
Week 12, as tolerated
Weeks 9 
through 11
Week 8
Visit dose
≤7.5 mg/day
Continue to taper to 
≤7.5 mg/day by Week 12, as 
tolerated
Week 12 Visit
Week 12
Week 8
Visit dose
≤7.5 mg/day
Taper as tolerated
Weeks 13 
through 15
Week 8
Visit dose
≤7.5 mg/day
Taper as tolerated
Week 16 Visit
Week 16
Week 8
Visit dose
≤7.5 mg/day
Taper as tolerated
Weeks 17 
through 23
Week 8
Visit dose
≤7.5 mg/day
No change in CS dosed
Week 24 Visit
Week 24
Week 8
Visit dose
≤7.5 mg/day
No change in CS dosed
Weeks 25 
through 39
Week 8
Visit dose
≤5 mg/day
Taper to ≤5 mg/day by 
Week 40, as tolerated
Week 40 Visit
Week 40
Week 8
Visit dose
≤5 mg/day
Taper as tolerated
Weeks 41 
through 52
Week 8
Visit dose
≤5 mg/day
No change in CS dosee
CS = Corticosteroids.
a 
Violation of requirements during the Screening Period results in screen-failure; treatment period violation may 
result in treatment failure and withdrawal from study. 
b 
Any dose change between Screening and Day 1 results in screen failure.
c
Subjects with CS dose < 7.5 mg/day at Day 1 may have up to 7.5 mg/day at Week 4.
d
Any dose increase during Weeks 17 to 24 results in treatment failure and withdrawal from study, dose may be 
tapered after Week 24 assessments have been completed.
e
Any dose increase during Weeks 41 to 52 results in treatment failure and withdrawal from study.
f
Although it is preferred that subjects do not receive a CS dose > 30 mg/day, subjects who receive > 30 mg/day 
between Day 1 and the Week 4 visit will not be withdrawn from the study if they are able to achieve a dose no 
higher than (≤) the Day 1 CS dose and ≤30 mg/day (whichever is lower) by the Week 4 visit.
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Overview / Key Points on Corticosteroid Dose During Study
!
CS dose must remain stable during the Screening Period.
!
From Day 1 to the Week 4 Visit, CS dose may be initiated, increased, decreased, or remain 
unchanged. 
!
Corticosteroid dose adjustment goals and restrictions during the DBPC Treatment Period:
o
By the Week 4 Visit, the dose must be ≤dose at Day 1. Subjects with CS dose 
< 7.5 mg/day at Day 1 may have up to 7.5 mg/day at Week 4.
o
By the Week 8 Visit, dose should be tapered to ≤10 mg/day, as tolerated
o
By the Week 12 Visit, dose should be tapered to ≤7.5 mg/day, as tolerated
o
No changes to CS dose should be made from Week 17 through completion of study 
assessments for Week 24.
o
Between study visits at Week 25 through Week 40, dose should be tapered to 
≤5 mg/day, as tolerated.
o
No changes to CS dose are allowed from Week 41 through completion of study 
assessments for Week 52/EOT.
!
During the LTE Period, CS doses may be initiated or increased up to 30 mg/day 
prednisone-equivalent, decreased, or remain the same. Investigators are strongly encouraged 
to decrease the CS dose of the subject as much as tolerated.
These rules are detailed in the next section (see Section 6.4.2.1).
6.4.2.1
Corticosteroid Use as Standard of Care
DBPC Period:
Screening Visit to Day 1 (No Change in CS Dose)
From the Screening Visit to Day 1, the corticosteroid dose should be maintained at the 
Screening Visit dose. If the corticosteroid dose is changed, the subject will be considered a screen
failure. The total daily prednisone-equivalent dosage must not be higher than 30 mg/day during 
the Screening Period.
Day 1 to Week 4 Visit (CS Dose Adjustable)
Corticosteroids may remain unchanged, be initiated, be increased, or be decreased after Day 1 but 
must be no higher than (<) the Day 1 CS dose  at the Week 4 Visit.
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Week 4 Visit and Week 4 Study Period
At the Week 4 Visit, the CS dose is required to be no higher than (≤) the Day 1 CS dose and total 
daily prednisone-equivalent dosage must be ≤30 mg/day (whichever is lower). However, subjects 
taking < 7.5 mg/day at the Screening Visit can have a dose of up to 7.5 mg/day at Week 4.
Weeks 5 to 8 (CS Dose Reduction)
By the Week 8 Visit, the CS dose should be tapered to as low a dose as tolerated, targeting a 
prednisone-equivalent dosage ≤10 mg/day and must be ≤the Week 4 dose. This is the new upper 
limit for subsequent doses, and is considered the Threshold Dose.
Weeks 9 to 16 (CS Dose Reduction/Rescue)
After Week 8, the CS dose must always be ≤Week 8 dose (Threshold Dose).
Decreases in the CS dose from the Week 8 dose level should be performed to reach the target of 
prednisone-equivalent ≤7.5 mg/day, as tolerated.
Treatment for flare as outlined below will be allowed once during this period.
Weeks 17 to 24 (No Change in CS Dose)
From Week 17 to 24, the 8 weeks prior to the 24 week assessment of disease activity, the 
corticosteroid dose must be maintained at the Week 16 dose, with no changes. If a corticosteroid 
dose increase is required to treat a flare, the subject will be considered a treatment failure and will 
be withdrawn from study.
Weeks 25 to 40 (CS Dose Reduction/Rescue)
After Week 24, the CS dose must always be ≤Week 8 dose (Threshold Dose).
Decreases in the CS dose from the Week 24 dose level should be performed to reach the target of 
prednisone-equivalent ≤5 mg/day, as tolerated. 
Treatment for flare as outlined below will be allowed once during this period.
Weeks 41-52 (No Change in CS Dose)
The CS dose must be maintained at the Week 40 dose, with no changes. No increases are allowed.
If a corticosteroid dose increase is required to treat a flare, the subject will be considered a 
treatment failure and will be withdrawn from study.
LTE Period:
Corticosteroid doses may be initiated or increased up to 30 mg/day prednisone-equivalent, 
decreased, or remain the same. Investigators are strongly encouraged to decrease the CS dose of 
the subject as much as tolerated.
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6.4.2.2
Corticosteroid Use as Rescue Medication in Treatment of 
Flare
Corticosteroid Dose Increases and Treatment of Flares: DBPC Treatment Period
Subjects may increase the CS dose up to 30 mg/day only two times as rescue for worsening of 
SLE activity or for other reasons during the DBPC Treatment Period of the study. Each rescue is 
allowed only once during each of the following two time periods: 1) once between Week 8 to
Week 16; and 2) once between Week 24 to Week 40. The CS dose can be increased up to 
prednisone-equivalent 30 mg/day, but must be returned to ≤Week 8 dose (Threshold Dose) within
seven days. A CS dose increase must not to be initiated within one week of a planned study visit.
A single dose of intramuscular steroid, no more than 80 mg of prednisolone equivalent, is 
permitted prior to the twelfth week of the DBPC Period. CS medications are part of the subject’s 
previous SLE treatment and thus will not be provided by the Sponsor. Doses for treatment of flares 
beyond these allowable rescue doses will result in the subject being considered a treatment failure, 
and withdrawal from the study (see Section 5.5.1).
Corticosteroid Dose Increases and Treatment of Flares: LTE Treatment Period
During the LTE Period, CS doses up to 30 mg/day are permitted. In addition, a single dose of 
intramuscular steroid, no more than 80 mg of prednisolone equivalent, is permitted prior to the 
twelfth week of the LTE Period. CS medications are part of the subject’s previous SLE treatment 
and thus will not be provided by the Sponsor. 
If medications which are not permitted (as per Section 6.5.2) are required to treat the flare, and/or 
the flare has been ongoing between 2 visits at least 12 weeks apart without improvement, the 
subject must be discussed with the Medical Monitor to determine if the subject should be 
considered a treatment failure, and must be withdrawn from the study (see Section 5.5.1).
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the study, from the date of signature of 
informed consent are to be recorded in the appropriate section of the eCRF, noting the name, dose, 
duration (i.e., start and end dates), dosing regimen (e.g., once daily, twice daily, etc.), and 
indication of each drug. Nondrug interventions and any changes to a concomitant medication or 
other intervention should also be recorded in the eCRF.
6.5.1
Permitted Medicines
Any medications that are considered necessary to protect subject welfare and will not interfere 
with the study medication may be given at the Investigator’s discretion.
Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions or anticipated emergency situations.
Additional treatments commonly given to subjects with SLE are permitted during the study as 
described in Section 6.5.1.4.
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6.5.1.1
Corticosteroids
Corticosteroid dose above 30 mg/day prednisone-equivalent is excluded (except between Day 1 
and Week 4). There is no minimum CS dose required during the study. Rules for CS dose changes 
are detailed in Section 6.4.2.1.
6.5.1.2
Non-Systemic Corticosteroids
Non-systemic corticosteroid medications in this study are defined as otic, topical, intranasal, 
inhaled, and ophthalmic. There are no restrictions on non-systemic corticosteroid dosing.
However, all injected corticosteroids, including local injections (e.g., intra-articular injections) are 
not permitted with the exception of a single dose of intramuscular steroid, no more than 80 mg of 
prednisolone equivalent prior to the twelfth week of the DBPC Treatment Period and once during 
the LTE Period (prior to the twelfth week).
6.5.1.3
Vaccinations
Subjects will be required to have had pneumococcal vaccination and seasonal flu vaccine, as per 
local guidance, to be eligible to participate in the study as per Section 5.3.1. In addition, it is 
strongly recommended that Investigators’ review the subject’s vaccination status, and ensure they 
are up to date with vaccines as per local guidelines. Live vaccinations will not be permitted as per 
Section 5.3.1 and Section 5.3.2.
6.5.1.4
Additional Permitted Medications
Additional background therapies commonly given to subjects with SLE are permitted during the 
study as follows:
! Vitamin D (≥400 IU/day) and calcium supplementation (≥800 mg/day) is encouraged per local 
SoC guidelines. Subjects not already taking these medications at Screening should, according 
to the Investigator's judgement, initiate treatment as soon as possible after Screening. These 
medications will not be supplied by the Sponsor. 
! Subjects taking an NSAID (including cyclooxygenase 2 inhibitors) for SLE symptoms at 
randomization can continue to do so throughout the study. Subjects may have the dose adjusted 
during the study, with any changes in dosage captured in the eCRF (see Section 6.5). The 
NSAIDs should not be used above the maximum allowable doses and site should perform 
regular AE monitoring of these concomitant medications. NSAIDs may not be initiated during 
the DBPC Treatment Period.
! Low-dose aspirin (≤350 mg/day) for cardiovascular prophylaxis. Low-dose aspirin for other 
indications may be permitted after discussion with medical monitor.
! Paracetamol (acetaminophen) up to 3 g/day may be initiated or continued for pain control of 
SLE symptoms during the study. This should be titrated off as tolerated. 
! Opioids are permitted for stable use for SLE if initiated by Day 1. Initiation of opioids and/or 
dosing of opioids as needed after Day 1 for SLE is not permitted during the DBPC Treatment 
Period. These may be titrated off as tolerated during the study.
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! Analgesics, including opiates, may be used at stable doses or as needed for temporary relief of 
symptoms not due to SLE, but then are strongly recommended to be unchanged 24 hours prior 
to each study visit.
! It is recommended that angiotensin-converting enzyme inhibitors and angiotensin receptor 
blockers if used at Screening be maintained at a stable dose during the study as subjects with 
proteinuria up to 4 g/day will be permitted into the study and the proteinuria will be followed, 
unless dose change or initiation is required for safety reasons. 
! Any medications (other than those excluded by the CTP) that are considered necessary for the 
subjects’ welfare and will not interfere with the study medication may be given at the 
Investigator’s discretion.
! Rescue medications may be administered to address ineffective treatment, anticipated adverse 
reactions or anticipated emergency situations (see Section 6.4.2.2 for CS treatment of flare).
! During the LTE Period: 
o
If a subject is on an immunosuppressant/immunomodulator when they rollover into 
the LTE Period, the dosage may be decreased or remain the same. After Week 24 
of the LTE Period, the dosage regimen for an immunosuppressant/
immunomodulator may be increased up to the limits permitted in Table 7 or 
initiated as long as only 1 immunosuppressant is used
o
Antimalarials may be initiated, increased, decreased, or remain the same
o
NSAIDs for SLE may be initiated, increased, decreased, or remain the same
o
Opioids may be initiated, increased, or decreased
o
NSAIDs and paracetamol may also be used for symptoms not due to SLE. It is 
strongly recommended that analgesics (including opioids), paracetamol, and 
NSAIDs are unchanged 24 hours prior to study visits when SLE assessments are 
completed (see SoA).
! Medical marijuana* use (as permitted by local and/or national law) is not excluded; however, it 
will require a case-by-case review and approval by the Medical Monitor and/or Sponsor. Site 
must provide information to confirm:
1.
The marijuana is medically prescribed,
2.
The condition for which it is prescribed is not exclusionary, 
3.
The medical marijuana use is not abuse (i.e., does not interfere with subject compliance 
or safety in the opinion of the Investigator), AND
4.
The dose is stable as to not interfere with the disease activity assessment.
*Not approved in Japan.
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6.5.2
Prohibited Medicines
The following treatments and therapies are not permitted during this study:
!
 
! Use of cyclophosphamide, thalidomide, or chlorambucil* (alkylating agents), tacrolimus, 
cyclosporine, or other immunosuppressant or immunomodulator therapies not listed in
Section 5.3.2 (*not approved in Japan).
! Use of more than one immunosuppressant therapy at any time (see Section 5.3.2 and 6.4.1).
! Biologic therapies for SLE are strictly prohibited. Biologic therapies for other indications must 
be discussed with the Medical Monitor on a case-by-case basis, with the exception of insulin 
and antibodies used for bone density (e.g., denosumab), which are permitted.
! JAK inhibitors (e.g., tofacitinib, baricitinib).
! Anticoagulants and anti-platelet therapy other than low dose of daily aspirin for 
cardioprotection.
! Fish oil.
! Ig therapy or plasmapheresis.
! Bone marrow transplant.
! Any solid organ transplant.
! Vaccines: Live and live-attenuated vaccines are prohibited within one month before Screening 
and during the Study Period. 
!
 
 
! Use of prohibited medications, including the use of oral CS doses that are not allowed or use of 
injectable CS (including intraarticular CS) as mentioned in Section 6.5. 
! New therapies for SLE should not be initiated during Screening or DBPC Treatment Period of 
the study. Initiation of any new immunosuppressant or immunomodulatory therapy would be 
considered a treatment failure and result in withdrawal of the subject from the IMP during the 
DBPC Treatment Period (see Section 5.5). For the LTE Period, see Section 6.4.1.
! Therapies for pulmonary hypertension, see Exclusion criterion 1. 
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6.5.3
Other Interventions
Other Trial Considerations
Women of childbearing potential must be willing to follow very specific restrictions for birth 
control as indicated in Section 5.3.1. While there is no requirement for contraception in male 
participants based on the nonclinical data, it is recommended that conception be avoided during 
exposure to M2951 as there is limited experience in humans.
Other Interventions/Therapies
Use of potentially excluded procedures such as acupuncture or joint replacement therapy is to be 
discussed with the Sponsor or designee on a case-by-case basis. Use of acupuncture is allowed to 
continue if it is started before the Screening Visit and may be initiated/and or modified during the 
LTE Period. Major elective surgeries such as abdominal, thoracic or joint replacement surgeries 
should not be planned to occur in the Study Period. Unplanned joint replacement surgery should 
be discussed at the earliest opportunity prior to the surgery with the Medical Monitor regarding 
continuation of the subject in the study.
6.5.4
Special Precautions
In this study, the inclusion and exclusion criteria, dosing regimens, and other precautionary 
measures specified within this CTP must be respected in addition to the recommendations provided 
in the Investigator’s Brochure.
6.5.4.1
For M2951
The IMP should be temporarily withheld or permanently withdrawn if laboratory abnormalities 
occur or recur as relevant per Section 5.5.2.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
No specific measures are proposed at this stage. Standard medical care will be provided at the 
study site for all AEs occurring during the study.
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6.6
Packaging and Labeling of the Investigational Medicinal 
Product
M2951 and matching placebo is supplied by the Sponsor. A description of pharmaceutical 
properties and composition of the formulation of M2951 is provided in the Investigator Brochure. 
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines. Additional details of packaging and labeling of the 
IMP will be defined in a separate Manual of Procedures.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
IMP must be carefully stored at the study site in a closed room or cabinet with restricted access 
and separately from other drugs.
Storage conditions for M2951 will be specified in a separate Manual of Procedures. Any deviations 
from the recommended storage conditions should be immediately reported to the Sponsor, and the 
medication should not be used until authorization has been received from the Sponsor.
M2951 must not be used for any purpose other than the study. The administration of M2951 to 
subjects who have not been enrolled into the study is not covered by the study insurance.
Disposal of IMP should be according to local regulations and institutional guidelines.
6.8
Investigational Medicinal Product Accountability
The Investigator is responsible for ensuring IMP accountability, including reconciliation of drugs 
and maintenance of records. For Japan only - The head of the study site is responsible for ensuring 
IMP accountability, including reconciliation of drugs and maintenance of records. The head of the 
study site can delegate the control of and accountability for the study drug to an investigational 
product storage manager.
! Upon receipt of IMP, the Investigator (or designee) will check for accurate delivery and 
acknowledge receipt in the IWRS and by signing or initialing and dating the appropriate 
documentation and returning it to the location specified. The original or a copy will be archived 
for the Investigator Site File. For Japan only - Upon receipt of IMP, the head of the study site
(or the investigational product storage manager) will check for accurate delivery and 
acknowledge receipt in the IWRS and by signing or initialing and dating the appropriate 
documentation and returning it to the location specified. The original or a copy will be archived 
for the Investigator Site File
! The dispensing of the study IMP will be carefully recorded on the appropriate drug 
accountability forms and an accurate accounting will be available for verification by the clinical 
research associate (CRA) at each Monitoring Visit.
! Study IMP accountability records will include the following:
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! Confirmation of IMP delivery, in good condition and in the defined temperature range to the 
study site.
! The inventory of IMP provided for the clinical study by the Sponsor and prepared at the site.
! The use of each kit by each subject.
! The disposition (including return, if applicable) of any unused IMP.
! Dates, quantities, batch numbers, kit numbers, expiry dates, as well as individual subjects’ 
study numbers.
The Investigator site should maintain records, which adequately document that subjects were 
provided the IMP specified in this CTP, and all IMPs provided by the Sponsor were fully 
reconciled.
The CRA will periodically collect the IMP accountability forms and will check them. Expired IMP 
can be destroyed at the study site according to local regulations and institutional guidelines while 
the study is ongoing if no shelf life prolongation is possible. 
Unused IMP must not be discarded or used for any purpose other than the present study. Any study
treatment that has been dispensed to a subject must not be re-dispensed to a different subject.
At the conclusion or termination of this study, study site personnel and the CRA will conduct a 
final product supply inventory on the investigational drug accountability forms and all used and
unused IMP kits will be destroyed at the study site according to local regulations and institutional 
guidelines. The study site personnel will be supplied with a copy for filing of the investigational 
drug accountability forms. This documentation must contain a record of clinical supplies used, 
unused, and destroyed and shall include information on:
! All administered units
! All unused units 
! All destroyed units (used and unused) during the study
! All destroyed units (used and unused) at the end of the study
! Date of destruction(s)
! Name and signature of the Investigator/pharmacist. For Japan only - Name and signature of the 
head of the study site or the investigational product storage manager.
It must be ensured at each study site that the study treatment is not used:
! After the expiry date
! After the retest date unless the study treatment is reanalyzed and its retest date is extended.
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6.9
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered at the site on study visit days as indicated in the SOA (Table 1). All 
other dosing will be done by the subject or subject’s caregiver at home throughout the rest of the 
study. Compliance may be assessed via the patient diary for dosing and food intake around dosing.
Subjects will be instructed to bring all IMP, including the used packaging, to each study visit to 
allow for the assessment of compliance with study treatment. Prior to discharge from each 
scheduled visit as determined by IWRS, subjects will be given sufficient IMP for at-home dosing 
until the next scheduled visit during the Treatment Period.
Insufficient compliance with the protocol-specified dosing regimen is defined as receiving < 80% 
of the required number of scheduled doses of study medication. If a subject has insufficient 
compliance, the Investigator or designee is to counsel the subject and ensure steps are taken to 
improve compliance.
6.10
Blinding
Treatment with M2951 and placebo will be double-blinded. Subjects, Investigators, study staff and 
the study teams (Sponsor and 
) will be blinded to treatment. All breaks of the study blind 
must be adequately documented.
Packaging and labeling will be prepared to protect the blinded nature of the study. IMP (M2951
or placebo) will not be distinguishable from each other and will be covered by suitable labels to 
prevent subjects and study personnel from noticing any differences in the tablets of M2951 versus
placebo. Blinded treatment kit numbers will be obtained through the IWRS as described in 
Section 6.3.
After Day 1, results of analyses that could reveal the PD effects of M2951 in an individual subject 
will be blinded to the study site, the Sponsor, and the CRO. These analyses will include: total Ig 
(IgA, IgM, and IgG), IgG subclasses, C3, C4, anti-dsDNA, ANA, other autoantibodies 
(anticardiolipin, anti-Smith antibody [anti-Sm]; an antibody to ribonucleoproteins; and antinuclear 
antibodies associated with autoimmune diseases including Sjögren syndrome and SLE [anti-Ro, 
anti-La]), and cell counts by flow cytometry (total B cells and B cell subsets). If the Investigator 
considers it necessary to have any of the above results for acute medical management of the subject 
after Day 1, then this should be discussed with the Medical Monitor. It should be noted that in the 
clinical utility of monitoring anti-dsDNA levels may be diminished due to an anticipated drop in 
levels as a consequence of M2951’s PD effects. Lymphocyte counts as assessed by routine 
complete blood counts will not be blinded, as these results are not anticipated to reveal PD effects, 
since B lymphocytes represent a small proportion of total lymphocytes (5% - 20%).
An IA for futility may be triggered when 100% of the planned enrollment required for the primary 
analysis reaches 24 weeks of treatment, or discontinues treatment prematurely prior to Week 24. 
The IDMC will be fully unblinded to treatment and will make a recommendation, as described in 
the IDMC charter. A limited set of endpoints will be analyzed for the IA, including Week 24 SRI-4 
response for the whole study population and Week 24 SRI-6 response for the HDA subgroup. 
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If the planned enrollment required for the primary analysis is slower than expected, consideration 
will be given to conducting the interim futility analysis at an earlier time point, when the first 50% 
of subjects enrolled of the planned enrollment reach 24 weeks of treatment, or discontinue 
treatment prematurely prior to Week 24. The unblinding procedures specified above will be 
followed, regardless of the timing of the interim futility analysis.
Only when the trigger event for the primary analysis (Section 5.1) is reached, the protocol 
violations are determined, and the database is locked, will the drug codes be broken and made 
available for the primary analysis.
If the Japan cohort enrollment is slow and cannot be fully included in the  primary analysis cohort, 
a consistency analysis (occurring after the primary analysis) will be scheduled for the purpose of 
analyzing the entire Japan cohort. Only when the trigger event for the consistency analysis (Section 
5.1) is reached, the protocol violations are determined, and the database is locked, will the drug 
codes be broken for the Japanese subjects not included in the primary analysis, and made available 
for the treatment effect consistency analysis with respect to non-Japan and Japan regions.
 
 
 
 
 
 
6.11
Emergency Unblinding
The Investigator will have the ability to break the blind with regard to IMP for any subject at any 
time through the IWRS. However, the Investigator should make every effort to contact the 
responsible Medical Monitor or their designee to discuss the subject’s emergency situation and the 
need to unblind prior to unblinding any subject and must contact the Sponsor or designee within 
1 working day after the event occurs without revealing to the Sponsor personnel the result of the 
code break. The Investigator will be able to access the subject’s treatment assignment 24 hours a 
day through the IWRS using a unique access code and user number (different from those used to 
assign subjects to treatment through the IWRS). Should the IWRS be unavailable for any reason, 
the Investigator will be able to break the blind via a telephone call to the IWRS help desk, which 
is available 24 hours a day. The help desk can access the database manually to perform the 
unblinding via telephone in the event that the IWRS is not operational. The Investigator must 
record the date of unblinding and the reason in the eCRF. Contact information for breaking the 
blind in an emergency is given on the subject emergency card provided to each subject (see 
Section 9.4).
Under certain circumstances, the IDMC or Drug Safety may be required to unblind the treatment 
assignment for an individual subject following a SAE or other serious event; (e.g., if an expedited 
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regulatory report is required). See Section 7.4.1.4 for further details on expedited reporting 
and SAEs.
6.11.1
Unblinding for Regulatory Authorities
In cases where unblinding is required for the purposes of reporting expedited safety events to 
country-specific regulatory agencies or IECs, the unblinding will be performed by an authorized 
person(s). A blinded version of any documents to be submitted to the authorities will be shared as 
appropriate with study staff and site personnel. Only the authorized person(s) within the CRO and 
regulatory affairs will have access to the unblinded version of any documents. The procedures for 
requesting and obtaining unblinded information and for maintaining the integrity of the data and 
clinical study are outlined in the pharmacovigilance plan for this study.
6.12
Treatment of Overdose
An overdose is defined as any dose greater than the highest total daily dose included in a CTP or 
planned for an individual subject enrolled in the study. 
 
 
 
 
. Any overdose must be recorded in the study medication section of the eCRF.
For monitoring purposes, any case of overdose – whether or not associated with an AE (serious or 
nonserious) – must be reported to the Sponsor’s Global Drug Safety department or designee in an 
expedited manner using the appropriate reporting form (see Section 7.4).
The effects of an overdose of M2951 are unknown, and there is no known specific treatment in 
case of overdose. In the event of overdose, subjects should be considered for hospitalization for 
observation if clinically indicated, and the Investigator or treating physician should use appropriate 
clinical judgment for the management of any clinical or investigational findings.
6.13
Medical Care of Subjects after End of Trial
After a subject has completed the study or has withdrawn early, the subject is free to access further 
treatment as deemed appropriate by the Treating Investigator. The Sponsor will not provide any 
additional care to subjects after they leave the study because such care should not differ from what
is normally SoC for subjects with SLE.
7
Trial Procedures and Assessments
Prior to performing any study assessments not part of the subject’s routine medical care, the 
Investigator will ensure that the subject has provided written informed consent according to the 
procedure described in Section 9.2.
Upon subject’s agreement, the subject’s primary health care provider can be informed about 
subject’s enrollment in the study.
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Throughout the study, subjects will undergo the assessments detailed in Table 1 and Table 2, 
including collection of patient-reported HRQoL data and blood sampling.
HRQoL and subject self-assessment questionnaires must be completed first at visits where these 
assessments are collected.
Unscheduled visits may occur at any time during the study in case of suspected flares or AEs 
(assessments to be performed according to the Investigator’s judgement).
7.1
Schedule of Assessments
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2.
7.1.1
Screening Visit
The subjects’ eligibility will be assessed at a Screening Visit that will occur up to four weeks prior 
to the Randomization Visit (Day 1). See Table 1 for a list of assessments done at Screening to 
determine the eligibility of the subject to participate in the study. 
Subjects should undergo the Day 1 Visit as soon as possible after eligibility for the study has been 
confirmed.
Subjects who do not meet all inclusion criteria or meet an exclusion criteria within the first 
Screening Period and are considered screen failures may undergo rescreening once after approval 
by the Medical Monitor. The second Screening Period is a new 28-day Screening Period, and the 
subject will receive a new identification number. Testing at rescreening is required to be redone as 
noted below:
Rescreening: 
Subjects who are considered screen failures after a first Screening Period may undergo rescreening 
once, after approval by the Medical Monitor. If a subject is rescreened, all Screening tests will 
need to be repeated except as follows:
a.
Documented CXR and TB testing if occurred within 3 months prior to the initial rescreening 
visit.
b. Hepatitis and Human Immunodeficiency Virus (HIV) testing if occurred within 1 month prior 
to the initial rescreening visit.
Retesting:
During the initial Screening Period or single rescreening period, testing may be repeated once for 
subjects if test results would preclude enrollment in the study and are thought to represent a 
laboratory error, or a reversible, clinically insignificant intermittent condition, or are inconsistent 
with the subject’s historical values, after discussion with the Medical Monitor. When a laboratory 
test needs to be repeated during the Screening Period, or to accommodate other unanticipated 
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events, the Screening Period may be extended to 8 weeks after discussion with the Medical 
Monitor.
Information collected during the Screening Visit will be entered in the appropriate eCRF.
Subjects who meet the Screening criteria and are to be randomized will be given instructions as to 
the date and time they are due back at the site for Day 1 (randomization/first day of dosing).
7.1.2
DBPC Treatment Period
The treatment should start the day of randomization (Day 1). While on IMP, subjects will be asked 
to visit the study site and undergo assessments according to the SOA in Table 1. The Day 1 Visit
will be considered the Baseline for disease activity [e.g., BILAG 2004 Disease Activity Index, 
SLEDAI-2K, PGA, and CLASI].
A subject diary should be provided to the subjects to capture information such as daily dosing, 
concomitant medications, and AEs. Site personnel should review the subject diaries with the 
subjects at each study visit. Site personnel will dispense IMP to the subjects, per the IWRS, during 
this Period.
! A scheduling window of up to three days before or after the scheduled visit day (±3 days) will 
be permitted as indicated in the SOA.
! Subjects who discontinue early must return for the EOT/Early Withdrawal Visit and Safety 
Follow-Up Visit. 
7.1.2.1
DBPC End of Treatment/Early Withdrawal Visit
The EOT Visit is scheduled on the last day of administration of study treatment. The EOT Visit
will include a full assessment for safety (e.g., physical examination, vital signs, weight, 
hematology and chemistry), and other assessments as described in Table 1. Subjects who complete 
the End of Treatment Visit will be given the opportunity to participate in the LTE Period.
Subjects who discontinue early from the study prior to completing 52 weeks of treatment are to 
complete the EOT Visit within five days after discontinuation, including assessments as detailed 
above and in Table 1. Subjects will also complete the Safety Follow-Up/End of Study Visit, as
required (see Section 7.1.3).
7.1.3
LTE Period
Subjects who completed the 52-week DBPC Treatment period will be offered participation in the 
open-label, LTE Period of the study as described in Section 5.1. The Investigator will obtain
written informed consent for the LTE. 
At all applicable visits, patient-reported outcome questionnaires must be performed prior to any 
other assessments. Scheduled assessments will be performed according to Table 2.
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All scheduled visits during the LTE Period may take place within the visit windows specified in
Table 2. Subjects who discontinue early must return for the LTE End of Treatment/Early 
Withdrawal Visit and Safety Follow-Up Visit. 
For WOCBP, additional highly sensitive urine pregnancy testing will be performed at home per 
SOA, Table 3. Urine pregnancy test kits will be provided to the subject at Week 16 (for testing at 
Week 20), Week 24 (for testing at Week 28, 32, and 36), Week 40 (for testing at Week 44 and 48), 
Week 52 (for testing at Week 56, 60, 64, 68, and 72), and Week 76 (for testing at Week 80, 84, 
88, 92, 96, and 100). At and/or prior to the Week 16 visit, the PI and/or delegated site staff will 
train the relevant subjects to self-administer the urine pregnancy tests and will call the subject to 
confirm completion of urine pregnancy testing and discuss results per Table 3.
7.1.3.1
LTE End of Treatment Visit
The LTE End of Treatment Visit will be performed at Week 104 or within 5 days of early 
discontinuation of treatment with the IMP. Subjects will undergo assessments as described in
Table 2. In case of premature discontinuation, the PRO assessments must be completed at the LTE
End of Treatment Visit. Subjects will enter the Safety Follow-Up Period after completing the LTE
End of Treatment Visit.
7.1.4
Safety Follow-Up/End of Study Visit
The Safety Follow-Up/End of Study Visit is scheduled four weeks (+ 5 days) after the last 
administration of study treatment. For subjects who do not participate in the LTE Period, the Safety 
Follow-Up Visit is scheduled four weeks (+ 5 days) after the last administration of study treatment 
in the DBPC Period. For subjects who participate in the LTE Period, the Safety Follow-Up Visit 
is delayed until four weeks (+ 5 days) after the last administration of study treatment in the LTE 
Period. Subjects who are approved to rollover into LTE Period after they entered, or completed, 
the DBPC Safety Follow-Up Period, may have two Safety Follow-Up Visits. Additional details of 
the Safety Follow-Up/ End of Study Visit are provided in the SOA.
Subjects who discontinue the IMP or withdraw from the trial early will attend the Safety 
Follow-Up Visit according to procedures described in Sections 5.5.1 or 5.5.2, respectively.
All SAEs ongoing at the Safety Follow-Up/End of Study Visit must be monitored and followed 
up by the Investigator until stabilization or until the outcome is known, unless the subject is 
documented as “lost to follow-up”.
7.2
Demographic and Other Baseline Characteristics
Demographic data such as date of birth, self-reported race and ethnic origin, gender, weight, 
height, and body mass index will be assessed at Screening. Information about previous and 
concomitant medications will also be recorded.
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7.2.1
Medical History
In order to determine the subject’s eligibility to the study, a complete medical history of each 
subject will be collected and documented during Screening, which will include, but may not be 
limited to the following:
! Past and concomitant disease.
! Physical examination including neurological assessment and serology.
! All medications (including herbal medications) taken and procedures carried out within 28 days 
prior to Screening. Any SLE-related medications and procedures from within one year prior to 
Screening should be documented. Additional medications and procedures (with particular 
attention to SLE-related medications and procedures), should be included as deemed relevant 
by the Investigator.
For the study entry, all of the subjects must fulfill all inclusion criteria described in Section 5.3.1, 
and none of the subjects should have any exclusion criterion from the list described in 
Section 5.3.2.
7.2.2
Diagnosis of Systemic Lupus Erythematosus
Date of documented diagnosis of SLE, and presence/absence of the SLICC criteria for diagnosis 
of SLE (see Appendix II) and/or the presence/absence of the 11 ACR criteria for classification of 
SLE (see Appendix III), serially or simultaneously, during any interval of observation, will be 
collected.
Diagnosis of SLE will be defined as having presence of (serially or simultaneously, during any 
interval of observation):
Presence of at least four criteria, including at least one clinical criterion and at least one 
immunological criterion; or biopsy proven lupus nephritis with positive ANA and/or positive 
anti-dsDNA; as specified in the SLICC Classification Criteria for SLE (see Appendix II),
Or,
Presence of at least four of the 11 ACR classification criteria for SLE.
The diagnosis must have been made and documented at least six months prior to Screening. If a 
potential subject has not been formally diagnosed with SLE, but has 6 months of documented and 
sufficient diagnostic criteria (ACR or SLICC, as above), they may be included in the study. The 
Investigator must review the medical history, confirm the retrospective diagnosis of SLE, and the 
Medical Monitor must provide documented approval.
Additionally, subjects will be required to have SLEDAI-2K total score ≥6 (including clinical 
SLEDAI ≥4) at Screening. Subjects with SLEDAI-2K total score ≥10 at Screening will be 
considered to have HDA.
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7.2.3
Other Baseline Assessments
The term ‘Baseline’ in this protocol is defined as Day 1, predose. Baseline measurements, such as 
vital signs, a complete physical examination, clinical laboratory parameters, 12-lead ECG, HRQoL
assessments (SLEDAI Flare Index [SFI], SLEDAI-2K, PGA, C-SSRS, BILAG 2004, CLASI, 
SLICC/ACR damage index), and PD parameters will be assessed as indicated in the SOA
(Table 1). The HRQoL assessments on Day 1 are to be completed after inclusion/exclusion criteria 
are reviewed, verified, and the subject is randomized.
7.3
Efficacy Assessments
Efficacy will be evaluated using the instruments and outcomes described below and at the visits 
specified in Table 1 and Table 2 in accordance with recommendations for outcome measures in 
SLE studies which suggest assessment of current disease activity, permanent damage, and HRQoL, 
ideally including an instrument sensitive to fatigue.
All data collection and all query handling will be done via an eCRF system. An electronic device 
(electronic PRO [ePRO] system) may be used to collect some of the HRQoL assessments.
7.3.1
British Isles Lupus Assessment Group 2004
The BILAG 2004 Disease Activity Index evaluates SLE activity in a number of organ systems, 
based on the principle of “physician’s intention to treat” (refer to Manual of Procedures). The 
primary purpose of the BILAG in this study is to assess possible worsening in specific organ 
systems. Additional analyses of improvements in disease activity as assessed by the BILAG 2004 
will also be done.
A separate alphabetic score is assigned to each organ system, corresponding in general to the 
following definitions:
! BILAG A: Severe disease activity requiring any of the following treatments (e.g., systemic high 
dose oral CS, intravenous pulse CS, systemic immunosuppressants, or therapeutic high dose 
anticoagulation in the presence of high dose CS or ≥20 mg prednisone). Note that in the context 
of a CTP with medication restrictions and blinded IMP, the term “requiring” is not taken 
literally, but indicates that if all else were equal this would be the degree of treatment indicated. 
It is also understood that some subjects respond to different levels of medication than others, so 
that in assessing subjects with the BILAG “intent to treat” really means that most subjects with 
this degree of symptom would require this level of treatment, not necessarily the subject in 
question. 
! BILAG B: Moderate disease activity requiring treatment with systemic low dose oral 
glucocorticoids, intramuscular or intra-articular or soft tissue CS injection, topical CS or 
immunosuppressants, or symptomatic therapy such as antimalarials or NSAIDs.
! BILAG C: Mild disease
! BILAG D: System previously affected but now inactive
! BILAG E: System never involved
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The BILAG 2004 is evaluated by scoring each of a list of signs and symptom as: improving (1); 
same (2); worse (3); new (4); not present (0); not done (ND). For some items, appropriate responses 
may be: Y/N or numerical values where indicated or Y/N confirm this is due to SLE activity.
All signs and symptoms scored must be due to SLE. Use of a glossary provided with the 
BILAG 2004 instrument and training of assessors in use of the instrument are essential to obtaining 
reliable and consistent results.
Use of the BILAG 2004 index for evaluating flares has been identified as a robust way of 
evaluating the efficacy of drugs; this judgment has been corroborated by external advisors and 
regulatory authorities. 
BILAG assessments should be conducted by a trained evaluator. 
Requirements for BILAG-based Composite Lupus Assessment (BICLA) response are: (1) BILAG
2004 improvement (all A scores at Baseline improved to B/C/D, and all B scores improved to C 
or D); (2) no worsening in disease activity (no new BILAG 2004 A scores and ≤1 new B score); 
(3) no worsening of total SLEDAI-2K score from Baseline; (4) no significant deterioration 
(< 10% worsening) in visual analogue PGA and (5) no treatment failure (defined as non-protocol 
treatment, i.e., new or increased immunosuppressives or antimalarials; or increased or parenteral 
corticosteroids; or premature discontinuation from study treatment) (Wallace 2014).
A copy of the BILAG 2004 and glossary is provided in the Manual of Procedures.
7.3.2
Physician Global Assessment 
The PGA is used to quantify disease activity and is measured using an anchored Visual Analog 
Scale (VAS) (see Figure 5). The PGA will be determined on a continuous VAS that asks the 
Investigator to assess the subject’s current disease activity from a score of 0 (none) to 3 (severe), 
with the assessment made relative not to the subject’s most severe state but the most severe state 
of SLE per the Investigator’s assessment. As per its validation method, the PGA is recommended 
to be completed prior to laboratory results from the individual study visit being available 
(Petri 1992).
This version of the PGA is not scored blindly. The assessor is instructed to look at the 
previous month’s PGA, decide whether the overall condition of the subject is same, better or worse 
and move the line accordingly.
A score change, where score is moved to the right from 2.5 or below in the previous month
to > 2.5 this month, denotes an arbitrary threshold for severe flare to be considered when 
determining if enough change has occurred to justify assessing the criterion as severe flare. A score 
change ≥1 unit to the right denotes a designation of mild/moderate flare.
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Figure 5
Physician Global Assessment Visual Analog Scale with Anchors
7.3.3
Systemic Lupus Erythematosus Disease Activity Index-2000
and Systemic Lupus Erythematosus Disease Activity Index 
Flare Index
SLEDAI-2K
The SLEDAI-2K is a reliable, valid, simple 1-page index that measures disease activity and records 
features of active lupus as present or not present (Gladman 2002). It is a modification for the 
SLEDAI to reflect persistent, active disease in those descriptors that had previously only 
considered new or recurrent occurrences. The SLEDAI-2K was validated against the original 
SLEDAI for evaluation over the previous 10 days. It has been shown to be reliable at different 
levels of disease activity (Gladman 1992, Gladman 1994). The properties of the SLEDAI-2K are 
summarized in a recent publication of Romero-Diaz et al (Romero-Diaz 2011).
Subsequently, use of the SLEDAI-2K for evaluating the previous 30 days was validated, and 
evaluation of the previous 30 days is now the approach recommended for use in clinical studies 
(Touma 2010, Touma 2011).
The SLEDAI-2K uses a weighted checklist to assign a numerical score based on the presence or 
absence of 24 symptoms at the time of assessment or during the previous 30 days. Each symptom 
present is assigned between 1 and 8 points based on its usual clinical importance, yielding a total 
score that ranges from 0 points (no symptoms) to 105 points (presence of all defined symptoms). 
However, if scored correctly, it is rare for even the sickest subjects to score more than 20 points. 
The assessor is also requested to assess the subject’s symptoms using the VAS for the PGA 
(see Section 7.3.2).
SLEDAI Flare Index 
The SFI can be used with any version of the SLEDAI, and will be used with the SLEDAI-2K for 
the purposes of this trial.
A mild/moderate flare is defined as any of the following
! Increase in SLEDAI instrument score of 3 points or more (but total score not to more than 12).
! New or worse discoid, photosensitive, profundus, cutaneous vasculitis, bullous lupus; or 
nasopharyngeal ulcers; or pleuritic; or pericarditis; or arthritis; or fever due to SLE.
! Increase in prednisone, but not to > 0.5 mg/kg/day.
! Added NSAID or hydroxychloroquine (or chloroquine) for SLE activity.
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! ≥1.0 increase in PGA score, but score not to exceed 2.5 (assuming the PGA score has been 
transformed to a 0-3 point scale).
! A severe flare is defined as any of the following:
! Increase in SLEDAI instrument score leading to total score > 12.
! New or worse central nervous system SLE; or vasculitis; or nephritis; or myositis; or 
platelets < 60,000/mm3, or hemolytic anemia with hemoglobin < 70 g/L or decrease in 
hemoglobin > 30 g/L AND requiring: double prednisone, or prednisone increase 
to > 0.5 mg/kg/day, or hospitalization due to SLE.
! Increase in prednisone to > 0.5 mg/kg/day.
! New cyclophosphamide, azathioprine, methotrexate, or mycophenolate for SLE activity.
! Hospitalization for SLE activity.
! Increase in PGA score leading to total score > 2.5 (assuming the PGA score has been 
transformed to a 0-3 point scale).
The SLEDAI-2K and SFI assessments should be conducted by a trained evaluator.
A copy of the SLEDAI-2K form is provided in a separate Manual of Procedures.
7.3.4
Cutaneous Lupus Erythematosus Disease Area and Severity 
Index
Cutaneous Lupus Erythematosus Disease Area and Severity Index is a validated measurement 
instrument for lupus erythematosus developed for use in clinical studies that consists of separate 
scores for the activity of the disease (CLASI-A) and the damage done by the disease (CLASI-D).
The CLASI activity score is calculated on the basis of erythema, scale/hyperkeratosis, mucous 
membrane involvement, acute hair loss and non-scarring alopecia. The CLASI damage score is 
calculated on the basis of dyspigmentation and scarring, including scarring alopecia. 
Dyspigmentation due to lesions is defined as lesions that remain visible for more than 12 months, 
which are considered to then be permanent (Albrecht 2005).
The CLASI assessment should be conducted by a trained evaluator, and a copy of the Index is 
provided in a separate Manual of Procedures.
7.3.5
Systemic 
Lupus 
International 
Collaborating 
Clinics /
American College of Rheumatology Damage Index
The SLICC/ACR Damage Index evaluates cumulative damage in SLE (Gladman 1996). These 
changes may or may not be related to SLE. In order to ensure that features are not reversible 
components of active inflammation, most items are scored only if they have been present for at 
least six months. Scores range from 0 to 47 points, with higher scores indicating greater cumulative 
damage. However it would be exceedingly rare to see a damage index score of greater than 5 and 
most subjects in clinical studies have scores ranging from 0-2.
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Further information on the SLICC/ACR Damage Index is provided in the Manual of Procedures.
7.3.6
Health Related Quality of Life Assessments
The impact of SLE on subjects’ lives is significant, and thus HRQoL outcomes are meaningful to 
both subjects and clinicians. As part of the study’s examination of efficacy, the effects of treatment 
on HRQoL will be assessed through changes in the SF-36v2, EQ-5D-5L, LupusQoL, PGIC, and 
FACIT-Fatigue scores (Hewlett 2005, McElhone 2007, Hurst 2004, Wolfe 1996, Yellen 1997). 
Each HRQoL assessment will be used in the countries for which validated translations are 
available. A copy of each HRQoL assessment is provided in the Manual of Procedures. 
7.3.6.1
Medical Outcomes Study 36-item Short Form Health Survey 
The SF-36v2 is a 36-item scale constructed to survey HRQoL on eight domains: limitations in 
physical activities due to health problems; limitations in social activities due to physical or 
emotional problems; limitations in usual role activities due to physical health problems; bodily 
pain; general mental health (psychological distress and well-being); limitations in usual role 
activities due to emotional problems; vitality (energy and fatigue); and general health perceptions 
(Ware 2008).
The SF-36v2 form asks for subjects to reply to questions (items) according to how they have felt 
over a specifically defined period of time. The items use Likert-type scales, some with 5 or 6 points 
and others with 2 or 3 points and yields scale scores for each of these eight health domains, and 
two summary measures of physical and mental health: the Physical Component Summary (PCS) 
and Mental Component Summary (MCS). The interval level scoring for all eight scales ranges 
from 0 (for worse health) to 100 (best possible health as measured by the questionnaire) with 
standardized summary scores for the PCS and MCS (mean = 50, SD = 10).
Higher scores represent a better quality of life. Low scores on the PCS indicate significant 
limitations in performing physical activities, high degree of bodily pain and poor general health, 
while high scores reflect little or no such limitations. Low scores on the MCS indicate frequent 
psychological distress, social and role disability due to emotional problems and poor general 
health, while higher scores reflect little or no psychological distress or limitations. At each 
Assessment Visit, the SF-36v2 will be completed by the subject prior to the initiation of any other 
study activities or treatments.
7.3.6.2
Lupus Quality of Life
The LupusQoL is a lupus-specific HRQoL questionnaire consisting of 34 items grouped in eight 
domains: physical health, pain, planning, intimate relationships, burden to others, emotional 
health, body image and fatigue (McElhone 2007). Subjects indicate their responses on a five point 
Likert response format, where 4 = never, 3 = occasionally, 2 = a good bit of the time, 1 = most of 
the time, and 0 = all of the time. Summary scores can be calculated for all eight domains. The 
LupusQoL showed good internal reliability, test-retest reliability, and concurrent validity with the 
SF-36v2 and discriminant validity for different levels of disease activity and damage in SLE 
subjects (McElhone 2007, McElhone 2016).
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7.3.6.3
Patient Global Impression of Change
The PGIC is a self-rated scale that asks the subject to describe the change in activity limitations, 
symptoms, emotions, and overall quality of life (QoL) related to the subject’s painful condition on 
the following scale: 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no 
change), 5 (minimally worse), 6 (much worse) and 7 (very much worse). The subject will select 
the number that matches the subject’s degree of change since beginning the treatment with M2951
(Hurst 2004).
The PGIC can be used as an anchor based method to assess clinically important change in which 
the judgment of meaningful change is made by the subject (Amirfeyz 2009). 
7.3.6.4
Functional Assessment of Chronic Illness Therapy-Fatigue
The FACIT-Fatigue is a 13-item questionnaire that assesses self-reported fatigue and its impact 
upon daily activities and function (Wolfe 1996). It uses a 5-point Likert-type scale (0 = not at all; 
1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). As each of the 13 items of the 
FACIT-Fatigue scale ranges from 0–4, the range of possible scores is 0-52, with 0 being the worst 
possible score and 52 the best. To obtain the 0-52 score, each negatively worded item response is 
recoded so that 0 is a bad response and 4 is good response. All responses are added with equal 
weight to obtain the total score. Fatigue is among the most prevalent symptoms of SLE, and can 
have profound effects on subjects’ HRQoL (Wolfe 1996, Yellen 1997). The FACIT-Fatigue has 
been validated in subjects with SLE being a valid and responsive measure of fatigue in subjects 
with SLE (Hewlett 2005, Kosinski 2013, Lai 2011, Strand 2015). 
7.3.6.5
EuroQoL 5 Dimension 5 Levels
The EQ-5D-5L questionnaire is a generic measure of health status that provides a simple 
descriptive profile and a single index value (Aggarwal 2009). 
The EQ-5D-5L profile defines health in terms of mobility, self-care, usual activities, pain or 
discomfort, and anxiety or depression. Each dimension has five levels: no problems, slight 
problems, moderate problems, severe problems, and extreme problems. The digits for five
dimensions can be combined in a five-digit number describing the respondent’s health state. 
EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, may be converted into a 
single index value. The index values, presented in country specific value sets, facilitate the 
calculation of quality-adjusted life years that are used to inform economic evaluations of health 
care interventions. 
The EuroQoL VAS records the respondent’s self-rated health on a 20 cm vertical, visual analogue 
scale with endpoints labelled ‘the best health you can imagine’ and ‘the worst health you can 
imagine’. This information can be used as a quantitative measure of health as judged by the 
individual respondents.
Higher scores on both EQ-5D-5L scales represent a better QoL.
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7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analysis of 
Baseline medical conditions; AEs; physical examination findings including vital signs, ECGs, and 
laboratory tests (including Ig as detailed Section 7.3.6 and B cell counts).
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the study. The Investigator will report 
any AEs, whether observed by the Investigator or reported by the subject (see Section 7.4.1.2). 
The Reporting Period for AEs is described in Section 7.4.1.3.
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An AE is any untoward medical occurrence in a subject or clinical investigation subject 
administered a pharmaceutical product, regardless of causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a medicinal product, whether 
or not considered related to the medicinal product. 
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity or toxicity of each AE.
Investigators will reference the National Cancer Institute - Common Terminology Criteria for AEs 
(NCI-CTCAE), version 4.03 CTCAE 2010, a descriptive terminology that can be used for 
AE reporting.
A general grading (severity/intensity; hereafter referred to as severity) scale is provided at the 
beginning of the above referenced document, and specific event grades are also provided.
Only if a particular AE’s severity is not specifically graded by the guidance document, the 
Investigator is to use the general NCI-CTCAE definitions of Grade 1 through Grade 5 following 
his or her best medical judgment.
The five general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening
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! Grade 5 or Death.
According to Sponsor convention, any clinical AE with severity of Grade 4 or 5 must also be 
reported as an SAE. However, a laboratory abnormality of Grade 4, such as anemia or neutropenia, 
is considered serious only if the condition meets one of the serious criteria described below.
If death occurs, the primary cause of death or event leading to death should be recorded and 
reported as an SAE. “Fatal” will be recorded as the outcome of this specific event and death will 
not be recorded as a separate event. Only, if no cause of death can be reported (e.g., sudden death, 
unexplained death), the death per se might then be reported as an SAE.
Investigators must also systematically assess the causal relationship of AEs to IMP(s)/study 
treatment (including any other non-IMPs, etc.) using the following definitions. Decisive factors 
for the assessment of causal relationship of an AE to the IMP include, but may not be limited to, 
temporal relationship between the AE and the IMP, known side effects of IMP, medical history, 
concomitant medication, course of the underlying disease, study procedures.
Unrelated:
Not reasonably related to the IMP/study treatment. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under study 
in this CTP. A reasonable alternative explanation must be available.
Related:
Reasonably related to the IMP/study treatment. AE could medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under study 
in this CTP.
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG trace) 
should not be reported as AEs unless they are associated with clinical signs and symptoms, lead to 
treatment discontinuation or are considered otherwise medically important by the Investigator. If 
a laboratory abnormality fulfills these criteria, the identified medical condition (e.g., anemia, 
increased ALT) must be reported as the AE rather than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
! Results in death.
! Is life-threatening. (Note: The term “life-threatening” refers to an event in which the subject is 
at risk of death at the time of the event, not an event that hypothetically might have caused death 
if it was more severe)
! Requires inpatient hospitalization or prolongs an existing hospitalization, except in the case of 
hospitalizations due to protocol-defined SLE flares.
! Results in persistent or significant disability or incapacity.
! Is a congenital anomaly or birth defect.
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! Is otherwise considered to be medically important. (Note: Important medical events that may 
not result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above. Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, 
or the development of drug dependency or drug abuse.)
For the purposes of reporting, any suspected transmission of an infectious agent via an IMP is also 
considered an SAE, as described in 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study treatment or study procedures (e.g., an 
overnight stay to facilitate intravenous therapy) are not considered SAEs. However, all events 
leading to unplanned hospitalizations or unplanned prolongation of an elective hospitalization 
(e.g., undesirable effects of any administered treatment) must be documented and reported as 
SAEs, except for unplanned hospitalizations due to flare of SLE.
Events Not to Be Considered as AEs/SAEs 
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions and are not to be considered AEs.
Worsening of the underlying disease is not routinely to be considered an AE or SAE, but is rather 
an efficacy endpoint, unless deemed to be causally related to the IMP.
However, if significant adverse signs or symptoms occur in association with complications or a 
prolonging of a hospitalization originally due to SLE flare, then these specific complications or 
hospital prolongation events should be recorded as AEs.
Exacerbation of SLE
SLE flares would not usually be reported as AEs unless they are unexpected in the context of the 
subject’s medical history. Further, the AE report should describe the event, rather than reporting 
an AE of “SLE flare” unless it is unavoidable. SAEs due to SLE flare are always reported, whether 
or not it is consistent with the subjects’ prior history. As for AE reports, the SAE report should 
describe the events, and avoid reporting an SAE of "SLE flare".
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each study visit, the subject will be asked about changes in his/her condition. During the 
Reporting Period of the study, any unfavorable changes in the subject’s condition will be recorded 
as AEs, whether reported by the subject or observed by the Investigator, unless it is a lupus flare 
that is not unexpected based on the subject’s medical history. 
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Complete, accurate and consistent data on all AEs experienced for the duration of the Reporting 
Period (defined below) will be reported on an ongoing basis in the appropriate section of the eCRF. 
All SAEs must be additionally documented and reported using an SAE Report Form as described 
in Section 7.4.1.4.
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates [and times to be completed when relevant and possible to assess the time of AE 
onset relative to treatment administration]), its severity, its relationship with the study treatment, 
any other potential causal factors, any treatment given or other action taken (including dose 
modification or discontinuation of the IMP) and its outcome. In addition, SAEs should be 
identified and the appropriate seriousness criteria documented. 
Specific guidance can be found in the eCRF Completion and Monitoring Conventions provided 
by the Sponsor or designee.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE Reporting Period for safety surveillance begins when the subject is screened (date of first 
signature of informed consent) and continues through the study’s Post Treatment Follow-Up 
Period, defined as the Safety Follow-Up Period (EOT through Follow-Up Week 4). SAEs 
occurring after a subject has taken the last dose of IMP will be collected throughout the subject’s 
participation until the end of the Safety Follow-Up Period, regardless of the Investigator’s opinion 
of causation. Thereafter, SAEs are not required to be reported unless the Investigator determines 
the SAE was related to IMP, or protocol procedure. 
Any SAE assessed as related to M2951 must be reported whenever it occurs, irrespective of the 
time elapsed since the last administration of M2951. 
7.4.1.4
Procedure for Reporting Serious Adverse Events
Serious Adverse Events
In the event of any new SAE occurring during the Reporting Period, the Investigator must 
immediately (i.e., within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee by completing the SAE Report form in the eCRF following specific 
completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, an SAE Report Form must be completed immediately thereafter.
Relevant pages from the eCRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may also be provided by the Investigator, if available (e.g.,
laboratory results, hospital report, autopsy report). In all cases, the information provided in the 
SAE Report Form (clinical trial) must be consistent with the data on the event that are recorded in 
the corresponding sections of the eCRF.
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The Investigator/reporter must respond to any request for follow-up information (e.g., additional 
information, outcome and final evaluation, specific records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as described for initial reports. 
This is necessary to permit a prompt assessment of the event by the Sponsor or designee and (as 
applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards and Investigators
The Sponsor or designee will send safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (and in particular, deaths) involving study subjects to the IEC/IRB that approved 
the study.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the study or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the study.” In particular and in line with 
respective regulations, the Sponsor/designee will inform the Investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (SUSARs). 
The Investigator should place copies of safety reports in the Investigator Site File. National 
regulations with regard to safety report notifications to Investigators will be taken into account.
For Japan only - In accordance with ICH GCP and the Japanese ministerial ordinance on GCP, the 
Sponsor/designee will inform the Investigator and the head of the study site of “findings that could 
adversely affect the safety of subjects, impact the conduct of the study or alter the IEC’s/IRB’s 
approval/favorable opinion to continue the study.” In particular and in line with respective 
regulations, the Sponsor/designee will inform the Investigator and the head of the study sites of 
AEs that are both serious and unexpected and are considered to be related to the administered 
product (SUSARs). The Investigator should place copies of safety reports in the Investigator Site 
File. National regulations with regard to safety report notifications to Investigators will be taken 
into account. The head of the study site should also maintain copies of safety reports appropriately.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for notifying the applicable IEC/IRB of any safety 
reports provided by the Sponsor/designee in accordance with applicable timelines and will be 
required to file copies of all reports and related correspondence in the Investigator Site File.
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For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/safety issues will be carried out in accordance with that 
Directive and with the related Detailed Guidance documents.
7.4.1.6
Monitoring of Subjects with Adverse Events
Any AE that occurs during the course of a clinical study and is considered to be possibly related 
to the IMP must be monitored and followed up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. Reasonable attempts 
to obtain this information must be made and documented. It is also the responsibility of the 
Investigator to ensure that appropriate additional therapeutic measures and follow-up procedures 
are performed if possible. The Sponsor or designee will actively follow-up and collect information 
on any AE that occurs during the course of a clinical study; however while this activity will 
continue for any SAEs until stabilization or until the outcome is known, it will be discontinued at 
the time of database lock for nonserious AEs.
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to study treatment (e.g., resulting 
from a drug interaction with a contraceptive medication) are considered to be AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 7.4.1.3 must 
be recorded by convention in the AE page/section of the eCRF. The same rule applies to 
pregnancies in female subjects and to pregnancies in female partners of male subjects. The 
Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy using the 
Pregnancy Report Form, which must be transmitted according to the same process as described 
for SAE reporting in Section 7.4.1.4. 
If possible, Investigators must actively follow-up, document and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the study (see Section 5.5.2). The Pregnancy 
Report Form will be used to report outcomes and in case of adverse outcomes, the AE Safety 
Report Form (Clinical Trials) will be used for events occurring to the subject and the 
Parent Child/Fetus AE Report Form will be used if the child/fetus sustains an AE.
Adverse outcomes must be reported in an expedited manner as described in Section 7.4.1.4, while 
nonadverse outcomes must be reported within 45 days from delivery. In the event of pregnancy in 
a subject occurring during the course of the study, the subject must be discontinued from study
medication immediately. The Sponsor must be notified without delay and the subject should be 
followed as described above.
7.4.3
Clinical Laboratory Assessments
Blood and urine samples will be collected for the following clinical laboratory tests (Table 11), 
following the timing noted in the SOA (Table 1 and Table 2). All samples should be clearly 
identified. Sample collection, preparation, and handling/shipment procedures are described in the 
laboratory manual. For WOCBP, including those who are postmenopausal for less than 12 months, 
serum pregnancy tests will be performed at initial Screening, and high sensitivity urine pregnancy 
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tests will be performed at the visits specified in Table 1 and Table 3. Pregnancy tests will be done 
whenever 1 menstrual cycle is missed during the active treatment period, when potential 
pregnancy is otherwise suspected, and at the end of the study to confirm the subject has not become 
pregnant during the study. Pregnancy tests may be repeated per request of institutional review 
boards (IRBs)/ethics committees (ECs) or if required by local regulations.
Additional laboratory tests may be performed after abnormal findings. Local safety testing as 
requested by the study team should be entered into the eCRF.
Table 11
Clinical Laboratory Evaluations
Type of 
Evaluation
Tests
Biochemistry
Albumin
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Lactate dehydrogenase
Total Ig Levels (IgG, IgA, IgM)b
Bilirubin (total) 
Protein (total)
Creatinine and eGFR
calculationa
Amylase
Lipase
Total carbon dioxide/serum 
biocarbonate
Blood urea nitrogen
Glucose
Sodium
Potassium
Chloride
Calcium
Magnesium
Phosphate
Uric acid
Supplementary 
LFT visits
Aspartate aminotransferase
Alanine aminotransferase
Alkaline phosphatase
γ-Glutamyl-transferase
Bilirubin (total) 
Hepatic Panel
International normalized ratio
Partial thromboplastin time
Fibrinogen
hsCRP
Hepatitis serology: 
anti HAV IgG, anti-HAV 
IgM, HBsAg, anti-HBc, anti 
HBsAg, anti-HCV, anti-HEV 
IgG and IgM, anti-VCA IgG 
and IgM, anti-EA IgG, anti-
EBNA IgG, anti-CMV IgG 
and IgM
Antinuclear antibody, anti-
smooth muscle antibody, 
antibody to liver kidney 
microsomes
Albumin
Hematology 
Hematocrit
Hemoglobin
Red blood cell count
Mean corpuscular volume
Mean corpuscular hemoglobin
Mean corpuscular hemoglobin 
concentration
Reticulocyte count
Platelet count 
White blood cell count
Flow cytometry for:
B cell countb
White blood cell differentials 
and absolute counts:
Basophils
Eosinophils
Lymphocytes
Monocytes
Neutrophils 
Coagulationb
International normalized ratio
Partial thromboplastin time
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Type of 
Evaluation
Tests
Urinalysis/
microscopyc
and urine 
chemistry
pH
Nitrite
Urobilinogen
Bilirubin
Glucose 
Ketone bodies
Protein
Blood
Microscopy (white blood 
cells, red blood cells, casts,
crystals)
Protein/creatinine ratio
Additional urine 
testing
β-hCG (women only)c
Other Screening 
testsd
HCV antibodies
Serum β-hCG (women only)
Serum β-glucan (Japan only)
HBV antibodies
HIVe
TSH
FSH
HBsAg
Quantiferon tuberculosis test
Reflex Testing 
for HBV DNA
HBV DNA PCR
β-hCG = Beta-Human Chorionic Gonadotropin, DNA = deoxyribonucleic acid, EA = early antigen,
EBNA = Epstein-Barr nuclear antigen, eGFR = Estimated Glomerular Filtration Rate, FSH = Follicle-Stimulating 
Hormone, HAV = Hepatitis A virus, HBc = Hepatitis B core antigen, HBsAg = Hepatitis B Surface Antigen,
HBV = Hepatitis B Virus, HCV = Hepatitis C Virus, HEV = Hepatitis E virus, HIV = Human Immunodeficiency Virus,
hsCRP = high sensitivity C-reactive protein, Ig = Immunoglobulin, MDRD = Modification of Diet In Renal Disease,
NK = Natural Killer Cells, PPD = Purified Protein Derivative, TSH = Thyroid Stimulating Hormone, VCA = viral capsid 
antigen. 
a
Calculated using the four-component MDRD equation (Levey 2006).
b
To be done only when specified in Table 1 and not as a standard laboratory evaluation. See Section 7.5.5.2
for details of flow cytometry assessments (safety and exploratory).
c
Urine samples will be collected using a clean catch method. If a female is actively menstruating, urine sample 
will be delayed and collected preferably within the visit window (but no later than 10 days from the visit). 
Microscopy will be performed at the central laboratory.
d
Performed only at Screening.
e
HIV testing is to be performed locally and is mandatory for participation in the study.
7.4.3.1.1
Immunological Assessments
Absolute values of and changes from Baseline in complement proteins (C3, C4) and anti-dsDNA 
antibodies may be predictive of disease development and reflective of disease activity and response 
to therapy in SLE (Bernatsky 2006, Reveille 2004). Total B cell counts and serum Ig levels may 
change given the mechanism of action of M2951 and are being collected as safety evaluations 
(see Table 1 and Table 2). These additional immunological assessments will be collected 
according to the SOA:
! Anti-dsDNA (at Screening, may be measured using 2 assays, 1 of which is a multiplex assay 
that includes anti-Ro and anti-RNP. Only anti-dsDNA is used to determine subject eligibility 
and will be reported to the sites.)
! Complement (C3 C4)
! ANA
! C-reactive protein
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7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Vital signs, including blood pressure (BP), pulse rate, respiratory rate, weight, and oral temperature 
will be assessed predose at all study visits (Table 1). Height will be measured at Screening only.
A semiautomated pulse rate and BP recording device with an appropriate cuff size will be utilized. 
Pulse rate and BP will be measured after 10 minutes rest in the semisupine position with the 
subject’s arm unconstrained by clothing or other material. The BP should be assessed on the same 
arm for each subject throughout the study.
7.4.4.2
Physical Examination
Physical examinations will be assessed as indicated in Table 1 and Table 2.
Physical examination includes assessment of the following: general appearance, skin, head and 
neck, mouth, lymph nodes, thyroid, abdomen, and nervous, musculoskeletal, cardiovascular, and 
respiratory systems. Physical examination findings during Screening before obtaining informed 
consent will be recorded as medical history events and new findings or worsening during the study
as AEs.
Abbreviated physical examination should always include assessment of head, ears, eyes, nose, 
throat, lungs, heart, abdomen, and extremities and other systems as required by symptoms.
Additional assessments (e.g., creatine phosphokinase, ECG, chest radiograph) should be 
performed as needed to fully obtain information needed for the BILAG 2004 and/or SLEDAI-2K
assessments (see Sections 7.3.1 and 7.3.3) if scheduled, as well as to fully evaluate any subject 
complaints or AEs.
7.4.4.3
Resting 12-lead Electrocardiogram and Chest X-ray
A 12-lead ECG will be performed as indicated in Table 1 and Table 2. The 12-lead ECG recordings 
will be obtained after 10 minutes of rest in a semisupine position.
The following ECG parameters will be obtained directly from the computerized 12-lead ECG 
recordings: rhythm, ventricular rate, PR interval, QRS duration, and QT interval. The corrected 
QT interval will be calculated using Fridericia’s formula. The overall evaluation 
(normal/abnormal) will be recorded on the eCRF, and if abnormal, the specific abnormality will 
be recorded. Abnormal evaluations will be judged as clinically significant or not clinically 
significant by the Investigator.
The printout of the ECG is to be signed, dated, and filed in the Investigator’s Site File along with 
a signed and dated copy (if the printouts are not on archive-quality paper). In addition, ECGs will 
also be stored digitally by the Sponsor.
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Posteroanterior CXRs will be performed during Screening according to local standard practice. 
Subjects who had a CXR performed for clinical reasons within three months prior to the 
Screening Visit do not need to have the CXR repeated. The CXR should show no evidence of 
active infective process, or any other clinically significant abnormalities. The overall evaluation 
(normal/abnormal) will be recorded on the eCRF, and if abnormal, the specific abnormality will 
be recorded. Abnormal evaluations will be judged as clinically significant or not clinically 
significant by the Investigator.
The 12-lead ECG and CXR will be performed and read locally.
7.4.4.4
Review of Concomitant Medications and Procedures
Data concerning concomitant medications and procedures will be collected throughout the study. 
These data will be obtained at scheduled and unscheduled study visits, based on information 
spontaneously provided by the subject and through questioning of the subject.
Data concerning concomitant medications and procedures may also be obtained from the subject 
diary, but information thus collected must be reviewed and assessed medically before it is 
transcribed to the eCRF.
7.4.4.5
Unscheduled Visits
Unscheduled visits may occur at any time during the study in case of suspected flares or AEs 
(assessments to be performed according to the Investigator’s judgment).
7.4.5
Columbia-Suicide Severity Rating Scale
The C-SSRS will be used for prospective suicidality assessment. The structured interview prompts 
recollection of suicidal ideation, including the intensity of the ideation, behavior and attempts with 
actual/potential lethality.
The scale will be administered by the Treating Investigator or a qualified designee at Screening to 
identify eligible subjects. It will be self-administered at other time points during the study as per 
Table 1 and Table 2, using a validated, electronic, self-rated version of the C-SSRS (eC-SSRS) 
(Mundt 2010, Mundt 2013). 
Subjects who answer “yes” to any suicidal behavior questions or to suicidal ideation questions 
4 or 5 on the C-SSRS during the study should be referred for appropriate psychiatric care and the 
Medical Monitor notified.
Please note that assessing the risk of suicide is a difficult and complex task when applied to the 
individual subject. No single clinical scale can replace a thorough medical examination and suicide 
risk assessment. Ultimately, the determination of the presence of suicidality depends on clinical 
judgment.
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7.5
Exploratory Assessments
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8
Statistics
8.1
Sample Size
A sample size of 103 evaluable subjects per group provides 80% power at the α = 0.025 one-sided 
significance level to detect 
! an absolute improvement of 20% in Week 52 SRI-4 response proportion for M2951-treated 
subjects relative to placebo-exposed subjects, among subjects with SLEDAI-2K total score ≥6
at Screening, assuming a placebo response proportion of 40%,
or
! an absolute improvement of 25% in Week 52 SRI-6 response proportion for M2951-treated 
subjects relative to placebo-exposed subjects, among subjects with SLEDAI-2K total 
score ≥10 at Screening (i.e., HDA), assuming a placebo response proportion of 30%,
assuming that each co-primary endpoint is tested via a chi-squared test of the odds ratio (OR) for 
treatment effect at the 0.0125 one-sided level, and assuming that approximately 50% of 
randomized subjects are in the HDA group. If the absolute improvement in Week 52 SRI-6
response proportion in HDA subjects is only 20%, the power is 76%. Approximately 108 subjects 
will be randomized per treatment group to protect against a loss of information due to drop-out 
(for reasons other than efficacy/safety) of 5% over 52 weeks. Given the randomization ratio 
1:1:1:1, the total sample size required for the primary analysis is planned to be 432 subjects.
Approximately 432 subjects will enter the main study. Assuming an 80% rate of continuation to 
LTE, approximately 346 subjects are expected to enter the LTE Period.
The Japan cohort size was determined to provide a reliable evaluation of consistency in the
Week 52 SRI-4 response proportion between the non-Japan and Japan regions. Assuming that:
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(i)
the Week 52 SRI-4 response proportion in the placebo group is 0.40 for both the 
non-Japan and Japan regions, 
(ii)
the Week 52 SRI-4 response proportion due to each of the 3 M2951 dose groups is 
0.60 for both regions, so that the true underlying effect size is 0.20 for both regions, 
(iii)
a total evaluable sample size of 412 (i.e., 309:103 randomization for M2951: placebo) 
is involved in analysis of the two regions, 
and applying “Method 2” from the PMDA Guidance, 32 evaluable subjects in the Japan cohort are 
required so that both observed region-specific effect sizes exceed 0.04 with probability of 80%.  
Taking into account a loss of information due to 5% drop-out at Week 52, for reasons unrelated to 
efficacy or safety, the total number of Japan subjects to be randomized is 36, or 8.3% of the total 
planned enrollment of 432.
If enrollment of Japanese subjects is slow, then the entire Japanese cohort will not be part of the 
primary analysis cohort. A maximum of n = 36 Japanese subjects will be analyzed for Week 52 
SRI-4 at a time point after the primary analysis for the purpose of assessing consistency.  
Therefore, the total enrollment will range from n = 432 to 468 , where 468 = 432 + 36 is the number 
enrolled if none of the 36 Japanese subjects enroll in time to be included in the primary analysis. 
The number of subjects enrolled per group will range from n = 108 to 117.
8.2
Randomization
Eligible subjects will be randomized into either one of three M2951 groups 
 or the placebo group in a ratio of 1:1:1:1, stratified 
according to race (Black versus non-Black), region (US and Western Europe, Japan, and RoW) 
and Screening disease activity (SLEDAI-2K total score < 10 versus ≥10 at Screening). A 
randomized allocation schedule for IMP assignment will be generated within the appropriate group 
of 
, by an individual who is not on the study team. Randomization will occur using the 
IWRS as described in Section 6.3 upon completion of the Screening/Baseline procedures and 
determination of subject eligibility.
To ensure enrollment of an adequate number of subjects with HDA, recruitment of subjects 
without HDA may be capped, depending on enrollment rates observed during the study of subjects 
with and without HDA.
8.3
Endpoints
8.3.1
Primary Endpoints of Efficacy and Safety
The co-primary efficacy endpoints are SRI response at Week 52: SRI-4 in all subjects and SRI-6
in a HDA subgroup. The SRI-4 response, a measure of reduced SLE disease activity, is defined by 
meeting all of the following conditions compared to Baseline:
1. ≥4 point reduction in SLEDAI-2K total score.
2. No significant worsening in PGA score (< 0.3 increase assuming the PGA score is on a 
0-3 scale).
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3. No new BILAG A organ domain scores and ≤1 new BILAG B organ domain score 
compared to Day 1 using BILAG 2004.
4. No discontinuation of investigational product and no institution of protocol-prohibited 
medication/treatment
The SRI-6 response is defined similarly to SRI-4, based on a ≥6 point reduction in SLEDAI-2K 
total score. For SRI response, Baseline is defined as Day 1 predose.
In this study, safety endpoints are considered to be primary endpoints. The safety endpoints are:
! Nature, severity, and incidence of AEs, SAEs, vital signs, ECGs, absolute values and change 
from Baseline in serum total Ig levels (IgG, IgA, IgM) and total B cell counts, and clinical 
laboratory parameters.
8.3.2
Secondary Endpoints
The key secondary endpoints are:
! Time to first severe flare, where a severe flare is defined as at least one BILAG A score in any 
organ system due to items that are new or worse, compared to the BILAG evaluation at the 
previous visit, during the Treatment Period
! SRI-4 response at Week 52, in the serologically active subgroup, which is defined as subjects 
with positive anti-dsDNA and/or low complement levels.
Other Secondary endpoints are:
! SRI-6 response at Week 52, in the serologically active subgroup, which is defined as subjects 
with positive anti-dsDNA and/or low complement levels.
! SRI-4 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams 
prednisone-equivalent per day or less (≤7.5 mg/day) and less than or equal to (≤) Day 1 dose
during Week 41 Through Week 52, in all subjects.
! SRI-6 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams 
prednisone-equivalent per day or less (≤7.5 mg/day) and less than or equal to (≤) Day 1 dose 
during Week 41 Through Week 52, in the HDA subgroup, defined as SLEDAI-2K ≥10 at 
Screening.
! SRI-4 Response at Week 52 with a Sustained Reduction of OCS Dose to 7.5 milligrams 
prednisone-equivalent per day or less (≤7.5 mg/day) and less than or equal to (≤) Day 1 dose 
during Week 41 Through Week 52, in the serologically active subgroup, which is defined as 
subjects with positive anti-dsDNA and/or low complement levels.
! Time to first flare, flare-free status at Week 52, and annualized flare rate, during the 
Treatment Period, will be analyzed separately, each assessed with flare defined as:
! BILAG A Severe flare 
! BILAG A or 2B Moderate to Severe flare 
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! SFI Severe flare 
! Disease activity over time, during the Treatment Period, as measured by:
! Low disease activity status, defined by SLEDAI-2K ≤ 2, at Week 52
! Low disease activity status, defined by clinical SLEDAI-2K (SLEDAI 2K excluding anti-
dsDNA and low complement parameters) ≤ 2, at Week 52
! Lupus low disease activity state (LLDAS), defined as meeting all of the following (Franklyn 
2016):
-
SLEDAI-2K ≤ 4
-
No activity in any major organ systems (renal, central nervous system, 
cardiopulmonary, vasculitis, fever)
-
No new features of disease activity compared with the previous assessment
-
Prednisone-equivalent ≤ 7.5 mg/day
-
Unchanged background immunosuppressive therapy
! Change from Baseline in SLEDAI-2K score by visit
! Change from Baseline in CLASI-A by visit
! BICLA response by visit
! Change from Baseline in BILAG-2004 by visit
! Change from Baseline in PGA by visit
! HRQoL over time, during the Treatment Period, as measured by:
! Change from Baseline in SF-36v2 PCS and MCS scores (and their components) by visit
! Change from Baseline in EQ-5D-5L score by visit
! Change from Baseline in LupusQoL score by visit
! PGIC score by visit
! Change from Baseline FACIT-Fatigue score by visit
! Corticosteroid usage over time, during the Treatment Period, as measured by:
! Reduction from Baseline in prednisone-equivalent CS dose by ≥25% to a dose 
of ≤7.5 mg/day, with no BILAG A or 2B flare in disease activity (at that visit)
! Change from Baseline to Week 52 in prednisone-equivalent CS daily dose
! Reduction from Baseline to Week 52 in prednisone-equivalent CS daily dose of zero
to < 25%, 25% to 50%, > 50%, or an increase
! Cumulative prednisone-equivalent CS dose from Baseline until completion of the Treatment 
Period
! Clinically meaningful reduction in CS dose from Baseline, defined by:
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o
A reduction of daily prednisone-equivalent CS dose ≥25% to a dose 
of ≤7.5 mg/day by Week 40 and sustained through Week 52
AND
o
No new BILAG A organ domain scores and no more than one new BILAG B organ 
domain score during Weeks 40 through 52.
8.3.3
Exploratory Endpoints
Exploratory endpoints are:
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8.3.4
Endpoints for Long-Term Extension Period
LTE Safety:
! Nature, severity, and incidence of AEs, SAEs, vital signs, ECGs, absolute values and change 
from Baseline in serum total Ig levels (IgG, IgA, IgM) and total B cell counts, and clinical 
laboratory parameters.
LTE Efficacy:
! The following LTE efficacy endpoints will be analyzed at Week 24, Week 52, and Week 104:
o
Changes over time in SRI response
o
Changes over time in Low Disease Activity status (LLDAS, SLEDAI-2K≤2, 
clinical SLEDAI-2K≤2).
o
Changes over time in CLASI-A, CLASI-D, and SLICC/ACR Damage Index organ 
damage scores
o
Changes over time in disease activity as measured by the BILAG, SLEDAI-2K, 
and PGA
o
Change over time in prednisone-equivalent CS dose
o
Changes over time in HRQoL
o
Changes over time in autoantibodies and complement levels
! Changes in HRU by visit, including but not limited to doctor/home/emergency visits, 
hospitalizations, paid assistance, and missed work
! Time to first flare; flare-free status at Weeks 24, 52, and 104; and annualized flare rate, will be 
analyzed separately, each assessed with flare defined as:
o
BILAG A Severe flare
o
BILAG A or 2B Moderate to Severe flare
o
SLEDAI Flare Index (SFI) Severe flare.
8.4
Analysis Sets
The statistical analyses described in this protocol will be based on the analysis sets defined below:
Enrolled
The Enrolled analysis set will include all subjects who sign the ICF.
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Intent-to-Treat
The Intent-to-Treat (ITT) Analysis Set will include all randomized subjects. Subjects will be 
analyzed according to randomized treatment.
Modified ITT
The modified Intent-to-Treat (mITT) Analysis Set will include all randomized subjects who have 
received at least one dose of IMP (M2951 or placebo), and have at least one Baseline and one 
post-Baseline disease assessment. Subjects will be analyzed according to randomized treatment.
Per-Protocol
The Per-Protocol (PP) Analysis Set will include all randomized and treated subjects who do not 
have any clinically important protocol deviations. Details of the criteria for exclusion from the PP 
analysis set will be provided in the IAP, including exclusion of subjects who take prohibited 
medications. Subjects will be analyzed according to randomized treatment.
Safety
The Safety Analysis Set will include all randomized subjects who receive at least one dose of IMP, 
and will be used for the evaluation of safety endpoints. Subjects will be analyzed according to the 
actual treatment they receive.
Long Term Extension Analysis Set
The LTE Analysis Set consists of all subjects who receive at least one dose of M2951 during the 
LTE.
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8.4.1
Subgroups
Descriptive analyses of efficacy will be performed for the following subgroups:
! Race (Black, non-Black) (see Section 6.3 for definitions of Race used in this study)
! Ethnicity (Japanese, non-Japanese) (Hispanic/Latino, non-Hispanic/Latino)
! Severity of disease at Screening (severe, mild/moderate). Severe is defined as at least one 
BILAG A; mild/moderate is defined as at least one BILAG B and no BILAG A. Analyses of 
subgroups defined in terms of SLEDAI-2K total score at Screening (< 10 versus ≥10) will also 
be performed.
! Serological activity status (positive versus negative). Serologically active is defined as positive 
anti-dsDNA and/or low complement levels.
! Age (< 65, ≥65).
! Gender (male, female).
! Region (US and Western Europe, Japan, and RoW).
! Subjects on background therapy that includes mycophenolate versus subjects not taking 
mycophenolate.
8.5
Description of Statistical Analyses
8.5.1
General Considerations
A general description of the statistical methods to be used to analyze the efficacy and safety data 
is outlined below. Prior to locking the database, a detailed IAP will be developed.
Continuous variables will be summarized descriptively using the number of observations, mean, 
SD, median, first quartile (Q1), third quartile (Q3), minimum, and maximum. Categorical variables 
will be summarized using frequency counts and percentages. The denominator for the percentages 
will be the total number of subjects in the treatment group and analysis set being presented, unless 
otherwise specified (e.g., on some occasions, percentages may be calculated based on the total 
number of subjects with available data at a particular time point).
Tests of treatment effect on each of the two co-primary efficacy endpoints will be conducted at a 
one-sided α-level of 0.0125, to maintain a study-wide one-sided α-level of 0.025. P-values and the 
two-sided CIs (97.5% or 95% as appropriate) will be presented where applicable. Actual p-values 
will be interpreted based on the multiple testing strategy, as specified in this protocol, and detailed 
further in the IAP. Treatment comparisons for each data type are described in later sections.
Alternative or additional statistical methods may be used as appropriate as outlined in the IAP.
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Data from all investigative sites will be pooled for all planned analyses. Analysis of individual site 
findings or country findings will be considered if necessary. For those measures that are analyzed 
using change from Baseline scores, observed scores may also be presented descriptively.
For SRI-4 or SRI-6 response at Week 52 (Week 24), a subject experiencing flare or CS dose 
increase during Weeks 41 to 52 (Weeks 17 to 24), or a subject with a missing response at Week 52
(Week 24), will be considered a non-responder. Four sensitivity analyses of the primary analysis 
are planned: (1) non-responder imputation for subjects discontinuing treatment for reasons due to 
efficacy/safety, with available observations used (in MMRM or multiple imputation) for subjects 
discontinuing treatment for reasons unrelated to efficacy/safety or completing treatment with 
missing response at Week 52, (2) unadjusted analysis, (3) completer analysis, and (4) per-protocol
analysis (i.e., excluding subjects with clinically important protocol violations). Additional 
procedures for handling missing, unused, or spurious data, and sensitivity analyses exploring the 
impact of missing data will be described in the IAP. 
The IAP will provide definitions of Baseline measurement as needed for change from Baseline
endpoints.
Treatment compliance will be assessed in terms of the percentage of the actual doses taken relative 
to the number of scheduled doses and summarized by descriptive statistics.
All subjects will be included in individual subject data listings. 
Any changes in the data analysis methods described in the protocol will require an amendment 
only if the change affects a principal feature of the protocol. Any other changes to the planned data 
analysis that does not require a protocol amendment will be described in the IAP and the CSR. 
8.5.2
Analysis of Primary Endpoints
The primary analysis of SRI-4 response at Week 52 among all subjects in the primary analysis 
cohort, and SRI-6 response at Week 52 among HDA subjects in the primary analysis cohort, will 
be an estimate of OR, together with associated two-sided 95% CI and p-value (testing null 
hypothesis H0: OR = 1.0), comparing each M2951 dose group to placebo, based on a logistic 
model for the odds of a given SRI response in the appropriate population, with M2951 dose group 
or placebo group as a factor and adjustment for covariates based on randomization strata.
Additional covariates may be included in the model as specified in the IAP. In the primary analysis 
of SRI-4 or SRI-6 response at Week 52, a subject experiencing flare or CS dose increase during 
Weeks 41 to 52, or a subject with a missing response at Week 52, will be considered a non-
responder.
The primary analysis of the co-primary efficacy endpoints will be based on the mITT analysis set, 
with supportive analyses based on the ITT and PP analysis sets, if the size of these analysis sets 
differ substantially (> 10%) from the size of the mITT analysis set. 
The Family-Wise type 1 error rate (FWER) due to the co-primary endpoints and multiple M2951 
dose group comparisons versus placebo will be controlled at the two-sided α = 0.05 level via a tree 
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gatekeeping procedure. The four hypotheses associated with the comparisons involving the co-
primary endpoints and the two highest dose groups will form the first family of hypotheses in the 
tree.  This family will be tested via the truncated Hochberg procedure, with truncation fraction pre-
specified in the IAP. The multiple-testing procedure for the remainder of the tree, including the 
hypotheses associated with the comparisons involving the co-primary endpoints and the lowest 
dose group will be specified in the IAP.
A test for monotonic dose-response relationship, between ordered M2951 dose and SRI-4 response 
OR relative to placebo, will be performed as a supportive analysis. Similarly, a test for monotonic 
dose-response relationship, between ordered M2951 dose and SRI-6 response OR relative to 
placebo, will be performed as a supportive analysis in the HDA subgroup.
Descriptive statistics for SRI-4 response, and for SRI-6 response in the HDA subgroup, will be 
provided for each treatment group by time point.
Safety endpoints are considered to be primary endpoints in this study. Analysis of safety data is 
described in Section 8.5.4.
8.5.3
Analysis of Secondary Endpoints
The analysis of secondary endpoints will be based on the mITT analysis set. Descriptive statistics 
for secondary endpoints will be provided by treatment group and time point. 
The multiple-comparison procedure for testing the key secondary efficacy endpoints will be 
provided in the IAP. Other secondary efficacy endpoints will be analyzed for 
. 
Key Secondary Endpoints
Time to first severe (BILAG A) flare during the Treatment Period in all subjects will be compared 
between M2951 and placebo via a stratified log rank test. The adjusted hazard ratio comparing 
M2951 to placebo will be estimated (together with 95% CI) via a Cox regression model, with 
treatment group as a factor, and controlling for covariates defining randomization strata. A subject 
who discontinues treatment or completes treatment without experiencing flare will have his/her 
time to flare censored at the last time point at which flare could be assessed. A test for trend in 
dose-response, using the same Cox model, will be reported as a supportive analysis.
Kaplan-Meier estimates of probability of surviving free of severe (BILAG A) flare as a function 
of time on treatment will be provided for each treatment group.
The analysis of SRI-4 response at Week 52 among serologically active subjects will be an estimate 
of OR, together with associated 95% CI and p-value, comparing each M2951 dose group to 
placebo, based on a logistic model for the odds of SRI-4 response in the serologically active
population, with M2951 dose group or placebo group as a factor and adjustment for covariates 
based on randomization strata. A test for trend in dose-response, using the same logistic model, 
will be reported as a supportive analysis.
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Descriptive statistics for SRI-4 response in the serologically active subgroup, will be provided for 
each treatment group by time point.
Other Secondary Endpoints
In the analysis of other secondary efficacy endpoints described in Section 8.3.2, binary endpoints 
will be modeled via logistic regression, time to event endpoints will be modeled via Cox regression
and tested via stratified log rank test, continuous endpoints measured longitudinally will be 
analyzed using Mixed-effect Model for Repeated Measures (MMRM), and count endpoints (i.e.,
annualized flare rate) will be modeled via negative binomial regression, with treatment group as a 
factor, and adjusting for covariates defining randomization strata. Analysis of annualized flare rate 
will use the log of observation time (in years) as an offset in the model. Change in a binary endpoint 
between two time points will be analyzed via McNemar’s test. The effect of treatment on change 
in a binary endpoint will be analyzed via logistic regression, with treatment group, time point, and 
interaction as predictors, and adjusting for covariates defining randomization strata. All tests of 
efficacy will be conducted at a two-sided α level of 0.05, with p-values considered nominal unless 
generated as part of the tree gatekeeping multiple testing strategy as described in the IAP. P-values 
and the 95% CIs will be presented where applicable.
Change in SF-36v2 PCS and MCS scores (and their components) over time, change in LupusQoL 
score over time, change in FACIT-Fatigue score over time, and change in EQ-5D-5L index over 
time, will be compared between M2951 treatment groups and placebo based on change from 
Baseline using MMRM, with treatment group as a factor, and adjustment for Baseline and 
covariates defining randomization strata.
The PGIC score will be analyzed based on absolute score, using MMRM to account for subjects 
with missing data, with treatment group as a factor, and adjustment for covariates defining 
randomization strata.
In the analysis of each secondary efficacy endpoint, other covariates may be included in the model, 
as appropriate.
8.5.4
Analysis of Safety 
Adverse events will be summarized by treatment group, severity, and relationship to IMP. Serious 
AEs, AEs leading to treatment discontinuation, and AEs leading to treatment withdrawal will be 
summarized by treatment group.
Adverse events will be coded according to the medical dictionary for regulatory activities 
(MedDRA). The severity of AEs will be graded using the NCI-CTCAE v4.03 grading scale
(Hahn 2012). 
The number and percentage of subjects experiencing one or more treatment-emergent AEs 
(TEAEs) will be summarized according to the MedDRA system organ classes and preferred terms 
by treatment group, relationship to IMP, and severity.
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Summary statistics will be used to present observed values and changes from Baseline in 
continuous laboratory, vital sign, and ECG data. Shift tables will be used to present changes in 
categorical laboratory parameters. Figures will be generated as needed to assist safety evaluation. 
Values for all safety variables will be listed by subject and time point.
8.5.5
Analysis of Exploratory Endpoints
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8.5.6
Analysis of LTE Endpoints
Efficacy and HRQoL data collected during the LTE Period will be summarized. Details will be 
provided in the IAP.
Safety data collected during the LTE Period will be analyzed as described in Section 8.5.4.
8.6
Interim and Additional Planned Analyses
Interim Analysis
There may be an IA for futility based on the highest dose of M2951, triggered when 100% of 
subjects enrolled in the primary analysis cohort reach Week 24 of treatment, or prematurely 
discontinue from treatment prior to Week 24. If enrollment is sufficiently slow, consideration will 
be given to triggering the IA at an earlier time point, when the first 50% of subjects enrolled in the 
primary analysis cohort reach Week 24 of treatment, or prematurely discontinue from treatment
prior to Week 24. Pharmacokinetic analysis will not be included in the IA.
The difference between Week 24 SRI-4 response proportion in all subjects in the primary analysis
cohort, comparing the highest dose of M2951 to placebo, will be estimated, together with a 
two-sided 97.5% confidence interval. Similarly, the difference between Week 24 SRI-6 response 
proportion in HDA subjects in the primary analysis cohort, comparing the highest dose of M2951
to placebo, will be estimated, together with a two-sided 97.5% confidence interval. If the response 
proportion difference for both co-primary endpoints is sufficiently low, as defined in the IAP, 
consideration will be given to termination of the study, in which case all subjects will be 
discontinued from IMP and scheduled for a four week Safety Follow-Up Visit/End of Study Visit.
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Descriptive statistics for the Week 24 SRI-4 response endpoint in all subjects in the primary 
analysis cohort, and for the Week 24 SRI-6 response endpoint in HDA subjects in the primary 
analysis cohort, will be presented by treatment group. A point estimate of the OR for the effect of 
treatment on Week 24 SRI-4 response, comparing each M2951 dose group to the placebo group, 
will be provided, together with a two-sided 97.5% CI. Similarly, a point estimate of the OR for the 
effect of treatment on Week 24 SRI-6 response, comparing each M2951 dose group to the placebo 
group among HDA subjects, will be provided, together with a two-sided 97.5% CI.
A test for a monotonic relationship, between ordered M2951 dose and Week 24 SRI-4 response 
OR, relative to placebo, among all subjects, will be performed as a supportive analysis. Similarly, 
a test for a monotonic relationship, between ordered M2951 dose and Week 24 SRI-6 response 
OR, relative to placebo, among HDA subjects, will be performed as a supportive analysis.
Primary Analysis
The primary analysis will occur only when primary analysis trigger event (Section 5.1) has 
occurred, the protocol violations are determined, and the database is locked.
Consistency Analysis
A separate analysis of treatment effect consistency between the non-Japan and Japan regions, may
be performed if the Japan cohort enrollment is too slow for the consistency evaluation to take place 
at the time of the primary analysis. This analysis will occur only when the consistency analysis 
trigger event (Section 5.1) has occurred, the protocol violations are determined, and the database 
is locked.
Final Analysis
The final analysis will occur only when the last subject completes all study parts (including the 
LTE and Safety Follow-Up Visits) or discontinues prematurely, the protocol violations are 
determined, and the database is locked.
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the study at the site and will ensure that the study
is performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, as well as with the ICH Note for Guidance on GCP (ICH Topic E6), and any other 
applicable regulations. The Investigator must ensure that only subjects who have given informed 
consent are included in the study. For Japan only - the Investigator is also responsible for the 
standards stipulated in Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Act 
in Japan; and “Ministerial Ordinance on Good Clinical Practice for Drugs” (GCP) in Japan.
According to United States Code of Federal Regulations Part 54.2 (e), for studies conducted in any 
country that could result in a product submission to the United States Food and Drug 
Administration for marketing approval and could contribute significantly to the demonstration of 
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efficacy and safety of an IMP (which are considered “covered clinical trials” by the FDA), the 
Investigator and all subinvestigators are obliged to disclose any financial interest which they, their 
spouses or their dependent children may have in the Sponsor or the Sponsor’s product under study. 
This information is required during the study and for 12 months following completion of the study.
This study is being conducted under a US Investigational New Drug (IND), therefore all 
investigational sites must complete an FDA Form 1572. 
9.2
Subject Information and Informed Consent
An unconditional prerequisite for a subject’s participation in the study is his/her written informed 
consent. The subject’s written informed consent to participate in the study must be given before 
any study-related activities are carried out. In Japan when a subject is < 20 years of age, the written 
informed consent must be obtained from the subject’s parent or guardian in addition to the 
subject’s voluntary written consent. The ICF must be approved by the IEC/IRB and regulatory 
authorities (in some countries) before it is provided to the subject. 
Adequate information must therefore be given to the subject by the Investigator before informed 
consent is obtained (a person designated by the Investigator may give the information, if permitted 
by local regulations). A subject information sheet in the local language and prepared in accordance 
with the Note for Guidance on GCP (ICH Topic E6, 1996) will be provided by the Sponsor for the 
purpose of obtaining informed consent. In Japan, a subject information sheet in the local language 
and prepared in accordance with Japan’s GCP and the Note for Guidance on GCP (ICH Topic E6, 
1996) will be provided by the Sponsor for the purpose of obtaining informed consent. In addition 
to providing this written information to a potential subject, the Investigator or his/her designate 
will inform the subject verbally of all pertinent aspects of the study, including potential 
 testing 
(see Section 9.3). The language used in doing so must be chosen so that the information can be 
fully and readily understood by lay persons. 
Depending on national regulations, a person other than the Investigator may inform the subject 
and sign the ICF, as above.
Where the information is provided by the Investigator, the ICF must be signed and personally 
dated by the subject and the Investigator. In Japan, where the information is provided by the 
Investigator, the ICF must be signed and personally dated by the subject and/or the subject’s legal 
representative as applicable, and the Investigator.
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived by the Investigator so that the forms can be retrieved at any time for 
monitoring, auditing and inspection purposes. A copy of the signed and dated information sheet 
and ICF should be provided to the subject prior to participation.
Whenever important new information becomes available that may be relevant to informed consent, 
the Investigator will revise the subject information sheet and any other written information to be
provided to the subjects and submit them to the IEC/IRB for review and favorable opinion. Using 
the approved revised subject information sheet and other written information, The Investigator will 
explain the changes to the previous version to each study subject and obtain new written consent 
for continued participation in the study. In Japan, the Investigator will explain the changes to the 
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previous version to each study subject and/or the subject’s legal representative as applicable and 
obtain new written consent for continued participation in the study. The subject will be given 
sufficient time to read the information and the opportunity to ask questions and to request 
additional information and clarification about the changes.
 
9.3
Subject Identification and Privacy
A unique subject number will be assigned to each subject at inclusion, immediately after informed 
consent has been obtained. This number will serve as the subject’s identifier in the study as well 
as in the clinical trial database.
The subject’s data collected in the study will be stored under this number. Only the Investigator
will be able to link the subject’s study data to the subject via an identification list kept at the site. 
The subject’s original medical data that are reviewed at the site during source data verification by 
the monitor, audits and Health Authority inspections will be kept strictly confidential.
Data protection and privacy regulations will be observed in capturing, forwarding, processing, and 
storing subject data. Subjects will be informed accordingly, and will be requested to give their 
consent on data handling procedures in accordance with national regulations.
Confidentiality of information relating to the 
sample testing will be protected to the extent 
permitted by law. To protect against the risk of loss of confidentiality, all DNA samples will be 
marked with a code number only and will not be identified by subject name. Upon receipt at the 
analytical laboratory, the samples are recoded with a specific code 
 that is different from 
the subject code number. The data generated with these samples will also be tracked with the 
. Only authorized personnel will have access to this code and to the key linking both codes.
The key will be maintained in a restricted location. The results obtained from the 
 samples in 
this study are for research purposes only. The results of the tests conducted with the 
samples 
will not be made available to the subject, members of their family, their personal physician, or 
other third parties, except as specified as follows.
Unless required by law or regulatory authorities for the purpose of verifying information obtained 
from this study, only the Sponsor’s authorized personnel and agents will have access to the 
confidential genetic data. The results and other information from the 
 tests study may be 
submitted to the regulatory authorities and governmental agencies in countries where the IMP may 
be considered for approval; however, the subject will be identified by subject and study number 
only. The subject will not be identified in any reports or publications resulting from this study.
By default, results from genotyping will only be accessible to the Sponsor’s authorized personnel 
and agents and be handled without disclosure of subject identification. However, upon written 
request by the subject, the results from genotyping will be made available to the subject, if 
permitted by local law and regulations. If required by law or regulatory authorities for the purpose 
of verifying information obtained from this study, only the Sponsor’s authorized personnel and 
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9.4
Emergency Medical Support and Subject Card
Subjects enrolled in this clinical study will be provided with Emergency Medical Support cards 
during their study participation, which will be furnished by the Sponsor. The Emergency Medical 
Support card is based on the need to provide clinical study subjects with a way of identifying 
themselves as participating in a clinical study, and subsequently to give health care providers 
access to the information about this participation that may be needed to determine the course of 
the subject’s medical treatment.
This service is designed to provide information to health care providers who are not part of the 
clinical study; and this may include the possibility of emergency unblinding if needed, in case of 
blinded studies.
Clinical study Investigators, who are already aware of the CTP and treatment, have other means 
of accessing the necessary medical information for the management of emergencies occurring in 
their subjects.
The first point of contact for all emergencies will be the clinical study Investigator caring for the 
affected subject. The Investigator agrees to provide his or her emergency contact information on 
the card for this purpose. If the Investigator is available when an event occurs, she or he will answer 
any questions. Any subsequent action (e.g., unblinding) will follow the standard processes 
established for the Investigators.
In cases where the Investigator is not available, Merck Serono/EMD Serono provides the 
appropriate means to contact a CRO/Sponsor physician. This includes the provision of a 24 hour 
contact number at a call center, whereby the health care providers will be given access to the 
appropriate CRO/Sponsor physician. The CRO/Sponsor physician will assist the health care 
provider in medical emergencies by providing information relating to the study and IMP. The 
CRO/Sponsor physician is not responsible or required for potential emergency unblinding, but 
should be notified as per Section 6.11 if emergency unblinding is to or has occurred, and may 
provide information if requested regarding the study and IMP.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating to the study. Insurance 
conditions shall meet good local standards, as applicable.
In Japan, the Sponsor is entirely responsible for AEs that are associated with this study and impair 
the health of the subjects, except for AEs caused by an intentional and/or significant deviation on 
the part of the Investigator, the study site, and/or the subject. The Sponsor will provide insurance 
to fulfill this responsibility.
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9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the study at a given site, the CTP will be submitted together with its 
associated documents to the responsible IEC/IRB for its favorable opinion/approval. The written 
favorable opinion/approval of the IEC/IRB will be filed in the Investigator Site File, and a copy 
will be filed in the Trial Master File.
The study must not start at a site before the Sponsor has obtained written confirmation of favorable 
opinion/approval from the concerned IEC/IRB. The IEC/IRB will be asked to provide 
documentation of the date of the meeting at which the favorable opinion/approval was given, and 
of the members and voting members present at the meeting. Written evidence of favorable 
opinion/approval that clearly identifies the study, the CTP version and the Subject Information and 
ICF version reviewed should be provided. Where possible, copies of the meeting minutes should 
be obtained.
Amendments to the clinical study will also be submitted to the concerned IEC/IRB, before 
implementation in case of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC/IRB during the course of the study in accordance with national regulations 
and requirements.
In Japan, the person installing an IEC/IRB must retain all records, including documents that relate 
to the clinical study for the required period in accordance with Japan’s GCP.
9.7
Health Authorities
The CTP and any applicable documentation (eg, IMP Dossier, Subject Information and ICF) will 
be submitted or notified to the Health Authorities in accordance with all local and national 
regulations for each site.
10
Trial Management
10.1
Case Report Form Handling
Refer to the Manual of Procedures for eCRF handling guidelines.
The main purpose of the eCRF is to obtain data required by the CTP in a complete, accurate, 
legible and timely. The data in the eCRF should be consistent with the relevant source documents.
The Investigator or designee will be responsible for entering study data in a timely manner in the 
eCRF provided by the CRO’s Data Management Group and follow the data standards of the 
Sponsor. It is the Investigator’s responsibility to ensure the accuracy of the data entered in the 
eCRFs. For subject-reported outcome data such as QoL and pain assessments, ePRO may be used.
The data will be entered in to a validated database (InForm version 5.5). The CRO’s Data 
Management Group will be responsible for data processing, in accordance with data management 
procedures agreed upon between the Sponsor and CRO. Database lock will occur once quality 
control procedure, and quality assurance procedures (if applicable) have been completed. Portable 
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document format files of the eCRFs will be provided to the Investigators at the completion of the 
study.
10.2
Source Data and Subject Files
The Investigator (or in Japan the head of study site) must keep a subject file (medical file, original 
medical records) on paper or electronically for every subject included in the study. This file will 
contain the available demographic and medical information for the subject, and should be as 
complete as possible. In particular, the following data should be available in this file: 
! Subject’s full name,
! Date of birth,
! Sex,
! Height,
! Weight,
! Race (as self-identified, in jurisdictions where permissible),
! Medical history and concomitant diseases,
! Prior and concomitant therapies (including changes during the study),
! Trial identification,
! Date of subject’s inclusion into the study (i.e., date of giving informed consent),
! Subject number in the study,
! Dates of the subject’s visits to the site,
! Any medical examinations and clinical findings predefined in the CTP,
! All AEs observed in the subject,
! Date of subject’s end of study, and
! Date of and reason for early withdrawal of the subject from the study or from IMP, if applicable.
It must be possible to identify each subject by using this subject file.
Additionally, any other documents containing source data must be filed. This includes original 
printouts of data recorded or generated by automated instruments, ECG recordings, and laboratory 
value listings. Such documents must bear at least the subject number and the date when the 
procedure was performed. Information should be printed by the instrument used to perform the 
assessment or measurement, if possible. Information that cannot be printed by an automated
instrument will be entered manually. Medical evaluation of such records should be documented as 
necessary and the documentation signed and dated by the Investigator.
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10.3
Investigator Site File and Archiving
Upon initiation of the study, the Investigator will be provided with an Investigator Site File 
containing all necessary study documents, which will be completed throughout the study and 
updated as necessary. The file must be available for review by the Monitor, during Sponsor audits
and for inspection by Health Authorities during and after the study, and must be safely archived 
for at least 15 years (or longer, per local requirements or as otherwise notified by the Sponsor) 
after the end of the study. The documents to be archived include the Subject Identification List and 
the signed subject Informed Consent Forms. If archiving of the Investigator Site File is no longer 
possible at the site, the Investigator must notify the Sponsor/designee.
All original subject files (medical records) must be stored at the site (hospital, research institute, 
or practice) for the longest possible time permitted by GCP the applicable regulations, and/or as 
per ICH GCP guidelines, whichever is longer. In any case, the Investigator should ensure that no 
destruction of medical records is performed without the written approval of the Sponsor.
In Japan, the head of the study site must retain all records, including documents and data, which 
relate to the clinical study in accordance with GCP. The head of the study site must retain the 
records at the site (hospital, research institute, or practice) for the longest possible time permitted 
by Japan’s GCP, and/or as per ICH GCP guidelines, whichever is longer. In any case, the head of 
the study site should ensure that no destruction of medical records is performed without the written 
approval of the Sponsor
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This study will be monitored in accordance with the ICH Note for Guidance on GCP (ICH Topic 
E6, 1996), and any other applicable regulations. The site Monitor will perform visits to the study
site at regular intervals.
The CTP, each step of the data capture procedure, and the handling of the data, including the final 
CSR, will be subject to independent Quality Assurance activities. Audits may be conducted at any 
time during or after the study to ensure the validity and integrity of the study data. Representatives 
of the Quality Assurance unit from the Sponsor or a designated organization, as well as Health 
Authorities, must be permitted to access all study documents and other materials at the site, 
including the Investigator Site File, the completed eCRFs, all IMP and IMP accountability records,
and the original medical records or files for each subject.
10.5
Changes to the Clinical Trial Protocol
Changes to the CTP will be documented in written protocol amendments. Major (substantial, 
significant) amendments will usually require submission to the Health Authorities and to the 
relevant IEC/IRB for approval or favorable opinion. In such cases, the amendment will be 
implemented only after approval or favorable opinion has been obtained.
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Minor (nonsubstantial) protocol amendments, including administrative changes, will be filed by 
the Sponsor and at the site. They will be submitted to the relevant IEC/IRB or to Health Authorities 
only where requested by pertinent regulations.
Any amendment that could have an impact on the subject’s agreement to participate in the study
requires the subject’s informed consent prior to implementation (see Section 9.2).
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the study, a CSR will be written by the Sponsor in consultation with the 
Coordinating Investigator following the guidance in ICH Topic E3 Publication.
 
10.6.2
Publication
The first publication will include the results of the analysis of the primary endpoint and will include 
data from all study sites.
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the study. Any publications and presentations of the results (abstracts in journals or 
newspapers, oral presentations, etc.), either in whole or in part, by Investigators or their 
representatives will require review by the Sponsor.
The Sponsor will not suppress publication, but maintains the right to delay publication in order to 
protect intellectual property rights.
Posting of data on applicable databases is planned and will occur 12 months after the last clinic 
visit of the final study subject or another appropriate date to meet applicable requirements.
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health-related quality of life measure, the LupusQol, for adults with systemic lupus erythematosus. 
Arthritis Rheum. 2007;57:972-9. 
McElhone K, Abbott J, Sutton C, et al. Sensitivity to change and minimal important differences of 
the LupusQoL in patients with systemic Lupus Erythematosus. Arthritis Care Res (Hoboken). 
2016;68(10):1505-13. 
Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in 
moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, 
phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 
2010;62(1):222-33.
Mina-Osorio P, LaStant J, Keirstead N, et al. Suppression of glomerulonephritis in lupus-prone 
NZB x NZW mice by RN486, a selective inhibitor of Bruton's tyrosine kinase. Arthritis Rheum. 
2013;65(9):2380-91.
Mundt JC, Greist JH, Gelenberg AJ, et al. Feasibility and validation of a computer-automated 
Columbia-Suicide severity rating scale using interactive voice response technology. Psychiatr Res. 
2010;44(16):1224–8. 
Mundt JC, Greist JH, Jefferson JW, et al. Prediction of suicidal behavior in clinical research by 
lifetime suicidal Ideation and behavior ascertained by the electronic Columbia-Suicide severity 
rating scale. J Clin Psychol. 2013;74(09):887–93. 
Naismith RT, Piccio L, Lyons JA, et al. Rituximab add-on therapy for breakthrough relapsing 
multiple sclerosis: a 52- week phase II trial. Neurology. 2010;74(23):1860-7.
Petri M, Hellmann D, Hochberg M. Validity and reliability of lupus activity measures in the routine 
clinical setting. J Rheumatol. 1992;19:53-9. 
Petri M, Orbai A-M, Alarcón GS, et al. Derivation and validation of the systemic Lupus 
international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis 
Rheum. 2012;64(8):2677–86. 
Reveille JD. Predictive value of autoantibodies for activity of systemic lupus erythematosus. 
Lupus. 2004;13:290-7.
Rituxan. Rituximab Prescribing Information. 2016.
Romero-Diaz J, Isenberg D, Ramsey-Goldman R, et al. Measures of adult systemic lupus 
erythematosus: updated version of British Isles Lupus Assessment Group (BILAG 2004), 
European Consensus Lupus Activity Measurements (ECLAM), Systemic Lupus Activity Measure, 
Revised (SLAM-R), Systemic Lupus Activity Questionnaire for Population Studies (SLAQ), 
Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K), and Systemic Lupus 
International Collaborating Clinics/American College of Rheumatology Damage Index (SDI).
Arthritis Care Res (Hoboken). 2011;63 Suppl 11:S37-46.
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Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active 
proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis 
Rheum. 2012;64(4):1215-26.
Stohl W, Hiepe F, Latinis KM, et al. Belimumab reduces autoantibodies, normalizes low 
complement, and reduces select B cell populations in patients with systemic lupus erythematosus. 
Arthritis Rheum. 2012;64(7):2328–37. 
Strand V, Levy RA, Cervera R, et al. Response to: “Belimumab and the measurement of fatigue” 
by Mazzoni. Ann Rheum Dis. 2015;74(9):e54. 
Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic 
lupus erythematosus. Arthritis Rheum. 1982;25(11):1271–7. 
Tanasescu R, Ionete C, Chou IJ, et al. Advances in the treatment of relapsing-remitting multiple 
sclerosis. Biomed J. 2014;37(2):41-9.
Tony HP, Burmester G, Schulze-Koops H, et al. Safety and clinical outcomes of rituximab therapy 
in patients with different autoimmune diseases: experience from a national registry (GRAID). 
Arthritis Res Ther. 2011;13(3):R75.
Touma Z, Urowitz MB, Gladman DD. SLEDAI-2K for a 30-day window. Lupus. 2010 
Jan;19(1):49-51.
Touma Z, Urowitz MB, Ibañez D, et al. SLEDAI-2K 10 days versus SLEDAI 2K 30 days in a 
longitudinal evaluation. Lupus. 2011;Jan 20(1):67-70.
Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with 
moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, 
randomised, 
double-blind, 
placebo-controlled, 
multicentre 
study. 
Ann 
Rheum 
Dis. 
2014;73(1):183-90. 
Ware JE Jr., Kosinski M, Bjorner JB, et al.  2008.  SF-36v2® Health Survey:  Administration 
guide for clinical trial investigators.  Lincoln, RI: QualityMetric Incorporated. 
Wolfe F, Hawley DJ, Wilson K.  The prevalence and meaning of fatigue in rheumatic disease. J 
Rheumatol. 1996;23:1407-17.
Xin G, Shi W, Xu LX, et al. Serum BAFF is elevated in patients with IgA nephropathy and 
associated with clinical and histopathological features. J Nephrol. 2013;26(4):683-90. 
Yellen SB, Cella DF, Webster K, et al.  Measuring fatigue and other anemia-related symptoms 
with the Functional Assessment of Cancer Therapy (FACT) measurement system.  J Pain 
Symptom Manage. 1997;13:63-74.
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Appendices
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Appendix I: Contraceptive Guidance and Woman of Childbearing Potential
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy.
Women in the following categories are not considered WOCBP
1. Premenopausal female with 1 of the following:
! Documented hysterectomy
! Documented bilateral salpingectomy
! Documented bilateral oophorectomy
Note: Documentation can come from the site personnel’s: review of participant’s medical 
records, medical examination, or medical history interview.
2. Premenarchal 
3. Postmenopausal female
! Females who are postmenopausal (age-related amenorrhea ≥12 consecutive months and 
increased follicle-stimulating hormone [FSH] > 40 mIU/mL), or who have undergone 
hysterectomy or bilateral oophorectomy are exempt from pregnancy testing. If necessary to 
confirm postmenopausal status, an FSH will be drawn at Screening.
! Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will 
be required to use one of the non-hormonal highly effective contraception methods if they wish 
to continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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Contraceptive Guidance
Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctlya. 
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulationb
!
oral 
!
intravaginalc
!
transdermalc
!
Progestogen-only hormonal contraception associated with inhibition of ovulationb
!
oral 
!
injectablec
Highly Effective Methods That Are User Independent 
!
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb,c
!
Intrauterine device (IUD)
!
Intrauterine hormone-releasing system (IUS)
!
bilateral tubal occlusion
!
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner is the sole male sexual 
partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of 
contraception should be used). 
!
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 drug. 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).
Barrier Methods
!
Male or female condom with or without spermicided
!
Cap, diaphragm, or sponge with spermicidec
a.
Typical use failure rates may differ from those when used consistently and correctly. Use should be consistent 
with local regulations regarding the use of contraceptive methods for participants participating in clinical studies. 
b.
Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of 
the contraceptive method. In this case, two highly effective methods of contraception should be utilized during 
the treatment period and for at least 90 days  after the last dose of study treatment
c.
Not approved in Japan. 
d.
For Japan only – the only approved barrier method is male condom with spermicide.
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Appendix II: Systemic Lupus International Collaborating Clinics Criteria for 
Systemic Lupus Erythematosus
The SLICC classification criteria (Petri 2012) require four criteria to be present, including at least 
one clinical criterion be present and one immunologic criterion be present; serially or 
simultaneously, during any period of observation; for classification of SLE. Alternatively, if 
biopsy proven nephritis consistent with lupus (lupus nephritis) is present, along with positive ANA 
and/or positive anti-dsDNA, SLE may be classified.
Clinical Criteria Used in the SLICC Classification Criteria
1.
Acute cutaneous lupus
including
lupus malar rash (do not count if 
malar discoid)
bullous lupus
toxic epidermal necrolysis     
variant of SL
maculopapular lupus rash
photosensitive lupus rash
in the absence of dermatomyositis
or subacute cutaneous lupus
(nonindurated psoriaform and/or annular polycyclic lesions that resolve without scarring, although 
occasionally with postinflammatory dyspigmentation or telangiectasias)
2.
Chronic cutaneous lupus
including 
classical discoid rash
localized (above the neck)
generalized (above and 
below the neck)
hypertrophic (verrucous) lupus
lupus panniculitis (profundus)
mucosal lupus
lupus erythematosus tumidus
chilblains lupus
discoid lupus/lichen planus 
overlap
3.
Oral ulcers:
palate 
buccal
tongue
or nasal ulcers
in the absence of other causes, such as vasculitis, Behcets, infection (herpes), inflammatory bowel 
disease, reactive arthritis, and acidic foods
4.
Nonscarring alopecia 
(diffuse thinning or hair fragility with visible broken hairs)
in the absence of other causes such as alopecia areata, drugs, iron deficiency, and androgenic alopecia
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5.
Synovitis involving two or more joints, characterized by swelling or effusion or tenderness in two or more 
joints and 30 minutes of more of morning stiffness.
6.
Serositis
Typical pleurisy for more than one day
or pericardial effusion
or pericardial rub
or pericarditis by ECG
in the absence of other causes, such as infection, uremia, and Dressler’s pericarditis
7.
Renal
Urine protein/creatinine (or 24 hour urine 
protein) representing 500 mg of 
protein/24 hour
or red blood cell casts
8.
Neurologic
seizures 
psychosis 
mononeuritis multiplex
in the absence of other known causes such as primary vasculitis
myelitis
Peripheral or cranial neuropathy
in the absence of other known causes such as primary vasculitis, infection, and diabetes millitus
Acute confusional state
in the absence of other known causes, including toxic-metabolic, uremia, drugs
9.
Hemolytic anemia
10. Leukopenia (< 4000/mm3 at least 
once)
in the absence of other causes such as Felty’s, drugs, and portal hypertension
or
Lymphopenia (< 1000/mm3 at least 
once)
in the absence of other known causes such as corticosteroids, drugs, and infection
11. Thrombocytopenia (< 100,00/mm3 at least once)
in the absence of other known causes such as drugs, portal hypertension, and TTP
Immunological Criteria Used in the SLICC Classification Criteria
1.
ANA above laboratory reference range
2.
Anti-dsDNA above laboratory reference range, except ELISA: twice above laboratory reference range
3.
Anti-Sm
4.
Antiphospholipid antibody
Any of the following:
lupus anticoagulant
false-positive RPR
medium or high titer anticardiolipin (IgA, IgG or IgM)
anti-β2 glycoprotein I (IgA, IgG or IgM)
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5.
Low complement
low C3
low C4
low CH50
6.
Direct Coombs test in the absence of hemolytic anemia
Criteria are cumulative and need not be present concurrently (Petri 2012).
ANA = Antinuclear Antibody(ies), Anti-dsDNA = Anti-Double-Stranded Deoxyribonucleic Acid, Anti-Sm = Anti-Smith 
Antibody, ECG = Electrocardiogram, ELISA = Enzyme-Linked Immunosorbent Assay, IgA = Immunoglobulin A,
IgG = Immunoglobulin G, IgM = Immunoglobulin M, RPR = Rapid Plasma Reagin, SLICC = Systemic Lupus 
International Collaborating Clinics, SL = Systemic Lupus, TTP = Thrombotic Thrombocytopenic Purpura.
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Appendix III: Revised American College of Rheumatology Criteria for 
Systemic Lupus Erythematosus
For the purpose of identifying subjects in clinical studies, a person shall be said to have systemic 
lupus erythematosus if any four or more of the 11 criteria are present, serially or simultaneously, 
during any interval of observation (Hochberg 1997, Tan 1982).
Criterion
Definition
1.
Malar Rash
Fixed erythema, flat or raised, over the malar eminences, tending to spare the 
nasolabial folds
2.
Discoid Rash
Erythematous raised patches with adherent keratotic scaling and follicular 
plugging; atrophic scarring occur in older lesions
3.
Photosensitivity
Skin rash as a result of unusual reaction to sunlight, by patient history or physician 
observation
4.
Oral Ulcers
Oral or nasopharyngeal ulceration, usually painless, observed by physician
5.
Nonerosive Arthritis
Involving two or more peripheral joints, characterized by tenderness, swelling, or 
effusion
6.
Pleuritis or Pericarditis
1.
Pleuritis: convincing history of pleuritic pain or rubbing heard by a physician 
or evidence of pleural effusion
or
2.
Pericarditis: documented by electrocardiogram or rub or evidence of 
pericardial effusion
7.
Renal Disorder
1.
Persistent proteinuria: > 0.5 g per day or > than 3+ if quantitation not 
performed
or
2.
Cellular casts: may be red cell, hemoglobin, granular, tubular, or mixed
8.
Neurologic Disorder
1.
Seizures: in the absence of offending drugs or known metabolic 
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance
or
2.
Psychosis: in the absence of offending drugs or known metabolic 
derangements; e.g., uremia, ketoacidosis, or electrolyte imbalance
9.
Hematologic Disorder
1.
Hemolytic anemia with reticulocytosis
or
2.
Leukopenia: < 4,000/mm3 on ≥two occasions
or
3.
Lymphopenia: < 1,500/mm3 on ≥two occasions
or
4.
Thrombocytopenia: < 100,000/mm3 in the absence of offending drugs
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Criterion
Definition
10. Immunologic Disorder
1.
Anti-DNA: antibody to native DNA in abnormal titer
or
2.
Anti-Sm: presence of antibody to Sm nuclear antigen
or
3.
Positive finding of antiphospholipid antibodies based any of the following: 
1.
an abnormal serum level of IgG or IgM anticardiolipin antibodies
2.
a positive test result for SLE anticoagulant using a standard method, or
3.
a false positive serologic test result for syphilis known to be positive for 
at least six months and confirmed by Treponema pallidum 
immobilization or fluorescent Treponemal antibody absorption test
11. Positive Antinuclear 
Antibody
An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent 
assay at any point in time and in the absence of drugs known to be associated with 
"drug-induced lupus" syndrome
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Appendix IV: Signature Pages and Responsible Persons for the Trial
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Signature Page – Principal Investigator
Trial Title
A Phase II, Randomized, Double-Blind, Placebo-
Controlled Dose-Ranging Study To Evaluate the 
Safety and Efficacy of M2951 in Subjects with 
Systemic Lupus Erythematosus (SLE)
IND Number
EudraCT Number
2016-002950-19
Clinical Trial Protocol Date / 
Version
22 May 2018 / Version 7.0.
Center Number
Principal Investigator
I, the undersigned, am responsible for the conduct of the trial at this site and affirm that I 
understand and will conduct the trial according to the clinical trial protocol, any approved protocol 
amendments, International Council on Harmonisation Good Clinical Practice (Topic E6) and all 
applicable Health Authority requirements and national laws.
I also affirm that I understand that Health Authorities may require the Sponsors of clinical trials to 
obtain and supply details about ownership interests in the Sponsor or Investigational Medicinal 
Product and any other financial ties with the Sponsor. The Sponsor will use any such information 
solely for the purpose of complying with the regulatory requirements. I therefore agree to supply 
the Sponsor with any necessary information regarding ownership interest and financial ties 
including those of my spouse and dependent children, and to provide updates as necessary to meet 
Health Authority requirements.
_____________________________________
____________________________
Signature
Date of Signature
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Sponsor Responsible Persons Not Named on the Cover Page
Name, academic degree:
Function / Title:
Institution:
EMD Serono Research & Development Institute
Address:
45A Middlesex Turnpike, Billerica, MA, 01821, USA
Telephone number:
Name, academic degree:
Function / Title:
Institution:
EMD Serono Research & Development Institute
Address:
45A Middlesex Turnpike, Billerica, MA, 01821, USA
Telephone number:
E-mail address:
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Appendix V: Protocol Amendments and List of Changes
Table of Amendments
Actual Amendment 
Number
Substantial
(Y/N)
Date
Region or 
Country
Included in 
the current 
document
(Y/N)
Version
Local Amendment 1
N
11 January 2017
Taiwan
Y
Not 
applicable
Global Amendment 1
Y
08 February 2017
Global
Y
2.0
Local Amendment 2
N
03 April 2017
Peru
Y
Not 
applicable
Global Amendment 3
Y
14 July 2017
Global
Y
3.0
Local Amendment 3
Y
21 July 2017
US
N
3.1
Local Amendment 4
Y
17 August 2017
Japan
N
3.2
Global Amendment 7
Y
31 August 2017
Global
Y
4.0
Local Amendment 8
Y
10 September 2017
US
Y
4.1
Local Amendment 9
Y
14 September 2017
Japan
Y
4.2
Local Amendment 10
Y
18 October 2017
Japan
Y
4.3
Local Amendment 11
N
02 November 2017
Germany, 
Italy, Poland, 
Romania
Y
4.4
Global Amendment 12
Y
20 November 2017
Global
Y
5.0
Global Amendment 13
Y
05 January 2018
Global
Y
6.0
Global Amendment 14
Y
22 May 2018
Global
Y
7.0
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Amendment 14
Protocol Version 6.0 (05 January 2018) was the global amended protocol. The revised global 
amended protocol (Version 7.0) was issued on 22 May 2018. 
Rationale
The major reason for this amendment was the addition of a LTE. In addition, minor changes 
throughout the document were added to clarify or correct minor errors.
The key changes for this global amended protocol are summarized below:
! A LTE was added into the study, including 2 new SoAs, and an additional study figure
! Table 7 (now Table 9) was modified for clarity on Day 1
! Stopping rules modified due to analysis of additional safety data
! Exclusion modified to permit low dose aspirin after medical review
! Administrative and Editorial changes: Minor edits for clarity and consistency that do not affect 
the substance of the protocol are not individually listed here, including the addition of the 
cross-references to the new SoA.
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Comparison with Clinical Trial Protocol Version 6.0, 05 January 2018(Global Amendment No. 13)
Change
Section
Page
Previous Wording
New Wording
Rationale
Last subject out 
updated.
Synopsis
14
Last subject out: Q2, 2020
Last subject out: Q2, 2020 Q3, 2022
The end of the 
study will be later 
due to the addition 
of the LTE.
Trial registry was 
updated.
Synopsis
14
-
clinicaltrials.jp
An additional 
registry was added 
as the study will 
soon be added to 
this registry.
An objective was 
added for the 
LTE.
Synopsis, 
4.4 Open-label 
Long-Term 
Extension (LTE) 
Period Objectives
16,
39
-
Open-label Long-Term Extension (LTE) Period 
Objectives
The objective of the LTE Period is:
•To evaluate the long-term safety, efficacy, and 
HRQoL of M2951 at an initial dose of 50 mg 
twice daily or the eventual Phase III dose when 
decided for an additional two years.
The LTE was 
added into the 
study.
Methodology text 
updated to 
include LTE.
Synopsis
16
All subjects will take five tablets per 
day (three in the morning, two in the 
evening), in combinations of active 
and placebo tablets to maintain 
blinding of all subjects to dose.
During the DBPC Treatment Period, aAll 
subjects will take five tablets per day (three in the 
morning, two in the evening), in combinations of 
active and placebo tablets to maintain blinding of 
all subjects to dose.
The LTE was 
added into the 
study.
Methodology text 
updated to 
include LTE.
Synopsis,
5.1 Overall Trial 
Design and Plan
16, 39
The study is composed of a 
Screening Period of four weeks, a 
DBPC Treatment Period of 
52 weeks, and a Safety Follow Up 
Period of four weeks. An open 
label, long-term extension (LTE) 
study may be conducted under a 
separate protocol for those 
completing 52 weeks of treatment.
The study is composed of a Screening Period of 
four weeks, a DBPC Treatment Period of 
52 weeks, an open-label LTE Period of 
104 weeks, and a Safety Follow-Up Period of 
four weeks. An open label, long-term extension 
(LTE) study may be conducted under a separate 
protocol for those completing 52 weeks of 
treatment.
The LTE was 
added into the 
study.
An additional 
secondary 
endpoint was 
added. 
Synopsis,
8.3.2 Secondary 
Endpoints
17, 105
-
o Lupus low disease activity state (LLDAS), 
defined as meeting all of the following 
(Franklyn 2016):
- SLEDAI-2K ≤ 4
- No activity in any major organ systems 
(renal, 
central 
nervous 
system, 
cardiopulmonary, vasculitis, fever)
Added per 
Coordinating 
Investigator 
suggestion.
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Change
Section
Page
Previous Wording
New Wording
Rationale
- No new features of disease activity 
compared with the previous assessment
- Prednisone-equivalent ≤ 7.5 mg/day
- Unchanged 
background 
immunosuppressive therapy
New endpoints 
were added for 
the LTE Period.
Synopsis,
8.3.4 Endpoints for 
Long-Term 
Extension Period
19,
107
-
Endpoints for Long-Term Extension Period
LTE Safety:
•Nature, severity, and incidence of AEs, SAEs, 
vital signs, ECGs, absolute values and change 
from Baseline in serum total Ig levels (IgG, 
IgA, IgM) and total B cell counts, and clinical 
laboratory parameters.
LTE Efficacy:
•The following LTE efficacy endpoints will be 
analyzed at Week 24, Week 52, and Week 104:
o
Changes over time in SRI response
o
Changes over time in Low Disease 
Activity status (LLDAS, SLEDAI-2K ≤ 2, 
clinical SLEDAI-2K ≤ 2).
o
Changes over time in CLASI-A, CLASI-D, 
and SLICC/ACR Damage Index organ 
damage scores
o
Changes over time in disease activity as 
measured by the BILAG, SLEDAI-2K, and 
PGA
o
Change 
over 
time 
in 
prednisone-equivalent CS dose
o
Changes over time in HRQoL
o
Changes over time in autoantibodies and 
complement levels
•Changes in HRU by visit, including but not 
limited to doctor/home/emergency visits, 
hospitalizations, paid assistance, and missed 
work
•Time to first flare; flare-free status at Weeks 
24, 52, and 104; and annualized flare rate, will 
be analyzed separately, each assessed with 
flare defined as:
o
BILAG A Severe flare
o
BILAG A or 2B Moderate to Severe flare
o
SLEDAI Flare Index (SFI) Severe flare.
The LTE was 
added into the 
study.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
155/205
Change
Section
Page
Previous Wording
New Wording
Rationale
Repetitious text 
removed.
Synopsis,
5.1 Overall Trial 
Design and Plan
19, 40
(e.g., BILAG 2004 Disease Activity 
Index, 
SLEDAI-2K, 
PGA, 
and 
CLASI).
(e.g., BILAG 2004 Disease Activity Index, 
SLEDAI-2K, PGA, and CLASI).
The text was 
repetitive and 
unnecessary.
Additional text 
related to the 
LTE was added.
Synopsis,
5.1 Overall Trial 
Design and Plan
19, 40
Subjects will receive the last dose of 
IMP at Week 52, which is the End of 
Treatment (EOT) for the study.
Subjects will receive the last dose of IMP at Week 
52, which is the End of Treatment (EOT) for the 
study, unless they enter the LTE Period.
Clarification was 
added due to the 
addition of the 
LTE.
New text 
describing the 
LTE was added.
Synopsis
20
-
Optional Open-Label Long-Term Extension 
Period
Subjects who completed the 52-week DBPC 
Treatment period will be offered participation 
in the 104-week open-label, LTE Period of the 
study. The purpose of the LTE Period is to 
allow all the subjects with the opportunity to 
receive active treatment with M2951 and to 
collect long term safety and efficacy data. The 
Investigator should review the optional LTE 
Period with the subject prior to the DBPC 
Week 52 visit. Signed consent will be obtained 
prior to participation in the LTE Period. The 
DBPC Week 52/EOT Visit will be considered 
the LTE Day 1 Visit.  The Safety Follow-Up Visit 
will be deferred until treatment is stopped in 
the LTE Period, due to either a subject’s 
premature withdrawal/early termination from
the LTE, termination of the study by the 
Sponsor, or completion of the LTE treatment 
period. 
In some cases, due to Institutional Review 
Board (IRB)/Independent Ethics Committee 
(IEC) approval, regulatory-specific, or other 
administrative 
delays, 
a 
subject 
may 
experience a treatment gap between the IMP 
last dose received in the DBPC Period (Week 
52/EOT visit) and the start of the LTE IMP 
treatment. Upon Principal Investigator (PI) 
request, these subjects may still be able to 
enroll in 
the LTE with 
approval
from 
Merck/EMD Serono, on a case by case basis. 
If the day of rollover to the LTE occurs after 
the DBPC Week 56/EOS visit, all assessments 
The LTE was 
added into the 
study.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
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New Wording
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noted at the LTE Day 1 visit will need to be 
completed. For subjects that rollover after the 
Week 52/EOT visit but prior to their scheduled 
Week 56/EOS visit, concomitant medications 
and AEs will need to be reviewed and updated, 
and the PI will need to ensure that the subject 
remains eligible for the study. No other 
additional assessments other than dispensing 
of IMP will need to be completed.
The description 
of the Safety 
Follow-Up Period 
was updated to 
include 
information on 
subjects going 
into the LTE.
Synopsis
20
Subjects will enter the Safety Follow 
Up Period directly from the DBPC
Treatment 
Period 
after 
the 
Week 52/EOT Visit. The Safety 
Follow Up Visit is scheduled to occur 
4 weeks after the last IMP dose. This 
includes subjects who stop the 
DBPC 
Treatment 
Period 
prematurely. The Safety Follow Up 
Visit is the End of Study Visit and is 
the last scheduled visit for subjects 
participating in this clinical study.
Subjects will enter the Safety Follow Up Period 
directly from the DBPC Treatment Period after the 
Week 52/EOT Visit. The Safety Follow-Up/End of 
Study Visit is scheduled to occur 4 four weeks 
(+ 5 days)
after administration of study 
treatment. the last IMP dose. This includes For
subjects who do not participate in stop the 
DBPC 
Treatment 
Period
LTE
Period,
prematurely.
tThe Safety Follow-Up Visit is 
scheduled four weeks (+ 5 days) after the last 
administration of study treatment in the DBPC 
Period. For subjects who participate in the 
LTE Period, the Safety Follow-Up Visit is 
delayed until four weeks (+ 5 days) after the 
last administration of study treatment in the 
LTE Period. Subjects who are approved to 
rollover into LTE Period after they entered, or 
completed, 
the 
DBPC 
Safety 
Follow-Up 
Period, may have two Safety Follow-Up Visits. 
Additional details of the Safety Follow-Up/ End 
of Study Visit are provided in the SOAthe End 
of Study Visit and is the last scheduled visit for 
subjects participating in this clinical study.
The LTE was 
added into the 
study.
Modification was 
made as 
1 injectable CS is 
now permitted.
Synopsis
21
Restrictions and guidance for the 
use of OCS during the course of the 
study include 
prohibiting doses 
above 30 mg/day after Week 4 of the 
Treatment 
Period, 
prohibiting 
injectable CSs, limits on when 
change in dose of CS may occur, 
recommendations to decrease CS 
dose within parameters allowed by 
Restrictions and guidance for the use of OCS 
during the course of the study include prohibiting 
doses above 30 mg/day after Week 4 of the 
Treatment Period, prohibiting injectable CSs 
(outside limited exceptions), limits on when 
change 
in 
dose 
of 
CS 
may 
occur, 
recommendations to decrease CS dose within 
parameters allowed by the study, and limits on the 
use of CS during treatment of SLE flares.
One injectable CS 
is now permitted.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
157/205
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New Wording
Rationale
the study, and limits on the use of CS 
during treatment of SLE flares.
Dose was added 
for the LTE.
Synopsis
21
-
Subjects who choose to participate in the LTE 
Period will receive open-label M2951 50 mg 
twice daily or the eventual Phase III dose when 
decided, taken orally for 104 weeks.
The LTE was 
added into the 
study.
Length of LTE 
was added.
Synopsis
21
-
The 
optional 
LTE 
Treatment 
Period 
is 
approximately 104 weeks in duration and will 
be offered to subjects after completion of the 
DBPC Period.
The LTE was 
added into the 
study.
Additional 
analyses are 
described due to 
the addition of 
the LTE.
Synopsis
22-23 
Two analyses are planned. A third 
analysis is possible depending on 
the enrollment rate of the Japanese 
subject cohort. 
The first analysis will be an interim 
futility analysis (IA). This IA will be 
based on Week 24 SRI-4 response 
among all subjects in the n = 432 
cohort and Week 24 SRI-6 response 
among HDA subjects in the n = 432 
cohort. The IA will be conducted 
when 100% of subjects enrolled, out 
of the planned enrollment of n = 432, 
reach Week 24 of treatment or 
prematurely 
discontinue 
from 
treatment. If enrollment is slower 
than expected, consideration will be 
given to conducting the interim futility 
analysis when the first 50% of the 
planned enrollment of n = 432 reach 
Week 
24 
of 
treatment, 
or 
prematurely 
discontinue 
from 
treatment. 
The second analysis is the primary
analysis, based on Week 52 SRI-4 
response among all subjects in the 
n = 432 cohort, and Week 52 SRI-6 
response among HDA subjects in 
the n = 432 cohort, triggered when 
100% of subjects enrolled, out of the 
planned enrollment of n = 432, 
complete 
safety 
follow 
up, 
or 
There will be at least two planned Two analyses 
in this study – the primary and final analyses
are planned. A third analysis is possible There 
may be up to four planned analyses, depending 
on the enrollment rate ofwhether the Japanese 
subject cohort. optional
The first analysis will be an interim futility interim
analysis (IA) is conducted, and whether the 
analysis for treatment effect consistency is 
coincident with the primary analysis, or is 
conducted after the primary analysis. If the 
futility IA is conducted, it. This IA will be based 
on Week 24 SRI-4 response among all subjects in 
the primary analysis
n = 432 cohort and 
Week 24 SRI-6 response among HDA subjects in 
the primary analysis n = 432 cohort. The IA will 
be conducted when 100% of subjects enrolled, 
out of the planned enrollment of n = 432, in the 
primary analysis cohort reach Week 24 of 
treatment 
or 
prematurely 
discontinue 
from 
treatment. If enrollment is slower than expected, 
consideration will be given to conducting the 
interim futility analysis when the first 50% of the 
primary analysis cohort planned enrollment of n 
= 432 reach Week 24 of treatment, or prematurely 
discontinue from treatment. 
The second analysis The primary analysis 
cohort consists of the first 432 subjects 
randomized.  However, if drop out for reasons 
unrelated to efficacy or safety is higher than 
expected, effectively reducing the power of 
the study, the IAP may prespecify that the 
The LTE was 
added into the 
study.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
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prematurely discontinue from study. 
The Japanese cohort may be fully, 
partially, or not included in this 
primary analysis, depending on the 
enrollment rate
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A third analysis may be scheduled if 
the Japanese cohort does not enroll 
in time to be included with the 
n = 432 subjects required for the 
primary analysis.  If the Japanese 
cohort enrolls in time to be included, 
the evaluation of consistency with 
respect to ethnicity of Week 52 
SRI-4 response can be performed at 
the time of the primary analysis.  If 
the Japanese cohort enrolls slowly, 
then the primary analysis will occur 
without inclusion of the Japanese 
cohort, and a third analysis for 
evaluation of consistency will be 
triggered when 100% of enrolled 
Japanese subjects: 
•Complete Week 52 of treatment 
and safety follow-up, or 
primary analysis cohort will include all subjects 
randomized., The primary analysis will be
based on Week 52 SRI-4 response among all 
subjects in the primary analysis n = 432 cohort, 
and Week 52 SRI-6 response among HDA 
subjects in the primary analysis n = 432 cohort.,
This analysis will be triggered when 100% of 
subjects in the primary analysis cohort.
enrolled, out of the planned enrollment of n = 432,
•Complete Week 52 of treatment and either 
enter the LTE or complete Ssafety Ffollow-Uup, 
or
•Pprematurely discontinue from study. treatment 
prior to Week 52 and complete Safety 
Follow-Up, or
•Prematurely discontinue from study without 
Safety Follow-up.
The Japanese cohort may be fully, partially, or not 
included in this primary analysis, depending on 
the enrollment rate. 
tThe Family-Wise 
type 1 error rate (FWER) due to the co-primary 
endpoints and
multiple M2951 dose group 
comparisons versus placebo will be controlled at 
the onetwo-sided α = 0.05
level via a 
 
tree 
gatekeeping 
procedure. The four hypotheses associated 
with 
the 
comparisons 
involving 
the 
co-primary endpoints and the two highest 
dose groups will form the first family of 
hypotheses in the tree.  This family will be 
tested via the truncated Hochberg procedure, 
with truncation fraction pre-specified in the 
IAP. The multiple-testing procedure, in which the 
 
for the remainder of the tree, 
including the hypotheses associated with the 
comparisons 
involving 
the 
co-primary 
endpoints and the lowest dose,
 
 
 
 
 
 
 
 
 
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A Phase II Study of M2951 in SLE
MS200527-0018
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•Prematurely 
discontinue 
from 
treatment and complete safety follow 
up, or 
•Prematurely 
discontinue 
from 
study. 
 
group, and the key 
secondary endpoints and all dose groups, will 
be pre-specified in the IAP.
A treatment effect consistency third analysis 
may be scheduled if the Japanese cohort does not 
enroll in time to be included with the n = 432 
subjects required for the primary analysis cohort. 
If the Japanese cohort enrolls in time to be 
included, the evaluation of consistency with 
respect to ethnicity of Week 52 SRI-4 response 
can be performed at the time of the primary 
analysis.  If the Japanese cohort enrolls slowly, 
then the primary analysis will occur without 
inclusion of the Japanese cohort, and a separate
third analysis for evaluation of
consistency 
analysis will be triggered when 100% of enrolled 
Japanese subjects: 
•Complete Week 52 of treatment and either enter 
LTE or complete and sSafety Ffollow-Uup, or 
•Prematurely discontinue from treatment prior to 
Week 52 and complete Ssafety Ffollow- Uup, or 
•Prematurely discontinue from study without 
Safety Follow-Up.
The final analysis will be triggered when 100% 
of subjects enrolled: 
•Complete Week 104 of the LTE and the Safety 
Follow-Up, or
•Complete Week 52 of treatment and the 
Safety Follow-Up (if they did not rollover into 
the LTE), or
•Prematurely discontinue from treatment and 
complete Safety Follow-Up, or
•Prematurely discontinue from study. 
The final analysis will be performed by 
 
staff when the final analysis trigger condition 
has been met, protocol violations determined, 
and the database is locked for the final 
analysis
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
160/205
Change
Section
Page
Previous Wording
New Wording
Rationale
Updates were 
made to the 
analysis cohort. 
Synopsis, 
8.5.2 Analysis of 
Primary Endpoints
23,
110
Analysis of Co-primary Efficacy 
Endpoints
The primary analysis of SRI-4 
response at Week 52 among all 
subjects in the n = 432 cohort, and 
SRI-6 response at Week 52 among 
HDA subjects in the n = 432 cohort, 
will be an estimate of OR, together 
with associated two-sided 97.5% CI 
and p-value, comparing each M2951 
dose group to placebo, based on a 
logistic model for the odds of a given 
SRI response in the appropriate 
population, with M2951 dose group 
or placebo group as a factor and 
adjustment for covariates based on 
randomization strata.
Analysis of Co-primary Efficacy Endpoints
The primary analysis of SRI-4 response at Week 
52 among all subjects in the primary analysis n 
= 432 cohort, and SRI-6 response at Week 52 
among HDA subjects in the n = 432 primary 
analysis cohort, will be an estimate of OR, 
together with associated two sided 957.5% CI and 
p-value (testing null hypothesis H0: OR = 1.0), 
comparing each M2951 dose group to placebo, 
based on a logistic model for the odds of a given 
SRI response in the appropriate population, with 
M2951 dose group or placebo group as a factor 
and 
adjustment 
for 
covariates 
based 
on 
randomization strata.
Drop-out rates 
unrelated to
efficacy or safety 
are higher than 
anticipated.
The analysis of 
the secondary 
endpoint was 
updated based 
on the addition of 
the LTE.
Synopsis
24
Analysis 
of 
Key 
Secondary 
Endpoints
Time to first severe (BILAG A) flare 
during the Treatment Period will be 
modeled via a Cox regression 
model, with treatment group as a 
factor, and controlling for covariates 
defining randomization strata. A 
subject who discontinues treatment 
or 
completes treatment 
without 
experiencing severe flare will have 
his/her time to flare censored at the 
last time point at which flare could be 
assessed. 
SRI-4 response at Week 52 among 
serologically active subjects will be 
an estimate of OR, together with 
associated 
two-sided 
CI 
and 
p-value, comparing each M2951 
dose group to placebo, based on a 
logistic model for the odds SRI-4 
response in the serologically active 
population, with M2951 dose group 
or placebo group as a factor and 
Analysis of Key Secondary Endpoints
Time to first severe (BILAG A) flare during the 
Treatment Period will be modeled in all subjects 
will be compared between M2951 and placebo 
via a stratified log rank test.  The adjusted 
hazard ratio comparing M2951 to placebo will 
be estimated (together with 95% CI) via a Cox 
regression model, with treatment group as a 
factor, and controlling for covariates defining 
randomization strata. A subject who discontinues 
treatment 
or 
completes 
treatment 
without 
experiencing severe flare will have his/her time to 
flare censored at the last time point at which flare 
could be assessed. 
Kaplan-Meier estimates of probability of 
surviving free of severe (BILAG A) flare as a 
function of time on treatment will be provided 
for each treatment group.
The analysis of SRI-4 response at Week 52 
among serologically active subjects will be an 
estimate of OR, together with associated 
two-sided 95% CI and p-value, comparing each 
M2951 dose group to placebo, based on a logistic 
model for the odds of SRI-4 response in the 
serologically active population, with M2951 dose 
The LTE was 
added into the 
study.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
161/205
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adjustment for covariates based on 
randomization strata. 
Descriptive 
statistics 
for 
SRI-4 
response in the serologically active 
subgroup, will be provided for each 
treatment group by time point. 
Analysis 
of 
Other 
Secondary 
Efficacy Endpoints
Binary endpoints will be modeled via 
logistic regression, time to event 
endpoints will be modeled via Cox 
regression, continuous endpoints 
measured 
longitudinally 
(i.e., 
HRQoL change from baseline) will 
be analyzed using Mixed effect 
Model 
for 
Repeated 
Measures 
(MMRM), and count endpoints (i.e., 
annualized 
flare 
rate) 
will 
be 
modeled 
via 
negative 
binomial 
regression, with treatment group as 
a factor, and adjusting for covariates 
defining 
randomization 
strata. 
Analysis of annualized flare rate will 
use observation time (in years) as an 
offset in the model. Change in a 
binary endpoint between two time 
points 
will 
be 
analyzed 
via 
McNemar’s test. The effect of 
treatment on change in a binary 
endpoint will be analyzed via logistic 
regression, with treatment group, 
time 
point, 
and 
interaction 
as 
predictors, 
and 
adjusting 
for 
covariates defining randomization 
strata. All tests of efficacy will be 
conducted at a two-sided α level of 
0.05, 
with 
p-values 
considered 
nominal unless generated as part of 
a hierarchical testing strategy as 
described in the Statistical Analysis 
Plan (SAP). P values and the 95% 
group or placebo group as a factor and 
adjustment for covariates based on randomization 
strata. A test for trend in dose-response, using 
the same logistic model, will be reported as a 
supportive analysis.
Descriptive statistics for SRI-4 response in the 
serologically active subgroup, will be provided for 
each treatment group by time point. 
Analysis 
of 
Other 
Secondary 
Efficacy 
Endpoints
Binary endpoints will be modeled via logistic 
regression, time to event endpoints will be 
modeled via Cox regression and tested via 
stratified log rank test, continuous endpoints 
measured longitudinally (i.e., HRQoL change 
from baseline) will be analyzed using Mixed effect 
Model for Repeated Measures (MMRM), and 
count endpoints (i.e., annualized flare rate) will be 
modeled via negative binomial regression, with 
treatment group as a factor, and adjusting for 
covariates defining randomization strata. Analysis 
of annualized flare rate will use the log of
observation time (in years) as an offset in the 
model. Change in a binary endpoint between 
two time points will be analyzed via McNemar’s 
test. The effect of treatment on change in a binary 
endpoint will be analyzed via logistic regression, 
with treatment group, time point, and interaction 
as predictors, and adjusting for covariates 
defining randomization strata. All tests of efficacy 
will be conducted at a two-sided α level of 0.05, 
with 
p-values 
considered 
nominal 
unless 
generated as part of a hierarchical the tree 
gatekeeping 
multiple
testing 
strategy 
as 
described in the Statistical Integrated Analysis 
Plan (ISAP). P values and the 95% CIs will be 
presented where applicable.
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Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
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Rationale
CIs 
will 
be 
presented 
where 
applicable.
The Sponsor 
designees were 
updated to 
remove 
repetition. 
2 Sponsor, 
Investigators, and 
Trial Administrative 
Structure
31
The Sponsor of this clinical study is 
EMD 
Serono 
Research 
& 
Development Institute, Inc. (EMD 
Serono R&D), Billerica, MA, in the 
USA, and Merck KGaA, Darmstadt, 
Germany, in rest of the world (RoW), 
except in Japan. In Japan, Merck 
Serono Co., Ltd. (Affiliate of Merck 
KGaA, Darmstadt, Germany) is the 
Sponsor of this clinical study.
The Sponsor of this clinical study is EMD Serono 
Research & Development Institute, Inc. (EMD 
Serono R&D), Billerica, MA, in the USA, and 
Merck KGaA, Darmstadt, Germany, in rest of the 
world (RoW), except in Japan. In Japan, Merck 
Serono Co., Ltd. (Affiliate of Merck KGaA, 
Darmstadt, Germany) is the Sponsor of this 
clinical study in Japan; and Merck KGaA, 
Darmstadt, Germany, in the rest of the world 
(RoW).
To remove 
repetition. 
 
 was 
updated to 
 
Services.
2 Sponsor, 
Investigators, and 
Trial Administrative
Structure
31
In Japan, 
 
, will 
undertake the operational aspects. 
Details of such structures and 
associated 
procedures 
will 
be 
defined in a separate Integrated 
Project Management Plan (IPMP).
In Japan, 
, will undertake the 
operational aspects. Details of such structures 
and associated procedures will be defined in a 
separate Integrated Project Management Plan 
(IPMP).
Updated to the 
rebranding of 
Slight 
modification in 
wording on 
interim analysis.
2.2 Trial 
Coordination/Monitor
ing
32
An independent data monitoring 
committee 
(IDMC) 
will 
be 
established to assess safety and 
tolerability of IMP during the conduct 
of the study and review the interim 
analysis (IA).
An independent data monitoring committee 
(IDMC) will be established to assess safety and 
tolerability of IMP during the conduct of the study 
and review the interim analysis (IA) if completed.
To allow flexibility 
in the analysis as 
other additional 
analyses will now 
be done due to the 
addition of the 
LTE.
A SMC was 
added for the 
LTE Period.
2.2 Trial 
Coordination/Monitor
ing
32
-
The IDMC will monitor the study until the last 
subject has either entered the LTE or 
completed 
the 
Safety 
Follow-Up 
Visit 
following the DBPC Treatment Period for 
subjects that did not rollover into the LTE, 
whichever occurs last. At that time, study 
monitoring may transition to an internal Safety 
Monitoring Committee (SMC). The SMC will 
review all available safety data on a regular 
basis during the open-label LTE. The SMC 
consists 
of 
Sponsor 
representatives 
(including, but not limited to, the Medical 
Responsible, the Drug Safety Product Lead, 
the biostatistician), the Medical Monitor from 
the CRO, and the Coordinating Investigator. 
The LTE was 
added into the 
study.
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A Phase II Study of M2951 in SLE
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The full membership, mandate, and processes 
of the SMC will be detailed in the SMC charter.
Benefit Risk text 
was updated.
3.1 Benefit and Risk
36
A signal of asymptomatic increases 
in transaminases has emerged from 
the ongoing study MS200527-0086 
among 
subjects 
randomized 
to 
evobrutinib or placebo.
A 
signal 
of 
asymptomatic 
increases 
in 
transaminases has emerged from the ongoing 
study 
MS200527-0086 
amongin 
multiple 
sclerosis and in MS200527-0018, affecting 
approximately 5% of subjects randomized to 
evobrutinib or placebo in both studies. Thus far, 
the elevations have been asymptomatic and 
reversible on discontinuation of IMP. There 
have been no Hy’s Law cases.
More recent 
information was 
available.
A SMC was 
added for the 
LTE.
3.1 Benefit and Risk
37
-
During the LTE, an internal SMC may review 
safety data on a regular basis during the LTE 
in lieu of the IDMC.
The LTE was 
added into the 
study.
A SMC was 
added for the 
LTE Period.
3.1 Benefit and Risk
37
More recent 
information was 
available.
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A Phase II Study of M2951 in SLE
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is continually reviewed and modified to 
incorporate input from the IDMCs.
Clarification was 
added on the 
treatment for 
those in the LTE.
5.1 Overall Trial 
Design and Plan
39
Therefore, the total enrollment will 
range from n = 432 to 468 (n = 108 
to 117 subjects per group). This trial 
will be conducted at approximately 
180 sites across 20 countries.
Therefore, the total enrollment will range from 
n = 432 to 468 (n = 108 to 117 subjects per 
group). 
 
 
 
 
This trial will be conducted at 
approximately 180 sites across 20 countries.
The LTE was 
added into the 
study.
Text on the LTE 
was changed 
from being a 
potential 
separate protocol 
to being 
integrated into 
this study.
5.1 Overall Trial 
Design and Plan
40
Long-Term Extension Study
Subjects who complete the 52-week 
DBPC 
period 
may 
be 
offered 
participation in an open label, 
long-term extension (LTE) study. 
Should the Sponsor decide to 
conduct the LTE study, it will be 
conducted 
under 
a 
separate 
protocol. Subjects continuing in the 
LTE study will receive the first dose 
of LTE study at Week 52 following 
the completion of all Week 52 
procedures. They will not attend the 
Safety Follow Up Visit until treatment 
is stopped in the LTE study, due to 
either 
a 
subject’s 
premature 
withdrawal/early termination from 
the LTE study, termination of the 
LTE study by the Sponsor, or 
completion of the LTE treatment 
period. It is expected the placebo 
group of this MS200527-0018 study 
will be switched over to M2951 
active treatment, at a dose to be 
identified in the IA of this study. 
Subjects in the M2951 treatment 
groups will remain on their original 
respective doses of M2951 when 
enrolled in the LTE study. Subjects 
are recommended to have signed 
the informed consent for the LTE
Optional Open-Label Long-Term Extension 
Study Period
Subjects who completed the 52-week DBPC 
Treatment
period 
will
may
be 
offered 
participation in the an 104-week open-label, LTE 
Period of the study. The purpose of the LTE 
Period is to allow all the subjects with the 
opportunity to receive active treatment with 
M2951 and to collect long-term extension (LTE) 
study. Should the Sponsor decide to conduct the 
LTE study, it safety and efficacy data. The 
Investigator should review the optional LTE 
Period with the subject prior to the DBPC 
Week 52 visit. Signed consent will be obtained 
prior to participation
conducted under a 
separate protocol. Subjects continuing in the LTE 
Period study will receive the first dose of LTE 
study at The DBPC Week 52 following the 
completion of all Week 52 procedures. They EOT 
Visit will not attend be considered the LTE 
Day 1 Visit. Tthe Safety Follow- Up Visit will be 
deferred until treatment is stopped in the LTE 
studyPeriod, due to either a subject’s premature 
withdrawal/early termination from the LTE study, 
termination of the LTE study by the Sponsor, or 
completion of the LTE treatment period. It is 
expected the placebo group of this MS200527-
0018 study will be switched over to M2951 active 
treatment, at a dose to be identified in the IA of 
this study. Subjects in the M2951 treatment 
groups will remain on their original respective 
doses of M2951 when enrolled in the LTE study. 
The LTE was 
added into the 
study.
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study at least four weeks prior to 
enrollment.
Subjects are recommended to have signed the 
informed consent for the LTE study at least four 
weeks prior to enrollment.
In some cases, due to Institutional Review 
Board (IRB)/Independent Ethics Committee 
(IEC) approval, regulatory-specific, or other 
administrative 
delays, 
a 
subject 
may 
experience a treatment gap between the IMP 
last dose received in the DBPC Period (Week 
52/EOT visit) and the start of the LTE IMP 
treatment. Upon Principal Investigator (PI) 
request, these subjects may still be able to 
enroll in 
the LTE with 
approval 
from 
Merck/EMD Serono, on a case by case basis. 
If the day of rollover to the LTE occurs after 
the DBPC Week 56/EOS visit, all assessments 
noted at the LTE Day 1 visit will need to be 
completed. For subjects that rollover after the 
Week 52/EOT visit but prior to their scheduled
Week 56/EOS visit, concomitant medications 
and AEs will need to be reviewed and updated, 
and the PI will need to ensure that the subject 
remains eligible for the study. No other 
additional assessments other than dispensing 
of IMP will need to be completed.
Clarification was 
added on the 
Safety 
Follow-Ups to 
account for the 
addition of the 
LTE.
5.1 Overall Trial 
Design and Plan
40-41
Subjects will enter the Safety Follow 
Up Period directly from the DBPC 
Treatment 
Period 
after 
the 
Week 52/EOT Visit. The Safety 
Follow Up Visit is scheduled to occur 
four weeks after the last IMP dose. 
This includes subjects who stop the 
DBPC 
Treatment 
Period 
prematurely. The Safety Follow Up 
Visit is the End of Study Visit and is 
the last scheduled visit for subjects 
participating in this clinical trial. 
Subjects participating in the LTE 
study, if conducted, will not attend 
the Safety Follow Up Visit, and will 
instead enter the LTE study.
Subjects will enter the Safety Follow Up Period 
directly from the DBPC Treatment Period after the 
Week 52/EOT Visit. The Safety Follow Up Visit is 
scheduled to occur four weeks after the last IMP 
dose. This includes subjects who stop the DBPC 
Treatment Period prematurely. The Safety Follow 
Up Visit is the End of Study Visit and is the last 
scheduled visit for subjects participating in this 
clinical trial. Subjects participating in the LTE 
study, if conducted, will not attend the Safety 
Follow Up Visit, and will instead enter the LTE 
study.
The Safety Follow-Up/End of Study Visit is 
scheduled four weeks (+ 5 days) after the last 
administration 
of 
study 
treatment. 
For 
subjects who do not participate in the LTE 
Period, 
the 
Safety 
Follow-Up 
Visit 
is 
The LTE was 
added into the 
study.
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scheduled four weeks (+ 5 days) after the last 
administration of study treatment in the DBPC 
Period. For subjects who participate in the 
LTE Period, the Safety Follow-Up Visit is 
delayed until four weeks (+ 5 days) after the 
last administration of study treatment in the 
LTE Period. Subjects who are approved to 
rollover into LTE Period after they entered, or 
completed, 
the 
DBPC 
Safety 
Follow-Up 
Period, may have two Safety Follow-Up Visits. 
Additional details of the Safety Follow-Up/ End 
of Study Visit are provided in the SOA.
Additional 
analyses are 
described due to 
the addition of 
the LTE.
5.1 Overall Trial 
Design and Plan
41-42
Two analyses are planned. A third 
analysis is possible depending on 
the enrollment rate of the Japanese 
subject cohort. 
The first analysis will be an interim 
futility analysis (IA). This IA will be 
based on Week 24 SRI-4 response 
among all subjects and Week 24 
SRI-6 
response 
among 
HDA 
subjects, and conducted when 100% 
of subjects enrolled, out of the 
planned enrollment, reach Week 24 
of 
treatment 
or 
prematurely 
discontinue from treatment. If the 
response proportion difference for 
both 
co-primary 
endpoints 
is 
sufficiently low at Week 24, as 
defined in the Statistical Analysis 
Plan (SAP), consideration will be 
given to termination of the study. If 
enrollment is slower than expected, 
consideration 
will 
be 
given 
to 
conducting 
the 
interim 
futility 
analysis when the first 50% of the 
planned enrollment reach Week 24 
of 
treatment, 
or 
prematurely 
discontinue 
from 
treatment. 
An 
IDMC 
will 
monitor 
safety 
and 
tolerability as well as review the data 
from the IA. The IA will be prepared 
Two analyses are planned. A third analysis is 
possible depending on the enrollment rate of the 
Japanese subject cohort. 
The first analysis will be an interim futility analysis 
(IA). This IA There will be at least two planned
analyses in this study – the primary and final 
analyses. There may be up to four planned 
analyses, depending on whether the optional 
futility interim analysis (IA) is conducted, and 
whether the analysis for treatment effect 
consistency is coincident with the primary 
analysis, or is conducted after the primary 
analysis.
If the futility IA is conducted, it will be based on 
Week 24 SRI-4 response among all subjects in 
the primary analysis cohort and Week 24 SRI-6 
response among HDA subjects In the primary 
analysis cohort. The IA will be, and conducted 
when 100% of subjects enrolled, out of in the 
planned enrollment primary analysis cohort, 
reach Week 24 of treatment or prematurely 
discontinue from treatment prior to Week 24. If 
the response proportion difference for both 
co-primary endpoints is sufficiently low at 
Week 24, as defined in the Integrated Statistical 
Analysis Plan (SAPIAP), consideration will be 
given to termination of the study. If enrollment is 
slower than expected, consideration will be given 
to conducting the interim futility analysis when the 
first 50% of the primary analysis cohort planned 
The LTE was 
added into the 
study.
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by a team independent of the study 
teams (Sponsor and 
).
The second analysis is the primary 
analysis, based on Week 52 SRI-4 
response among all subjects in the 
n = 432 cohort, and Week 52 SRI-6 
response among HDA subjects in 
the n = 432 cohort. This analysis is 
triggered when 100% of subjects 
enrolled:
•Complete Week 52 of treatment 
and safety follow-up, or
•Prematurely 
discontinue 
from 
treatment and complete safety follow 
up, or
•Prematurely 
discontinue 
from 
study.
The Japanese cohort may be fully, 
partially, or not included in this 
primary analysis, depending on the 
enrollment 
rate. 
The 
primary 
analysis will be performed by 
 
staff when the primary analysis 
trigger condition has been met, 
protocol violations determined, and 
the database is locked for the 
primary analysis.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
enrollment
reach Week 24 of treatment, or 
prematurely discontinue from treatment. An IDMC 
will monitor safety and tolerability as well as 
review the data from the IA. The IA will be 
prepared by a team independent of the study 
teams (Sponsor and 
).
The second analysis primary analysis cohort 
consists of the first 432 subjects randomized.  
However, if drop-out for reasons unrelated to 
efficacy or safety is higher than expected, 
effectively reducing the power of the study, 
the IAP may prespecify that the primary analysis
cohort may include all subjects randomized. 
The primary analysis will be, based on Week 52 
SRI-4 response among all subjects in the n = 432
primary analysis cohort, and Week 52 SRI-6 
response among HDA subjects in the n = 432
primary analysis cohort. This analysis is 
triggered when 100% of subjects enrolled in the 
primary analysis cohort:
•Complete Week 52 of treatment and safety 
follow-up either enter LTE or complete Safety 
Follow-Up, or
•Prematurely discontinue from treatment prior to 
Week 52 and complete Safety Follow-Up safety 
follow up, or
•Prematurely discontinue from study without 
Safety Follow-Up.
The Japanese cohort may be fully, partially, or not 
included in this primary analysis, depending on 
the enrollment rate. The primary analysis will be 
performed by 
 staff when the primary 
analysis trigger condition has been met, protocol 
violations determined, and the database is locked 
for the primary analysis.
 
 
 
 
The 
Family-Wise type 1 error rate (FWER) due to the 
co-primary endpoints and multiple M2951 dose 
group comparisons versus placebo will be 
controlled at the two
-sided α = 0.0125 level 
via a tree gatekeeping 
 
 
. 
The 
four 
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A third analysis may be scheduled if 
the Japanese cohort does not enroll 
in time to be included with the 
n = 432 subjects required for the 
primary analysis.  If the Japanese 
cohort enrolls in time to be included, 
the evaluation of consistency with 
respect to ethnicity of Week 52 
SRI-4 response can be performed at 
the time of the primary analysis.  If 
the Japanese cohort enrolls slowly, 
then the primary analysis will occur 
without inclusion of the Japanese 
cohort, and a third analysis for 
evaluation of consistency will be 
triggered when 100% of enrolled 
Japanese subjects:
•Complete Week 52 of treatment 
and safety follow-up, or 
•Prematurely 
discontinue 
from 
treatment and complete safety follow 
up, or 
hypotheses associated with comparisons 
involving the co-primary endpoints and the 
two highest dose groups 
 
will form the first family 
of hypotheses in the tree. This family will be 
tested via the truncated Hochberg procedure, 
with truncation fraction pre-specified in the 
IAP. The multiple-testing procedure for the 
remainder 
of 
the 
tree, 
including 
the 
hypotheses associated with the comparisons 
involving the co-primary endpoints and the
lowest dose group, and the key secondary 
endpoints and all dose groups, will be 
pre-specified in the IAP.,
 
 
 
 
A treatment effect consistency analysis third 
analysis may be scheduled if the Japanese cohort 
does not enroll in time to be included with the 
n = 432 subjects required for the primary analysis
cohort.  If the Japanese cohort enrolls in time to 
be included, the evaluation of consistency with 
respect to ethnicity of Week 52 SRI-4 response 
can be performed at the time of the primary 
analysis.  If the Japanese cohort enrolls slowly, 
then the primary analysis will occur without 
inclusion of the Japanese cohort, and a third 
analysis for evaluation of separate consistency
analysis will be triggered when 100% of enrolled 
Japanese subjects:
•Complete Week 52 of treatment and either enter 
LTE or complete Safety Follow-Upsafety follow-
up, or 
•Prematurely discontinue from treatment prior to 
Week 52 and complete Safety Follow-Up safety 
follow up, or 
•Prematurely discontinue from study without 
Safety Follow-Up. 
The final analysis will be triggered when 100% 
of subjects enrolled: 
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•Prematurely 
discontinue 
from 
study. 
•Complete Week 104 of the LTE and the Safety 
Follow-Up, or
•Complete Week 52 of treatment and the 
Safety Follow-Up (if they did not rollover into 
the LTE), or
•Prematurely discontinue from treatment and 
complete Safety Follow-Up, or
•Prematurely discontinue from study. 
The final analysis will be performed by 
 
staff when the final analysis trigger condition 
has been met, protocol violations determined, 
and the database is locked for the final 
analysis.
Text was 
removed.
5.2.1 Scientific 
Rationale for Study 
Design
44
Important potential risks to subjects 
are based on nonclinical safety data 
of M2951 and clinical data on 
adverse drug effects associated with 
compounds 
of 
a 
similar 
pharmacological class. They include 
infection, 
leukopenia, 
thrombocytopenia, 
hemorrhage, 
gastrointestinal intolerance, renal 
toxicity, hepatocellular injury, atrial 
fibrillation, drug-drug interactions, 
and embryo-fetal toxicity. These 
risks will be mitigated through the 
use of risk minimization measures 
inherent to early phase clinical trials 
and are considered adequate for the 
proposed clinical trial in subjects with 
SLE. An IDMC will continually review 
available safety and tolerability data 
and will be mandated to make 
immediate decisions regarding the 
conduct of the trial; no additional risk 
minimization 
measures 
are 
proposed.
Given the predicted therapeutic 
benefit in the majority of the subjects 
at each dose, the tolerability and 
safety profile demonstrated, and the 
risk minimization measures in place 
Important potential risks to subjects are based on 
nonclinical safety data of M2951 and clinical data 
on 
adverse 
drug 
effects
associated 
with 
compounds of a similar pharmacological class. 
They 
include 
infection, 
leukopenia, 
thrombocytopenia, hemorrhage, gastrointestinal 
intolerance, renal toxicity, hepatocellular injury, 
atrial fibrillation, drug-drug interactions, and 
embryo-fetal toxicity. These risks will be mitigated 
through the use of risk minimization measures 
inherent to early phase clinical trials and are 
considered adequate for the proposed clinical trial 
in subjects with SLE. An IDMC will continually 
review available safety and tolerability data and 
will be mandated to make immediate decisions 
regarding the conduct of the trial; no additional 
risk minimization measures are proposed.
Given the predicted therapeutic benefit in the 
majority of the subjects at each dose, the
tolerability and safety profile demonstrated, and 
the risk minimization measures in place for this 
trial, benefit risk considerations support conduct of 
the proposed clinical Study MS200527-0018 in 
subjects with SLE.
The text is already 
present in 
Section 3.1.
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for 
this 
trial, 
benefit 
risk 
considerations support conduct of 
the 
proposed 
clinical 
Study 
MS200527-0018 in subjects with 
SLE.
Minor update to 
text was added 
on data for 
doses.
5.2.2 Justification for 
Dose
46
 
 
 
 
.
 
 
 
Data is no longer 
preliminary.
Updated to 
include 
unanticipated 
events.
5.3 Selection of Trial 
Population
47
When a laboratory test must be 
repeated 
during 
the 
Screening 
period, the Screening Period can be 
extended to 8 weeks after discussion 
with the Medical Monitor.
When a laboratory test must be repeated during 
the Screening pPeriod or an unanticipated 
event occurs, the Screening Period can be 
extended to 8 weeks after discussion with the 
Medical Monitor.
To allow flexibility 
for unanticipated 
events.
Two drugs were 
added to the list 
of exclusion 6.
5.3.2 Exclusion 
Criteria
52
6.
Within two months prior to 
Screening or during Screening: 
initiation of or change in dose of 
antimalarial, 
methotrexate,  
mycophenolate (mofetil [MMF] or 
sodium [MPS]*), or azathioprine 
(*not approved in Japan).
6.
Within two months prior to Screening or 
during Screening: initiation of or change in dose 
of antimalarial, methotrexate, 6-mercaptopurine, 
sulfasalazine, mycophenolate (mofetil [MMF] or 
sodium [MPS]*), or azathioprine (*not approved in 
Japan).
To add clarification 
as these drugs 
were intended to 
be on this list 
previously.
Clarification was 
added for the use 
of low dose 
aspirin.
5.3.2 Exclusion 
Criteria
52
14.
On 
anticoagulation 
(e.g., 
vitamin K antagonists) or antiplatelet 
therapy (e.g., clopidogrel) other than 
daily aspirin for cardioprotection.
14.
On 
anticoagulation 
(e.g., 
vitamin 
K 
antagonists) 
or 
antiplatelet 
therapy 
(e.g., 
clopidogrel) other than daily low dose aspirin 
(≤350 mg/day) for cardioprotection. Low-dose 
aspirin therapy for other indications may be 
permitted after discussion with medical 
monitor.
To allow inclusion, 
after medical 
review, of subjects 
for whom low-dose 
aspirin is SoC for 
reasons other than 
cardioprotection. 
A note was 
added for 
additional 
information on 
Hepatitis B 
vaccination.
5.3.2 Exclusion 
Criteria
53
2.
Hepatitis B antibody positive 
subjects who are HBV DNA negative 
OR have detectable HBV DNA 
< 20 IU/mL are not excluded from 
the study. However, these subjects 
will have HBV DNA measured by 
PCR at Weeks 4, 8, 12, 16, 20, 24, 
36, 48, 52/EoT/Early Withdrawal, 
and 56/Safety Follow-Up/End of 
Study visits.
2.
Hepatitis B antibody positive subjects who 
are HBV DNA negative OR have detectable HBV 
DNA < 20 IU/mL are not excluded from the study. 
However, these subjects will have HBV DNA 
measured by PCR at Weeks 4, 8, 12, 16, 20, 24, 
36, 48, 52/EoT/Early Withdrawal, and 56/Safety 
Follow-Up/End of Studyat visits noted in the 
SOA.
Note: Subjects who have previously been 
vaccinated for Hepatitis B will not be tested for 
anti-hepatitis B surface antibody, as they will 
be positive for anti-hepatitis B surface 
Clarification 
regarding testing 
performed for 
subjects previously 
vaccinated for 
Hepatitis B, versus 
those who have 
not been 
vaccinated. 
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antibody as the protective consequence of 
vaccination.
A note was 
added regarding 
the prophylactic 
use of 
antituberculous 
drugs.
5.3.2 Exclusion 
Criteria
54
-
Note: Prophylactic use of antituberculous 
drugs is not permitted during the study, and if 
used must be discontinued prior to the first 
dose of study medication. If an Investigator 
feels that a subject requires antituberculous 
prophylaxis while participating in the study, 
this may be allowed after review of the case by 
the Medical Monitor.
Added to clarify 
protocol 
restrictions on use 
of antituberculous 
prophylaxis in 
some countries as 
not permitted in 
this study. 
The exclusion 
was modified to 
cross reference 
another exclusion 
and not repeat.
5.3.2 Exclusion 
Criteria
54
26.
Antiphospholipid 
antibody 
syndrome 
associated 
with 
a 
thromboembolic 
event 
in 
the 
12 months 
prior 
to 
or 
during 
Screening. 
Anticoagulation 
or 
anti-platelet therapy is exclusionary, 
with the exception of daily aspirin for 
cardioprotection (see criterion 14).
26.
Antiphospholipid 
antibody 
syndrome 
associated with a thromboembolic event in the 
12 months prior to or during Screening. See 
Exclusion Criterion 14 for discussion of
Aanticoagulation 
or 
anti-platelet 
therapy
is 
exclusionary, with the exception of daily aspirin for 
cardioprotection (see criterion 14).
Additional details 
for aspirin were 
added into 
Exclusion 14 and 
therefore removed 
from here.
Additional text 
was added to 
possibly increase 
enrollment.
5.5.1 Withdrawal 
from the Trial
58
Subjects who are withdrawn after 
randomization (e.g., due to AEs or 
lack of efficacy) will not be replaced. 
Subjects who are withdrawn from the 
study will not be allowed to re-enroll 
in the study.
Subjects who are withdrawn after randomization 
(e.g., due to AEssafety or lack of efficacy) will not 
be replaced. Consideration will be given to 
increasing enrollment to compensate for loss 
of information due to subjects who withdraw 
for reasons unrelated to safety or lack of 
efficacy. Subjects who are withdrawn from the 
study will not be allowed to re-enroll in the study.
Drop-out rates 
unrelated to 
efficacy or safety 
are higher than 
anticipated.
Additional text 
was added about 
the potential use 
of some 
prohibited 
medications.
5.5.2 Withdrawal 
from the 
Investigational 
Medicinal Product
58
•Use of a prohibited medication, as 
defined in Section 6.5.2. However, 
any medications that are considered 
necessary 
for 
the 
subject’s 
well-being may be given at the 
discretion of the Investigator.
•Use of a prohibited medication, as defined in 
Section 6.5.2. However, any medications that are 
considered necessary for the subject’s well-being 
may be given at the discretion of the Investigator. 
If, in the view of the Investigator, the use of a 
prohibited medication should not impact 
subject safety or bias efficacy assessments, 
the Investigator can request the Medical 
Monitor review the case. Such a request must 
be made as soon as the Investigator is aware 
of the use of prohibited medication, and the 
Medical Monitor, along with the Sponsor, will 
determine if the subject must be permanently 
withdrawn from IMP. See Section 6.4.2.2 for 
specifics regarding treatment of flares during 
To allow some 
flexibility for the 
Investigators 
based on 
Investigator 
feedback.
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the DBPC and LTE treatment periods of the 
study and withdrawal from IMP.
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Clarifications 
were added to 
IMP withdrawal 
criteria.
5.5.2 Withdrawal 
from the 
Investigational 
Medicinal Product
58-60
The IMP should be temporarily 
withheld or permanently withdrawn if 
the 
following 
laboratory 
abnormalities occur or re-occur, as 
relevant, and re-initiation following 
temporarily 
withholding 
of 
IMP 
should 
be 
discussed 
with 
the 
Medical Monitor. If a subject’s 
pre-dose baseline value falls within 
any of the below criteria, consult with 
the 
Medical 
Monitor 
regarding 
potential 
withdrawal, 
continued 
participation in study, and additional 
monitoring if needed:
•For a neutrophil count < 500/mm3 or 
platelet count < 25,000/mm3 or a 
lymphocyte count < 200/mm3 (Grade 
4) or neutrophil count 500 to 
999/mm3 (Grade 3) with fever or 
platelet count 25,000 to 49,999/mm3
(Grade 3) with bleeding, the IMP 
should be permanently withdrawn.
•For 
a 
Grade 
3 
decrease 
in 
neutrophil count without fever or 
Grade 3 decrease in platelet count 
without bleeding, temporarily hold 
the IMP and recheck the value. If the 
value is still Grade 3, permanently 
discontinue the IMP. For a decrease 
to Grade 2, temporarily hold the IMP 
and recheck the value. Reinitiate the 
IMP 
after 
discussion 
with 
the 
Medical 
Monitor 
if 
no 
further 
downward trend is observed.
The IMP should be temporarily withheld or 
permanently withdrawn if the following laboratory 
abnormalities occur or re-occur, as relevant, and 
re-initiation following temporarily withholding of 
IMP should be discussed with the Medical 
Monitor. If a subject’s pre-dose baseline value is 
abnormal and/or falls within any of the below 
criteria, 
consult 
with 
the 
Medical 
Monitor 
regarding 
potential 
withdrawal, 
continued 
participation in study, and additional monitoring if 
needed. Retesting should be completed within 
1 week:
•For a neutrophil count < 5001000/mm3 (Grade 3 
or 4) or platelet count < 2550,000/mm3 or a 
lymphocyte count < 200/mm3
(Grade 4) or 
neutrophil count 500 to 999/mm3 (Grade 3) with 
fever or platelet count 25,000 to 49,999/mm3
(Grade 3) with bleeding, the IMP should be 
permanently withdrawn.
•For a Grade 3 decrease in neutrophil count 
without fever or Grade 3 decrease in platelet 
count without bleeding, (Grade 3 or 4) temporarily 
hold the IMP and recheck the value. If the value is 
still Grade 3 or 4, permanently discontinue the 
IMP; if the value improves to Grade 2, Grade 1 
or is within normal limits, IMP may be 
reinitiated after discussion with the Medical 
Monitor. For a recheck value that decreases to 
Grade 2, perform repeat testing within 1 
month. decrease to Grade 2, temporarily hold the
IMP and recheck the value. Reinitiate the IMP 
after discussion with the Medical Monitor if no 
further downward trend is observed.
•For a lymphocyte count <200/mm3 (Grade 4), 
temporarily hold the IMP and recheck the 
value. If the value is still Grade 4, permanently 
discontinue the IMP; if the value improves to a 
Grade 3, discuss with the Medical Monitor; if 
the value improves to Grade 2, Grade 1 or is 
within normal limits, IMP may be reinitiated 
after discussion with the Medical Monitor. For 
a recheck value that improves to Grade 2, 
perform repeat testing within 1 month.
Clarified 
confirmatory retest 
process, provided 
guidance for 
additional testing if 
subject is not 
scheduled for a 
monthly visit 
during the LTE 
period, and 
revised based on 
review of safety 
data from ongoing 
studies.
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specialists, such as a hepatologist, 
can be considered at the discretion 
of the Investigator and in conjunction 
with the Medical Monitor.
•For an increase in bilirubin to 
Grade 2, temporarily hold the IMP 
and recheck the value. Reinitiate the 
IMP 
after 
discussion 
with 
the 
Medical Monitor if no further upward 
trend is observed.
•A comprehensive hepatic panel is 
requested for any subjects, for whom 
above AST or ALT withdrawal 
criteria 
are 
met 
and 
who 
permanently discontinue dosing due 
to elevated liver function tests. 
Subjects should be referred to a 
hepatologist who may recommend
testing in addition to the following:
o INR, PTT, fibrinogen, hsCRP
o Hepatitis 
serology: 
anti-HAV 
IgG, anti-HAV IgM, HBsAg, anti-
HBc, 
anti-HBsAg, 
anti-HCV, 
anti-HEV IgG and IgM, anti-VCA 
IgG and IgM, anti-EA IgG, anti-
EBNA IgG, anti-CMV IgG and 
IgM
o Antinuclear 
antibody, 
anti-
smooth muscle antibody, and 
liver-kidney 
microsomal 
antibody
o Albumin
•For an increase in amylase or lipase 
to > 2 to 5X ULN (Grade 3), 
temporarily 
hold 
the 
IMP 
and 
recheck the value within 24 hours of 
receipt. If the value is still Grade 3, 
permanently discontinue the IMP. 
•For an increase in amylase or lipase 
to Grade 2, temporarily hold the IMP 
and 
recheck 
the 
value 
within 
24 hours of receipt. Discontinue the 
IMP if the value does not decrease, 
or reinitiate the IMP after discussion 
•For an increase in aspartate aminotransferase 
(AST) or alanine aminotransferase (ALT) to 
> 3X× ULN (Grade 2 or higher), temporarily hold 
the IMP and recheck the value. If the value is 
still Grade 2 or higher, the IMP should be 
permanently withdrawn. The subject should be 
followed with additional testing as needed until a 
return to ULN or acceptable value as agreed upon 
by 
the 
Investigator 
and 
Medical 
Monitor. 
Consultations 
with specialists, 
such 
as 
a 
hepatologist, can be considered at the discretion 
of the Investigator and in conjunction with the 
Medical Monitor.
•For an increase in bilirubin to > 1.5×ULN 
(Grade 2 or higher), temporarily hold the IMP and 
recheck the value. Reinitiate If the value is still 
Grade 2 or higher, the IMP after discussion with 
the Medical Monitor if no further upward trend is 
observed should be permanently withdrawn.
•A comprehensive hepatic panel is requested for 
any subjects, for whom above AST or ALT 
withdrawal criteria are met and who permanently 
discontinue dosing due to elevated liver function 
tests. 
Subjects 
should 
be 
referred 
to 
a 
hepatologist who may recommend testing in 
addition to the following:
o INR, PTT, fibrinogen, hsCRP
o Hepatitis serology: anti-HAV IgG, anti-HAV 
IgM, HBsAg, anti-HBc, anti-HBsAg, anti-HCV, 
anti-HEV IgG and IgM, anti-VCA IgG and IgM, 
anti-EA IgG, anti-EBNA IgG, anti-CMV IgG 
and IgM
o Antinuclear antibody, anti-smooth muscle 
antibody, 
and 
liver-kidney 
microsomal 
antibody
o Albumin
•For an increase in amylase or lipase to > 2 to 5×
ULN (Grade 3 or 4), temporarily hold the IMP and 
recheck the value within 24 hours of receipt. If the 
value is still Grade 3
or 4,
permanently 
discontinue the IMP.
•For an increase in amylase or lipase to Grade 2, 
temporarily hold the IMP and recheck the value 
within 24 hours of receipt. Discontinue the IMP if 
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with the Medical Monitor if a 
downward trend is observed.
•For an increase in serum creatinine 
to > 3X from Baseline (Grade 3 or 
higher), 
the 
IMP 
should 
be 
permanently withdrawn. 
•For any other increase in serum 
creatinine > 1.5X from Baseline, 
temporarily 
hold 
the 
IMP 
and 
recheck the value within 24 hours of 
receipt. Discontinue the IMP if the 
value does not decrease, or reinitiate 
the IMP after discussion with the 
Medical Monitor if a downward trend 
is observed.
•For any serum IgG level < 3 g/L, 
confirmed by repeat testing, the IMP 
should be permanently withdrawn.
…
•For 
any 
other 
laboratory 
abnormality of Grade 4 severity, the 
IMP 
should 
be 
permanently 
withdrawn. 
•For 
any 
other 
laboratory 
increase/decrease 
(as 
relevant) 
from Baseline to Grade 3, consider 
temporarily holding the IMP, unless 
otherwise indicated in this section of 
the protocol. Recheck values within 
24 hours and discuss results with 
Medical 
Monitor, 
unless 
an 
improving trend is observed.
the value does not decrease, or reinitiate the IMP
improves to Grade 2, Grade 1, or is within 
normal limits, IMP may be reinitiated after 
discussion with the Medical Monitor. For if a 
recheck value that improves to Grade 2, 
perform 
repeat 
testing 
within 
1 
monthdownward trend is observed.
•For an increase in serum creatinine to > 3X× from
Baseline (Grade 3 or higher4), temporarily hold 
the IMP and recheck the value. If the value is 
still a Grade 3 or 4, the IMP should be
permanently discontinue the IMP withdrawn. 
•For any other increase in serum creatinine > 1.5×
from Baseline to ≤3× Baseline (Grade 2), 
temporarily hold the IMP and recheck the value
within 24 hours of receipt. Discontinue the IMP iIf 
the value is still Grade 2, discuss with the 
Medical Monitor, if the value does not decrease, 
or reinitiate the IMP improves to Grade 1 or is 
within normal limits, IMP may be reinitiated
after discussion with the Medical Monitor if a 
downward trend is observed.
•For any serum IgG level < 3 g/L, confirmed by 
repeat testingtemporarily hold the IMP and 
recheck the value. If the value is still < 3 g/L, 
the IMP should be permanently withdrawn.
…
•For any other laboratory abnormality of Grade 4 
severity, temporarily hold the IMP and recheck 
the value. If the value is still a Grade 4, the IMP 
should be permanently withdrawn. If the restest 
value improves, discuss with the Medical 
Monitor.
•For any other laboratory increase/decrease (as 
relevant) from Baseline to Grade 3, consider 
temporarily holding the IMP, (unless otherwise 
indicated in this section of the protocol),
temporarily hold the IMP, recheck the value,
.Recheck values within 24 hours and discuss 
results with Medical Monitor, unless an improving 
trend is observed.
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Dosing 
information for 
the LTE was 
added. 
6.2 Dosage and 
Administration
62
The LTE was 
added into the 
study.
Clarification was 
added due to the 
addition of the 
LTE.
6.4.1 Background 
Systemic Lupus 
Erythematosus 
Therapies
64
Initiation 
of 
any 
new 
immunosuppressant 
or 
immunomodulator therapy would be 
considered a treatment failure and
should result in withdrawal of the 
subject from the IMP and study (see 
Section 5.5).
Initiation of any new immunosuppressant or 
immunomodulator therapy would be considered a 
treatment failure during the DBPC Treatment 
Period and should result in withdrawal of the 
subject from the IMP and study (see Section 5.5).
The LTE was 
added into the 
study.
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Clarification was 
added that a 
single dose of 
steroid could be 
given.
6.4.2 Corticosteroids
65
DBPC Period
…
Furthermore, 
injectable 
corticosteroids (e.g., intramuscular, 
intravenous, 
subcutaneous, 
and 
intra-articular) are prohibited during 
the study.
DBPC Period
…
Furthermore, injectable corticosteroids (e.g., 
intramuscular, intravenous, subcutaneous, and 
intra-articular) are prohibited during the study.
with the exception of a single dose of 
intramuscular steroid, no more than 80 mg of 
prednisolone equivalent, permitted prior to the 
twelfth week of the DBPC Period.
Updated to permit 
one time 
intramuscular 
steroid dose within 
the first 12 weeks 
of the DBPC 
Period as 
administration will 
not bias efficacy 
endpoints or 
impact patient 
safety.
Additional 
information was 
added on 
corticosteroid use 
during the LTE.
6.4.2 Corticosteroids
65
The rules for CS dose changes are 
outlined in Table 7. There is no 
minimum CS dose required during 
the study.
…
-
Screening to Week 52
There 
are 
no 
restrictions 
on 
non-systemic corticosteroid dosage 
(see Section 6.5.1.2).
The rules for CS dose changes during Screening 
and the DBPC Treatment Period are outlined in 
Table 7Table 9. There is no minimum CS dose 
required during the study.
…
LTE Period
During the LTE Period, CS doses up to 
30 mg/day 
prednisone-equivalent 
(see 
Table 8) 
are 
permitted. 
Injectable 
corticosteroids 
(e.g., 
intramuscular, 
intravenous, 
subcutaneous, 
and 
intra-articular) remain prohibited during the 
LTE Period, with the exception of a single 
dose of intramuscular steroid, no more than 
80 mg of prednisolone equivalent, permitted 
prior to the twelfth week of the LTE Period.
Screening to Week 52Period, DBPC Period, 
and LTE Period
There are no restrictions on non-systemic 
corticosteroid dosage (see Section 6.5.1.2).
The LTE was 
added into the 
study.
Additional 
information was 
added on 
corticosteroid use 
during the LTE.
6.4.2 
Corticosteroids, 
Table 
68
Overview 
/ 
Key 
Points 
on 
Corticosteroid Dose During Study
•CS dose must remain stable during 
the Screening Period.
•From Day 1 to the Week 4 Visit, CS 
dose may be initiated (no later than 
Week 
2/Day 
14), 
increased, 
decreased, or remain unchanged. 
Overview / Key Points on Corticosteroid Dose 
During Study
•CS dose must remain stable during the 
Screening Period.
•From Day 1 to the Week 4 Visit, CS dose may be 
initiated (no later than Week 2/Day 14), increased, 
decreased, or remain unchanged. 
•Corticosteroid dose adjustment goals and 
restrictions during the DBPC Treatment Period:
The LTE was 
added into the 
study.
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•Corticosteroid 
dose 
adjustment 
goals and restrictions 
o By the Week 4 Visit, the dose 
must be ≤ dose at Day 1. 
Subjects with CS dose < 7.5 
mg/day at Day 1 may have up 
to 7.5 mg/day at Week 4.
o By the Week 8 Visit, dose should 
be tapered to ≤ 10 mg/day, as 
tolerated
o By the Week 12 Visit, dose 
should be tapered to ≤ 7.5 
mg/day, as tolerated
o No changes to CS dose should 
be made from Week 17 through 
completion 
of 
study 
assessments for Week 24.
o Between study visits at Week 25 
through Week 40, dose should 
be tapered to ≤ 5 mg/day, as 
tolerated.
o No changes to CS dose are 
allowed from Week 41 through 
completion 
of 
study 
assessments for Week 52/EOT.
o By the Week 4 Visit, the dose must be ≤ dose 
at Day 1. Subjects with CS dose < 7.5 
mg/day at Day 1 may have up to 7.5 mg/day 
at Week 4.
o By the Week 8 Visit, dose should be tapered 
to ≤ 10 mg/day, as tolerated
o By the Week 12 Visit, dose should be 
tapered to ≤ 7.5 mg/day, as tolerated
o No changes to CS dose should be made 
from Week 17 through completion of study 
assessments for Week 24.
o Between study visits at Week 25 through 
Week 40, dose should be tapered to ≤ 5 
mg/day, as tolerated.
o No changes to CS dose are allowed from
Week 41 through completion of study 
assessments for Week 52/EOT.
•During the LTE Period, CS doses may be 
initiated or increased up to 30 mg/day 
prednisone equivalent, decreased, or remain 
the 
same. 
Investigators 
are 
strongly 
encouraged to decrease the CS dose of the 
subject as much as tolerated.
Additional 
information was 
added on 
corticosteroid use 
during the LTE.
6.4.2.1 
Corticosteroid Use 
as Standard of Care
68
Screening Visit to Day 1 (No 
Change in CS Dose)
From the Screening Visit to Day 1, 
the corticosteroid dose should be 
maintained at the Screening Visit 
dose. If the corticosteroid dose is 
changed, 
the 
subject 
will 
be 
considered a screen failure. The 
total daily prednisone  equivalent 
dosage must not be higher than 
30 mg/day during the Screening 
Period.
Day 1 to Week 4 Visit (CS Dose 
Adjustable)
Corticosteroids 
may 
remain 
unchanged, be increased, or be 
DBPC Period
Screening Visit to Day 1 (No Change in CS 
Dose)
From the Screening Visit to Day 1, the 
corticosteroid dose should be maintained at the 
Screening Visit dose. If the corticosteroid dose is 
changed, the subject will be considered a screen 
failure. The total daily prednisone  equivalent 
dosage must not be higher than 30 mg/day during 
the Screening Period.
Day 1 to Week 4 Visit (CS Dose Adjustable)
Corticosteroids may remain unchanged, be 
initiated, be increased, or be decreased during 
this time. The increased dose, if needed, must 
occur within the first two weeks after the Day 1. 
The total daily prednisone equivalent dosage but
The LTE was 
added into the 
study.
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decreased during this time. The 
increased dose, if needed, must 
occur within the first two weeks after 
the Day 1. The total daily prednisone 
equivalent dosage must not be 
higher than 30 mg/day at the Week 4 
Visit.
must not be no higher than 30 mg/day(<) the 
Day 1 CS dose  at the Week 4 Visit.
Additional 
information was 
added on 
corticosteroid use 
during the LTE.
6.4.2.1 
Corticosteroid Use 
as Standard of Care
69
-
LTE Period
Corticosteroid
doses may be initiated or 
increased up to 30 mg/day prednisone 
equivalent, decreased, or remain the same. 
Investigators are strongly encouraged to 
decrease the CS dose of the subject as much 
as tolerated.
The LTE was 
added into the 
study.
Additional 
information was 
added on 
corticosteroid use 
during the LTE.
6.4.2.2 
Corticosteroid Use 
as Rescue 
Medication in 
Treatment of Flare
70
Corticosteroid 
Dose 
Increases 
and Treatment of Flares
Subjects may increase the CS dose 
up to 30 mg/day only two times as 
rescue for worsening of SLE activity 
or for other reasons. Each rescue is 
allowed only once during each of the 
following two time periods: 1) once 
between Week 8 to Week 16; and 2) 
once between Week 24 to Week 40. 
The CS dose can be increased up to 
prednisone-equivalent 30 mg/day, 
but must be returned to ≤ Week 8 
dose (Threshold Dose) within seven 
days. A CS dose increase must not 
to be initiated within one week of a 
planned study visit. CS medications 
are part of the subject’s previous 
SLE treatment and thus will not be 
provided by the Sponsor. Doses for 
treatment of flares beyond these 
allowable rescue doses will result in 
the subject being considered a 
treatment failure, and withdrawal 
from the study (see Section 5.5.1).
Corticosteroid Dose Increases and Treatment 
of Flares: DBPC Treatment Period
Subjects may increase the CS dose up to 
30 mg/day only two times as rescue for worsening 
of SLE activity or for other reasons. during the 
DBPC Treatment Period of the study. Each 
rescue is allowed only once during each of the 
following two time periods: 1) once between 
Week 8 to Week 16; and 2) once between Week 
24 to Week 40. The CS dose can be increased up 
to prednisone-equivalent 30 mg/day, but must be 
returned to ≤ Week 8 dose (Threshold Dose) 
within seven days. A CS dose increase must not 
to be initiated within one week of a planned study 
visit. A single dose of intramuscular steroid, no 
more than 80 mg of prednisolone equivalent, 
is permitted prior to the twelfth week of the 
DBPC Period. CS medications are part of the 
subject’s previous SLE treatment and thus will not 
be provided by the Sponsor. Doses for treatment 
of flares beyond these allowable rescue doses will 
result in the subject being considered a treatment 
failure, and withdrawal from the study (see 
Section 5.5.1).
Corticosteroid Dose Increases and Treatment 
of Flares: LTE Treatment Period
During the LTE Period, CS doses up to 
30 mg/day are permitted. In addition, a single 
The LTE was 
added into the 
study.
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dose of intramuscular steroid, no more than 
80 mg of prednisolone equivalent, is permitted 
prior to the twelfth week of the LTE Period. CS 
medications are part of the subject’s previous 
SLE treatment and thus will not be provided by 
the Sponsor. 
If medications which are not permitted (as per 
Section 6.5.2) are required to treat the flare, 
and/or the flare has been ongoing between 
2 visits at least 12 weeks apart without 
improvement, the subject must be discussed 
with the Medical Monitor to determine if the 
subject should be considered a treatment 
failure, and must be withdrawn from the study 
(see Section 5.5.1).
Additional 
information was 
added on 
corticosteroid use 
during the LTE.
6.5.1.2 
Non-Systemic 
Corticosteroids
70
Non-systemic 
corticosteroid 
medications in this study are defined 
as otic, topical, intranasal, inhaled, 
and ophthalmic. There are no 
restrictions 
on 
non-systemic 
corticosteroid dosing. However, all 
injected corticosteroids, including 
local injections (e.g., intra-articular 
injections) are not permitted.
Non-systemic corticosteroid medications in this 
study are defined as otic, topical, intranasal, 
inhaled, and ophthalmic. There are no restrictions 
on non-systemic corticosteroid dosing. However, 
all 
injected 
corticosteroids, 
including 
local 
injections (e.g., intra-articular injections) are not 
permitted. with the exception of a single dose 
of intramuscular steroid, no more than 80 mg 
of prednisolone equivalent prior to the twelfth 
week of the DBPC Treatment Period and once 
during the LTE Period (prior to the twelfth 
week).
The LTE was 
added into the 
study.
Clarification was 
added for the use 
of low dose 
aspirin.
6.5.1.4 Additional 
Permitted 
Medications
71
•Low-dose aspirin (≤ 350 mg/day) for 
cardiovascular prophylaxis.
•Low-dose 
aspirin 
(≤ 
350 
mg/day) 
for 
cardiovascular prophylaxis. Low-dose aspirin 
for other indications may be permitted after 
discussion with medical monitor.
To allow inclusion, 
after medical 
review, of subjects 
for whom low-dose 
aspirin is SoC for 
reasons other than 
cardioprotection.
Additional 
information was 
added due to the 
addition of the 
LTE.
6.5.1.4 Additional 
Permitted 
Medications
71
•Opioids are permitted for stable use 
for SLE if initiated by Day 1. Initiation 
of opioids and/or dosing of opioids 
as needed after Day 1 for SLE is not 
permitted. 
•Opioids are permitted for stable use for SLE if 
initiated by Day 1. Initiation of opioids and/or 
dosing of opioids as needed after Day 1 for SLE 
is not permitted during the DBPC Treatment 
Period. 
The LTE was 
added into the 
study.
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Additional 
information was 
added due to the 
addition of the 
LTE.
6.5.1.4 Additional 
Permitted 
Medications
72
-
•During the LTE Period: 
o 
If 
a 
subject 
is 
on 
an 
immunosuppressant/immunomodulator 
when they rollover into the LTE Period, 
the dosage may be decreased or remain 
the same. After Week 24 of the LTE 
Period, the dosage regimen for an 
immunosuppressant/ 
immunomodulator may be increased up 
to the limits permitted in Table 7 or 
initiated 
as 
long 
as 
only 
1 immunosuppressant is used. 
o Antimalarials may be initiated, increased, 
decreased, or remain the same
o
NSAIDs for SLE may be initiated, 
increased, decreased, or remain the 
same.
o
Opioids may be initiated, increased, or 
decreased.
o
NSAIDs and paracetamol may also be 
used for symptoms not due to SLE. It is 
strongly recommended that analgesics 
(including opioids), paracetamol, and 
NSAIDs are unchanged 24 hours prior to 
study visits when SLE assessments are 
completed (see SoA).
The LTE was 
added into the 
study.
Additional 
information was 
added due to the 
addition of the 
LTE.
6.5.2 Prohibited
Medicines
73
•New therapies for SLE should not 
be 
initiated 
during 
the 
study. 
Initiation 
of 
any 
new 
immunosuppressant 
or 
immunomodulatory therapy would 
be considered a treatment failure 
and result in withdrawal of the 
subject 
from 
the 
IMP 
(see 
Section 5.5).
•New therapies for SLE should not be initiated 
during Screening or DBPC Treatment Period of
the 
study. 
Initiation 
of 
any 
new 
immunosuppressant 
or 
immunomodulatory 
therapy would be considered a treatment failure 
and result in withdrawal of the subject from the 
IMP during the DBPC Treatment Period (see 
Section 5.5). 
For 
the 
LTE 
Period, 
see 
Section 6.4.1.
The LTE was 
added into the 
study.
Additional 
information was 
added due to the 
addition of the 
LTE.
6.5.3 Other 
Interventions
74
Use 
of 
potentially 
excluded 
procedures such as acupuncture or 
joint replacement therapy is to be 
discussed with the Sponsor or 
designee on a case-by-case basis. 
Use of acupuncture is allowed to 
continue if it is started before the 
Use of potentially excluded procedures such as 
acupuncture or joint replacement therapy is to be 
discussed with the Sponsor or designee on a 
case-by-case basis. Use of acupuncture is 
allowed to continue if it is started before the 
Screening Visit and may be initiated/and or 
modified during the LTE Period. Major elective 
The LTE was 
added into the 
study.
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Screening 
Visit. 
Major 
elective 
surgeries 
such 
as 
abdominal, 
thoracic 
or 
joint 
replacement 
surgeries should not be planned to 
occur 
in 
the 
Study 
Period. 
Unplanned 
joint 
replacement 
surgery should be discussed at the 
earliest opportunity prior to the 
surgery with the Medical Monitor 
regarding continuation of the subject 
in the study.
surgeries such as abdominal, thoracic or joint 
replacement surgeries should not be planned to 
occur in the Study Period. Unplanned joint 
replacement surgery should be discussed at the 
earliest opportunity prior to the surgery with the 
Medical Monitor regarding continuation of the 
subject in the study.
C3 and C4 were 
added to Section 
6.10.
6.10 Blinding
77
These analyses will include:  total Ig 
(IgA, IgM, and IgG), IgG subclasses, 
anti-dsDNA, 
ANA, 
other 
autoantibodies (anticardiolipin, anti 
Smith 
antibody 
[anti 
Sm]; 
an 
antibody to ribonucleoproteins; and 
antinuclear antibodies associated 
with autoimmune diseases including 
Sjögren syndrome and SLE [anti-Ro, 
anti-La]), and cell counts by flow 
cytometry (total B cells and B cell 
subsets).
These analyses will include:  total Ig (IgA, IgM, 
and IgG), IgG subclasses, C3, C4, anti-dsDNA, 
ANA, other autoantibodies (anticardiolipin, anti 
Smith antibody [anti Sm]; an antibody to 
ribonucleoproteins; and antinuclear antibodies 
associated with autoimmune diseases including 
Sjögren syndrome and SLE [anti-Ro, anti-La]), 
and cell counts by flow cytometry (total B cells and 
B cell subsets).
Updated to align 
with text from 
Section 7.5.2. 
Additional text 
related to the 
LTE was added.
6.10 Blinding
77-78
An IA for futility will be triggered 
when 
100% 
of 
the 
planned 
enrollment required for the primary 
analysis reaches 24 weeks of 
treatment, or discontinues treatment 
prematurely. The IDMC will be fully 
unblinded to treatment and will make 
a recommendation, as described in 
the IDMC charter. A limited set of 
endpoints will be analyzed for the IA, 
including Week 24 SRI-4 response 
for the whole study population and 
Week 24 SRI-6 response for the 
HDA subgroup. 
If the planned enrollment required for 
the primary analysis is slower than 
expected, consideration will be given 
to conducting the interim futility 
analysis at an earlier time point, 
An IA for futility willmay be triggered when 100% 
of the planned enrollment required for the primary 
analysis reaches 24 weeks of treatment, or 
discontinues treatment prematurely.
prior to 
Week 24. The IDMC will be fully unblinded to 
treatment and will make a recommendation, as 
described in the IDMC charter. A limited set of 
endpoints will be analyzed for the IA, including 
Week 24 SRI-4 response for the whole study 
population and Week 24 SRI-6 response for the 
HDA subgroup. 
If the planned enrollment required for the primary 
analysis is slower than expected, consideration 
will be given to conducting the interim futility 
analysis at an earlier time point, when the first 
50% of subjects enrolled of the planned 
enrollment reach 24 weeks of treatment, or 
discontinue treatment prematurely.
prior to 
Week 24. The unblinding procedures specified 
The LTE was 
added into the 
study.
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when the first 50% of subjects 
enrolled of the planned enrollment 
reach 24 weeks of treatment, or 
discontinue treatment prematurely. 
The unblinding procedures specified 
above will be followed, regardless of 
the timing of the interim futility 
analysis.
The 
primary 
analysis 
will 
be 
triggered when 100% of subjects in 
the n = 432 cohort have completed 
safety 
follow 
up, 
or 
have 
discontinued 
study 
prematurely. 
Only when the last subject in the 
n = 432 cohort completes safety 
follow-up or discontinues from the 
study prematurely, the protocol 
violations are determined, and the 
database is locked, will the drug 
codes be broken and made available 
for the data analysis.
If the Japan cohort enrollment is 
slow and cannot be fully included in 
the n = 432 enrollment planned for 
the primary analysis, a third analysis 
(occurring after the primary analysis) 
will be scheduled for the purpose of 
analyzing the entire Japan cohort. 
Only when the last subject in the 
Japan 
cohort 
completes 
safety 
follow-up or discontinues from the 
study prematurely,
the protocol 
violations are determined, and the 
database is locked, will the drug 
codes be broken for the Japanese 
subjects not included in the primary 
analysis, and made available for the 
third data analysis evaluating the 
consistency of efficacy with respect 
to non-Japan and Japan regions.
The 
bioanalytical 
laboratory(ies) 
responsible for the analysis of the 
above will be followed, regardless of the timing of 
the interim futility analysis.
The primary analysis will be triggered when 100% 
of subjects in the n = 432 cohort have completed 
safety follow up, or have discontinued study 
prematurely. Only when the last subject in the 
n = 432 cohort completes safety follow-up or 
discontinues from the study prematurelyOnly 
when the trigger event for the primary analysis 
(Section 5.1) is reached, the protocol violations 
are determined, and the database is locked, will 
the drug codes be broken and made available for 
the dataprimary analysis.
If the Japan cohort enrollment is slow and cannot 
be fully included in the n = 432 enrollment planned 
for 
the
primary 
analysis 
cohort, 
a 
third 
analysisconsistency analysis (occurring after 
the primary analysis) will be scheduled for the 
purpose of analyzing the entire Japan cohort. 
Only when the last subject intrigger event for the 
Japan cohort completes safety follow-up or 
discontinues 
from 
the 
study 
prematurelyconsistency analysis (Section 5.1) 
is 
reached, 
the 
protocol 
violations 
are 
determined, and the database is locked, will the 
drug codes be broken for the Japanese subjects 
not included in the primary analysis, and made 
available for the third data analysis evaluating 
thetreatment 
effect
consistency 
of 
efficacyanalysis with respect to non-Japan and 
Japan regions.
 
 
 
 
 
 
 
 
 
 
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.
 
 
 
 
 
 
 
 
 
Clarification was 
added to the 
overdose text.
6.12 Treatment of 
Overdose
79
An overdose is defined as any dose 
greater than the highest total daily 
dose included in a CTP or planned 
for an individual subject enrolled in 
the study. Any overdose must be 
recorded in the study medication 
section of the eCRF.
An overdose is defined as any dose greater than 
the highest total daily dose included in a CTP or 
planned for an individual subject enrolled in the 
study.
 
 
 
 
 
 
 
Any overdose 
must be recorded in the study medication section 
of the eCRF.
Updated to be in 
alignment with 
Section 6.2 and 
provide flexibility 
for subject 
scheduling
Updated to 
include 
unanticipated 
events.
7.1.1 Screening Visit
80-81
When a laboratory test needs to be 
repeated 
during 
the 
Screening 
Period, the Screening Period may be 
extended to 8 weeks after discussion 
with the Medical Monitor.
When a laboratory test needs to be repeated 
during the Screening Period, or to accommodate 
other unanticipated events,
the Screening 
Period may be extended to 8 weeks after 
discussion with the Medical Monitor.
To allow flexibility 
for unanticipated 
events.
Updated due to 
addition of LTE.
7.1.2 Treatment 
Period
81
7.1.2 Treatment Period
7.1.2 DBPC Treatment Period
The LTE was 
added into the 
study.
Updated due to 
addition of LTE.
7.1.2.1 End of 
Treatment/Early 
Withdrawal Visit
81
7.1.2.1 End 
of 
Treatment/Early 
Withdrawal Visit
The EOT Visit is scheduled on the 
last day of administration of study 
7.1.2.1 DBPC
End 
of 
Treatment/Early 
Withdrawal Visit
The EOT Visit is scheduled on the last day of 
administration of study treatment. The EOT Visit 
The LTE was 
added into the 
study.
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treatment. The EOT Visit will include 
a full assessment for safety (e.g., 
physical examination, vital signs, 
weight, hematology and chemistry), 
and other assessments as described 
in Table 1
will include a full assessment for safety (e.g., 
physical 
examination, 
vital 
signs, 
weight, 
hematology 
and 
chemistry), 
and 
other 
assessments as described in Table 1. Subjects
who complete the End of Treatment Visit will 
be given the opportunity to participate in the 
LTE Period.
Updated due to 
addition of LTE.
7.1.3 LTE Period
81
-
7.1.3 LTE Period
Subjects who completed the 52-week DBPC 
Treatment period will be offered participation 
in the open-label, LTE Period of the study as 
described in Section 5.1. The Investigator will 
obtain written informed consent for the LTE.
At all applicable visits, patient-reported 
outcome questionnaires must be performed 
prior to any other assessments. Scheduled 
assessments will be performed according to 
Table 2.
All scheduled visits during the LTE Period 
may take place within the visit windows 
specified in Table 2. Subjects who discontinue 
early must return for the LTE End of 
Treatment/Early Withdrawal Visit and Safety 
Follow -up Visit. 
For WOCBP, additional highly sensitive urine 
pregnancy testing will be performed at home 
per SOA, Table 3. Urine pregnancy test kits 
will be provided to the subject at Week 16 (for 
testing at Week 20), Week 24 (for testing at 
Week 28, 32, and 36), Week 40 (for testing at 
Week 44 and 48), Week 52 (for testing at Week 
56, 60, 64, 68, and 72), and Week 76 (for testing 
at Week 80, 84, 88, 92, 96, and 100).At and/or 
prior to the Week 16 visit, the PI and/or 
delegated site staff will train the relevant 
subjects 
to 
self-administer 
the 
urine 
pregnancy tests and will confirm completion 
of urine pregnancy testing and discuss results 
per Table 3.
The LTE was 
added into the 
study.
Updated due to 
addition of LTE.
7.1.3.1 LTE End of 
Treatment Visit
81
7.1.3.1 LTE End of Treatment Visit
The LTE End of Treatment Visit will be 
performed at Week 104 or within 5 days of 
The LTE was
added into the 
study.
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early discontinuation of treatment with the 
IMP. Subjects will undergo assessments as 
described in Table 2. In case of premature 
discontinuation, the PRO assessments must 
be completed at the LTE End of Treatment 
Visit. Subjects will enter the Safety Follow-Up 
Period after completing the LTE End of 
Treatment Visit.
Updated due to 
addition of LTE.
7.1.4 Safety 
Follow-Up/End of 
Study Visit
81
The Safety Follow Up/End of Study 
Visit 
is 
scheduled 
four weeks 
(+ 5 days) 
after 
the 
last 
administration of study treatment. 
Additional details of the Safety 
Follow Up/ End of Study Visit are 
provided in the SOA. Subjects who 
discontinue the IMP or withdraw 
from the trial early will attend the 
Safety Follow Up Visit according to 
procedures described in Sections 
5.5.1 or 5.5.2, respectively.
The Safety Follow-Up/End of Study Visit is 
scheduled four  weeks (+ 5 days) after the last 
administration of study treatment. For subjects 
who do not participate in the LTE Period, the 
Safety Follow-Up Visit is scheduled four 
weeks (+ 5 days) after the last administration 
of study treatment in the DBPC Period. For 
subjects who participate in the LTE Period, the 
Safety Follow-Up Visit is delayed until four 
weeks (+ 5 days) after the last administration 
of study treatment in the LTE Period. Subjects 
who are approved to rollover into LTE Period 
after they entered, or completed, the DBPC 
Safety Follow-Up Period, may have two Safety 
Follow-Up Visits. Additional details of the Safety 
Follow-Up/ End of Study Visit are provided in the 
SOA.
The LTE was 
added into the 
study.
Clarification was 
added to AEs 
related to flares.
7.4.1.1 Adverse 
Event Definitions
91
SLE flares would not usually be 
reported as AEs unless they are 
unexpected in the context of the 
subject’s medical history. SAEs due 
to SLE are always reported whether 
or not consistent with the subject’s 
prior medical history.
SLE flares would not usually be reported as AEs 
unless they are unexpected in the context of the 
subject’s medical history. Further, the AE report 
should describe the event, rather than 
reporting an AE of “SLE flare” unless it is 
unavoidable. SAEs due to SLE flare are always 
reported, whether or not it is consistent with the 
subject’s’ prior medical
history. As for AE 
reports, the SAE report should describe the 
events, and avoid reporting an SAE of "SLE 
flare".
Clarification 
added.
Updated due to 
addition of LTE.
7.4.1.3 Definition of 
the Adverse Event 
Reporting Period
92
For subjects entering the LTE study, 
if conducted, safety reporting for this 
trial would end upon the subject’s 
enrollment into the LTE study, with 
subsequent AEs being reported in 
the LTE study.
For subjects entering the LTE study, if conducted, 
safety reporting for this trial would end upon the 
subject’s enrollment into the LTE study, with 
subsequent AEs being reported in the LTE study.
The LTE was 
added into the 
study.
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Additional text 
was added 
regarding local 
safety testing.
7.4.3 Clinical 
Laboratory 
Assessments
95
-
Local safety testing as requested by the study 
team should be entered into the eCRF.
Added to permit 
inclusion of local 
safety testing 
results requested 
by study team into 
the database.
Clarification on 
anti-dsDNA 
assay was 
added.
7.4.3.1.1 
Immunological 
Assessments
96
•Anti-dsDNA
•Anti-dsDNA (at Screening, may be measured 
using 2 assays, 1 of which is a multiplex assay 
that includes anti-Ro and anti-RNP. Only 
anti-dsDNA is used to determine subject 
eligibility and will be reported to the sites.)
Clarification was 
added as anti-Ro 
and anti-RNP are 
run by nature of 
the assay used for 
anti-dsDNA.
Updated due to 
addition of LTE.
Minor error 
updated.
Updated due to 
addition of LTE.
8.1 Sample Size
103
-
Approximately 432 subjects will enter the main 
study. Assuming an 80% rate of continuation 
to LTE, approximately 346 subjects are 
expected to enter the LTE Period.
The LTE was 
added into the 
study.
Updated due to 
addition of LTE.
8.4 Analysis Sets
107
-
Long Term Extension Analysis Set
The LTE Analysis Set consists of all subjects 
who receive at least one dose of M2951 during 
the LTE.
The LTE was 
added into the 
study.
Updated due to 
addition of LTE.
8.5.1 General 
Considerations
109-
110
For SRI-4 or SRI-6 response at 
Week 52 (Week 24), a subject 
experiencing flare or CS dose 
increase during Weeks 41 to 52 
(Weeks 17 to 24), or a subject with a 
missing response at Week 52, will be 
considered a non-responder. Four 
sensitivity analyses of the primary
analysis are planned:  (1) unadjusted 
analysis, 
(2) 
non-responder 
imputation 
for 
treatment 
discontinuers, with last observation 
carried 
forward 
imputation 
for 
treatment completers with missing 
response (NR LOCF), (3) completer 
For SRI-4 or SRI-6 response at Week 52 (Week 
24), a subject experiencing flare or CS dose 
increase during Weeks 41 to 52 (Weeks 17 to 24), 
or a subject with a missing response at Week 52, 
(Week 24), will be considered a non-responder. 
Four sensitivity analyses of the primary analysis 
are planned:  (1) unadjusted analysis, (2)
non-responder 
imputation 
for 
subjects 
discontinuing
treatment 
discontinuersfor 
reasons due to efficacy/safety, with last 
observation 
carried 
forwardavailable 
observations used (in MMRM or multiple
imputation) for subjects discontinuing treatment 
completersfor 
reasons 
unrelated 
to 
efficacy/safety or completing treatment with 
The LTE was 
added into the 
study.
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analysis, and (4) PP analysis (i.e., 
excluding subjects with clinically 
important 
protocol 
violations). 
Additional procedures for handling 
missing, unused, or spurious data, 
and sensitivity analyses exploring 
the impact of missing data will be 
described in the SAP.
missing response (NR-LOCF), (at Week 52, (2) 
unadjusted analysis, (3) completer analysis, and 
(4) PPper-protocol
analysis (i.e., excluding 
subjects 
with 
clinically 
important 
protocol 
violations). Additional procedures for handling 
missing, unused, or spurious data, and sensitivity 
analyses exploring the impact of missing data will 
be described in the SIAP.
Additional details 
on 
non-responders 
were added.
8.5.2 Analysis of 
Primary Endpoints
110
-
In the primary analysis of SRI-4 or SRI-6 
response at Week 52, a subject experiencing 
flare or CS dose increase during Weeks 41 to 
52, or a subject with a missing response at 
Week 52, will be considered a non-responder.
To align with 
updated analyses.
The analysis of 
the primary 
endpoint was 
updated based 
on the addition of 
the LTE.
8.5.2 Analysis of 
Primary Endpoints
110
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For a given co primary endpoint, the p-value 
testing the one-sided null hypothesis H0: OR ≤ 1.0 
for each M2951 dose group will be reported, 
where OR denotes odds ratio comparing a given 
M2951 dose group to placebo. The FWER, i.e., 
overall type I error rate for the analysis of each 
co-primary endpoint, will be controlled at the 
one-sided α = 0.0125 level by testing the three 
hypotheses, corresponding to the three M2951 
dose groups, via a hierarchical hypothesis testing 
procedure, in which the M2951 dose groups are 
compared to placebo from highest to lowest dose, 
and where formal comparisons are terminated at 
the first hypothesis test that results in a non 
significant p value. After a non-significant p-value, 
subsequent hypothesis tests in a hierarchy will be 
considered 
The Family-Wise type 1 error rate (FWER) due 
to the co-primary endpoints and multiple 
M2951 dose group comparisons versus 
placebo will be controlled at the two-sided 
α = 0.05 
level 
via 
a 
tree 
gatekeeping 
procedure. The four hypotheses associated 
with 
the 
comparisons 
involving 
the 
co-primary endpoints and the two highest 
dose groups will form the first family of 
hypotheses in the tree.  This family will be 
tested via the truncated Hochberg procedure, 
with truncation fraction pre-specified in the 
The LTE was 
added into the 
study.
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IAP. The multiple-testing procedure for the 
remainder 
of 
the 
tree, 
including 
the 
hypotheses associated with the comparisons 
involving the co-primary endpoints and the 
lowest dose group will be specified in the IAP.
The analysis of 
the secondary 
endpoint was 
updated based 
on the addition of 
the LTE.
8.5.3 Analysis of 
Secondary Endpoint
111
Key Secondary Endpoints
Time to first severe (BILAG A) flare 
during the Treatment Period will be
modeled via a Cox regression, with 
treatment group as a factor, and 
controlling for covariates defining 
randomization strata. A subject who 
discontinues treatment or completes 
treatment 
without 
experiencing 
severe flare will have his/her time to 
flare censored at the last time point 
at which flare could be assessed. A 
test for trend in dose-response, 
using the same Cox model, will be 
reported as a supportive analysis.
SRI-4 response at Week 52 among 
serologically active subjects will be 
an estimate of OR, together with 
associated 
two-sided 
CI 
and 
p-value, comparing each M2951 
dose group to placebo, based on a 
logistic model for the odds SRI-4 
response in the serologically active 
population, with M2951 dose group 
or placebo group as a factor and 
adjustment for covariates based on 
randomization strata. 
Descriptive 
statistics 
for 
SRI-4 
response in the serologically active 
subgroup, will be provided for each 
treatment group by time point. 
Other 
Secondary 
Efficacy 
Endpoints
In the analysis of other secondary 
efficacy
endpoints described 
in
Section 8.3.2, binary endpoints will 
be modeled via logistic regression, 
Key Secondary Endpoints
Time to first severe (BILAG A) flare during the 
Treatment Period in all subjects will be modeled
compared between M2951 and placebo via a 
stratified log rank test. The adjusted hazard 
ratio comparing M2951 to placebo will be 
estimated (together with 95% CI) via a Cox 
regression model, with treatment group as a 
factor, and controlling for covariates defining 
randomization strata. A subject who discontinues 
treatment 
or 
completes 
treatment 
without 
experiencing severe flare will have his/her time to 
flare censored at the last time point at which flare 
could be assessed. A test for trend in 
dose-response, using the same Cox model, will 
be 
reported 
as 
a 
supportive 
analysis. 
Kaplan-Meier estimates of probability of 
surviving free of severe (BILAG A) flare as a 
function of time on treatment will be provided 
for each treatment group.
The analysis of SRI-4 response at Week 52 
among serologically active subjects will be an 
estimate of OR, together with associated 
two-sided 95% CI and p-value, comparing each 
M2951 dose group to placebo, based on a logistic 
model for the odds SRI-4 response in the 
serologically active population, with M2951 dose 
group or placebo group as a factor and 
adjustment for covariates based on randomization 
strata. A test for trend in dose-response, using 
the same logistic model, will be reported as a 
supportive analysis.
Descriptive statistics for SRI-4 response in the 
serologically active subgroup, will be provided for 
each treatment group by time point. 
Other Secondary Efficacy Endpoints
The LTE was 
added into the 
study.
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time to event endpoints will be 
modeled 
via 
Cox 
regression, 
continuous 
endpoints 
measured 
longitudinally will be analyzed using 
Mixed effect Model for Repeated 
Measures 
(MMRM), 
and 
count 
endpoints (i.e., annualized flare rate) 
will 
be 
modeled 
via 
negative 
binomial regression, with treatment 
group as a factor, and adjusting for 
covariates defining randomization 
strata. Analysis of annualized flare 
rate will use observation time (in 
years) as an offset in the model. 
Change 
in 
a 
binary 
endpoint 
between two time points will be 
analyzed via McNemar’s test. The 
effect of treatment on change in a 
binary endpoint will be analyzed via 
logistic regression, with treatment 
group, time point, and interaction as 
predictors, 
and 
adjusting 
for 
covariates defining randomization 
strata. All tests of efficacy will be 
conducted at a two-sided α level of 
0.05, 
with 
p-values 
considered 
nominal unless generated as part of 
a hierarchical testing strategy as 
described in the SAP. P values and 
the 95% CIs will be presented where 
applicable.
In the analysis of other secondary efficacy
endpoints described in Section 8.3.2, binary 
endpoints will be modeled via logistic regression, 
time to event endpoints will be modeled via Cox 
regression and tested via stratified log rank 
test, 
continuous 
endpoints 
measured 
longitudinally will be analyzed using Mixed effect 
Model for Repeated Measures (MMRM), and 
count endpoints (i.e., annualized flare rate) will be 
modeled via negative binomial regression, with 
treatment group as a factor, and adjusting for 
covariates defining randomization strata. Analysis 
of annualized flare rate will use the log of 
observation time (in years) as an offset in the 
model. Change in a binary endpoint between 
two time points will be analyzed via McNemar’s 
test. The effect of treatment on change in a binary 
endpoint will be analyzed via logistic regression, 
with treatment group, time point, and interaction 
as predictors, and adjusting for covariates 
defining randomization strata. All tests of efficacy 
will be conducted at a two-sided α level of 0.05, 
with 
p-values 
considered 
nominal 
unless 
generated as part of a hierarchical the tree 
gatekeeping 
multiple 
testing 
strategy 
as 
described in the SAP IAP. P values and the 
95% CIs will be presented where applicable.
Clarification 
added.
 
112
Updated for clarity.
Updated due to 
addition of LTE.
8.5.6 Analysis of 
LTE Endpoints
113
-
8.5.6 Analysis of LTE Endpoints
Efficacy and HRQoL data collected during the 
LTE Period will be summarized. Details will be 
provided in the IAP.
Safety data collected during the LTE Period 
will be analyzed as described in Section 8.5.4.
The LTE was 
added into the 
study.
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A Phase II Study of M2951 in SLE
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Rationale
Updates added 
to the primary 
analysis cohort 
description.
8.6 Interim and 
Additional Planned
Analyses
114
There will be an IA for futility based 
on the highest dose of M2951, 
triggered when 100% of subjects 
enrolled in the n = 432 cohort reach 
Week 
24 
of 
treatment, 
or 
prematurely 
discontinue 
from 
treatment. If enrollment is sufficiently 
slow, consideration will be given to 
triggering the IA at an earlier time 
point, when the first 50% of subjects 
enrolled in the n = 432 cohort reach 
Week 
24 
of 
treatment, 
or 
prematurely 
discontinue 
from 
treatment. Pharmacokinetic analysis 
will not be included in the IA.
The difference between Week 24 
SRI-4 response proportion in all 
subjects in the n = 432 cohort, 
comparing the highest dose of 
M2951 to placebo, will be estimated, 
together with a two-sided 97.5% 
confidence interval. Similarly, the 
difference between Week 24 SRI-6 
response proportion in HDA subjects 
in the n = 432 cohort, comparing the 
highest dose of M2951 to placebo, 
will be estimated, together with a 
two-sided 
97.5% 
confidence 
interval. If the response proportion 
difference 
for 
both 
co-primary 
endpoints is sufficiently low, as 
defined in the SAP, consideration 
will be given to termination of the 
study, in which case all subjects will 
be discontinued from IMP and 
scheduled for a four week Safety 
Follow Up Visit/End of Study Visit.
Descriptive statistics for the Week 24 
SRI-4 response endpoint in all 
subjects in the n = 432 cohort, and 
for the Week 24 SRI-6 response 
endpoint in HDA subjects in the 
There willmay be an IA for futility based on the 
highest dose of M2951, triggered when 100% of 
subjects enrolled in the n = 432primary analysis
cohort 
reach 
Week 
24 
of 
treatment, 
or 
prematurely discontinue from treatment prior to 
Week 24. If enrollment is sufficiently slow, 
consideration will be given to triggering the IA at 
an earlier time point, when the first 50% of 
subjects enrolled in the n = 432primary analysis
cohort 
reach 
Week 
24 
of 
treatment, 
or 
prematurely discontinue from treatment prior to 
Week 24. Pharmacokinetic analysis will not be 
included in the IA.
The difference between Week 24 SRI-4 response 
proportion in all subjects in the n = 432primary 
analysis cohort, comparing the highest dose of 
M2951 to placebo, will be estimated, together with 
a two-sided 97.5% confidence interval. Similarly, 
the difference between Week 24 SRI-6 response 
proportion in HDA subjects in the n = 432primary 
analysis cohort, comparing the highest dose of 
M2951 to placebo, will be estimated, together with 
a two-sided 97.5% confidence interval. If the 
response 
proportion 
difference 
for 
both 
co-primary endpoints is sufficiently low, as defined 
in the SIAP, consideration will be given to 
termination of the study, in which case all subjects 
will be discontinued from IMP and scheduled for a 
four week Safety Follow-Up Visit/End of Study 
Visit.
Descriptive statistics for the Week 24 SRI-4 
response endpoint in all subjects in the 
n = 432primary analysis cohort, and for the 
Week 24 SRI-6 response endpoint in HDA 
subjects in the n = 432primary analysis cohort, 
will be presented by treatment group.
Drop-out rates 
unrelated to 
efficacy or safety 
are higher than 
anticipated.
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n = 432 cohort, will be presented by 
treatment group.
Updated due to 
addition of LTE.
8.6 Interim and 
Additional Planned 
Analyses
114
Primary Analysis
The primary analysis will occur only 
when the last subject in the n = 432 
cohort completes all study parts, the 
protocol violations are determined, 
and the database is locked.
Third Analysis
The 
third 
analysis, 
evaluating 
efficacy consistency between the 
non-Japan and Japan regions, may 
be performed if the Japan cohort 
enrollment is too slow for the 
consistency evaluation to take place 
at the time of the primary analysis. 
The third analysis will occur only 
when the last subject in the Japan 
cohort completes all study parts, the 
protocol violations are determined, 
and the database is locked.
Primary Analysis
The primary analysis will occur only when the last 
subject in the n = 432 cohort completes all study 
partsprimary analysis trigger event (Section 
5.1) has occurred, the protocol violations are 
determined, and the database is locked.
Third AnalysisConsistency Analysis
The third
A separate
analysis, evaluating efficacy
of 
treatment effect consistency between the non-
Japan and Japan regions, may be performed if the 
Japan cohort enrollment is too slow for the 
consistency evaluation to take place at the time of 
the primary analysis. The thirdThis analysis will 
occur only when the last subject in the Japan 
cohort completes all study partsconsistency 
analysis trigger event (Section 5.1) has 
occurred, the protocol violations are determined, 
and the database is locked.
Final Analysis
The final analysis will occur only when the last 
subject completes all study parts (including 
the LTE and Safety Follow-Up Visits) or 
discontinues 
prematurely, 
the 
protocol 
violations are determined, and the database is 
locked.
The LTE was 
added into the 
study.
Clarification was 
added to the 
contraceptive 
guidance.
Appendix 1 
Contraceptive 
Guidance and 
Women of 
Childbearing 
Potential 
128
•Male or female condom with or 
without spermicidec
•Cap, diaphragm, or sponge with 
spermicidec
…
c. Not approved in Japan apart from 
male condom. 
•Male or female condom with or without 
spermicidecd
•Cap, diaphragm, or sponge with spermicidec
…
c. Not approved in Japan apart from.
d. For Japan only – the only approved barrier 
method is apart from male condom with 
spermicide. 
The approved 
methods are 
different for Japan 
versus the rest of 
the world.
'RFXPHQW1R

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
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
193/205
Updated Schedule of Assessments and Updated Protocol Amendment List
Updated Schedule of Assessments 
Schedule of Assessments; Screening and Treatment Period (All Subjects), End of Study (Subjects Not Entering LTE Period)
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
uUp/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-3/+5
Informed consent
X
LTE informed 
consent
X
Inclusion/exclusion 
criteria
X
Xb
Demographics and 
medical historyc
X
Chest X-rayd
X
12-lead ECG
X
X
X
X
X
X
Xe
Physical 
examination
X
Xf
Xg
Xg
Xg
Xg
Xg
Xg
X
Xh
Xh
Xh
Xh
Xh
Xh
X
X g
Vital signs, weight, 
height i
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SFI, SLEDAI-2K, 
PGA, BILAG 2004, 
CLASI
X
Xf
Xj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
'RFXPHQW1R

2EMHFW1R

CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
194/205
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
uUp/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-3/+5
SLICC/ACR 
Damage Index
Xf
X
C-SSRS
X
X
X
X
X
X
X
X
X
IMP 
administrationk
Daily administration of IMP
Urinalysis and 
microscopy
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Routine 
hematology, 
chemistrym
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X 
X
Supplementary 
LFTsn
X
X
X
Total Ig Levels 
(IgG, IgA, IgM)
X
Xf
X
X
X
X
X
X
X
Total B cell counto
Xp
Xf
Xf
Xf
Xf
X
Coagulation (INR, 
PTT)
X
HIVq, HCV, and 
HBV testing
X
Reflex testing for 
HBV DNAr
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy 
and FSH testings
X
'RFXPHQW1R

2EMHFW1R

CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
195/205
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
uUp/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-3/+5
Serum β-D-glucant
X
TSH
X
Tuberculosis 
assessmentl
X
Urine pregnancy 
tests
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
UPCR
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36v2, 
LupusQoL, FACIT-
Fatigue, EQ-5D-
5Lu
X
X
X
X
X
X
X
X
X
X
HRU
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGICu
X
X
X
X
X
X
X
X
X
Dispense IMP 
X
Dispense as needed, using IWRS
Dispense subject 
diary 
X
Dispense as needed.
Concomitant 
medications / 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
'RFXPHQW1R

2EMHFW1R

CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
196/205
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
uUp/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-3/+5
Immunological Assessments
Anti-dsDNA, 
Complement 
(C3, C4), CRP
X
Xf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ANA, anti-Sm
X
Autoantibodies
X
X
X
X
'RFXPHQW1R

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
CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
197/205
Trial Period
Screening
Visit Weeks During Treatment Period
Follow-Up Visit 
4 weeks
Post-Last 
Dosea
Week
0
2
4
6
8
10
12
14
16
20
24
28
32
36
40
44
48
52/
EOT/Early 
Withdrawal
56/
Safety Follow-
uUp/End of 
Study
Trial Day
-28 to -1
1
15
29
43
57
71
85
99
113
141
169
197
225
253
281
309
337
365
393
Visit
Day 
1
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
20
Wk
24
Wk
28
Wk
32
Wk
36
Wk
40
Wk
44
Wk
48
Wk
52
Wk
56
Visit window 
(±day)
+7
-
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
-3/+5
ACR -= American College of Rheumatology;, ALT -= alanine aminotransferase;, ANA -= Antinuclear Antibody(ies);, Anti-dsDNA -= Anti-Double-Stranded 
Deoxyribonucleic Acid;, Anti-Sm –= anti-Smith antibody;, AST -= aspartate aminotransferase;, BILAG -= British Isles Lupus Assessment Group;, BP –= blood 
pressure;,
;, CLASI -= Cutaneous Lupus Erythematosus Disease Area and Severity Index;, CRP –= C-Reactive Protein;,
C-SSRS -= Columbia-Suicide Severity Rating Scale;, DNA -= deoxyribonucleic acid;, ECG -= Electrocardiogram;, EOT -= End of Treatment;, EQ-5D-5L -
= EuroQoL 5 Dimension 5 Levels;, FACIT -= Functional Assessment of Chronic Illness Therapy;, GGT -= γ-Glutamyl-transferase;, Ig -= Immunoglobulin;, IMP -
= Investigational Medicinal Product;, IWRS -= Interactive Web Response System;, HBV -= Hepatitis B Virus;, HCV -= Hepatitis C Virus;, HIV -= Human 
Immunodeficiency Virus;, HRQoL -= Health Related Quality of Life;, HRU -= Health Resource Utilization;, INR -= International Normalized Ratio;, LFT -= liver 
function test;, LTE = long-term extension, LupusQoL -= Lupus Quality of Life;, mRNA -= messenger Ribonucleic Acid;,
 PCR -= polymerase 
chain reaction;, PGA -= Physician’s Global Assessment;, PGIC -= Patient Global Impression of Change;,
;, PTT -= Partial Thromboplastin 
Time;, SF-36v2 -= Medical Outcomes Study 36-Item Short Form Health Survey;, SFI -= SLEDAI Flare Index;, SLEDAI-2K -= Systemic Lupus Erythematosus 
Disease Activity Index-2000;, SLICC -= Systemic Lupus International Collaborating Clinics;, TB -= tuberculosis;, TSH -= Thyroid Stimulating Hormone;, UPCR -
= Urine Protein To Creatinine Ratio;, Wk –= Week.
a
Safety Follow -Up Visits will be conducted at four weeks after the last dose of IMP for subjects who have been discontinued from IMP or have completed 
the 52-week Treatment Period, unless subjects have entered the LTE period.
b
Subject eligibility to be confirmed on Day 1 prior to randomization.
c
Medical history includes documentation of SLE classification criteria, SLE medical history, medications, and surgery/procedures (see Section 7.2.1).
d
The results of a chest X-ray performed within three months prior to the Screening Visit (if available) are acceptable, provided there is no reason to suspect 
any clinical changes, per Investigator discretion.
e
Only required if change noted at Wk52/EOT, when compared to Baseline ECG.
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
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CCI
CCI
CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
198/205
f
Predose sample/procedure to be collected/performed before the first daily dose.
g
Abbreviated physical examination at these visits (see Section 7.4.4.2).
h
Abbreviated physical examination may be performed at Primary Investigator discretion, as required to fully obtain information needed for the BILAG and/or 
SLEDAI assessments, if scheduled, as well as required to fully evaluate any subject complaints or adverse events. 
i
Vital signs include arterial BP, pulse rate, respiratory rate, and body temperature. Height will be measured at Screening only. Body weight will be 
measured with a balance beam scale, if possible. Pulse rate and BP will be measured after 10 minutes rest in the semisupine position with the subject’s 
arm unconstrained by clothing or other material. The BP should be assessed on the same arm for each subject throughout the study.
j
Only CLASI assessed at Week 2.
k
On Study Visit Days, IMP should be administered during the Study Visit; otherwise, IMP should be self-administered at home at a set time each day (every 
12 hours ± 2 hours). Investigational medicinal product administration at Week 52 will only occur for subjects rolling over into the LTE.
l
A Quantiferon test will be performed centrally. Prior TB testing results must be entered into the eCRF.
m
See Table 9Table 11 for list of clinical laboratory evaluations.
n
Supplementary LFTs include AST, ALT, alkaline phosphatase, GGT, and bilirubin.
p
To be collected at Screening only in subjects who have previously received B cell depleting therapy (see Exclusion Criterion 33, in Section 5.3.2).
q
HIV testing will be performed locally.
r
For subjects who are negative for hepatitis B surface antigen (HBsAg) but are anti-hepatitis B surface antibody positive and/or anti-hepatitis B core antibody 
positive, an HBV DNA PCR reflex test is to be completed at screening. If the subject enters is able to enter the study with positive HBV DNA negative OR 
has have detectable HBV DNA < 20 IU/mL only, additional HBV DNA PCR testing must be performed (see Exclusion criteria 20, in Section 5.3.2).
s
For women of childbearing potential or who are postmenopausal see inclusion criterion 7. A follicle-stimulating hormone (FSH) must be drawn at Screening 
if necessary to confirm postmenopausal status. The urine pregnancy test being used at all time points in this study must be a highly sensitive urine 
pregnancy test. 
t
For Japan only.
u
HRQoL Questionnaires should be completed before any other procedures are performed.
v
On Day 1, samples will be collected predose (before the first daily dose) and 0.25, 0.5, 1.0, 2.0, and 4.0 hours postdose (after the first daily dose) obtained 
within 10% of the nominal time from dosing, with the exception of the predose sample which must be collected predose. On Week 4, Week 24, and 
Week 52, a sample will be collected before the first daily dose (within 30 minutes prior to administered dose), and a sample will be collected two to eight 
hours postdose (after the first daily dose) (See Section 7.5.1). At the Week 2, Week 6, Week 8, Week 10, Week 12, Week 14, and Week 16, a sample will 
be collected during the study visit, irrespective of the time IMP was last dosed. The exact date/time of dosing and sample collections should be recorded in 
the eCRF.
'RFXPHQW1R

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CCI
CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
199/205
New Table Schedule of Assessments – Optional Long-Term Extension Period
LTE Trial Period
Visit Weeks During LTE Treatment Period
Follow-Up Visit 
4 weeks
Post-Last Dosea
Week
0
2
4
6
8
10
12
14
16
24
40
52
76
Week 104/
LTE 
EOT/Early 
Withdrawal
Week 108/
Safety Follow-
Up/LTE End of 
Study
Trial Day
1
15
29
43
57
71
85
99
113
169
281
365
545
745
774
Visit
Day 1b
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
24
Wk
40
Wk
52
Wk
76
Wk
104
Wk
108
Visit window (±day)
-
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
+5
Informed Consent
X
Verify subject remains 
eligible for the study 
(no prohibited 
medication, etc.)
X
Vital signs, weightc
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
Xd
Physical examination
X
Xe
Xe
Xe
Xe
Xe
Xe
Xe
Xe
X
Xe
Routine hematology,
urinalysis, chemistry
X
X
X
X
X
X
X
X
X
X
Urine microscopy
X
X
X
X
Supplementary LFT 
labs
X
X
X
X
X
Total Ig Levels 
(IgG, IgA, IgM)
X
X
X
X
X
X
X
X
X
X
Total B cell countf
X
X
X
X
X
X
Urine pregnancy testg
X
X
X
X
X
X
X
X
X
X
X
Urine pregnancy test 
kit dispensationg
X
X
X
X
X
Reflex testing for HBV 
DNAh
X
X
X
X
X
X
X
X
X
X
X
UPCR
X
X
X
X
'RFXPHQW1R

2EMHFW1R

CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
200/205
LTE Trial Period
Visit Weeks During LTE Treatment Period
Follow-Up Visit 
4 weeks
Post-Last Dosea
Week
0
2
4
6
8
10
12
14
16
24
40
52
76
Week 104/
LTE 
EOT/Early 
Withdrawal
Week 108/
Safety Follow-
Up/LTE End of 
Study
Trial Day
1
15
29
43
57
71
85
99
113
169
281
365
545
745
774
Visit
Day 1b
Wk
2
Wk
4
Wk
6
Wk
8
Wk
10
Wk
12
Wk
14
Wk
16
Wk
24
Wk
40
Wk
52
Wk
76
Wk
104
Wk
108
Visit window (±day)
-
±3
±3
±3
±3
±3
±3
±3
±3
±7
±7
±7
±7
±7
+5
IMP dispensationi
X
Dispense as needed, using IWRS and complete compliance documentation
IMP administrationj
Daily Administration of Evobrutinib
C-SSRS
X
X
X
X
X
X
X
SFI, SLEDAI-2K, PGA, 
BILAG 2004, CLASI
X
X
X
X
SLICC/ACR Damage 
Index
X
X
X
X
SF-36v2, LupusQoL, 
FACIT-Fatigue, EQ-5D-
5Lk
X
X
X
X
PGICk
X
X
X
X
HRU
X
X
X
X
X
X
X
X
X
X
X
Concomitant 
medications / 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunological Assessments
Anti-dsDNA 
Complement (C3, C4), 
CRP
X
X
X
X
ANA and other 
Autoantibodies
X
X
X
X
'RFXPHQW1R

2EMHFW1R

CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
201/205
ACR = American College of Rheumatology, ANA = Antinuclear Antibody(ies), Anti-dsDNA = Anti-Double-Stranded Deoxyribonucleic Acid, BILAG 2004 =
British Isles Lupus Assessment Group 2004, CLASI = Cutaneous Lupus Erythematosus Disease Area and Severity Index, C-SSRS = Columbia-Suicide 
Severity Rating Scale, D = day, DNA = deoxyribonucleic acid, ECG = Electrocardiogram, EOT = End of Treatment, EQ-5D-5L = EuroQoL 5 Dimension 5 
Levels, FACIT = Functional Assessment of Chronic Illness Therapy, HBsAg = hepatitis B surface antigen, HBV = Hepatitis B Virus, HRU = Health 
Resource Utilization, Ig = Immunoglobulin, IMP = Investigational Medicinal Product, LFT = liver function test, LTE = Long-Term Extension,
LupusQoL = Lupus Quality of Life, PGA = Physician’s Global Assessment, PGIC = Patient Global Impression of Change,
, SFI
= SLEDAI Flare Index, SLEDAI-2K = Systemic Lupus Erythematosus Disease Activity Index-2000, SLICC = Systemic Lupus International Collaborating 
Clinics, SoA = Schedule of Assessments, UPCR = Urine Protein To Creatinine Ratio, Wk = Week, WOCBP = women of childbearing potential.
a
Safety Follow-Up Visits will be conducted at four weeks after the last dose of IMP for subjects who have been discontinued from IMP or have 
completed the LTE Treatment Period.
b
The LTE D1 visit is the EOT/Wk 52 visit from the DBPC Period unless a subject rollsover more than four weeks after the Wk 52/EOT visit. If a 
subject exceeds the four weeks due to unanticipated causes (e.g., regulatory approval delay), prior approval from the Medical Monitor is 
required and the subject will need to complete the LTE D1 visit (see Section 7.1.3).
c
Vital signs including weight, oral temperature, seated blood pressure, pulse rate, and respiratory rate.
d
Only required if change noted at Wk 104/EOT, when compared to Baseline ECG.
e
Abbreviated physical examination may be performed at Primary Investigator discretion, as required to fully obtain information needed for the 
BILAG and/or SLEDAI assessments, if scheduled, as well as required to fully evaluate any subject complaints or adverse events (see 
Section 7.4.4.2).
f
Only total B cell counts, flow cytometry for the other cell types and subsets, including B-cell subsets, will not be performed.
g
The urine pregnancy test being used at all time points in this study must be a highly sensitive urine pregnancy test. In-between visit urine 
pregnancy tests will be dispensed and performed at home per SOA (Table 3) for WOCBP. The site staff will confirm completion of the home 
pregnancy testing and discuss results (Section 7.1.3).
h
Additional HBV DNA PCR testing must be performed for subjects who entered the study with negative HBsAg and positive for anti-hepatitis B 
surface antibody and/or anti-hepatitis B core antibody with an HBV DNA negative OR detectable HBV DNA < 20 IU/mL only.
i
The IMP will be dispensed per IWRS and IMP compliance documented using pill counts. All remaining IMP will be collected at Week 104 for all 
subjects.
j
IMPs will be self-administered at a set time each day (± 2 hours).
k
HRQoL Questionnaires should be completed before any other procedures are performed.
'RFXPHQW1R

2EMHFW1R

CCI
CCI
CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
202/205
New Table: Additional Pregnancy Testing for Long-Term Extension
LTE Trial 
Period
Visit Weeks During LTE Treatment Period
Week
20
28
32
36
44
48
56
60
64
68
72
80
84
88
92
96
100
Trial Day
143
200
229
258
315
344
402
430
459
488
516
574
602
631
660
688
717
Visit
8a
9a
9b
9c
10a
10b
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
12f
Visit window 
(±day)
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
±3
Highly 
sensitive 
urine 
pregnancy 
testa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE = adverse events, LTE = Long-Term Extension.
a
In-between visit urine pregnancy test will be performed at home. The site staff will call the subject to confirm completion of the home pregnancy 
testing and discuss results. Any occurrence of pregnancy results in subject withdrawal from IMP and the trial (see Section 5.5.1 and 5.5.2). 
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
203/205
New Figure Added
Study Design for Long-Term Extension
BID = twice daily, D = day, LTE = Long-Term Extension, QD = once daily; SFU = Safety Follow-Up, SLE =
Systemic Lupus Erythematosus, WOCBP = women of child bearing potential.
** = Subjects will receive an initial dose of 50 mg BID. When a Phase 3 dose is determined, all subjects may 
be switched to this dose at the Sponsor’s discretion.
* = For subjects entering the Open-Label Extension, the Week 52 visit is considered the Day 1 visit for the 
Open-Label LTE Period.
NOTE: For WOCBP, urine pregnancy tests will be performed at home to ensure monthly pregnancy testing.
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
204/205
Previous Table 7, now Table 9, Updated 
Oral Corticosteroid Dose (in prednisone-equivalent) and Taper Guidance
Study Visit
Study 
Period
Maximum 
Allowable Dosea
Target Dose
Action for CS dosing
Screening 
Screening 
Period
30 mg/day
≤30 mg/day
No change in CS doseb
Day 1 Week 01
30 mg/day
≤30 mg/day
Initiate After Day 1, may 
initiate, increase, decrease, or
have no change to dose. 
Dose must be tapered to 
≤Day 1 dose by Week 4
Taper to ≤Day 1 dose by Week 
4
Week 1 
through 3
30 mg/dayf
≤30 mg/day
Week 4 Visit
Week 4
Day 1 dosec
≤Dose at Day 1 Visit
Begin taper to ≤10 mg/day by 
Week 8, as tolerated
Weeks 5 
through 7
Week 4 
Visit dose 
≤10 mg/day
Continue to taper to 
≤10 mg/day by Week 8, as 
tolerated
Week 8 Visit
Week 8
Week 4
Visit dose
≤10 mg/day
Begin taper to ≤7.5 mg/day by 
Week 12, as tolerated
Weeks 9 
through 11
Week 8
Visit dose
≤7.5 mg/day
Continue to taper to 
≤7.5 mg/day by Week 12, as 
tolerated
Week 12 Visit
Week 12
Week 8
Visit dose
≤7.5 mg/day
Taper as tolerated
Weeks 13 
through 15
Week 8
Visit dose
≤7.5 mg/day
Taper as tolerated
Week 16 Visit
Week 16
Week 8
Visit dose
≤7.5 mg/day
Taper as tolerated
Weeks 17 
through 23
Week 8
Visit dose
≤7.5 mg/day
No change in CS dosed
Week 24 Visit
Week 24
Week 8
Visit dose
≤7.5 mg/day
No change in CS dosed
Weeks 25 
through 39
Week 8
Visit dose
≤5 mg/day
Taper to ≤5 mg/day by 
Week 40, as tolerated
Week 40 Visit
Week 40
Week 8
Visit dose
≤5 mg/day
Taper as tolerated
Weeks 41 
through 52
Week 8
Visit dose
≤5 mg/day
No change in CS dosee
CS – Corticosteroids.
a 
Violation of requirements during the Screening Period results in screen-failure; treatment period violation may 
result results in treatment failure and withdrawal from study. 
b 
Any dose change between Screening and Day 1 results in screen failure.
c 
Subjects with CS dose < 7.5 mg/day at Day 1 may have up to 7.5 mg/day at Week 4.
d 
Any dose increase during Weeks 17 to 24 results in treatment failure and withdrawal from study, dose may be 
tapered after Week 24 assessments have been completed.
e 
Any dose increase during Weeks 41 to 52 results in treatment failure and withdrawal from study.
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CCI

Evobrutinib (M2951)
A Phase II Study of M2951 in SLE
MS200527-0018
205/205
f
Although it is preferred that subjects do not receive a CS dose > 30 mg/day, subjects who receive > 30 mg/day 
between Day 1 and the Week 4 visit will not be withdrawn from the study if they are able to achieve a dose no 
higher than (≤) the Day 1 CS dose and ≤30 mg/day (whichever is lower) by the Week 4 visit.
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CCI