Clinical trial NCT02784106
Conditions: Rheumatoid Arthritis
Keywords: Rheumatoid Arthritis M2951 Bruton's Tyrosine Kinase (BTK)
Sponsor: EMD Serono Research & Development Institute, Inc.
Start date: 2016-07-31; Completion date: 2017-11-14
Enrollment: 65 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
M2951 is an investigational drug under evaluation for treatment of autoimmune and inflammatory disorders. The purpose of the study is to assess the efficacy of M2951 in participants with rheumatoid arthritis (RA) currently treated with stable dose of methotrexate (MTX).

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: Placebo intervention 2: M2951 intervention 3: M2951
Intervention descriptions: intervention 1: Participants received placebo matched to M2951 twice daily up to Day 84 during the double-blind treatment period. intervention 2: Participants received 50 milligrams (mg) M2951 orally twice daily up to Day 84 during the double-blind treatment period. intervention 3: Participants who received placebo matched to M2951 or M2951 in double-blind treatment period, received 50 mg M2951 orally twice daily up to 26-weeks during the open label extension period.

Protocol documents:
Prot_002.pdf: 


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Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................6
Table of In-Text Figures......................................................................................................6
List of Abbreviations ...........................................................................................................7
1
Synopsis..............................................................................................10
2
Sponsor, Investigators, and Trial Administrative Structure ...............21
3
Background Information.....................................................................21
3.1
Potential Risks and Benefits...............................................................24
4
Trial Objectives ..................................................................................25
4.1
Primary Objective...............................................................................25
4.2
Key Secondary Objective ...................................................................25
4.3
Other Secondary Objectives (during the double-blind period)...........25
4.3.1
Safety..................................................................................................25
4.3.2
Pharmacokinetics and Pharmacodynamics.........................................25
4.3.3
Other Secondary Efficacy Objectives.................................................26
4.4
Exploratory Objectives .......................................................................26
4.5
Open-label Extension Objectives .......................................................26
5
Investigational Plan ............................................................................27
5.1
Overall Trial Design and Plan ............................................................27
5.2
Discussion of Trial Design .................................................................29
5.2.1
Inclusion of Special Populations ........................................................30
5.3
Selection of Trial Population..............................................................30
5.3.1
Inclusion Criteria ................................................................................30
5.3.2
Exclusion Criteria...............................................................................32
5.4
Criteria for Randomization and Initiation of Trial Treatment............33
5.5
Criteria for Subject Withdrawal..........................................................34
5.5.1
Withdrawal from Trial Therapy..........................................................34
5.5.2
Withdrawal from the Trial..................................................................34
5.6
Premature Termination of the Trial ....................................................35
5.7
Definition of End of Trial...................................................................35
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6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................36
6.1
Description of the Investigational Medicinal Product........................36
6.2
Dosage and Administration ................................................................36
6.3
Assignment to Treatment Groups.......................................................37
6.4
Noninvestigational Medicinal Products to be Used............................37
6.5
Concomitant Medications and Therapies ...........................................37
6.5.1
Permitted Medicines...........................................................................37
6.5.2
Prohibited Medicines..........................................................................38
6.5.3
Other Interventions.............................................................................40
6.5.4
Special Precautions.............................................................................40
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................42
6.6
Packaging and Labeling of the Investigational Medicinal Product....42
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................42
6.8
Investigational Medicinal Product Accountability.............................42
6.9
Assessment of Investigational Medicinal Product Compliance .........43
6.10
Blinding ..............................................................................................43
6.11
Emergency Unblinding.......................................................................44
6.12
Treatment of Overdose .......................................................................45
6.13
Medical Care of Subjects after End of Trial.......................................45
7
Trial Procedures and Assessments......................................................45
7.1
Schedule of Assessments....................................................................46
7.1.1
Screening Period.................................................................................46
7.1.2
Treatment Period ................................................................................47
7.1.3
Optional Extension Period..................................................................47
7.1.4
Safety Follow-Up Visit.......................................................................48
7.2
Demographic and Other Baseline Characteristics ..............................48
7.2.1
Demography .......................................................................................48
7.2.2
Medical History ..................................................................................48
7.3
Efficacy Assessments .........................................................................48
7.3.1
Disease Activity Assessments ............................................................48
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7.3.2
Rheumatoid Factor, anti-CCP, and hsCRP.........................................52
7.3.3
Erythrocyte Sedimentation Rate.........................................................53
7.4
Assessment of Safety..........................................................................53
7.4.1
Adverse Events ...................................................................................53
7.4.2
Pregnancy and In Utero Drug Exposure.............................................57
7.4.3
Clinical Laboratory Assessments .......................................................58
7.4.4
Vital Signs, Physical Examinations, and Other Assessments.............59
7.5
Pharmacokinetic Assessments............................................................60
7.6
Pharmacodynamic Immunoglobulin Levels Assessments..................61
7.7
Pharmacodynamic Biomarker Assessments.......................................61
7.7.1
B cell number and B cell Subtypes Assessment.................................61
7.7.2
Other Exploratory Assessments..........................................................62
8
Statistics..............................................................................................62
8.1
Sample Size ........................................................................................62
8.2
Randomization....................................................................................63
8.3
Endpoints............................................................................................63
8.3.1
Primary Endpoints ..............................................................................63
8.3.2
Secondary Endpoints ..........................................................................63
8.3.3
Other Endpoints..................................................................................64
8.3.4
Endpoints for Open-label Extension...................................................64
8.4
Analysis Sets.......................................................................................65
8.5
Description of Statistical Analyses.....................................................66
8.5.1
General Considerations.......................................................................66
8.5.2
Analysis of Primary Endpoints...........................................................67
8.5.3
Analysis of Secondary Endpoints.......................................................67
8.5.4
Analysis of Exploratory Endpoints.....................................................69
8.5.5
Analysis of Safety and Other Endpoints.............................................69
8.5.6
Analysis of Open-label Extension Endpoints.....................................70
8.6
Interim and Additional Planned Analyses ..........................................70
9
Ethical and Regulatory Aspects..........................................................71
9.1
Responsibilities of the Investigator ....................................................71
9.2
Subject Information and Informed Consent .......................................71
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9.3
Subject Identification and Privacy......................................................72
9.4
Emergency Medical Support and Subject Card..................................72
9.5
Clinical Trial Insurance and Compensation to Subjects.....................73
9.6
Independent Ethics Committee or Institutional Review Board..........73
9.7
Health Authorities...............................................................................73
10
Trial Management...............................................................................73
10.1
Case Report Form Handling...............................................................73
10.2
Source Data and Subject Files............................................................74
10.3
Investigator Site File and Archiving...................................................75
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................75
10.5
Changes to the Clinical Trial Protocol................................................75
10.6
Clinical Trial Report and Publication Policy......................................76
10.6.1
Clinical Trial Report...........................................................................76
10.6.2
Publication..........................................................................................76
11
References Cited in the Text...............................................................76
12
Appendices .........................................................................................79
Appendix A 
Signature Pages and Responsible Persons for the Trial......................79
Signature Page – Protocol Lead.........................................................................................80
Signature Page – Coordinating Investigator ......................................................................81
Signature Page – Principal Investigator.............................................................................82
Sponsor Responsible Persons Not Named on the Cover Page ..........................................83
Appendix B
Joint Count Assessment Forms...........................................................84
Appendix C
Blood Volumes...................................................................................85
Appendix D
Protocol Versions and List of Changes ..............................................86
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Table of In-Text Tables
Table 1
Schedule of Assessments....................................................................18
Table 2
Examples of Inhibitors or Inducers of CYP3A Enzymes or 
Substrates with Narrow Therapeutic Range .......................................40
Table 3
CTCAE Grades for Relevant Laboratory Parameters ........................42
Table 4
Clinical Safety Laboratory Evaluations..............................................59
Table of In-Text Figures
Figure 1
Schematic of the Trial Design ............................................................29
Figure 2
Physician Global Assessment Scale ...................................................51
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List of Abbreviations
Δ
Difference
ACR
American College of Rheumatology
AE
adverse event
AIID
autoimmune and inflammatory disorders
ALT
alanine aminotransferase
Anti-CCP
anti-cyclic citrullinated peptide
AST
aspartate aminotransferase
AUC0-6h
area under the concentration-time curve from time zero to 6 hours
β-hCG
beta human chorionic gonadotropin
BTK
Bruton’s tyrosine kinase
C
Collect
CI
confidence interval
Cmax
maximum observed plasma concentration
Cpre
plasma concentration observed immediately before next dosing
CTCAE
Common Terminology Criteria for Adverse Events
CXR
chest X-ray
CYP
cytochrome P450
D
Dispense
DAS28
Disease Activity Score-28 joints
DMARD
disease-modifying antirheumatic drug
ECG
electrocardiogram
eCRF
Case Report Form, electronic
ESR
erythrocyte sedimentation rate
EULAR
The European League Against Rheumatism 
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
HAQ-DI
Health Assessment Questionnaire-Disability Index
HBsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
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IA
interim analysis
IB
Investigator’s Brochure
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
Ig
immunoglobulin
IMP
investigational medicinal product
IRB
Institutional Review Board
ITT
intent-to-treat
IWRS
Interactive Web Response System
LDH
lactate dehydrogenase
LFT
liver function test(s)
LLN
lower limit of normal
LLOQ
lower limit of quantification
LTBI
latent tuberculosis infection
MAD
multiple ascending doses
mITT
modified intent-to-treat
MOP
Manual of Procedures
MS
multiple sclerosis
MTX
methotrexate 
NSAID
nonsteroidal anti-inflammatory drugs
PBMC
peripheral blood mononuclear cell
PD
pharmacodynamics
PiC
powder-in-capsule
PK
pharmacokinetics
R
Review
RA
rheumatoid arthritis
Racc(AUC0-6h)
accumulation ratio for AUC0-6h
Racc(Cmax)
accumulation ratio for Cmax
RF
rheumatoid factor
RNA
ribonucleic acid
SAD
single ascending doses
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SAE
serious adverse event
SAP
Statistical Analysis Plan
SD
standard deviation
SJC
swollen joint count
SLE
systemic lupus erythematosus
SOCs
system organ classes
t½
terminal half-life
TB
Tuberculosis
TEAE
treatment-emergent adverse event
TJC
tender joint count
tmax
time to reach maximum observed concentration
TNF-α
tumor necrosis factor alpha
TSH
thyroid stimulating hormone
ULN
upper limit of normal
VAS
visual analogue scale
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Subjects who continue to receive M2951 during the extension period will also be required to 
undergo the Safety Follow-up Visit scheduled for approximately 28 days after the last treatment 
visit.
Planned number of subjects: A total of 64 subjects with RA.
Primary endpoint: The primary endpoint is the ACR20 response at Day 85.
Key secondary endpoints:
The key secondary endpoint is the percent change in hsCRP from Baseline to Day 29.
Other secondary endpoints (during the double-blind treatment period):
Safety endpoints (from signing ICF until Safety Follow-Up Visit):
! Nature, incidence, and severity of treatment-emergent adverse events
! Changes from Baseline in vital signs and 12-lead electrocardiogram (ECG) results 
! Changes from Baseline in standard hematology and chemistry laboratory parameters 
including liver function tests, amylase/lipase, and urinalysis.
Efficacy endpoints:
! ACR50/ACR70 response at each time point assessed 
! Percent change in hsCRP from Baseline to Day 85
! Change from Baseline in Disease Activity Score based on 28 joints (DAS28-hsCRP) score 
at Day 29 
! Change from Baseline in DAS28-hsCRP score at Day 85
! Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Day 85
! Percentage of subjects with DAS28-hsCRP < 2.6 at Day 85
! Change from Baseline in erythrocyte sedimentation rate (ESR), anti- cyclic citrullinated 
peptide (CCP), and rheumatoid factor ([RF] at Days 29 and 85)
! Change from Baseline to Day 85 in subject’s self-assessments including: 
o Global assessment of disease activity
o Self-assessment of pain
o Self-assessment of disability (Health Assessment Questionnaire – Disability Index; 
HAQ-DI)
! Change from Baseline to Day 85 in Physician’s Global Assessment of Disease Activity.
Pharmacokinetics: Pharmacokinetic parameters calculated for Days 1 and 29 include: plasma 
concentrations of M2951, area under the plasma concentration-time curve from time zero to 
6 hours (AUC0-6h) after administration, maximum observed plasma concentration (Cmax), 
concentration observed immediately before next dosing (Cpre) (Day 29), time to reach 
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Diagnosis and key inclusion and exclusion criteria: 
The current trial will enroll subjects who fulfill the following key inclusion criteria:
! Men or women 18 to 75 years of age at the time of informed consent signature
! Confirmed diagnosis of RA according to 2010 American College of Rheumatology (ACR)/
The European League Against Rheumatism (EULAR) RA classification criteria of at least 
6 months duration
! Positive RF and/or anti-CCP (anti-cyclic citrullinated peptide)
! Persistently active disease defined as ≥6 swollen joints (of 66 counted) and ≥6 tender joints 
(of 68 counted)
! hsCRP ≥3.6 mg/L
! Treatment for ≥12 weeks with 10 to 25 mg/week MTX at a stable dose for at least 4 weeks 
prior to dosing with the IMP and maintained throughout the trial
! Women of childbearing potential must use a highly effective method of contraception 
combined with one supplementary barrier method for 4 weeks prior to randomization, 
throughout the trial, and for 90 days after the last dose of IMP. For the purposes of this trial:
o
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
o
The definition of highly effective contraception includes:

combined 
(estrogen 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation; oral, intravaginal 
or transdermal

progestogen-only hormonal contraception associated with inhibition of 
ovulation; oral, injectable, implantable

intrauterine device (IUD)

intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

vasectomized partner

sexual abstinence
o
Supplementary barrier methods include:

male or female condom with or without spermicide

cap, diaphragm or sponge with spermicide
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! Women of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at Day 1/randomization before dosing.
Subjects who fulfill any of the following key exclusion criteria should not be enrolled into this 
trial: 
! Use of oral corticosteroids > 10 mg daily prednisone equivalent, use of injectable 
corticosteroids, or change in dose of corticosteroids within 2 weeks prior to Screening or 
during Screening
! Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 
2 weeks prior to Screening
! Treatment with tofacitinib, other BTK inhibitors, or a biologic disease-modifying 
antirheumatic drug (DMARD; eg, anti-tumor necrosis factor alpha [anti-TNF-α], 
tocilizumab 
[anti-interleukin-6 receptor], 
abatacept 
[CTLA4-Fc]), 
or 
other 
immunosuppressive drugs (sulfasalazine would be acceptable at a stable dose) other than 
methotrexate within 3 months prior to Screening or during Screening
! Treatment with anti-CD20 therapy (eg, rituximab) within 12 months prior to Screening or 
during Screening
! Immunologic disorder other than RA, with the exception of secondary Sjogren’s syndrome 
associated with RA, and well-controlled diabetes or thyroid disorder, or any other condition 
requiring oral, intravenous, intramuscular, or intra-articular corticosteroid therapy
! Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
! Active, clinically significant, viral, bacterial, or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 
4 weeks of Screening or during Screening, or completion of oral anti-infectives within 
2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of the 
same type of infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis,
and genital or oral herpes simplex virus considered by the Investigator to be sufficiently 
controlled would not be exclusionary. 
! History of or positive testing for human immunodeficiency virus (HIV), hepatitis C antibody 
and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis 
B core total, and/or IgM antibody (+) at Screening.
! History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent 
TB infection (LTBI); untreated LTBI (as determined by documented results within 3 months 
of the Screening Visit of a positive TB skin test with purified protein derivative with 
induration ≥5 mm, a positive QuantiFERON®-TB test or positive or borderline T-SPOT 
[Elispot] test); or positive QuantiFERON-TB test at Screening. Subjects with documented 
completed appropriate LTBI treatment would not be excluded and are not required to be 
tested.
! Subjects with current household contacts with active TB will also be excluded.
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! Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be 
considered positive if retest results are positive or indeterminate.
! History of cancer, except adequately treated basal cell or squamous cell carcinomas of the 
skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical 
intraepithelial neoplasia of the uterine cervix, unless considered cured > 5 years.
! Clinically significant abnormality on ECG, or an active infective process or any other 
clinically significant abnormality on Screening chest X-ray (CXR) taken within 4 weeks of 
the first dose, per Investigator opinion. If a CXR has been taken within the previous 
3 months and results are available and normal, the CXR does not need to be carried out
! B cell (CD19) count < 50% of the lower limit of normal at Screening
! Significant cytopenia including absolute neutrophil count < 1,500/ mm3, platelet count 
< 100,000/mm3, or absolute lymphocyte count < 1,000/mm3
Investigational Medicinal Product: dose/mode of administration/dosing schedule: 
M2951 (50 mg twice daily [bid]) will be administered as 2 x 25 mg capsules bid during the
12-week treatment period. Identical capsules filled with mannitol for placebo will be provided.
M2951 will be administered as 2 x 25 mg tablets bid during the optional extension period.
Reference therapy: dose/mode of administration/dosing schedule: Not applicable.
Planned trial and treatment duration per subject: Total duration of subject participation is 
approximately between 5 months (20 weeks) to 11 months (46 weeks), which includes:
! Screening: 28 days (4 weeks)
! Treatment: 84 days (12 weeks)
! Optional 6-month open-label extension period (26 weeks)
! Safety Follow-Up: 28 days (4 weeks)
After completing the 12-week treatment period, subjects will be offered the opportunity to 
participate in an optional 6-month open-label extension period with M2951. For subjects who 
choose to participate in the optional extension period, the duration of participation will last a 
total of approximately 11 months.
Statistical methods:
The sample size of 60 evaluable subjects was chosen to provide 80% power to demonstrate 
superiority of M2951+MTX to placebo + MTX for the primary endpoint at the 1-sided 10% 
level. Eligible subjects will be randomized 1:1 to treatment with M2951 or placebo through a 
central randomization process by an Interactive Web Response System (IWRS). 
Approximately 64 subjects will be randomized under the assumption of a 6.25% drop-out rate. 
There will be 3 analyses: (1) an interim analysis (IA), triggered when subjects from the first 
50% of the planned enrollment have reached Day 29 of treatment and have available Day 29 
hsCRP data, or have discontinued treatment prior to Day 29, (2) a primary analysis, triggered 
when 100% of subjects enrolled have reached Day 85 of treatment or have discontinued 
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treatment prior to Day 85, and (3) a final analysis, triggered when 100% of subjects enrolled 
complete all study parts, or discontinue prematurely from study.
The percent change in hsCRP from Baseline to Day 29 will be the key endpoint evaluated at 
the IA. Point estimate and confidence interval (CI) estimates of the Day 29 hsCRP change from 
Baseline difference, comparing the 2 treatment groups, will be estimated for use in internal 
decision making. In addition, the change in DAS28-hsCRP from Baseline to Day 29 will be 
evaluated using the same approach as used for change in hsCRP. The IA will not be used to 
alter the design of the trial. No adjustment will be made to the 1-sided α of 10% to be used in 
the primary analysis at the end of the first treatment period (12 weeks). 
The Day 85 ACR20 proportion and a 2-sided 80% CI will be provided for each treatment 
group. The difference (Δ) in 12-week ACR20 proportions between M2951+MTX and placebo
+ MTX, and a 2 sided 80% CI for Δ, based on the “corrected Miettinen-Nurminen” method 
will be provided. The primary analysis will be based on the mITT Analysis Set using Last 
Observation Carried Forward for imputation of missing values and will reject the null 
hypothesis (H0): Δ ≤0 if the lower limit of the CI exceeds zero.  
The Day 85 ACR50 and ACR70 proportions will be analyzed in the same way as the Day 85 
ACR20 proportions.
Safety data will be listed and summarized using descriptive statistics.
In addition, efficacy and safety data collected during the open-label extension period will be 
summarized.
Pharmacokinetics
M2951 concentrations and PK parameters will be listed and summarized by trial day. 
Pharmacodynamics
Data on immunoglobulin levels, 
, and B cell numbers and subsets will be 
summarized in tabular and/or graphic format, as appropriate to the data. Potential PK/PD 
correlations may be explored and reported separately.
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Table 1
Schedule of Assessments
Trial Period
Screening
Treatment Period
Optional Open-Label Extension Period
Safety 
Follow-Up/
End of Trial 
Visita
Trial Visit #
1
2
3
4
5
6
7
8/End of 
Treatmentb
9
10
11
12
Trial Week
W1 W2 W3
W5
W7
W9
W13
Trial Day
-28 to -1
1
8
15
29
43
57
85/Day 1 
OLE
Day 14
Month 1
Month 3
Month 6
~28 days post 
last dose
Visit Window (days)
-
-
±2
±2
±2
±4
±4
±2
±7
±7
±7
Informed consent
X
(X)b
Demographics
X
RA and other medical 
history, medications 
history
X
Inclusion/exclusion 
criteria
X
X
Complete physical 
examinationc
X
X
X
X
X
X
X
X
Vital signsd
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG 
X
X
X
X
Chest X-raye
X
Concomitant 
medicationsf and 
procedures
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology, chemistry 
(incl. LFTs)g
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulationh
X
Urinalysis, microscopy, 
urine protein/creatinine 
ratio
X
X
X
X
X
X
X
X
X
X
Immunoglobulinsi
X
X
X
X
X
RF and anti-CCPj
X
X
X
X
X
X
X
ESRj
X
X
X
X
X
X
X
hsCRPk
X
X
X
X
X
X
X
X
B cell numbers and 
subtypesl
X
X
X
X
X
X
X
Viral serologym
X
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Trial Period
Screening
Treatment Period
Optional Open-Label Extension Period
Safety 
Follow-Up/
End of Trial 
Visita
Trial Visit #
1
2
3
4
5
6
7
8/End of 
Treatmentb
9
10
11
12
Trial Week
W1 W2 W3
W5
W7
W9
W13
Trial Day
-28 to -1
1
8
15
29
43
57
85/Day 1 
OLE
Day 14
Month 1
Month 3
Month 6
~28 days post 
last dose
Visit Window (days)
-
-
±2
±2
±2
±4
±4
±2
±7
±7
±7
Tuberculosis testm
X
TSH
X
Pregnancy test
(serum β-hCG)n
X
Urine pregnancy testn
X
X
X
X
X
X
X
X
X
Pharmacokinetic 
samplingo
X
X
RA disease activity 
assessmentr
X
X
X
X
X
X
X
Randomization
X
Dispense/review/collect 
subject diary
D
R
R
R
R
R
R/C
IMP dispensations
X
X
X
X
X
X
(X)
X
X
X
IMP administrationt
Daily oral administration
IMP complianceu
X
X
X
X
X
X
X
X
X
X
AE evaluationv
X
X
X
X
X
X
X
X
X
X
X
X
X
ACR=American College of Rheumatology, AE=adverse event, anti-CCP=anti-cyclic citrullinated peptide, β-hCG=beta human chorionic gonadotropin,
 C=collect, D=dispense, DAS28=Disease Activity Score, ECG=electrocardiogram, ESR=erythrocyte sedimentation rate, 
hsCRP=high sensitivity C-reactive protein, Ig=immunoglobulin, IMP=investigational medicinal product, LFT=liver function test, OLE=open-label extension, 
PD=pharmacodynamics, PK=pharmacokinetics, R=review, RA=rheumatoid arthritis, RF=rheumatoid factor, RNA=ribonucleic acid, TSH=thyroid stimulating 
hormone.
a All subjects, whether not continuing to the optional extension period, continuing to the optional extension period, or early terminating from the study will undergo 
the Safety Follow-Up/End of Trial Visit approximately 28 days after last dose.
b Subjects who participate in the optional extension period will sign an ICF at Visit 8. The End of Treatment Visit during the treatment period (Visit 8) will be 
considered Day 1 of the optional extension period.
c A complete physical examination will be performed at Screening, and repeated on Days 29, 85, at each visit during the optional extension period, and the Safety 
Follow-up visit.
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2
Sponsor, Investigators, and Trial Administrative Structure
The administrative structure of the trial is described in the following:
This clinical trial will be sponsored by Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, 
Germany. The trial will be conducted at approximately 50 sites in 10 countries.
Sites to be used will include clinical centers, Phase I units, academic centers, inpatient or 
outpatient, etc.
The Coordinating Investigator represents all Investigators for decisions and discussions regarding 
this trial, consistent with the 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 trial design and execution and is responsible 
for the review and signoff of the clinical trial report. 
Signature pages for the Protocol Lead and the Coordinating Investigator as well as a list of Sponsor 
responsible persons are in Appendix A.
The trial will appear in the following clinical trial registries: Clinicaltrials.gov.
 will be responsible for the clinical trial documents to be submitted to regulatory 
authorities, the conduct of the clinical trial, the central laboratory including coordination and 
distribution of laboratory supplies, drug supply and distribution, data management, statistical 
analysis, and clinical trial reporting. Further details will be provided in a separate document and 
updated as necessary. Clinical quality assurance will be performed under the responsibility of the 
Development Quality Assurance department at Merck KGaA Darmstadt.
An Independent Data Monitoring Committee (IDMC) will be established to continually review 
available safety and tolerability data. The IDMC will be composed of independent physicians with 
expertise in rheumatoid arthritis (RA) and an independent biostatistician who will serve as a voting 
member. Ad hoc members will be consulted as needed. IDMC meetings will take place every 
4 months and at the interim analysis (IA). The full list of IDMC members and IDMC
responsibilities will be included in the IDMC charter.
The Investigational medicinal products (IMP) will be supplied by the Clinical Trial Supply
Department at Merck and packaged and labeled by 
.
Details of structures and associated procedures will be defined in a separate Manual of Operations, 
which will be prepared under the supervision of the Clinical Trial Leader.
3
Background Information
Bruton’s tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase expressed in cells of 
hematopoietic origin, and participates in both innate and adaptive immunity. BTK is involved in a 
variety of B cell functions, including proliferation, antigen presentation, and production of 
PPD
PPD
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inflammation and subsequent joint destruction can lead to progressive functional impairment with 
increasing disability (15).
Conventional RA therapy consists of treatments with nonsteroidal anti-inflammatory drugs 
(NSAIDs), corticosteroids, and disease modifying anti rheumatic drugs (DMARDs). 
Methotrexate (MTX) represents one of the most widely used DMARDs for RA, yet less than half 
of patients with RA show substantial and sustained clinical improvement in disease signs and 
symptoms (16). The emergence of biologic therapies for RA, such as tumor necrosis factor-alpha 
(TNF-α) inhibitors, represent treatment options that mitigate the clinical manifestations of RA by 
selectively targeting key inflammatory molecules. However, approximately 30% of patients with 
RA, usually those with more severe disease, will not experience satisfactory clinical improvement 
with use of currently available therapies (17). Accordingly, a significant unmet need remains for 
more effective treatments for RA.
This Phase IIa, 12-week trial with M2951 will be performed to assess: 1) the efficacy, safety, and 
tolerability of M2951 in subjects with RA, 2) the pharmacokinetics (PK) and pharmacodynamics 
(PD) profile in subjects with RA to compare the PK/PD relationship to that seen in healthy 
volunteers for use in the future development in this population, and 3) the early effects of 
M2951 on markers of RA disease activity.
3.1
Potential Risks and Benefits
The safety assessments of M2951 rely on data accumulated during product development and from 
data on other BTK inhibitors. Based on the nonclinical and clinical data available to date, the 
conduct of the trial is regarded as justifiable at the planned dose. 
M2951, is being considered for the treatment of autoimmune diseases, including RA, SLE, and 
MS. 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 RA 
and other autoimmune diseases. 
No identified risks or new potential risks have emerged from the first-in-human trial,
Trial EMR200527-001. M2951 was well tolerated
 
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 embryofetal toxicity. 
It is unknown whether there are additive risks of cytopenias and elevated transaminases when 
M2951 is given with MTX; however, these potential risks will be readily monitored.
Risk minimization measures inherent to early phase clinical trials are considered adequate for the 
proposed clinical trial in RA patients. An IDMC will be set up to 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.
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The dose of M2951 (50 mg bid) selected for the proposed trial is well within the dose ranges 
studied in Trial EMR200527-001 and showed high levels of target occupancy in healthy 
volunteers.
Taking the above information into account, benefit-risk considerations support conduct of the 
proposed clinical trial EMR200527-0081 in patients with RA.
For full details, refer to the latest IB for further information about the nonclinical and clinical 
programs and Guidance for the Investigator.
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP
guidelines, and any additional applicable regulatory requirements.
4
Trial Objectives
4.1
Primary Objective
To assess the efficacy of M2951 in subjects with active RA on stable MTX therapy, as measured 
by the American College of Rheumatology (ACR) 20% (ACR20) response rate over a duration of 
84 days.
4.2
Key Secondary Objective
To assess the level of disease activity at 4 weeks in subjects with active RA as assessed by the 
percent change in high-sensitivity C-reactive protein (hsCRP) from Baseline to Day 29.
4.3
Other Secondary Objectives (during the double-blind period)
4.3.1
Safety
To assess the safety and tolerability of M2951 in subjects with active RA on stable MTX therapy
from signing ICF until Safety Follow-up Visit, as assessed by the:
! Nature, incidence, and severity of TEAEs
! Changes from Baseline in vital signs and 12-lead electrocardiogram (ECG) data 
! Changes from Baseline in standard hematology and chemistry laboratory parameters including 
liver function tests, amylase/lipase, and urinalysis.
4.3.2
Pharmacokinetics and Pharmacodynamics
To evaluate the PK and PD of M2951 in subjects with RA on stable MTX therapy, as assessed by:
! Pharmacokinetic parameters will include:
o Cmax, tmax, plasma concentration observed immediately before next dosing (Cpre [Day 29]), 
area under the concentration-time curve from time zero to 6 hours (AUC0-6h),accumulation 
ratio for AUC0-6h (Racc[AUC0-6h]), and accumulation ratio for Cmax (Racc[Cmax])
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Subjects will have trial visits weekly for the first 3 weeks of treatment; bi-weekly up until 8 weeks 
of treatment; a final On-Treatment Visit on Day 85 (12 weeks), and then return for 1 Follow-Up 
Visit approximately 28 days (4 weeks) after the last dose of IMP.
The optional Extension Period includes four scheduled visits (Visits 9, 10, 11, and 12), which 
correspond with Day 14, and the end of Months 1, 3, and 6. Subjects will also attend a Safety 
Follow-Up Visit approximately 28 days after the last dose of IMP.
The IDMC will meet at times to be laid out in the IDMC charter during the trial to monitor the 
safety of participants throughout the trial.
A schematic presentation of the trial design is presented in Figure 1.
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Figure 1
Schematic of the Trial Design
a All subjects, whether not entering the optional open-label extension period, continuing on to the open-label 
extension period, on early terminating from the study will attend a Safety Follow-up Visit approximately 28 days 
after the last dose of IMP.
b Subjects who decide to participate in the optional open-label extension period will sign a consent form at Visit 8, 
which will be considered Day 1 of the optional extension period.
c Corresponds to the days (D) or months (M) during open-label extension period.
Bid=twice daily, OLE=open-label extension.
5.2
Discussion of Trial Design
This will be a double-blind trial. Eligible subjects will be randomized to treatment with M2951 or 
placebo. The 50 mg bid dose of M2951 was selected for this trial based on the results from the 
first-in-man trial in healthy subjects.
The primary objective of this trial is to assess the efficacy of M2951 in subjects with active RA on 
stable MTX background therapy as measured by the ACR20 over Day 85 of treatment. The key 
secondary objective is to evaluate the level of disease activity at Day 29 in subjects with active RA 
as assessed by percent change in hsCRP from Baseline to Day 29. 
An open-label extension of 6 months duration will be offered to subjects completing the initial 
12-week treatment period. The purpose is to allow all subjects the opportunity to be on active 
treatment with M2951 and to collect longer term safety data.
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3. Positive RF and/or anti-CCP
4. Persistently active disease defined as ≥6 swollen joints (of 66 counted) and ≥6 tender joints 
(of 68 counted)
5. hsCRP ≥3.6 mg/L
6. Treatment for ≥12 weeks with 10 to 25 mg/week MTX at a stable dose for at least 4 weeks 
prior to dosing with the IMP and maintained throughout the trial
7. Women of childbearing potential must use a highly effective method of contraception 
combined with one supplementary barrier method for 4 weeks prior to randomization, 
throughout the trial, and for 90 days after the last dose of IMP. For the purposes of this trial:
o
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
o
The definition of highly effective contraception includes:

combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation; oral, intravaginal or transdermal

progestogen-only hormonal contraception associated with inhibition of 
ovulation; oral, injectable or implantable

intrauterine device (IUD)

intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

vasectomized partner

sexual abstinence
o
Supplementary barrier methods include:

male or female condom with or without spermicide

cap, diaphragm or sponge with spermicide 
8. Men must agree to use and to have their female partners use a highly effective method of
contraception combined with one supplementary barrier method as defined above for at least 
90 days after the last IMP administration. 
9. Women of childbearing potential must have a negative serum pregnancy test at the Screening 
Visit and a negative urine pregnancy test at Day 1/randomization before dosing
10. History of vaccinations as follows: 1) against Streptococcus pneumoniae with PPSV23 or 
PCV13 with repeat administration as necessary to be up to date as per local guidelines; and 2) 
against influenza virus (as seasonally required); or vaccination against these pathogens during 
Screening. Subjects receiving 1 or more of these vaccinations during Screening must have at 
least 2 weeks between the vaccination(s) and the date of randomization
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11. Signed and dated informed consent indicating that the subject has been informed of all the 
pertinent aspects of the trial prior to enrollment and will comply with the requirements of the 
protocol.
5.3.2
Exclusion Criteria
Subjects who fulfill any of the following should not be enrolled into this trial: 
1. Use of oral corticosteroids > 10 mg daily prednisone equivalent, use of injectable
corticosteroids, or change in dose of corticosteroids within 2 weeks prior to Screening or during 
Screening
2. Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 2 weeks 
prior to Screening
3. Treatment with tofacitinib, other BTK inhibitors, or a biologic DMARD (eg, anti-TNF-α, 
tocilizumab 
[anti-interleukin-6 receptor], 
abatacept 
[CTLA4-Fc]), 
or
other 
immunosuppressive drugs (sulfasalazine would be acceptable at a stable dose) other than MTX 
within 3 months prior to Screening or during Screening
4. Treatment with anti-CD20 therapy (eg, rituximab) within 12 months prior to Screening or 
during Screening
5. Immunologic disorder other than RA, with the exception of secondary Sjogren’s syndrome 
associated with RA, and well-controlled diabetes or thyroid disorder, or any other condition 
requiring oral, intravenous, intramuscular, or intra-articular corticosteroid therapy
6. Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening
7. Severe drug allergy or history of anaphylaxis, or allergy to the IMP or any of its excipients
8. Active, clinically significant viral, bacterial, or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 4 weeks 
of Screening or during Screening, or completion of oral anti-infectives within 2 weeks before 
or during Screening, or a history of recurrent infections (ie, 3 or more of the same type of 
infection in a 12-month rolling period). Vaginal candidiasis, onychomycosis, and genital or 
oral herpes simplex virus considered by the Investigator to be sufficiently controlled would not 
be exclusionary
9. History of or positive testing for human immunodeficiency virus (HIV), hepatitis C antibody 
and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or hepatitis B 
core total, and/or IgM antibody (+) at Screening
10. History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent TB 
infection (LTBI); untreated LTBI (as determined by documented results within 3 months of 
the Screening Visit of a positive TB skin test with purified protein derivative with induration 
≥5 mm, a positive QuantiFERON®-TB test or positive or borderline T-SPOT [Elispot] test); 
or positive QuantiFERON-TB test at Screening. Subjects with documented completed 
appropriate LTBI treatment would not be excluded and are not required to be tested.
o
Subjects with current household contacts with active TB will also be excluded.
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o
Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be 
considered positive if retest results are positive or indeterminate.
11. History of splenectomy at any time, or any major surgery within 2 months prior to Screening
12. History of myocardial infarction or cerebrovascular event within 6 months prior to Screening, 
or current active angina pectoris, symptomatic heart failure, uncontrolled seizures, untreated 
hypertension, GI bleeding, or any other significant active medical condition in the 
Investigator’s opinion 
13. On anticoagulation or antiplatelet therapy other than daily aspirin for cardioprotection
14. On fish oil (unless discontinued prior to first dose)
15. History of cancer, except adequately treated basal cell or squamous cell carcinoma of the skin 
(no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical 
intraepithelial neoplasia of the uterine cervix, unless considered cured > 5 years
16. Breastfeeding/lactating or pregnant women
17. Clinically significant abnormality on ECG, or an active infective process or any other clinically 
significant abnormality on Screening chest X-ray (CXR) taken within 4 weeks of the first dose, 
per Investigator opinion. If a CXR has been taken within the previous 3 months and results are 
available and normal, the CXR does not need to be carried out
18. Estimated glomerular filtration rate by the 4-variable Modification of Diet in Renal Disease 
equation (19) of < 45 mL/min/1.73 m2
19. TSH < 0.01 or ≥7.1 mIU/L at Screening
20. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), amylase, or lipase 
> 2X above upper limit of normal (ULN) of laboratory reference range, total bilirubin 
> 1.5X ULN, any other clinically significant laboratory abnormality
21. B cell (CD19) count < 50% of the lower limit of normal at Screening
22. Significant cytopenia, including absolute neutrophil count < 1,500/mm3, platelet count 
< 100,000/mm3, or absolute lymphocyte count < 1,000/mm3
23. Has taken an investigational drug within 1 month or 5 half-lives of the investigational drug, 
whichever is longer, prior to Screening
24. Subjects currently receiving (or unable to stop using prior to receiving the first dose of IMP) 
medications or herbal supplements known to be potent inhibitors of cytochrome (CYP)3A 
(must stop at least 1 week prior), potent inducers of CYP3A (must stop at least 3 weeks prior),
or drugs mainly metabolized by CYP3A with a narrow therapeutic index (must stop at least 
1 day prior).
5.4
Criteria for Randomization and Initiation of Trial Treatment
Randomization should occur on Day 1 (Visit 2) after all Screening procedures have been 
completed; subject eligibility must be reviewed again and confirmed at the site on Day 1 prior to 
randomization. If a subject does not meet eligibility criteria, the subject can be retested and 
rescreened once at the Investigator’s discretion as described in Section 7.1.1.
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Eligible subjects will be randomized to treatment with M2951 (50 mg bid) or placebo through a 
central randomization process by an Interactive Web Response System (IWRS). This will be a 
double-blind trial.
5.5
Criteria for Subject Withdrawal
Subjects will be informed they have the right to withdraw from the trial at any time, without 
prejudice to their medical care, and they are not obliged to state a reason for withdrawing. Any 
withdrawal must be fully documented in the electronic case report form (eCRF) and source 
documents, and should be followed up by the Investigator.
The Investigator may withdraw a subject at any time if this is considered to be in the subject’s best 
interest.
5.5.1
Withdrawal from Trial Therapy
Subjects who withdraw from therapy must immediately return for an End of Treatment Visit 
followed by the Safety Follow-Up/End of Trial Visit 4 weeks later. A subject must be withdrawn
from M2951 or placebo if any of the following occur:
! Adverse events, if discontinuation of IMP is desired or considered necessary by the Investigator 
and/or subject
! Use of prohibited medications, 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.
! Pregnancy
! Protocol noncompliance judged as significant by the Investigator and/or the Sponsor
! Subject withdrew consent
! Subject lost to follow-up
! Lack of efficacy
! Death
! Participation in another investigational clinical trial.
Withdrawal due to special precautions are described in Section 6.5.4.
5.5.2
Withdrawal from the Trial
Subjects may withdraw from the trial at any time without giving a reason. Withdrawal of consent 
will be considered withdrawal from the trial. Subjects who withdraw from the trial while still on 
the IMP should return immediately for an End of Treatment Visit upon discontinuation of the IMP 
and a Safety Follow-Up Visit 4 weeks after the last administered dose of IMP. Subjects who 
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withdraw and are no longer on the IMP must complete the Safety Follow-Up/End of Trial Visit 
assessments described in Section 7.1.4.
A subject must be withdrawn if any of the following occurs during the trial:
! Pregnancy (for further details in case of pregnancy, see Section 7.4.2)
! Subject withdrew consent
! Participation in another investigational clinical trial
! Lost to follow-up
! Death
! Any events that endanger the safety of the subject.
If a subject fails to return for the post-treatment Safety 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 trial (eg, for personal reasons), an attempt 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 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. A complete final evaluation at the time of the subject's 
withdrawal should be made and any AEs followed up until resolution or a period of 30 days after 
the last Safety Visit (or withdrawal from the trial).
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible.
Subjects who are withdrawn after randomization (eg, due to AEs or lack of efficacy) will not be 
replaced. Subjects who are withdrawn from the trial will not be allowed to re-enroll in the trial.
Participation in any other trial during the duration of this trial will not be allowed.
5.6
Premature Termination of the Trial
The clinical trial 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 trial if it becomes unjustifiable for medical or ethical reasons, 
for poor enrollment, or because of discontinuation of clinical development of an IMP or 
comparator from the market for safety reasons.
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards (IRBs)
will be informed about the discontinuation of the trial in accordance with applicable regulations.
5.7
Definition of End of Trial
The end of the trial is defined as the last contact date with the last subject who participates in this 
trial (last subject’s last visit).
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A clinical trial protocol 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 Follow-Up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term IMP refers to an active substance or a placebo being tested or used as a reference therapy 
in a clinical trial, 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.
6.1
Description of the Investigational Medicinal Product
During the 12-week treatment period, the active IMP is M2951 (2 x 25 mg bid), which is supplied 
as a capsule (size 0, color Swedish Orange) formulation for oral administration. No other 
excipients are used.
Identical capsules for placebo are filled with mannitol.
During the optional extension period, M2951 (2 x 25 mg bid) will be supplied as tablet formulation
for oral administration.
The Sponsor, Merck KGaA, will provide IMP (M2951 and placebo) to the trial site, manufactured 
and tested according to applicable current Good Manufacturing Practice requirements for clinical 
trial supplies and a confirmation the IMPs are released for human use in clinical trials.
6.2
Dosage and Administration
During the 12-week treatment period, subjects will receive 50 mg bid M2951 or placebo
administered as 2 matching oral capsules twice daily for 84 days. Subjects will self-administer the 
IMP at a set time each day (± 2 hours). Subjects must take their daily dose more than 1 hour prior 
to a meal or snack and more than 2 hours after a meal or snack. Clear fluids are allowed at any 
time. On trial visit days, the IMP will be administered during the trial visit after the scheduled trial
visit procedures (other than post-treatment PK/PD sampling and post-treatment ECGs) are 
completed.
After completing the treatment period, subjects will be offered the opportunity to participate in an 
optional 6-month M2951 extension period on Day 85 (Visit 8). Subjects who received M2951
during the treatment period will continue with the same dose of M2951 (in tablet formulation). All 
subjects in the placebo group during the treatment period will discontinue placebo and start 
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treatment with 50 mg bid M2951 tablets on Day 85/Day 1 of OLE. On trial visit days, the IMP 
will be administered during the trial visit after the scheduled trial visit procedures are completed.
Subjects will take 2 matching oral tablets twice daily for 6 months. Subjects will self-administer 
the IMP at a set time each day (± 2 hours). Subjects must take their daily dose more than 1 hour 
prior to a meal or snack and more than 2 hours after a meal or snack. Clear fluids are allowed at 
any time. On trial visit days, the IMP will be administered during the trial visit after the scheduled 
trial visit procedures are completed.
If a dose is missed, the subject can take the missed dose up to 6 hours after the scheduled time. If 
more than 6 hours have elapsed since the dose was missed, the subject should skip the dose for 
that period, make note of the missed dose, and take the next dose at the regularly scheduled time.
6.3
Assignment to Treatment Groups
Eligible subjects will be randomized through a central stratified randomization process by the 
IWRS to receive 50 mg bid M2951 or placebo in a 1:1 ratio prior to dosing on Visit 2/Day 1.
Treatment kits will contain enough medication for administration for 1 week (+ 2 days). In addition 
to the subject and Investigator/site, all Sponsor and CRO trial staff will be blinded to the treatment 
group assignment.
Subjects continuing to the open-label extension period will be dispensed additional treatment kits 
for 6 months of treatment.
6.4
Noninvestigational Medicinal Products to be Used
Throughout the study, patients will remain on their chronic stable doses of MTX at the time of 
Screening (refer to Section 5.3.1) as part of their standard of care and adjusted only for safety 
reasons.
6.5
Concomitant Medications and Therapies
All concomitant medications taken by the subject during the trial from the date of signature of 
informed consent (including those participating in and during the extension period) are to be 
recorded in the appropriate section of the eCRF, noting the name, dose, duration, 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
Permitted medications are any medications required per the medical history and not specifically 
prohibited by the protocol during the trial. These standard of care medications are part of the 
subject’s previous RA treatment and will therefore not be provided by the Sponsor. Any such 
medications prescribed or used should be recorded in the eCRF.
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The standard of care therapies for RA that are allowed to be continued during the trial include the 
following immunosuppressive or immunomodulating therapies: 
! MTX (up to 25 mg/week) background therapy is required
! Sulfasalazine (up to 3 g/day)
! Oral corticosteroids (up to 10 mg/day prednisone equivalent)
Other permitted therapies that are allowed to be continued during the trial include antimalarials, 
such as hydroxychloroquine, quinacrine, and chloroquine.  
With the exception of corticosteroids, the dose of which can be decreased, the dose of these 
medications must remain stable during the Screening Period and throughout the subject’s 
participation in the trial, unless changes are required for safety issues.  
The following additional treatments commonly given to subjects with RA are permitted to be 
continued during the trial and should be maintained at a stable dose during the trial unless a dose 
change is required for safety reasons:
! Nonsteroidal anti-inflammatory medications 
! Opioids and other analgesics.
Any medications (other than those excluded as 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 trial medication may be given at the Investigator’s discretion.
6.5.2
Prohibited Medicines
The following medications and therapies are not permitted during the trial and would require 
discontinuation of the trial treatment:
! Initiation of an immunosuppressant or immunomodulator, or increase in immunosuppressant 
beyond the maximum allowable dose
! Oral corticosteroid dose > 10 mg/day or use of intramuscular or intravenous steroids
! Intra-articular steroids
! Biologic therapies
! Intravenous Ig therapy and/or plasmapheresis
! Live and live-attenuated vaccines
! Herbal supplements including, but not limited to, St. John’s wort, grapefruit, Seville oranges, 
cranberries, or juices of these fruits
! Moderate or strong inhibitors or inducers of CYP3A or drugs mainly metabolized by CYP3A 
with a narrow therapeutic index (see Table 2). The additive effects of weak inhibitors taken in 
combination must also be taken into account.
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New therapies for RA should not be initiated during the trial. Initiation of any new 
immunosuppressant or immunomodulatory therapy would be considered a treatment failure and 
should result in withdrawal of the subject from the IMP (see Section 5.5.1).
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Table 2
Examples of Inhibitors or Inducers of CYP3A Enzymes or Substrates 
with Narrow Therapeutic Range
Inhibitors
Strong 
Moderate 
Weak 
Boceprevir, clarithromycin, conivaptan,
grapefruit juice,a indinavir, 
itraconazole, ketoconazole, 
lopinavir/ritonavir, mibefradil, 
nefazodone, nelfinavir, posaconazole, 
ritonavir, saquinavir, telaprevir, 
telithromycin, voriconazole
Amprenavir, aprepitant, atazanavir, 
ciprofloxacin, darunavir/ritonavir, 
diltiazem, erythromycin, fluconazole, 
fosamprenavir, grapefruit juice,a
matinib, verapamil
Alprazolam, amiodarone, amlodipine, 
atorvastatin, bicalutamide, cilostazol, 
cimetidine, cyclosporine, fluoxetine, 
fluvoxamine, ginkgo, goldenseal, 
soniazid, nilotinib, oral contraceptives, 
ranitidine, ranolazine, 
tipranavir/ritonavir, zileuton
Inducers
Strong 
Moderate 
Weak 
Avasimibe, carbamazepine, phenytoin, 
rifampin, St. John’s wort
Bosentan, efavirenz, etravirine, 
modafinil, nafcillin
Amprenavir, aprepitant, armodafinil, 
echinacea, pioglitazone, prednisone, 
rufinamide
Substrates With a Narrow Therapeutic Range
Alfentanil, astemizole,b cisapride,b cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, 
sirolimus, tacrolimus, terfenadineb
a The effect of grapefruit juice varies widely among brands and is concentration, dose, and preparation dependent. 
Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain preparation is used (eg, 
high dose, double strength) or as a “moderate CYP3A inhibitor” when another preparation is used (eg, low dose, 
single strength).
b Withdrawn from the US and certain other markets because of safety reasons.
Note: This is not an exhaustive list. For an updated list, see Tables 5, 6, and 7 in the following link: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm0804
99.htm
Note: A strong inhibitor is defined as an inhibitor that increases the AUC of a substrate sensitive for that CYP ≥5-fold 
or decreases clearance by > 80%, and a strong inducer decreases AUC of a substrate by ≥80%.
Note: A moderate inhibitor is defined as an inhibitor that increases the AUC of a substrate sensitive for that CYP 
≥2-fold but < 5-fold or decreases clearance by 50%-80%, and a strong inducer decreases AUC by 50%-80%.
Note: A weak inhibitor is defined as an inhibitor that increases the AUC of a sensitive substrate for that CYP < 2-fold 
or decreases clearance 20%-50%, and a weak inducer decreases AUC by 20%-50%.
Note: CYP substrates with narrow therapeutic range refers to drugs whose exposure-response relationship indicates 
that small increases in their exposure levels by the concomitant use of CYP inhibitors may lead to serious safety 
concerns (eg, Torsades de pointes).
6.5.3
Other Interventions
Not applicable.
6.5.4
Special Precautions
The IMP should be temporarily withheld or permanently withdrawn if the following abnormalities 
occur or re-occur, as relevant, and only 1 re-initiation is allowed if the IMP is temporarily withheld:
! For a neutrophil count < 500/mm3 or platelet count < 25,000/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. 
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o 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 within 24 hours of 
receipt. If the value is still Grade 3, permanently discontinue the IMP. For a decrease from 
normal to Grade 1, or Grade 1 to Grade 2, temporarily hold the IMP and recheck the value 
within 24 hours of receipt. Discontinue the IMP if the neutrophil or platelet count continues 
to decrease, and re-initiate the IMP if no downward trend is observed.
! For an increase in AST or ALT to > 3X ULN or increase in bilirubin to > 1.5X ULN (Grade 2 
or higher), the IMP should be permanently withdrawn. 
! For an increase in amylase or lipase to > 5X ULN (Grade 4), the IMP should be permanently 
withdrawn. 
o 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 any other increase from Baseline to another grade, temporarily 
hold the IMP and recheck the value within 24 hours of receipt. Discontinue the IMP if the 
value does not decrease, or re-initiate the IMP 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. 
o 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 re-initiate the IMP if a downward trend is observed.
! For any other laboratory abnormality of Grade 4 severity, the IMP should be permanently 
withdrawn. 
o For any other laboratory increase/decrease (as relevant) from Baseline to a higher severity 
grade, temporarily hold the IMP and recheck the value within 24 hours of receipt. 
Discontinue the IMP if the value does not improve, or re-initiate the IMP if an improving 
trend is observed.
Duplicate blood samples will be collected for selected safety laboratories to be processed by both 
the central laboratory and local laboratories. A detailed list of these tests is provided in the 
Laboratory Manual. The Investigator should review local laboratory results within 24 hours and 
should base decisions regarding retesting or IMP dose interruption or discontinuation on local 
laboratory results if local laboratory results are obtained prior to the central laboratory results and 
show an abnormality requiring action. The local laboratory reference range should be used to 
determine grade in this case. Only the central laboratory results will be automatically reported and 
used for analyses. If an action is taken to retest or adjust the IMP dose based on local laboratory
results, the results should be entered in the eCRF (with date, time and result, and local reference
range) on an unscheduled visit page to document why the decision was made.
Laboratory values corresponding to Common Terminology Criteria for AEs (CTCAE) 
Grades 1 to 4 are presented for selected laboratory parameters in Table 3. For all other laboratory 
abnormalities, refer to the CTCAE, version 4.03 (20).
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Table 3
CTCAE 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 3X ULN
> 3 to 5X ULN
> 5 to 20X ULN
> 20X ULN
Bilirubin
< ULN to 1.5X ULN
> 1.5 to 3X ULN
> 3 to 10X ULN
> 10X ULN
Amylase and lipase
< ULN to 1.5X ULN
> 1.5 to 2X ULN
> 2 to 5X ULN
> 5X ULN
Creatinine
> Baseline to ≤ 1.5X 
Baseline, or > ULN to 
1.5X ULN
> 1.5 to 3X Baseline 
or > 1.5 to 3X ULN
> 3X Baseline, or 
> 3 to 6X ULN
> 6X ULN
ALT=alanine aminotransferase, AST=aspartate aminotransferase, CTCAE=Common Terminology Criteria for 
Adverse Events, LLN=lower limit of normal, ULN=upper limit of normal.
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.
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 trial 
site for all AEs occurring during the trial.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
M2951 and matching placebo is supplied by the Sponsor. A description of the pharmaceutical 
properties and composition of the formulation of M2951 is provided in the IB. Additional details 
of packaging and labeling of the IMP will be defined in a separate Operations Manual.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
Because the Investigator is blinded to trial treatment, subjects will be instructed on the proper 
handling and storage of the IMP by the trial nurse or pharmacist. Storage at or below 25°C is 
recommended.
Any unused product should be returned to the trial site.
6.8
Investigational Medicinal Product Accountability
The Investigator or designee is responsible for ensuring IMP accountability, including 
reconciliation of drugs and maintenance of records.
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! Upon receipt of the IMP, the responsible person will check for accurate delivery and
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File.
! IMP dispensing will be recorded on the appropriate drug accountability forms so accurate 
records will be available for verification at each monitoring visit.
! Trial site IMP accountability records will include the following:
o Confirmation of IMP receipt, in good condition and in the defined temperature range
o The inventory of IMP provided for the clinical trial and prepared at the site
o The use of each dose by each subject
o The disposition (including return, if applicable) of any unused IMP
o Dates, quantities, batch numbers, expiry dates, and the individual subject trial numbers.
The Investigator site should maintain records, which adequately document the subjects were 
provided the doses specified in this protocol, and all IMPs provided were fully reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. No IMP 
dispensed to a subject may be redispensed to a different subject.
A Trial Monitor will periodically collect the IMP accountability forms.  
6.9
Assessment of Investigational Medicinal Product Compliance
The IMP will be administered at the site on trial visit days as defined in Table 1. All other dosing 
will be done by the subject at home throughout the rest of the trial. Subjects will be asked to record 
the date and time of dosing and food intake around dosing in a subject diary. Diaries will be 
collected and reviewed at the trial visits specified in Table 1.
Subjects will be instructed to bring all IMP, including the used packaging, to each trial visit to 
allow for the assessment of compliance with trial treatment. Prior to discharge from each scheduled 
visit, subjects will be given sufficient IMP for at-home dosing until the next scheduled visit during 
the treatment period.
6.10
Blinding
This will be a double-blind trial. After Day 1, the study site staff, the Sponsor, and the 
 
study team will be blinded to:
! Results that can reveal the PD effects of M2951 in an individual subject (ie, immunoglobulins 
[IgA, IgM, IgG, and its subclasses], 
, and B cell numbers and subtypes) and
! Results that can reveal the efficacy of M2951 in an individual subject (ie, hsCRP, ESR, 
anti-CCP, and RF).
Blinding to treatment codes or laboratory results capable of revealing treatment will be maintained 
throughout the trial duration, except for the unblinded IDMC, limited unblinding for the purposes 
PPD
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of the IA, partial unblinding to support early analysis of PK/PD data, or in the event that emergency 
unblinding is necessary (see Section 6.11). The blind may also be broken in the case of a pregnancy 
should the subject desire this information. Randomization data will be kept strictly confidential, 
accessible only to authorized staff, until the limited unblinding for the IA and full unblinding for 
the analysis at the end of 12 weeks of treatment for all randomized patients.
In order to maintain the blinded nature of the study, only the randomization statistician, an 
independent person at the study site responsible for receiving local laboratory ESR results and 
conveying those results to the central laboratory, and an independent statistician team (independent 
of the 
 study team) responsible for production of the IA outputs, will be fully unblinded
during study conduct. The bioanalytical laboratory(ies) responsible for the analysis of the PK and 
PD samples will be allowed to be partially unblinded during study conduct using masked subject 
identifiers, to support association of PK/PD data with treatment codes for timely decision making, 
but prevent association of treatment codes with any other clinical data, such as safety data. A
subteam of the Sponsor study team tasked with review of the IA data (medical responsible, Drug 
Safety representative, and biostatistician) will be unblinded to the IA results, which will be 
presented in the form of summary tables on a limited set of endpoints for subjects enrolled at the 
time of the IA: 4-week hsCRP, 4-week DAS28-hsCRP, safety, baseline characteristics, and 
disposition. The IDMC will also be unblinded to treatment, as described in the IDMC charter.
All other trial-related individuals, ancillary site staff, other clinical research associates/monitors, 
investigators, Sponsor staff other than those identified above, and 
staff other than those 
identified above, will remain blinded to treatment codes or laboratory results capable of revealing
treatment. Results from PK and PD testing or the IA will not be reported back to the sites or the 
 study team, with the exception of ESR results. The ESR results will be analyzed at a 
laboratory local to the site, received by a person at the site independent of study staff at the site, 
and conveyed to the central laboratory without sharing with study staff at the study site, the 
Sponsor, or the 
 study team. There will be no communication of results between the 
 study team tasked with conduct of the study and the independent statistician team 
responsible for the production of IA outputs.
Only when the 12-week Treatment Period is completed for all patients, the data file verified, 
protocol violations determined, statistical analysis plan (SAP) signed and database partially locked
for the 12-week treatment period, will the drug codes be broken and made available, along with 
laboratory results capable of revealing treatment, for the primary data analysis. The final analysis 
will be performed after all subjects have completed the Safety Follow-up or discontinued from 
study early, with assessment of some safety and key efficacy variables.
All breaks of the trial blind must be adequately documented.
Processes to maintain blinding during the IA are described in Section 8.6.
6.11
Emergency Unblinding
There is no known antidote to M2951, so symptomatic and supportive treatment of any suspected 
and related AE, if necessary, is to be undertaken as clinically indicated.
PPD
PPD
PPD
PPD
PPD
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The trial blind may be broken for an individual only if knowledge of the IMP is essential for 
clinical management of the subject. Contact information for breaking the blind in an emergency is 
given on the subject emergency card provided to each subject (see Section 9.4).
The Investigator will have the ability to break the blind with regard to IMP for any subject 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. The Investigator 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). The Investigator must record the date and reason 
for unblinding in the subject’s eCRF and source documents.
Under certain circumstances, Drug Safety may be required to unblind the treatment assignment for 
an individual subject following an SAE or other serious event, eg, if an expedited regulatory report 
is required. See Section 7.4.1.4 for further details on expedited reporting and SAEs.
If emergency unblinding is required, discontinuation of the affected subject from the IMP and/or 
trial is not mandatory unless there are other circumstances that require subject discontinuation. If 
the affected subject is discontinued from the IMP, the subject must immediately complete the End 
of Treatment Visit, followed 4 weeks later by the Safety Follow-Up/End of Trial Visit. 
6.12
Treatment of Overdose
For purposes of this protocol, an overdose is defined as any dose greater than twice the highest 
daily dose included in the clinical trial protocol or planned for an individual subject enrolled in the 
trial, administered on 3 or more consecutive days. Even if it does not meet other criteria for an 
SAE, any overdose must be recorded in the trial medication section and AE section of the eCRF
and reported to Drug Safety in an expedited manner using the paper SAE Report Form, and 
following the same timelines in Section 7.4.
6.13
Medical Care of Subjects after End of Trial
After a subject has completed the trial or has withdrawn early, the subject is free to access further 
treatment as deemed appropriate by the treating physician.
7
Trial Procedures and Assessments
During the Screening Visit, 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.
Throughout the trial, subjects will undergo the assessments detailed in Table 1, including blood 
sampling. The maximum amount of blood to be obtained during the trial is within the commonly 
accepted maximum of 275 mL over 4 weeks and 550 mL over 8 weeks. Details of the blood 
volumes to be collected for each sample/visit will be detailed in the Laboratory Manual. 
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Instructions on how samples will be collected, labeled, processed, stored, and shipped as well as 
specification on bioanalytical methods will be detailed in the Laboratory Manual.
All blood and urine tests will be analyzed by a central laboratory, with the following exceptions:
! Urine testing for beta-human chorionic gonadotropin (β-HCG) will be conducted at the local 
laboratories
! PK samples and 
 samples will be analyzed by the analytical laboratories 
specified by the Sponsor
! Blood samples will be sent for duplicate analysis of selected safety tests by both central and 
local laboratories. These duplicate safety samples are listed in the Laboratory Manual.
! ESR will be analyzed by local laboratories
Every effort should be made to perform assessments as close as possible to the scheduled time 
points, within the range of days noted for each day on trial as noted in Table 1. The details of 
efficacy assessments and safety assessments are described in Sections 7.3 and 7.4, respectively.
The Schedule of Assessments for the trial is presented in Table 1 and details of the trial procedures 
are provided in Section 7.1.1 for the Screening Period, Section 7.1.2 for the Treatment Period, and 
Section 7.1.4 for the Follow-Up Period.
The Sponsor and CRO should be notified immediately of any major violations of the trial 
procedures. Major and minor protocol violations will be defined in the Manual of Procedures 
(MOP) and in the SAP. Procedures for documenting protocol violations will be provided in the 
MOP.
7.1
Schedule of Assessments
Assessments during the trial will be performed according to Table 1. Patient reported outcome 
questionnaires must be performed prior to any other assessments at all visits. For volumes of blood 
collected, see Appendix C.
7.1.1
Screening Period
At the Screening Visit (Visit 1), the prospective subject will be informed of the trial objectives and 
overall requirements, and informed consent will be obtained prior to initiating any screening 
procedures or collecting any data. Screening procedures will be performed within 28 days prior to 
the first administration of the IMP according to assessments in Table 1.
After signing of informed consent, Screening assessments will include, but are not limited to, 
recording of demographic information and other Baseline characteristics, detailed RA history, 
medical history, and medications history and reviewing of inclusion/exclusion criteria. If a subject 
does not meet eligibility criteria, the subject can be retested and rescreened once within the 
Screening Period at the Investigator’s discretion and on discussion with the Medical Monitor.
If a subject is rescreened, the subject will be assigned a new subject number and reconsented.
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Subjects who have completed the Screening assessments and have fulfilled all of the eligibility 
criteria will be entered into the trial.
7.1.2
Treatment Period
At all trial visits, patient reported outcome questionnaires must be performed prior to any other 
assessments. At the Day 1 Visit (Visit 2), assessments should be performed prior to randomization 
and the administration of trial treatment. Scheduled assessments will be performed according to 
Table 1 before administration of the IMP, with the exception of relevant postdose blood draws (eg, 
PK and 
). 
At subsequent visits (Visit 3 through 7), all scheduled visits during the treatment period may take 
place within the visit windows specified in Table 1. Subjects who discontinue early must return 
for the End of Treatment Visit.
Subjects must be fasted for 8 hours prior to PK sampling as specified in Table 1. Subjects must 
also fast for 1 hour postdose at these visits with PK sampling.
7.1.2.1
End of Treatment Visit
The End of Treatment Visit (Visit 8) will be performed on Day 85 or within 5 days after early 
discontinuation of treatment with the IMP. Subjects will undergo the assessments as described in 
the Schedule of Assessments (Table 1).
Any ongoing SAEs must be followed up until the SAE/AE has resolved, is considered stable, or 
is considered no longer clinically relevant by the Investigator.
Subjects opting to participate in the optional extension period will sign a new ICF at this visit. The 
Investigator will discuss the benefits with the subject and the subject well-being. Subjects are free 
not to sign the new ICF for the extension period.
7.1.3
Optional Extension Period
After completing the treatment period (Visits 2 through 8), subjects will be offered the opportunity 
to participate in an optional 6-month M2951 extension period. Subjects electing to participate in 
the Extension Period will sign an ICF at Visit 8. Subjects who received M2951 during the treatment 
period will continue with M2951. Subjects who received placebo during the treatment period will 
discontinue placebo and start treatment with M2951 on Day 85/Day 1 of OLE. The End of 
Treatment Visit during the treatment period (Visit 8) will be considered Day 1 of the optional 
extension period. 
The Optional Extension Period includes four scheduled visits (Visits 9, 10, 11, and 12), which 
correspond with Day 14, and the end of Months 1, 3, and 6. Subjects who signed the additional 
ICF at Visit 8 will undergo the Optional Extension Period assessments as described in the Schedule 
of Assessments (Table 1).  
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If a subject discontinues early from the optional extension period, he/she should complete the 
Safety Follow-Up Visit.
7.1.4
Safety Follow-Up Visit
For subjects who complete the first treatment period of 12 weeks, but do not continue to the 
optional extension period, assessments during the Safety Follow-Up/End of Trial Visit will be 
performed approximately 28 days after the last dose of IMP.
Subjects who withdraw from trial treatment or 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 subjects discontinuing the Optional Extension Period prematurely, or completing the Optional 
Extension Period, will have a Safety Follow-up visit.
7.2
Demographic and Other Baseline Characteristics
7.2.1
Demography
At Screening, the following demographic data will be collected: date of birth, sex (gender), race, 
and ethnicity.
7.2.2
Medical History
Information regarding previous medications (as part of medical history) and concomitant 
medications and procedures will also be recorded.
Medical and RA history data will be recorded, and a complete physical examination, will be 
performed. Vital signs, including oral temperature, heart rate, respiratory rate, blood pressure, and 
height will be obtained. All other Baseline measurements, such as safety laboratory parameters, 
ECG, and CXR, will be assessed.
7.3
Efficacy Assessments
The following tests and procedures have been selected to evaluate the efficacy of M2951 and 
describe clinical improvement in subjects with RA and will be performed according to the 
Schedule of Assessments (Table 1).
7.3.1
Disease Activity Assessments
Assessments for RA disease activity will include ACR response criteria, hsCRP analyses,
DAS28-hsCRP, ESR, and subject and physician visual analog scales, which are described below.
7.3.1.1
American College of Rheumatology Response Rates
The primary efficacy endpoint is ACR20 at Day 85 in subjects with RA. The individual 
components that make up the ACR Core Set of measures for RA are described below. Relief of 
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signs and symptoms will be assessed using the ACR Responder Index, a composite of clinical, 
laboratory, and functional measures in RA. The ACR responses are presented as the minimal 
numerical improvement from Baseline in multiple disease assessment criteria. The response 
criteria is based on the 68-joint tender/painful joint count, the 66-joint swollen joint count, and the 
hsCRP level.
ACR Core Set
a.
Tender Joint Count (TJC)
For ACR measures, the number of tender and painful joints will be determined by examination of 
68 joints (34 joints on each side of the subject’s body; see Appendix B). The 68 joints to be 
assessed and classified as tender or not tender include: 2 temporomandibular joints, 
2 sternoclavicular joints, 2 acromioclavicular joints, 2 shoulder joints, 2 elbow joints, 2 wrist 
joints, 10 metacarpophalangeal joints, 2 interphalangeal joints of the thumb, 8 proximal 
interphalangeal joints of the hands, 8 distal interphalangeal joints of the hands, 2 hip joints, 2 knee 
joints, 2 ankle joints, 2 tarsus, 10 metatarsophalangeal joints of the feet, 2 great toes (first proximal 
interphalangeal joint of the feet), and 8 proximal interphalangeal joints of the feet. 
Joints will be assessed for tenderness by pressure and joint manipulation on physical examination. 
The subject will be asked for pain sensations on these manipulations and watched for spontaneous 
pain reactions. Any positive response on pressure, movement, or both will then be translated into 
a single tender-versus-nontender dichotomy. Joint assessments of 1 particular subject should be 
performed (if at all possible) by the same assessor throughout the trial to minimize inter-observer 
variation.
Missing, replaced, ankylosed, or arthrodesed joints will be identified by the Investigator at the 
Screening Visit and will be excluded from evaluation during the trial. The locations (or a listing) 
of surgical procedures should be documented in the subject’s source documents/eCRF pages.
b.
Swollen Joint Count (SJC)
For ACR measures, the number of swollen joints will be determined by examination of 66 joints 
(33 joints on each side of the subject’s body). The 66 joints to be assessed and classified as swollen 
or not swollen include: 2 temporomandibular joints, 2 sternoclavicular joints, 2 acromioclavicular 
joints, 2 shoulder joints, 2 elbow joints, 2 wrist joints, 10 metacarpophalangeal joints, 
2 interphalangeal joints of the thumb, 8 proximal interphalangeal joints of the hands, 8 distal 
interphalangeal joints of the hands, 2 knee joints, 2 ankle joints, 2 tarsus, 10 metatarsophalangeal 
joints of the feet, 2 great toes (first proximal interphalangeal joint of the feet), and 8 proximal 
interphalangeal joints of the feet.
Joints will be classified as either swollen or not swollen. Swelling is defined as palpable fluctuating 
synovitis of the joint. Swelling secondary to osteoarthrosis will be assessed as not swollen, unless 
there is unmistakable fluctuation. Joint assessments of 1 particular subject should be performed by 
the same assessor (if at all possible) throughout the trial to minimize inter-observer variation.  
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Missing, replaced, ankylosed, or arthrodesed joints will be identified by the Investigator at the 
Screening Visit and will be excluded from evaluation during the trial. The locations (or a listing) 
of surgical procedures should be documented in the subject’s source documents/eCRF pages.
c.
High sensitivity C-Reactive Protein
High sensitivity C-reactive protein will be the ACR Core Set measure of acute phase reactant. It 
will be measured at the central laboratory to help assess the effect of M2951 on the subject’s RA.
ACR20
The ACR20 is a primary efficacy measure for which, at Day 85, a subject must have at least
20% improvement in the following ACR Core Set values.
! TJC (68 joint count) and
! SJC (66 joint count) and
! An improvement of at least 20% in at least 3 of the following 5 assessments:
o Subject’s Global Assessment of Disease Activity 
o Subject’s Assessment of Pain
o Subject’s Assessment of Physical Function as measured by the HAQ-DI
o Physician’s Global Assessment of Disease Activity
o Acute phase reactant as measured by hsCRP.
In this trial, ACR20 response calculations will use the HAQ-DI for the subject’s assessment of 
physical function and hsCRP as the measure of acute phase reactant.
ACR50 and ACR70
ACR50 and ACR70 are defined in the same way as the ACR20 using at least 50% and 
70% improvement, respectively.
7.3.1.2
Visual Analog Scales
Visual analog scales will include the subject’s assessment of disease activity and pain, and the
HAQ-DI and physician’s assessment of disease activity. Patient reported outcome questionnaires 
(including global assessment of disease activity, self-assessment of pain, and HAQ-DI) must be 
performed prior to any other assessments at all visits.
Subject’s Global Assessment of Disease Activity
The subject’s overall assessment of his or her disease activity during the last 24 hours will be 
recorded using the 100 mm horizontal visual analog scales (VAS) where the left end represents no 
disease activity (symptom free and no arthritis symptoms) and the right end represents maximum 
disease activity (maximum arthritis disease activity).
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7.3.1.3
Disease Activity Score-C-Reactive Protein (DAS28-hsCRP)
The DAS28-hsCRP is a measure of disease activity in 28 joints that consists of a composite 
numerical score of the following variables: TJC, SJC, hsCRP, and Subject’s Global Assessment 
of Disease Activity (21).  
For DAS28-hsCRP, the 28 joints to be examined and assessed as tender or not tender for TJC and 
to be examined and assessed as swollen or not swollen for SJC include 14 joints on each side of 
the subject’s body: 2 shoulders, 2 elbows, 2 wrists, 10 metacarpophalangeal joints, 
2 interphalangeal joints of the thumb, 8 proximal interphalangeal joints, and 2 knees (22).
DAS28-hsCRP will be derived using the following formula from the DAS28 website (23):
DAS28-hsCRP =  0.56*√(TJC28) +0.28*√(SJC28)+0.014*GH+0.36*ln(hsCRP+1)+0.96
Where:
! TJC28=28 joint count for tenderness
! SJC28=28 joint count for swelling
! ln(hsCRP)=natural logarithm of hsCRP
! GH=the general health component of the DAS (ie, patient’s global assessment of disease 
activity).
7.3.1.4
Health 
Assessment 
Questionnaire 
–
Disability 
Index 
(HAQ-DI)
The HAQ-DI is a subject-reported questionnaire that is commonly used in RA to measure 
disease-associated disability (assessment of physical function). It consists of 24 questions referring 
to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and activities 
(24-26).  
The disability section of the questionnaire scores the subject’s self-perception on the degree of 
difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, and 
3 = unable to do) covering the following domains: dressing and grooming, arising, eating, walking, 
hygiene, reach, grip, and performing other daily activities. The reported use of special aids or 
devices and/or the need for assistance of another person to perform these activities is also assessed. 
The scores for each of the functional domains will be averaged to calculate the functional disability 
index. 
Validated translated versions of the HAQ-DI will be used for each country participating in this 
trial.
7.3.2
Rheumatoid Factor, anti-CCP, and hsCRP
Samples for RF, anti-CCP, and hsCRP will be collected at visits indicated in Table 1.
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Samples will be analyzed by the central laboratory. Samples will be collected, labeled, processed, 
stored, and shipped according to the instructions in the Laboratory Manual.
7.3.3
Erythrocyte Sedimentation Rate
Samples for ESR will be collected at visits indicated in Table 1.
Samples will be analyzed by the local laboratory. Samples will be collected, labeled, processed, 
stored, and shipped according to the instructions in the Laboratory Manual.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting, and analysis of 
Baseline medical conditions, adverse events (AEs), and physical examination findings including 
vital signs and laboratory tests.
Comprehensive assessment of any apparent toxicity experienced by each subject will be performed 
from the time of giving informed consent and throughout the trial. 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 CTCAE, version 4.03 (publication date: 
14 June 2010); a descriptive terminology that will be provided in the Manual of Procedures 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.
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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 5 general grades are:
! Grade 1 or Mild
! Grade 2 or Moderate
! Grade 3 or Severe 
! Grade 4 or Life-threatening  
! Grade 5 or Death.
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 1 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 (eg, 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)/trial
treatment (including any other non-IMPs, radiation therapy, 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 the 
IMP, medical history, concomitant medication, course of the underlying disease, trial procedures.
Unrelated:
Not reasonably related to the IMP/trial treatment. The AE could not medically 
(pharmacologically/clinically) be attributed to the IMP/trial treatment under trial in 
this clinical trial protocol. A reasonable alternative explanation must be available.
Related:
Reasonably related to the IMP/trial
treatment. The AE could medically 
(pharmacologically/clinically) be attributed to the IMP/trial treatment under trial in 
this clinical trial protocol. 
Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (eg, 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 (eg, 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:
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! 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
! Results in persistent or significant disability or incapacity
! Is a congenital anomaly or birth defect
! 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 Section 7.4.1.4.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify trial treatment or trial procedures (eg, an
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (eg, undesirable effects of any administered treatment) 
must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial trial visit that do not worsen in severity or frequency during 
the trial are defined as Baseline Medical Conditions, and are not to be considered AEs.
7.4.1.2
Methods of Recording and Assessing Adverse Events
At each trial visit, the subject will be queried on changes in his or her condition. During the 
reporting period, any unfavorable changes in the subject’s condition will be recorded as AEs, 
whether reported by the subject or observed by the Investigator. 
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 the appropriate 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 when it is important to assess the time of AE onset relative to the 
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recorded treatment administration time), its severity, its causal relationship with the trial 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, serious cases 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.
7.4.1.3
Definition of the Adverse Event Reporting Period
The AE reporting period for safety surveillance begins when the subject is initially included in the 
trial (date of first signature of informed consent/date of first signature of first informed consent) 
and continues until the Safety Follow-Up/End of Trial Visit.
Any SAE occurring within 30 days after the last dose of IMP must be reported, even if the subject 
has discontinued from the trial. Any SAE assessed as related to the IMP must be reported whenever 
it occurs, irrespective of the time elapsed since the last administration of the IMP. 
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 (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee using the SAE Report Form following specific completion instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone; 
in these cases, the eCRF must be completed.
Relevant pages from the eCRF may be provided in parallel (eg, medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (eg, laboratory 
results, hospital report, autopsy report). In all cases, the information provided on the SAE Report 
Form must be consistent with the data about the event recorded in the eCRF.
The Investigator must respond to any request for follow-up information (eg, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee and 
(as applicable) to allow the Sponsor to meet strict regulatory timelines associated with expedited 
safety reporting obligations.
Requests for follow-up will usually be made via the responsible Medical Monitor, although in 
exceptional circumstances, the Global Drug Safety department may contact the Investigator 
directly to obtain further information or to discuss the event.
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7.4.1.5
Safety Reporting to Health Authorities, Independent Ethics 
Committees/ Institutional Review Boards, and Investigators
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with the ICH GCP guidelines, the Sponsor/designee will inform the Investigator of 
“findings that could adversely affect the safety of subjects, impact the conduct of the trial, or alter 
the IEC’s/IRB’s approval/favorable opinion to continue the trial.” 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 (“suspected 
unexpected serious adverse reactions” or 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.
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 promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For trials 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
Adverse events are recorded and assessed continuously throughout the trial (see Section 7.4.1.3) 
and are assessed for final outcome at the Safety Follow-Up Visit/End of Trial Visit. All SAEs 
ongoing at the Safety Follow-Up Visit/End of Trial 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.” Reasonable attempts to obtain this information must be made and 
documented. It is also the responsibility of the Investigator to ensure that any necessary additional 
therapeutic measures and follow-up procedures are performed. 
7.4.2
Pregnancy and In Utero Drug Exposure 
Only pregnancies considered by the Investigator to be related to trial treatment (eg, 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 
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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
paper Pregnancy Report Form, which must be transmitted according to the same timelines as 
described for SAE reporting in Section 7.4.1.4. 
Investigators must actively follow-up, document, and report on the outcome of all these 
pregnancies, even if the subjects are withdrawn from the trial.
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy Report 
Form. If an abnormal outcome occurs, the SAE Report Form will be used if the subject sustains 
an event and the Parent-Child/Fetus Adverse Event Report Form if the child/fetus sustains an 
event.
Any abnormal outcome must be reported in an expedited manner as described in Section 7.4.1.4, 
while normal outcomes must be reported within 45 days after delivery.
In the event of a pregnancy in a subject occurring during the course of the trial, the subject must 
be discontinued from the IMP immediately. The Sponsor/designee must be notified without delay 
and the subject must be followed as mentioned above.
7.4.3
Clinical Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in Table 4, 
following the timing noted in the Schedule of Assessments (Table 1). All samples should be clearly 
identified. Sample collection, preparation, and handling/shipment procedures are described in the 
Laboratory Manual.
For women of childbearing potential, including those who are postmenopausal for less than 
12 months, serum pregnancy tests will be performed at initial screening, and urine pregnancy tests 
will be performed at the visits specified in Table 1.
Additional laboratory tests may be performed after abnormal findings.
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Table 4
Clinical Safety Laboratory Evaluations
Screening 
virologya
!
Human immunodeficiency virus I and II antibodies
!
Hepatitis C antibody
!
Hepatitis C virus polymerase chain reaction (reflex test if hepatitis C antibody positive)
!
Hepatitis B core total and IgM antibody
!
Hepatitis B surface antigen
Biochemistry
!
Albumin
!
Aspartate 
aminotransferase
!
Alanine aminotransferase
!
Alkaline phosphatase
!
γ-Glutamyl-transferase
!
Lactate dehydrogenase
!
Bilirubin (total) 
!
Protein (total)
!
Creatinineb
!
Amylasec
!
Lipasec
!
Total carbon dioxide 
!
Blood urea nitrogen
!
Glucose
!
Sodium
!
Potassium
!
Chloride
!
Calcium
!
Magnesium
!
Phosphate
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
!
White blood cell 
differentials and absolute 
counts:
o
Basophils
o
Eosinophils
o
Lymphocytes
o
Monocytes
o
Neutrophils 
Coagulation
!
International normalized ratio
!
Partial thromboplastin time
Urinalysis/micros
copy
!
pH
!
Nitrite
!
Protein
!
Blood
!
Glucose 
!
Ketone bodies
!
Urobilinogen
!
Bilirubin 
!
Specific gravity
!
Microscopy (white blood 
cells, red blood cells, 
casts)d
Spot Urine
!
Protein
!
Creatinine
Other screening 
testsa
!
Quantiferon tuberculosis 
test
!
Thyroid-stimulating 
hormone
!
Serum β-hCG (women 
only)
Urine 
!
Urine β-hCG
β-hCG=beta-human chorionic gonadotropin, IgM=immunoglobulin M.
a.
Performed only at Screening.
b.
Estimated glomerular filtration rate will be derived from serum creatinine.
c.
Reflex test for iso enzymes if results are > 2X upper limit of normal.
d.
Microscopy will be performed if urinalysis results are abnormal for blood, protein, or nitrite.
7.4.4
Vital Signs, Physical Examinations, and Other Assessments
7.4.4.1
Vital Signs
Vital signs, including seated blood pressure, pulse rate, respiratory rate, weight, height, and oral 
temperature will be assessed predose at all trial visits (Table 1).
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A semi-automated pulse rate and blood pressure recording device with an appropriate cuff size 
will be utilized. Pulse rate and blood pressure will be measured after 10 minutes rest in the 
semi-supine position with the subject’s arm unconstrained by clothing or other material. The blood 
pressure should be assessed on the same arm for each subject throughout the trial.
7.4.4.2
Physical Examinations
Physical examinations will be assessed as indicated in Table 1. Physical examination includes 
assessment of the following: general appearance, skin, head and neck, mouth, lymph nodes, 
thyroid, abdomen, and musculoskeletal, cardiovascular, and respiratory systems. Physical 
examination findings during Screening will be recorded as medical history events and findings 
during the trial as AEs.
7.4.4.3
12-Lead ECG and Chest X-Ray
A 12-lead ECG will be performed during Screening, predose on Day 85, Month 1 of OLE, and 
Month 6 of OLE. The 12-lead ECG recordings will be obtained after 10 minutes of rest in a semi-
supine 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).
Posterioanterior CXRs will be performed during Screening according to local standard practice. 
Subjects who had a CXR performed for clinical reasons within 3 months prior to Day 1 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.
7.5
Pharmacokinetic Assessments
For the PK analysis, plasma levels of M2951 will be analyzed by the analytical laboratory selected 
under responsibility of the Sponsor, using an appropriate validated bioanalytical method. 
Venous blood samples for PK analysis will be collected per the Schedule of Assessments (Table 1).
Subjects must be fasting 8 hours prior to visits with PK sampling. Subjects must also fast for 1 hour 
postdose at these visits. Blood samples for PK analysis will be collected predose and 0.25, 0.5, 
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A total of approximately 64 subjects will be randomized to provide 60 mITT subjects in the 
presence of a 6.25% dropout rate.
An IA will be conducted when subjects from the first 50% of the planned enrollment have reached 
Day 29 of treatment and have available Day 29 hsCRP data and DAS28-hsCRP data, or have 
discontinued treatment prior to Day 29. Point and CI estimates of the Day 29 hsCRP change from 
Baseline difference, comparing the 2 treatment groups, will be estimated for use in internal 
decision making. A similar analysis of Day 29 DAS28-hsCRP will be performed. The IA will not 
be used to alter the design of the trial. No adjustment will be made to the 1-sided α of 10% to be 
used in the primary analysis at the end of the 12-week blinded treatment period.
A final analysis will be conducted at the end of the trial when all subjects have completed the 
Safety Follow-up visit or prematurely discontinued from study.
8.2
Randomization
Eligible subjects will be randomized in a blinded fashion by the IWRS in a ratio of 1:1 to M2951 
dose of 50 mg bid + MTX or placebo + MTX, 
 
8.3
Endpoints
8.3.1
Primary Endpoints
The primary endpoint is the ACR20 response rate at Day 85.
8.3.2
Secondary Endpoints
The key secondary endpoint is the percent change in hsCRP from Baseline to Day 29. 
Other secondary endpoints (during the double-blind treatment period):
Efficacy:
! ACR50/ACR70 response at each time point assessed
! Percent change in hsCRP from Baseline to Day 85
! Change from Baseline in DAS28-hsCRP score at Day 29 
! Change from Baseline in DAS28-hsCRP score at Day 85
! Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Day 85
! Percentage of subjects with DAS28-hsCRP < 2.6 at Day 85
! Change from Baseline in ESR, anti-CCP, rheumatoid factor (at Days 29 and 85)
! Change from Baseline to Day 85 in subject’s self-assessments including:
o Global assessment of disease activity (VAS, see Section 7.3.1.1)
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! Change from Baseline in DAS28-hsCRP score at Month 6
! Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Month 6
! Percentage of subjects with DAS28-hsCRP < 2.6 at Month 6
! Change from Baseline in ESR, anti-CCP, rheumatoid factor (at Month 6)
! Change from Baseline to Month 6 in subject’s self-assessments including:
o Global assessment of disease activity (VAS, see Section 7.3.1.2)
o Self-assessment of pain (VAS)
o Self-assessment of disability (HAQ-DI)
! Change from Baseline to Month 6 in Physician’s Global Assessment of Disease Activity (VAS).
8.4
Analysis Sets
Safety Analysis Set
The Safety Analysis Set will include all subjects who received at least 1 dose of M2951 or placebo. 
The Safety Analysis Set will be used for all demographic/baseline characteristics and safety 
analyses.
The open-label extension (OLE) Safety Analysis Set will include all subjects who received at least 
1 dose of M2951 during the open-label extension period. The OLE Safety Analysis Set will be 
used for all safety analyses at time of final analysis.
Modified Intent to Treat Analysis Set
The Modified Intent-to-Treat (mITT) Analysis Set will include all subjects who received at least 
1 dose of M2951 or placebo and have at least 1 available ACR20 evaluation at a time point 
postdose. The mITT Analysis Set will be used for the analysis of all efficacy endpoints. For the 
IA, the mITT Analysis Set will include all subjects who received at least 1 dose of M2951 or 
placebo and have at least 1 available hsCRP evaluation at a time point postdose.
The OLE Modified Intent-to-Treat (OLE mITT) Analysis Set will include all subjects who 
received at least 1 dose of M2951 during open-label extension period and have at least 1 available 
ACR20 evaluation at a time point after first dose in open-label extension period. The OLE mITT 
Analysis Set will be used for the analysis of all efficacy endpoints at time of final analysis.
Pharmacokinetic Analysis Set
The PK Analysis Set will include all subjects who receive at least 1 dose of M2951 and have at 
least 1 quantifiable M2951 plasma concentration at a scheduled PK time point postdose without 
any important deviations or events that may impact the quality of the data or alter the evaluation 
of the PK. The PK Analysis Set will be used for all PK analyses. Subjects who receive placebo 
will not be included.
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account for the 2-sided 80% CI for the difference Δ in Day 29 hsCRP change from Baseline
between M2951 + MTX and placebo + MTX, estimated at the time of the IA. Indeed, the IA will 
not be used to alter the design of the trial; it will be conducted only for internal decision making.
8.5.2
Analysis of Primary Endpoints
The hypotheses tested are as follows:
! H0: Difference in ACR20 response rates at Day 85 (M2951 versus placebo) ≤0.
! H1: Difference in ACR20 response rates at Day 85 (M2951 versus placebo) > 0.
Tests will be based on the 2-sided 80% CI for Δ. 
The Day 85 ACR20 proportion and a 2-sided 80% CI will be provided for each treatment group. 
The difference Δ in ACR20 proportions between M2951 + MTX and placebo + MTX, and a 
2-sided 80% CI for Δ, based on the “corrected Miettinen-Nurminen” method (29) - method of Mee 
interval corrected with Miettinen and Nurminen factor n/(n+1), n being the total number of 
evaluable randomized subjects - will be provided. The primary analysis will be based on the mITT 
Analysis Set using Last Observation Carried Forward for imputation of missing values and will 
reject the null hypothesis H0: Δ ≤0 if the lower limit of the CI exceeds zero.  
A sensitivity analysis will be performed based on non-responder imputation for missing values, 
ie, subjects without observed data at Day 85 are considered non-responders.
8.5.3
Analysis of Secondary Endpoints
8.5.3.1
Efficacy Endpoints
Descriptive statistics for the percent change in hsCRP from Baseline to Day 29 will be presented 
by treatment group. A point estimate and 2-sided 80% CI for the difference Δ in Day 29 hsCRP 
change from Baseline between subjects treated with M2951+MTX and subjects treated with 
placebo + MTX will be provided.
The Day 85 hsCRP change from Baseline will be analyzed in the same way as the Day 29 hsCRP 
change from Baseline. This analysis will also be applied to Day 85 DAS28-hsCRP score change 
from Baseline.
! The Day 85 ACR50 and ACR70 proportions will be analyzed in the same way as the Day 85
ACR20 proportions. This analysis will also be applied to Day 85 “DAS28-hsCRP < 3.2” 
proportion and Day 85 “DAS28-hsCRP < 2.6” proportion.
The 
ACR20/50/70 
proportions 
and 
proportion 
of 
subjects 
achieving 
DAS28-hsCRP < 3.2 (well-controlled disease) or DAS28-hsCRP < 2.6 will be tabulated by 
treatment group and time point.
Descriptive statistics will be tabulated by treatment group and time point for the following 
continuous variables, both absolute value and change from baseline: DAS28-hsCRP score, hsCRP, 
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ESR, anti-CCP, and rheumatoid factor, subject’s global assessment of disease activity, subject’s 
assessment of pain, subject’s self-assessment of disability (HAQ-DI), and Physician’s Global 
Assessment of Disease Activity. 
8.5.3.2
Safety Endpoints
Analysis of safety secondary endpoints is described in Section 8.5.5.
8.5.3.3
Pharmacokinetics
Pharmacokinetic calculations will be performed, if appropriate, using noncompartmental analysis, 
using commercial software such as Phoenix® WinNonlin® (Version 6.4 or higher). The actual 
elapsed time from dose will be used in the final PK parameter calculations. Data handling and 
analysis procedures will be detailed in the SAP.
Plasma concentrations and derived PK parameters of M2951 will be presented descriptively by 
time point for the PK analysis set. The PK variables will be summarized by the number of 
observations, mean, geometric mean, median, SD, standard error of mean, minimum, maximum,
and coefficient of variation. Concentration values below the lower limit of quantification (LLOQ)
will be taken as zero for descriptive statistics.
Individual plasma and mean (± SD) concentration time plots will be provided using a linear and 
semi-logarithmic scale.  
For each subject with PK data, the following PK parameters will be calculated for M2951:
Day 1 and Day 29
! AUC0-6h Area under the plasma concentration-time curve from time zero to 6 hours after dosing
! Cmax
Maximum observed plasma concentration
! Cpre
The concentration observed immediately before next dosing (Day 29 only)
! tmax
Time to reach maximum plasma concentration
! Racc(AUC0-6h)
Accumulation ratio for AUC, calculated as AUC0-6h,Day29/AUC0-6h,Day1
! Racc(Cmax)
Accumulation ratio for Cmax, calculated as Cmax,Day29/Cmax,Day1
Other parameters may be added as appropriate. Final PK parameters reported will be detailed in 
the SAP.
The concentrations of M2951 and PK parameters will be listed and summarized by trial day. In 
addition to standard descriptive statistics (mean, SD, median, minimum/maximum, and 25th and 
75th percentile), analysis of PK data will include the geometric mean, the geometric coefficient of 
variation, and a 95% CI for the geometric mean. The PK concentration values below the LLOQ
will be set to zero prior to computing descriptive statistics of PK concentrations. An additional 
descriptive statistics table will be created with values below the LLOQ set to missing.
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Observed values and change from Baseline in vital signs and ECG data will be summarized for 
each treatment group using descriptive statistics. Clinically noteworthy physical examination, 
ECG, and CXR findings for individual subjects will be listed and summarized as appropriate.
At the end of the study, for final analysis, safety endpoints will be reported both for the first 
12-week treatment period and for entire study, by treatment group, based on OLE Safety Analysis 
Set.
8.5.6
Analysis of Open-label Extension Endpoints
Efficacy data collected from the 6-month open-label extension period will be summarized. Details 
will be provided in the SAP.
Safety data collected from the 6-month open-label extension period will be analyzed as described 
in Section 8.5.5.
8.6
Interim and Additional Planned Analyses
There will be 3 analyses: (1) an interim analysis (IA), triggered when subjects from the first 50% 
of the planned enrollment have reached Day 29 of treatment and have available Day 29 hsCRP 
data, or have discontinued treatment prior to Day 29, (2) a primary analysis, triggered when 100% 
of subjects enrolled have reached Day 85 of treatment or have discontinued treatment prior to 
Day 85, and (3) a final analysis, triggered when 100% of subjects enrolled complete all study parts, 
or discontinue prematurely from study.
Interim Analysis
The percent change in hsCRP from Baseline to Day 29 will be the key endpoint evaluated at the 
IA. Descriptive statistics will be presented by treatment group. A point estimate and 2-sided 80% 
CI for the difference Δ in Day 29 hsCRP change from Baseline between subjects treated with 
M2951+MTX and subjects treated with placebo + MTX will be provided. In addition, the change 
in DAS28-hsCRP from Baseline to Day 29 will be evaluated using the same approach as used for 
change in hsCRP. Some safety, baseline characteristics, and disposition data will also be 
summarized by treatment group at the time of IA.
The results of this IA will be used for internal decision making only and will not impact the conduct 
of the trial. See Section 6.10 for more details regarding limited unblinding.
Primary Analysis
When the last subject reaches Day 85 of treatment or discontinues from treatment prematurely
prior to Day 85, the protocol violations are determined, the SAP is signed, the database is locked 
for the first 12-week treatment period for all randomized patients for the primary analysis, and the 
data file verified, the drug codes will be broken and made available for the primary data analysis. 
All endpoints, demographics and safety data will be analyzed at that time.
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Final Analysis
The final analysis will occur only when the last subject completes all study parts, the protocol 
violations are determined, the database is locked for the final analysis, and the data file verified. 
Only some safety and key efficacy data will be summarized. 
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Investigator is responsible for the conduct of the trial at the site and will ensure the trial is 
performed in accordance with this protocol, the ethical principles outlined in the Declaration of 
Helsinki, ICH GCP guidelines, and any other applicable regulations. The Investigator must ensure 
that only subjects who have given informed consent are included in the trial.
According to United States Code of Federal Regulations Part 54.2 (e), for trials conducted in any 
country that could result in a product submission to the US Food and Drug Administration for 
marketing approval and could contribute significantly to the demonstration of efficacy and safety 
of an IMP (which are considered “covered clinical trials” by the Food Drug Administration), the 
Investigator and all Subinvestigators are obliged to disclose any financial interest in which they, 
their spouses, or their dependent children may have in the Sponsor or the Sponsor’s product under 
trial. This information is required during the trial and for 12 months following completion of the 
trial.
9.2
Subject Information and Informed Consent
An unconditional prerequisite for each subject prior to participation in the trial is written informed
consent, which must be given before any trial-related activities are carried out. Adequate 
information must therefore be given to the subject by the Investigator or an appropriate designee 
(if local regulations permit) before informed consent is obtained.
A Subject Information Sheet must be prepared in the local language in accordance with the ICH
GCP guidelines and 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 a
designate will inform the subject verbally of all pertinent aspects of the trial, using language chosen 
so that the information can be fully and readily understood by laypersons. The subject will be given 
sufficient time to read the information and the opportunity to ask questions and to request 
additional information and clarification.
If permitted by national regulations, a person other than the Investigator may inform the subject 
about the trial and sign the Informed Consent Form, as above.
After the information is provided by the Investigator, the Informed Consent Form must be signed 
and dated by the subject and the Investigator. 
The signed and dated declaration of informed consent will remain at the Investigator’s site, and 
must be safely archived so that the forms can be retrieved at any time for monitoring, auditing, and 
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inspection purposes. A copy of the signed and dated information and Informed Consent Form 
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 IRB for review and opinion. Using the approved 
revised Subject Information Sheet and other written information, the Investigator will explain the 
changes to the previous version to each trial subject and obtain new written consent for continued 
participation in the trial. 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.
A separate Subject Information Sheet and Informed Consent Form will be signed prior to collection 
of samples for biomarker analysis.
A separate ICF will be signed at the End of Treatment Visit by subjects wishing to participate in 
the optional extension period.
9.3
Subject Identification and Privacy
A unique number will be assigned to each subject immediately after informed consent has been 
obtained. This number will serve as the subject’s identifier in the trial as well as in the clinical trial 
database. All subject data collected in the trial will be stored under the appropriate subject number. 
Only the Investigator will be able to link trial data to an individual subject via an identification list 
kept at the site. For each subject, original medical data will be accessible for the purposes of source 
data verification by the Medical Monitor, audits, and regulatory inspections, but patient
confidentiality will be strictly maintained.
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.
The duration of storage of blood samples for biomarkers after trial completion will be according 
to the ICF and according to country regulation. The samples may be reanalyzed for newly 
identified markers or with new or improved technology. The samples will be destroyed or fully 
anonymized according to ICF and according to country regulation.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the Sponsor for use
during trial participation in order to provide the clinical trial subjects with a way of identifying 
themselves as participating in a clinical trial and to give health care providers access to any
information about this participation that may be needed to determine the course of medical 
treatment for the subject. The information provided on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable).
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The first point of contact for all emergencies will be the clinical trial 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, they will answer 
any questions. Any subsequent action (eg, unblinding) will follow the standard process established 
for Investigators.
In cases where the Investigator is not available, the Sponsor provides the appropriate means to 
contact a 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 Sponsor physician 
to assist with the medical emergency and to provide support for the potential unblinding of the 
subject concerned.
9.5
Clinical Trial Insurance and Compensation to Subjects
Insurance coverage will be provided for each country participating in the trial. Insurance conditions 
shall meet good local standards, as applicable.
9.6
Independent Ethics Committee or Institutional Review Board
Prior to commencement of the trial at a given site, this clinical trial protocol will be submitted 
together with its associated documents to the responsible IEC or IRB for its favorable opinion or 
approval, which will be filed in the Investigator Site File. A copy will be filed in the Sponsor Trial 
Master File at EMD Serono.
The IEC or IRB will be asked to document the date of the meeting at which the favorable opinion
or approval was given and the members and voting members were present. Written evidence of 
the favorable opinion or approval that clearly identifies the trial, the clinical trial protocol version,
and the Subject Information Sheet and Informed Consent Form version reviewed should be 
provided. Where possible, copies of the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC or IRB 
before implementation of substantial changes (see Section 10.5). Relevant safety information will 
be submitted to the IEC or IRB during the course of the trial in accordance with national 
regulations and requirements.
9.7
Health Authorities
The clinical trial protocol and any applicable documentation (eg, IMP Dossier, Subject 
Information Sheet, and Informed Consent Form) 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 Operations for eCRF handling guidelines.  
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The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a complete, 
accurate, legible, and timely manner. The data in the eCRF should be consistent with the relevant 
source documents.
The Investigator or designee is responsible for ensuring the data collected in the course of this trial 
is accurate and documented appropriately on all applicable forms. They will then be processed, 
evaluated, and stored in anonymous form in accordance with applicable data protection 
regulations. The Investigator must ensure the eCRFs and any other associated documents 
forwarded to the Sponsor or its designated organization contain no mention of any subject names.
For subject-reported outcome data such as QoL and pain assessments, ePRO will be used.
The data will be entered into a validated database. The Sponsor or its designee will be responsible 
for data processing, in accordance with the Sponsor’s data management procedures. Database lock 
will occur once quality control and quality assurance procedures have been completed. Electronic 
PDF files of the eCRFs will be provided to the Investigators at the completion of the trial.
10.2
Source Data and Subject Files
The Investigator must keep a file (medical file, original medical records) on paper or electronically 
for every subject in the trial. It must be possible to identify each subject by using this subject file. 
This file will contain the demographic and medical information for the subject listed below and 
should be as complete as possible. 
! Subject’s full name, date of birth, sex, height, weight
! Medical history and concomitant diseases
! Prior and concomitant therapies (including changes during the trial)
! Trial identification, ie, the Sponsor trial number for this clinical trial and subject number
! Dates for entry into the trial (informed consent) and visits to the site
! Any medical examinations and clinical findings predefined in this clinical trial protocol
! All AEs
! Date the subject left the trial including any reason for early withdrawal from the trial or IMP (if 
applicable).
All documents containing source data must be filed including, but not limited to, CT or MRI scan 
images, ECG recordings, and laboratory results. Such documents must bear the subject number 
and the date of the procedure. If possible, this information should be printed by the instrument 
used to perform the assessment or measurement. As necessary, medical evaluation of such records 
should be performed; all evaluations should be documented, signed, and dated by the Investigator.
For data that may be recorded directly in the eCRF such as a questionnaire or diary, there will be 
no record in the original subject file and therefore the data entered in the eCRF will be considered 
source data. The clinical trial protocol or the Manual of Operations should clearly and completely 
specify all subject data in the eCRF to be considered source data. 
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Electronic subject files will be printed whenever the Medical Monitor performs source data 
verification. Printouts must be signed and dated by the Investigator, countersigned by the Medical 
Monitor, and kept in a safe place at the site.
10.3
Investigator Site File and Archiving
Upon initiation of the trial, the Investigator will be provided with an Investigator Site File 
containing all necessary trial documents, which will be completed throughout the trial and updated 
as necessary. The file must be available for review by the Medical Monitor, during Sponsor audits
and for inspection by Health Authorities during and after the trial, 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 trial. 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 the applicable regulations, and/or as per the
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.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
This trial will be monitored in accordance with the ICH GCP guidelines and any other applicable 
regulations. The site Medical Monitor will perform visits to the trial site at regular intervals.
The clinical trial protocol, each step of the data capture procedure, and the handling of the data, 
including the final clinical trial report, will be subject to independent Quality Assurance activities. 
Audits may be conducted at any time during or after the trial to ensure the validity and integrity of 
the trial 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 trial 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 clinical trial protocol will be documented in writing. Substantive 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.
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 affect the subject’s 
agreement to participate in the trial requires additional informed consent prior to implementation 
following the process as described in Section 9.2.
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10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After completion of the trial, a clinical trial report will be written by the Sponsor in consultation 
with the Coordinating Investigator following the guidance in ICH Topic E3 within the legally 
required period of the participating countries. 
10.6.2
Publication
The Investigator will inform the Sponsor in advance about any plans to publish or present data 
from the trial. 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 before submission. The Sponsor will not 
suppress publication, but maintains the right to delay publication in order to protect intellectual 
property rights.
Posting of data on clinicaltrials.gov is planned and will occur 12 months after the last clinic visit 
of the final trial subject or another appropriate date to meet applicable requirements.
11
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12
Appendices
Appendix A
Signature Pages and Responsible Persons for the Trial
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M2951
Phase IIa in Rheumatoid Arthritis 
MS200527-0081
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Signature Page – Principal Investigator
Trial Title:
A 
Phase 
IIa 
Randomized, 
Double-Blinded, 
Placebo-Controlled Trial to Evaluate the Efficacy and 
Safety of M2951 in Subjects with Rheumatoid 
Arthritis on Stable Methotrexate Therapy
EudraCT Number:
2016-000064-42
Clinical Trial Protocol Date / 
Version:
02 September 2016/Version 3.0
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 for 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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Phase IIa in Rheumatoid Arthritis 
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Sponsor Responsible Persons Not Named on the Cover Page
Name, academic degree:
Function / Title:
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike, Billerica MA 01821, USA
Telephone number:
E-mail address:
Name, academic degree:
Function / Title:
Institution:
Address:
Telephone number:
E-mail address:
Name, academic degree:
Function / Title:
Biostatistician
Institution:
EMD Serono Research & Development Institute, Inc.
Address:
45A Middlesex Turnpike, Billerica, MA 01821, USA
Telephone number:
Fax number:
E-mail address:
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
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Phase IIa in Rheumatoid Arthritis 
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Appendix C
Blood Volumes
Blood will be drawn on 9 separate days/occasions. On the day of PK/PD sampling, subjects will 
have an intravenous catheter inserted to facilitate obtaining the multiple samples required. The 
planned maximum volume of blood to be drawn in this trial is approximately 271.2 mL over the 
4-week Screening Period, 12-week Treatment Period, and 4-week Follow-Up Period (20 weeks 
total) and 72 mL during the Extension Period.  
Assay
Sample 
(mL)
Number of 
Samples 
during 12-
week 
Treatment 
Period
Subtotal 
Volume 
(mL) during 
12-week 
Treatment 
Period
Number of 
Samples 
during 
Extension 
Period
Subtotal 
Volume 
(mL) 
during 
Extension 
Period
Screening tests: hematology, 
chemistry (including LFTs), 
coagulation, β-hCG, viral serology 
(HBsAg, Anti-HCV, HIV)
17.2
1
17.2
n/a
n/a
Chemistry (including LFTs), 
hematologya
5.5
8
44
4
42
Immunoglobulinsb
5
3
15
2
10
RF, anti-CCP
8
6
48
1
8
ESR
2
6
12
1
2
QuantiFERON-TB test
3
1
3
n/a
n/a
PK
1
14
28
n/a
n/a
B cell count and subtypes
5
5
25
2
10
Total
271.2
72
Note: Blood volumes are estimated based on samples expected to be taken during scheduled visits.
ALT=Alanine aminotransferase, AST=Aspartate aminotransferease, β-hCG=beta human chorionic gonadotropin, 
 
 CCP=cyclic citrullinated peptide, ESR=erythrocyte sedimentation rate, GGT=gamma-glutamyl transferase, 
HBsAg=hepatitis B surface antigen, HCV=hepatitis C virus, HIV=human immunodeficiency virus, hsCRP=high sensitivity C-
reactive protein, LDH=lactate dehydrogenase, LFT=liver function tests, n/a=not applicable, RF=rheumatoid factor, 
PK=pharmacokinetics, TB=tuberculosis.
a Chemistry including LFTs will include: sodium, potassium, chloride, CO2, blood urea nitrogen, creatinine, glucose, calcium, 
magnesium, phosphorus, total protein, albumin, amylase, lipase, AST, ALT, GGT, LDH, alkaline phosphatase, lactate 
dehydrogenase, bilirubin, uric acid as shown in Table 4.
b Immunoglobulins  will include IgA, IgG, IgM, IgG1, IgG2, IgG3, and IgG4.
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Appendix D
Protocol Versions and List of Changes
Table of Protocol Versions
Protocol
Submission to 
Health Authority
(Yes/No/
Notification only)
Date
Region or Country
Included in the 
current document    
(Y/N)
Version 2.0
Yes
11 May 2016
Global
Yes
Version 3.0
Yes
02 September 2016
Global
Yes
Protocol Version 2
Scope: 
Global
Effective date: 
11 May 2016
Rationale
The purpose of this protocol amendment is to incorporate feedback from the Voluntary 
Harmonisation Procedure assessment:
! To modify the text for contraceptive measures to specify “highly effective” contraception, 
according to the definitions provided by the Clinical Trials Facilitation Group Guideline.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical trial protocol text was already bold, changes are 
shown in bold and underlined, deletions are marked using strike through.
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Comparison with Clinical Trial Protocol Version 1.0, 28 February 2016
Change
Section(s)
Previous Wording
New Wording
Modification 
of text to 
specify 
‘highly 
effective’ 
contraceptive 
measures
Synopsis, 
Diagnosis and 
key inclusion 
and exclusion 
criteria
5.3.1 
Inclusion 
Criteria
[…]
!
Women of childbearing potential must use 
acceptable methods of contraception for 4 
weeks prior to randomization, throughout the 
trial, and for 90 days after the last dose of IMP. 
For the purposes of this trial:
o
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
o
Acceptable contraception is 
defined as use of either 2 barrier 
methods (eg, female diaphragm 
and male condom), or 1 barrier 
method in conjunction with one 
of the following: spermicide, an 
intrauterine device, or hormonal 
contraceptives (implant or oral)
[…]
[…]
!
Women of childbearing potential must use a highly effective acceptable 
methods of contraception combined with one supplementary barrier 
method for 4 weeks prior to randomization, throughout the trial, and for 90 
days after the last dose of IMP. For the purposes of this trial:
o
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
o
Acceptable contraception is defined as use of either 2 
barrier methods (eg, female diaphragm and male condom), 
or 1 barrier method in conjunction with one of the following: 
spermicide, an intrauterine device, or hormonal 
contraceptives (implant or oral) The definition of highly 
effective contraception includes:

combined 
(estrogen 
and 
progestogen 
containing) hormonal contraception associated 
with inhibition of ovulation; oral, intravaginal or 
transdermal

progestogen-only 
hormonal 
contraception 
associated with inhibition of ovulation; oral, 
injectable, implantable

intrauterine device (IUD)

intrauterine hormone-releasing system (IUS)

bilateral tubal occlusion

vasectomized partner

sexual abstinence
o
Supplementary barrier methods include:

male or female condom with or without
spermicide

cap, diaphragm or sponge with spermicide
[…]
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Change
Section(s)
Previous Wording
New Wording
Modification 
of text to 
specify 
‘highly 
effective’ 
contraceptive 
measures
5.3.1 
Inclusion 
Criteria
[…]
Men must agree to use and to have their female 
partners use acceptable contraception as defined 
above for at least 90 days after the last IMP 
administration.
[…]
Men must agree to use and to have their female partners use acceptable a 
highly effective method of contraception combined with one 
supplementary barrier method as defined above for at least 90 days after 
the last IMP administration.
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Protocol Version 3
Scope: 
Global
Effective date: 
02 September 2016
Rationale
The purpose of this protocol amendment is to include an optional open label extension period for
subjects to continue receiving benefit from the IMP.
List of Changes
Changes to the clinical trial protocol text are presented in the table below. Additions and amended 
text are shown in bold. If the original clinical trial protocol text was already bold, changes are
shown in bold and underlined, deletions are marked using strike through.
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Change
Section(s)
Previous Wording
New Wording
•
Self-assessment of pain (VAS)
•
Self-assessment of disability (HAQ-DI)
•
Change from Baseline to Month 6 in Physician’s Global 
Assessment of Disease Activity (VAS).
Modification to 
align with 
main text
Synopsis: 
Inclusion/exclusion 
criteria
•
hsCRP ≥ 3.0  mg/L
[…]
•
Subjects with current household contacts 
with active TB will also be excluded unless treated 
and evidence of household contacts being treated.
[…]
•
Significant cytopenia including neutrophil 
count < 1,500/ mm3, or platelet count < 75,000/mm3.
•
hsCRP ≥ 3.6  mg/L
[…]
•
Subjects with current household contacts with active TB will also be 
excluded unless treated and evidence of household contacts being treated.
[…]
•
Significant cytopenia including absolute neutrophil count < 
1,500/mm3, or platelet count 
< 10075,000/mm3., or absolute lymphocyte count < 1,000/mm3
Modification of 
text to include 
open-label 
extension 
period
Synopsis: Planned 
trial and treatment 
duration per subject
Planned trial and treatment duration per subject:
Total duration of subject participation is 
approximately 140 days (20 weeks), which includes:
•
Screening: 28 days (4 weeks)
•
Treatment: 84 days (12 weeks)
•
Safety Follow-Up: 28 days (4 weeks)
Planned trial and treatment duration per subject: Total duration of 
subject participation is approximately between 5 months (20 weeks) to 11 
months (46 weeks)140 days (20 weeks), which includes:
•
Screening: 28 days (4 weeks)
•
Treatment: 84 days (12 weeks)
•
Optional 6-month open-label extension period (26 weeks)
•
Safety Follow-Up: 28 days (4 weeks)
After completing the 12-week treatment period, subjects will be 
offered the opportunity to participate in an optional 6-month open-
label extension period with M2951. For subjects who choose to 
participate in the optional extension period, the duration of 
participation will last a total of approximately 11 months.
Modification of 
text to include 
open-label 
extension 
period
Synopsis: Statistical 
methods
The sample size of 60 evaluable subjects was 
chosen to provide 80% power to demonstrate 
superiority of M2951+MTX to placebo + MTX for the 
primary endpoint at the 1-sided 10% level. Eligible 
subjects will be randomized 1:1 to treatment with 
M2951 or placebo through a central randomization 
process by an Interactive Web Response System 
(IWRS).  Approximately 64 subjects will be 
randomized under the assumption of a 6.25% drop-
out rate. 
An interim analysis (IA) will be conducted when 
subjects from the first 50% of the planned 
enrollment have reached Day 29 of treatment and 
have available Day 29 hsCRP data, or have 
The sample size of 60 evaluable subjects was chosen to provide 80% 
power to demonstrate superiority of M2951+MTX to placebo + MTX for the 
primary endpoint at the 1-sided 10% level. Eligible subjects will be 
randomized 1:1 to treatment with M2951 or placebo through a central 
randomization process by an Interactive Web Response System (IWRS).  
Approximately 64 subjects will be randomized under the assumption of a 
6.25% drop-out rate. 
There will be 3 analyses: (1) an interim analysis (IA), triggered when 
subjects from the first 50% of the planned enrollment have reached 
Day 29 of treatment and have available Day 29 hsCRP data, or have 
discontinued treatment prior to Day 29, (2) a primary analysis, 
triggered when 100% of subjects enrolled have reached Day 85 of 
treatment or have discontinued treatment prior to Day 85, and (3) a 
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Change
Section(s)
Previous Wording
New Wording
discontinued treatment prior to Day 29. Point 
estimate and confidence interval (CI) estimates of 
the Day 29 hsCRP change from Baseline difference, 
comparing the 2 treatment groups, will be estimated 
for use in internal decision making. In addition, the 
change in DAS28-hsCRP from Baseline to Day 29 
will be evaluated using the same approach as used 
for change in hsCRP. The IA will not be used to alter 
the design of the trial. No adjustment will be made to 
the 1-sided α of 10% to be used in the final analysis 
at the end of the trial.
final analysis, triggered when 100% of subjects enrolled complete all 
study parts, or discontinue prematurely from study.
An interim analysis (IA) will be conducted when subjects from the first 50% 
of the planned enrollment have reached Day 29 of treatment and have 
available Day 29 hsCRP data, or have discontinued treatment prior to Day 
29. The percent change in hsCRP from Baseline to Day 29 will be the 
key endpoint evaluated at the IA. Point estimate and confidence interval 
(CI) estimates of the Day 29 hsCRP change from Baseline difference, 
comparing the 2 treatment groups, will be estimated for use in internal 
decision making. In addition, the change in DAS28-hsCRP from Baseline to 
Day 29 will be evaluated using the same approach as used for change in 
hsCRP. The IA will not be used to alter the design of the trial. No 
adjustment will be made to the 1-sided α of 10% to be used in the final
primary analysis at the end of the first treatment period (12 weeks)trial.
[…]
In addition, efficacy and safety data collected during the open-label 
extension period will be summarized.
Modification of 
text to include 
open-label 
extension 
period
Table 1 - Schedule 
of Assessments
(Refer to Table 1 in previous version)
a A complete physical examination will be performed 
at Screening, and repeated on Days 29, 85, 
and 113.
b Vital signs including height, weight, oral 
temperature, seated blood pressure, pulse rate, and 
respiratory rate will be assessed predose at every 
trial visit (height measured only at Screening).
[…]
d Concomitant medications will be recorded at 
Screening and Day 1, and any changes 
solicited/recorded at every trial visit, and with any ad 
hoc telephone contacts.
e Blood samples for hematology and chemistry will 
be obtained at Screening, predose at Visits 2 
through 8, and at Safety Follow-Up (Visit 9). See 
Table 4 for detailed assessments.
[…]
h Samples for rheumatoid factors (IgG-RF, IgM-RF, 
IgA-RF) and anti-CCP antibodies will be obtained at 
Screening, predose at Visits 4, 5, 7, 8, and at Safety 
Follow-Up (Visit 9). ESR will also be collected 
(Trial week numbers were corrected as follows: W4 changed to W5, W6 to 
W7, W8 to W9, and W12 to W13. The Safety Follow-Up/End of Trial Visit 
was clarified to occur at approximately 28 days post last dose. At Visit 8, an 
“(X)” was added to the ICF row to indicate signature of a new ICF will be 
collected for those participating in the optional extension period. An “(X)” 
was also added to IMP dispensation to reflect the changes due to OLE. 
Columns for Visits 9-12 and assessments performed during the optional
open-label extension period were inserted as shown below. Footnotes a 
and b were added to Table 1 and lettering of subsequent footnotes were 
updated sequentially.)
Trial Period
Optional Open-Label Extension Period
Trial Visit #
9
10
11
12
Trial Week
Trial Day
Day 14
Month 1
Month 3
Month 6
Visit Window (days)
±2
±7
±7
±7
Informed consent
Demographics
RA and other medical history, medications 
history
Inclusion/exclusion criteria
Complete physical examinationc
X
X
X
X
Vital signsd
X
X
X
X
12-lead ECG 
X
X
Chest X-raye
Concomitant medicationsf and procedures
X
X
X
X
Hematology, chemistry (incl. LFTs)g
X
X
X
X
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Change
Section(s)
Previous Wording
New Wording
separately at these same time points.
i Samples for hsCRP will be obtained at Screening, 
predose at Visits 2, 4, 5, 7, 8, and at Safety Follow-
Up (Visit 9).
[…]
l For female subjects only, a serum pregnancy test 
will be collected at Screening, and a urine 
pregnancy test will be collected predose at Visits 1, 
5, 7, 8, and at Safety Follow-Up (Visit 9).
m Subjects should be fasting 8 hours prior to visits 
with PK sampling. Blood samples for PK analysis 
will be collected predose and 0.25, 0.5, 1.0, 2.0, 4.0, 
and 6.0 hours postdose at Day 1 (Visit 2) and Day 
29 (Visit 5). Subjects who discontinue IMP prior to 
PK sampling visit days will not have blood obtained 
for PK. 
[…]
q The IMP will be dispensed after randomization on 
Day 1 and thereafter at each planned trial visit. All 
remaining IMP will be collected at Visit 8.
Coagulationh
Urinalysis, microscopy, urine protein/creatinine 
ratio
X
X
X
X
Immunoglobulinsi
X
X
RF and anti-CCPj
X
ESRj
X
hsCRPk
X
B cell numbers and subtypesl
X
X
Viral serologym
Tuberculosis testm
TSH
Pregnancy test
(serum β-hCG)n
Urine pregnancy testn
X
X
X
X
Pharmacokinetic samplingo
RA disease activity assessmentr
X
Randomization
Dispense/review/collect subject diary
IMP dispensations
X
X
X
IMP administrationt
Daily oral administration
IMP complianceu
X
X
X
X
AE evaluationv
X
X
X
X
a All subjects, whether not continuing to the optional extension 
period, continuing to the optional extension period, or early 
terminating from the study will undergo the Safety Follow-Up/End of 
Trial Visit approximately 28 days after last dose.
b Subjects who participate in the optional extension period will sign an 
ICF at Visit 8. The End of Treatment Visit during the treatment period 
(Visit 8) will be considered Day 1 of the optional extension period.
c A complete physical examination will be performed at Screening, and 
repeated on Days 29, 85, and 113at each visit during the optional 
extension period, and the Safety Follow-up visit.
d Vital signs including height, weight, oral temperature, seated blood 
pressure, pulse rate, and respiratory rate will be assessed predose at every 
trial visit (height measured only at Screening), including visits during the 
optional extension period and Safety Follow-up visit.
[…]
f Concomitant medications will be recorded at Screening and Day 1, and 
any changes solicited/recorded at every trial visit (including visits during 
the optional extension period), and with any ad hoc telephone contacts.
g Blood samples for hematology and chemistry will be obtained at 
Screening, predose at Visits 2 through 8, at each visit during the optional 
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Change
Section(s)
Previous Wording
New Wording
extension period, and at the Safety Follow-Up (Visit 9). See Table 4 for 
detailed assessments.
[…] 
j Samples for rheumatoid factors (IgG-RF, IgM-RF, IgA-RF) and anti-CCP 
antibodies will be obtained at Screening, predose at Visits 4, 5, 7, 8, (at 
Visit 12 during OLE), and at Safety Follow-Up (Visit 9). ESR will also be 
collected separately at these same time points.
k Samples for hsCRP will be obtained at Screening, predose at Visits 2, 4, 
5, 7, 8, (at Visit 12 during OLE), and at Safety Follow-Up (Visit 9).
[…] 
n For female subjects only, a serum pregnancy test will be collected at 
Screening, and a urine pregnancy test will be collected predose at Visits 
12, 5, 7, 8, and at Safety Follow-Up (Visit 9)., and at every visit during the 
optional extension period.
o Subjects shouldmust be fasting 8 hours prior to visits with PK sampling.
Subjects must also fast for 1 hour postdose at these visits. Blood 
samples for PK analysis will be collected predose and 0.25, 0.5, 1.0, 2.0, 
4.0, and 6.0 hours postdose at Day 1 (Visit 2) and Day 29 (Visit 5). 
Subjects who discontinue IMP prior to PK sampling visit days will not have 
blood obtained for PK. 
[…]
s The IMP (capsule formulation) will be dispensed after randomization on 
Day 1 and thereafter at each planned trial visit during the Treatment 
Period. Patients participating in the OLE will be dispensed IMP (tablet 
formulation) at Visit 8/Day1 of OLE and at Visits 9, 10, and 11 during 
the OLE. Patients participating in the OLE will be administered IMP 
(tablet formulation) at Visit 8/Day 1 OLE. All remaining IMP capsules will 
be collected at Visit 8 for all patients. Remaining IMP tablets will be 
collected at Visit 12 for those participating in OLE.
Modification of 
heading to 
clarify 
objectives 
during 
treatment 
period from 
open-label 
extension 
period
Section 4.3 - Other 
Secondary 
Objectives
4.3 Other Secondary Objectives
4.3  Other Secondary Objectives (during the double-blind period)
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Change
Section(s)
Previous Wording
New Wording
Modification of 
text to include 
open-label 
extension 
period
Section 4.5 - Open-
label Extension 
Objective
n/a
Open-label Extension Objectives
The open-label objective of this study is to evaluate the on-going 
safety and efficacy of M2951 in an open-label extension with treatment 
at 50 mg bid for an additional 6 months.
Modification of 
text to include 
open-label 
extension 
period
Section 5.1 - Overall 
Trial Design and 
Plan
Total duration of subject participation is 
approximately 140 days (20 weeks):
•
Screening: 28 days (4 weeks)
•
Treatment: 84 days (12 weeks)
•
Safety Follow-Up: 28 days (4 weeks).
Total duration of subject participation is approximately between 5 months 
(20 weeks) to 11 months (46 weeks), which includes140 days (20 
weeks):
•
Screening: 28 days (4 weeks)
•
Treatment: 84 days (12 weeks)
•
Optional 6-month open-label extension period (26 weeks)
•
Safety Follow-Up: 28 days (4 weeks).
After completing the 12-week treatment period, subjects will be 
offered the opportunity to participate in an optional 6-month open-
label extension period where all subjects will receive M2951. For 
subjects who choose to participate in the optional extension period, 
the duration of participation will last a total of approximately 11
months. 
Subjects who continue to receive M2951 during the extension period 
will also be required to undergo the Safety Follow-up Visit scheduled 
for approximately 28 days after the last treatment visit.
[…]
The optional Extension Period includes four scheduled visits (Visits 9, 
10, 11, and 12), which correspond with Day 14, and the end of Months 
1, 3, and 6. Subjects will also attend a Safety Follow-Up Visit 
approximately 28 days after the last dose of IMP.
Modification of 
text to include 
open-label 
extension 
period
Section 5.1 - Overall 
Trial Design and 
Plan
(Refer to previous Figure 1 in previous version.)
(Updated Figure 1 in Section 5.1 to include open-label extension period.)
Modification of 
text to include 
open-label 
extension 
period
Section 5.2 -
Discussion of Trial 
Design
The primary objective of this trial is to assess the 
efficacy of M2951 in subjects with active RA on 
stable MTX background therapy as measured by the 
ACR20 over Day 85 of treatment. The key 
secondary objective is to evaluate the level of 
disease activity at Day 29 in subjects with active RA 
as assessed by percent change in hsCRP from 
Baseline to Day 29.
The primary objective of this trial is to assess the efficacy of M2951 in 
subjects with active RA on stable MTX background therapy as measured 
by the ACR20 over Day 85 of treatment. The key secondary objective is to 
evaluate the level of disease activity at Day 29 in subjects with active RA as 
assessed by percent change in hsCRP from Baseline to Day 29.
An open-label extension of 6 months duration will be offered to 
subjects completing the initial 12-week treatment period. The purpose 
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is to allow all subjects the opportunity to be on active treatment with 
M2951 and to collect longer term safety data.
Modification of 
text to 
increase 
cutoff for 
hsCRP
Section 5.3.1 -
Inclusion Criteria
5. hsCRP ≥3 mg/dL
5. hsCRP ≥33.6 mg/dL
Formatting 
change for 
consistency
Section 5.3.1 -
Inclusion Criteria
n/a
(Formatting change only to change bullet points to numbers.)
Erratum
Section 5.3.2 -
Exclusion Criteria
3.
Treatment with tofacitinib, other BTK 
inhibitiors,
13.
Treatment with tofacitinib, other BTK inhibitiorsinhibitors,
Modification of 
text to clarify 
definition of 
cytopenia
Section 5.3.2 -
Exclusion Criteria
22.
Significant cytopenia, including neutrophil 
count < 1,500/ mm3, or platelet count < 75,000/mm3
22.
Significant cytopenia, including absolute neutrophil count < 
1,500/mm3, or platelet count < 10075,000/mm3, or absolute lymphocyte 
count < 1,000/mm3
Modification of 
text to clarify 
exclusion 
criteria
Section 5.3.2 -
Exclusion Criteria
23.
Participation in any investigational drug trial 
within 1 month or 5 half-lives of the investigational 
drug, whichever is longest, prior to Screening
23.
Has taken an investigational drug trial within 1 month or 5 half-lives 
of the investigational drug, whichever is longer longest, prior to Screening
Section 6.1 -
Description of the 
Investigational 
Medicinal Product
In this trialDuring the 12-week treatment period, the active IMP is M2951 
(2 x 25 mg bid), which is supplied as a white to yellow powder in a gelatin
capsule (size 0, color Swedish Orange) formulation for oral administration. 
No other excipients are used.
Identical capsules for placebo are filled with mannitol .
During the optional extension period, M2951 (2 x 25 mg bid) will be 
supplied as tablet formulation for oral administration.
Modification of 
text to include 
open-label 
extension 
period
Section 6.2 - Dosage 
and Administration
Subjects will receive 50 mg bid M2951 or placebo 
administered as 2 matching oral capsules twice daily 
for 84 days. Subjects will self-administer the IMP at 
a set time each day (± 2 hours). Subjects must take 
their daily dose more than 1 hour prior to a meal or 
snack and more than 2 hours after a meal or snack. 
Clear fluids are allowed at any time. On trial visit 
days, the IMP will be administered during the trial 
visit after the scheduled trial visit procedures (other 
than post-treatment PK/PD sampling and post-
treatment ECGs) are completed.
During the 12-week treatment period, sSubjects will receive 50 mg bid 
M2951 or placebo administered as 2 matching oral capsules twice daily for 
84 days. Subjects will self-administer the IMP at a set time each day (± 2 
hours). Subjects must take their daily dose more than 1 hour prior to a meal 
or snack and more than 2 hours after a meal or snack. Clear fluids are 
allowed at any time. On trial visit days, the IMP will be administered during 
the trial visit after the scheduled trial visit procedures (other than post-
treatment PK/PD sampling and post-treatment ECGs) are completed.
After completing the treatment period, subjects will be offered the 
opportunity to participate in an optional 6-month M2951 extension 
period on Day 85 (Visit 8). Subjects who received M2951 during the 
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treatment period will continue with the same dose of M2951 (in tablet 
formulation). All subjects in the placebo group during the treatment 
period will discontinue placebo and start treatment with 50 mg bid 
M2951 tablets on Day 85/Day 1 of OLE. On trial visit days, the IMP will 
be administered during the trial visit after the scheduled trial visit 
procedures are completed. Subjects will take 2 matching oral tablets 
twice daily for 6 months. Subjects will self-administer the IMP at a set 
time each day (± 2 hours). Subjects must take their daily dose more 
than 1 hour prior to a meal or snack and more than 2 hours after a 
meal or snack. Clear fluids are allowed at any time. On trial visit days, 
the IMP will be administered during the trial visit after the scheduled 
trial visit procedures are completed.
Modification of
text to include 
open-label 
extension 
period
Section 6.3 -
Assignment to 
Treatment Groups
Treatment kits will contain enough medication for 
administration for 1 week (+ 2 days). In addition to 
the subject and Investigator/site, all Sponsor and 
CRO trial staff will be blinded to the treatment group 
assignment.
Treatment kits will contain enough medication for administration for 1 week 
(+ 2 days). In addition to the subject and Investigator/site, all Sponsor and 
CRO trial staff will be blinded to the treatment group assignment.
Subjects continuing to the open-label extension period will be 
dispensed additional treatment kits for 6 months of treatment.
Modification of 
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open-label 
extension 
period
6.5 - Concomitant 
Medications and 
Therapies
All concomitant medications taken by the subject 
during the trial from the date of signature of informed 
consent are to be recorded in the appropriate 
section of the eCRF, noting the name, dose, 
duration, and indication of each drug. Nondrug 
interventions and any changes to a concomitant 
medication or other intervention should also be 
recorded in the eCRF.
All concomitant medications taken by the subject during the trial from the 
date of signature of informed consent (including those participating in 
and during the extension period) are to be recorded in the appropriate 
section of the eCRF, noting the name, dose, duration, and indication of 
each drug. Nondrug interventions and any changes to a concomitant 
medication or other intervention should also be recorded in the eCRF.
Modification of 
text to clarify 
IMP 
packaging
Section 6.6 -
Packaging and 
Labeling of the 
Investigational 
Medicinal Product
M2951 and placebo capsules will be packaged as 
alu/alu blister packs in cartons, protected from light.
M2951 and placebo capsules will be packaged as alu/alu blister packs in 
cartons, protected from light.
M2951 and matching placebo is supplied by the Sponsor. A description 
of the pharmaceutical properties and composition of the formulation of 
M2951 is provided in the IB. Additional details of packaging and 
labeling of the IMP will be defined in a separate Operations Manual.
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team 
members and 
to include 
open-label 
extension 
period
6.10 - Blinding
Blinding to treatment codes or laboratory results 
capable of revealing treatment will be maintained 
throughout the trial duration, except for the unblinded 
IDMC, limited unblinding for the purposes of the IA, 
partial unblinding to support early analysis of PK/PD 
data, or in the event that emergency unblinding is 
necessary (see Section 6.11). The blind may also be 
broken in the case of a pregnancy should the subject 
desire this information. Randomization data will be 
kept 
strictly 
confidential, 
accessible 
only 
to 
authorized staff, until the limited unblinding for the IA 
and full unblinding for the final analysis.
In order to maintain the blinded nature of the study, 
only 
the 
randomization 
statistician, 
the 
site 
pharmacists, an independent person at the study site 
responsible for receiving local laboratory ESR results 
and conveying those results to the central laboratory, 
and an independent statistician team (independent of 
the 
 study team) responsible for production 
of the IA outputs, will be fully unblinded during study 
conduct. 
The 
bioanalytical 
laboratory(ies) 
responsible for the analysis of the PK and PD 
samples will be allowed to be partially unblinded 
during 
study 
conduct 
using 
masked 
subject 
identifiers, to support association of PK/PD data with 
treatment codes for timely decision making, but 
prevent association of treatment codes with any other 
clinical data, such as safety data. A subteam of the 
Sponsor study team tasked with review of the IA data 
(medical responsible, Drug Safety representative, 
and biostatistician) will be unblinded to the IA results, 
which will be presented in the form of summary tables
(not subject listings) on a limited set of endpoints for 
subjects enrolled at the time of the IA: 4-week 
hsCRP, 4-week DAS28-hsCRP, safety, baseline 
characteristics, and disposition. The IDMC will also 
be unblinded to treatment, as described in the IDMC 
charter.
Blinding to treatment codes or laboratory results capable of revealing 
treatment will be maintained throughout the trial duration, except for the 
unblinded IDMC, limited unblinding for the purposes of the IA, partial 
unblinding to support early analysis of PK/PD data, or in the event that 
emergency unblinding is necessary (see Section 6.11). The blind may also 
be broken in the case of a pregnancy should the subject desire this 
information. Randomization data will be kept strictly confidential, accessible 
only to authorized staff, until the limited unblinding for the IA and full 
unblinding for the final analysis at the end of 12 weeks of treatment for all 
randomized patients.
In order to maintain the blinded nature of the study, only the randomization 
statistician, the site pharmacists,an independent person at the study site 
responsible for receiving local laboratory ESR results and conveying those 
results to the central laboratory, and an independent statistician team 
(independent of the 
study team) responsible for production of the 
IA outputs, will be fully unblinded during study conduct. The bioanalytical 
laboratory(ies) responsible for the analysis of the PK and PD samples will be 
allowed to be partially unblinded during study conduct using masked subject 
identifiers, to support association of PK/PD data with treatment codes for 
timely decision making, but prevent association of treatment codes with any 
other clinical data, such as safety data. A subteam of the Sponsor study team 
tasked with review of the IA data (medical responsible, Drug Safety 
representative, and biostatistician) will be unblinded to the IA results, which 
will be presented in the form of summary tables (not subject listings) on a 
limited set of endpoints for subjects enrolled at the time of the IA: 4-week 
hsCRP, 4-week DAS28-hsCRP, safety, baseline characteristics, and 
disposition. The IDMC will also be unblinded to treatment, as described in 
the IDMC charter.
[…]
Only when the 12-week Treatment Period trial is completed for all 
patients, database locked, the data file verified, and protocol violations 
determined, statistical analysis plan (SAP) signed and database partially 
locked for the 12-week treatment period, will the drug codes be broken 
and made available, along with laboratory results capable of revealing 
treatment, for the primaryfinal data analysis. The final analysis will be 
performed after all subjects have completed the Safety Follow-up or 
PPD
PPD
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[…]
Only when the trial is completed, database locked, 
the data file verified, and protocol violations 
determined will the drug codes be broken and made 
available, along with laboratory results capable of 
revealing treatment, for the final data analysis. 
discontinued from study early, with assessment of some safety and key 
efficacy variables.
Modification of 
text to clarify 
fasting for PK 
sampling
7.1.2 - Treatment 
Period
Subjects should be fasted for 8 hours prior to PK 
sampling as specified in Table 1.
Subjects mustshould be fasted for 8 hours prior to PK sampling as 
specified in Table 1. Subjects must also fast for 1 hour postdose at 
these visits with PK sampling.
Modification of 
text to include 
open-label 
extension 
period
7.1.2.1 - End of 
Treatment Visit
Any ongoing SAEs must be followed up until the 
SAE/AE has resolved, is considered stable, or is 
considered no longer clinically relevant by the 
Investigator.
Any ongoing SAEs must be followed up until the SAE/AE has resolved, is 
considered stable, or is considered no longer clinically relevant by the 
Investigator.
Subjects opting to participate in the optional extension period will 
sign a new ICF at this visit. The Investigator will discuss the benefits 
with the subject and the subject well-being. Subjects are free not to 
sign the new ICF for the extension period.
Modification of 
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open-label 
extension 
period
7.1.3 - Optional 
Extension Period
(new section)
After completing the treatment period (Visits 2 through 8), subjects 
will be offered the opportunity to participate in an optional 6-month 
M2951 extension period. Subjects electing to participate in the 
Extension Period will sign an ICF at Visit 8. Subjects who received 
M2951 during the treatment period will continue with M2951. Subjects 
who received placebo during the treatment period will discontinue 
placebo and start treatment with M2951 on Day 85/Day 1 of OLE. The 
End of Treatment Visit during the treatment period (Visit 8) will be 
considered Day 1 of the optional extension period. 
The Optional Extension Period includes four scheduled visits (Visits 
9, 10, 11, and 12), which correspond with Day 14, and the end of 
Months 1, 3, and 6. Subjects who signed the additional ICF at Visit 8
will undergo the Optional Extension Period assessments as described 
in the Schedule of Assessments (Table 1).
If a subject discontinues early from the optional extension period, 
he/she should complete the Safety Follow-Up Visit.
Modification of 
text to include 
open-label 
extension 
period
7.1.4 - Safety Follow-
Up Visit
(previously Section 
7.1.3)
For subjects who complete treatment, assessments 
during the Safety Follow-Up/End of Trial Visit (Visit 
9) will be performed on Day 113 ± 7 days according 
to Table 1.
For subjects who complete the first treatment period of 12 weeks, but do 
not continue to the optional extension period, assessments during the 
Safety Follow-Up/End of Trial Visit (Visit 9) will be performed approximately 
28 days after last dose of IMP.
[...]
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All subjects discontinuing the Optional Extension Period prematurely, 
or completing the Optional Extension Period, will have a Safety 
Follow-up Visit.
Modification of 
in-figure text 
to clarify that 
the physician 
completes the 
assessment
7.3.1.2 - Visual 
Analog Scales
Figure 2 reads: “How do you assess your current 
arthritis disease activity?"
[…]
Results should be recorded on the appropriate page 
of the eCRF.
Figure 2 now reads: “How do you assess rate your the subject’s current 
arthritis disease activity?"
[…]
Results should be recorded on the appropriate page of the eCRF.
Erratum
7.3.1.3 - Disease 
Activity Score-
C-Reactive Protein 
(DAS28-hsCRP)
DAS28-hsCRP will be derived using the following 
formula from the DAS28 website (23):
DAS28-hsCRP =  0.56*√(TJC28) 
+0.28*√(SJC28)+0.014*GH+0.36*ln(hsCRP+1)+0.96
Where:
•
TJC28=28 joint count for tenderness
•
SJC28=28 joint count for swelling
•
ln(hsCRP)=natural logarithm of hsCRP
•
ln(ESR)=natural logarithm of ESR
•
GH=the general health component of the 
DAS (ie, patient’s global assessment of disease 
activity).
DAS28-hsCRP will be derived using the following formula from the DAS28 
website (23):
DAS28-hsCRP =  0.56*√(TJC28) 
+0.28*√(SJC28)+0.014*GH+0.36*ln(hsCRP+1)+0.96
Where:
•
TJC28=28 joint count for tenderness
•
SJC28=28 joint count for swelling
•
ln(hsCRP)=natural logarithm of hsCRP
•
ln(ESR)=natural logarithm of ESR
•
GH=the general health component of the DAS (ie, patient’s global 
assessment of disease activity).
Addition of 
blood to 
laboratory 
parameters 
assessed with 
urinalysis
Section 7.4.3 -
Clinical Laboratory 
Assessments
(see Table 4)
(see Table 4 above) “Blood” was added to the list of parameters tested 
during urinalysis/microscopy assessments.
Footnote d was modified to include “if urinalysis results are abnormal for 
blood, protein, or nitrite.”
Addition of 
ECG analysis 
during OLE
Section 7.4.4.3 - 12-
Lead ECG and 
Chest X-Ray
A 12-lead ECG will be performed during Screening 
and predose on Day 85. The 12-lead ECG
recordings will be obtained after 10 minutes of rest 
in a semi-supine position.
A 12-lead ECG will be performed during Screening and, predose on Day 
85, Month 1 of OLE, and Month 6 of OLE. The 12-lead ECG recordings 
will be obtained after 10 minutes of rest in a semi-supine position.
Modification of 
text to clarify 
fasting for PK 
sampling
Section 7.5 -
Pharmacokinetic 
Assessments
Subjects should be fasting 8 hours prior to visits with 
PK sampling. Blood samples for PK analysis will be 
collected predose and 0.25, 0.5, 1.0, 2.0, 4.0, and 
6.0 hours postdose at Day 1 (Visit 2) and Day 29 
(Visit 5). See Appendix C for PK blood sample 
volumes. Subjects who discontinue IMP prior to PK 
Subjects mustshould be fasting 8 hours prior to visits with PK sampling. 
Subjects must also fast for 1 hour postdose at these visits. Blood 
samples for PK analysis will be collected predose and 0.25, 0.5, 1.0, 2.0, 
4.0, and 6.0 hours postdose at Day 1 (Visit 2) and Day 29 (Visit 5). See 
Appendix C for PK blood sample volumes. Subjects who discontinue IMP 
prior to PK sampling visit days will not have blood obtained for PK.
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sampling visit days will not have blood obtained for 
PK.
Errata and 
modification of 
text to include 
open-label 
extension 
period
Section 8.1 - Sample 
Size
The trial is powered to demonstrate superiority of 
M2951+MTX to placebo + MTX in ACR20 response 
proportion after 85 days of treatment, using a test of 
the null hypothesis H0: Δ ≤ 0 based on the 2-sided 
80% confidence interval (CI) for Δ, where Δ is the 
difference in Day 85 ACR20 response proportion 
comparing the 2 treatment groups. The null 
hypothesis H0 will be rejected if the lower limit of the 
2-sided 80% CI exceeds zero. It is assumed that the 
Day 85 ACR20 response proportion in the placebo + 
MTX treatment group is 0.21 (27), and that the 
difference in Day 85 ACR20 response proportions 
between the 2 treatment groups under the 
alternative hypothesis H1: Δ > 0 is Δ = 0.25 (27, 28).
[…]
An IA will be conducted when subjects from the first 
50% of the planned enrollment have reached Day 
29 of treatment and have available Day 29 hsCRP 
data and DAS28-hsCRP data, or have discontinued 
treatment prior to Day 29. Point and CI estimates of 
the Day 29 hsCRP change from Baseline difference, 
comparing the 2 treatment groups, will be estimated 
for use in internal decision making. A similar 
analysis of Day 29 DAS28 hsCRP will be performed. 
The IA will not be used to alter the design of the trial. 
No adjustment will be made to the 1-sided α of 10% 
to be used in the final analysis at the end of the trial.
The trial is powered to demonstrate superiority of M2951+MTX to placebo + 
MTX in ACR20 response proportion after 8485 days of treatment, using a 
test of the null hypothesis H0: Δ ≤ 0 based on the 2-sided 80% confidence 
interval (CI) for Δ, where Δ is the difference in Day 85 ACR20 response 
proportion comparing the 2 treatment groups. The null hypothesis H0 will 
be rejected if the lower limit of the 2-sided 80% CI exceeds zero. It is 
assumed that the Day 85 ACR20 response proportion in the placebo + 
MTX treatment group is 0.21 (27), and that the difference in Day 85 ACR20 
response proportions between the 2 treatment groups under the alternative 
hypothesis H1: Δ > 0 is Δ = 0.25 (27, 28).
[…]
An IA will be conducted when subjects from the first 50% of the planned 
enrollment have reached Day 29 of treatment and have available Day 29 
hsCRP data and DAS28-hsCRP data, or have discontinued treatment prior 
to Day 29. Point and CI estimates of the Day 29 hsCRP change from 
Baseline difference, comparing the 2 treatment groups, will be estimated for 
use in internal decision making. A similar analysis of Day 29 DAS28 hsCRP 
will be performed. The IA will not be used to alter the design of the trial. No 
adjustment will be made to the 1-sided α of 10% to be used in the primary
final analysis at the end of the 12-week blinded treatment period trial.
A final analysis will be conducted at the end of the trial when all 
subjects have completed the Safety Follow-up Visit or prematurely 
discontinued from study.
Modification of 
text to include 
open-label 
extension 
period
8.3 - Endpoints 
8.3.2 Secondary Endpoints
The key secondary endpoint is the percent change 
in hsCRP from Baseline to Day 29.
Other secondary endpoints:
[…]
8.3.2 Secondary Endpoints
The key secondary endpoint is the percent change in hsCRP from Baseline 
to Day 29.
Other secondary endpoints (during the double-blind treatment 
period):
[…]
8.3.4  Endpoints for Open-label Extension
The endpoints for the open-label extension are as follows:
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Safety:
•
Nature, incidence, and severity of TEAEs
•
Change from Baseline in vital signs and 12-lead ECG data 
•
Change from Baseline in standard hematology and chemistry 
laboratory parameters including liver function tests, amylase/lipase, 
and urinalysis.
Efficacy: 
•
ACR50/ACR70 response at Month 6
•
Percent change in hsCRP from Baseline to Month 6
•
Change from Baseline in DAS28-hsCRP score at Month 6
•
Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled 
disease) at Month 6
•
Percentage of subjects with DAS28-hsCRP < 2.6 at Month 6
•
Change from Baseline in ESR, anti-CCP, and rheumatoid factor 
(at Month 6)
•
Change from Baseline to Month 6 in subject’s self-assessments 
including:
o
Global assessment of disease activity (VAS, see Section 7.3.1.1)
o
Self-assessment of pain (VAS)
o
Self-assessment of disability (HAQ-DI)
•
Change from Baseline to Month 6 in Physician’s Global 
Assessment of Disease Activity (VAS).
Modification of 
text to include 
open-label 
extension 
period
Section 8.4 -
Analysis Sets
The Safety Analysis Set will include all subjects who 
received at least 1 dose of M2951 or placebo. The 
Safety Analysis Set will be used for all 
demographic/baseline characteristics and safety 
analyses.
[…]
The Modified Intent-to-Treat (mITT) Analysis Set will 
include all subjects who received at least 1 dose of 
M2951 or placebo and have at least 1 available 
ACR20 evaluation at a time point postdose. The 
mITT Analysis Set will be used for the analysis of all 
efficacy endpoints. For the IA, the mITT Analysis Set 
will include all subjects who received at least 1 dose 
of M2951 or placebo and have at least 1 available 
hsCRP evaluation at a time point postdose.
The Safety Analysis Set will include all subjects who received at least 1 dose 
of M2951 or placebo. The Safety Analysis Set will be used for all 
demographic/baseline characteristics and safety analyses.
The open-label extension (OLE) Safety Analysis Set will include all 
subjects who received at least 1 dose of M2951 during the open-label 
extension period. The OLE Safety Analysis Set will be used for all safety 
analyses at time of final analysis.
[…]
The Modified Intent-to-Treat (mITT) Analysis Set will include all subjects who 
received at least 1 dose of M2951 or placebo and have at least 1 available 
ACR20 evaluation at a time point postdose. The mITT Analysis Set will be 
used for the analysis of all efficacy endpoints. For the IA, the mITT Analysis 
Set will include all subjects who received at least 1 dose of M2951 or placebo 
and have at least 1 available hsCRP evaluation at a time point postdose.
The OLE Modified Intent-to-Treat (OLE mITT) Analysis Set will include 
all subjects who received at least 1 dose of M2951 during open-label 
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extension period and have at least 1 available ACR20 evaluation at a 
time point after first dose in open-label extension period. The OLE mITT 
Analysis Set will be used for the analysis of all efficacy endpoints at 
time of final analysis.
Modification of 
text to include 
open-label 
extension 
period
Section 8.5.5 -
Analysis of Safety 
and Other Endpoints
The analysis set for the safety assessments will be 
the Safety Analysis Set.
All safety endpoints will be summarized by treatment 
group unless otherwise specified. 
[…]
The number and percentage of subjects 
experiencing 1 or more TEAEs will be summarized 
according to the MedDRA system organ classes and 
preferred terms by treatment group, relationship to 
IMP, and severity. 
The analysis set for the safety assessments will be the Safety Analysis Set 
for the primary analysis and the OLE Safety Analysis Set for final 
analysis.
All safety endpoints will be summarized by treatment group unless otherwise 
specified. Analyses including both for the first 12-week treatment period 
and open-label extension period data will be summarized according to 
treatment groups ‘M2951+MTX’ and ‘Placebo+MTX/M2951 ’.
[…]
The number and percentage of subjects experiencing 1 or more TEAEs will 
be summarized according to the MedDRA system organ classes and 
preferred terms by treatment group, relationship to IMP, and severity. 
Exposure-adjusted incidence rates of TEAEs will also be reported 
according to the MedDRA system organ class and preferred term.
[…]
At the end of the study, for final analysis, safety endpoints will be 
reported both for the first 12 week treatment period and for entire study, 
by treatment group, based on OLE Safety Analysis Set.
Modification of 
text to include 
open-label 
extension 
period
Section 8.5.6 -
Analysis of Open-
label Extension 
Endpoints
(new section)
Efficacy data collected from the 6-month open-label extension period 
will be summarized. Details will be provided in the SAP.
Safety data collected from the 6-month open-label extension period will 
be analyzed as described in Section 8.5.5.
Modification of 
text to clarify 
interim 
analyses
8.6 - Interim and
Additional Planned 
Analyses 
An IA will be conducted when subjects from the first 
50% of the planned enrollment have reached Day 
29 of treatment and have Day 29 data, or have 
discontinued treatment prior to Day 29. The percent 
change in hsCRP from Baseline to Day 29 will be 
the key endpoint evaluated at the IA. Descriptive 
statistics will be presented by treatment group. A 
point estimate and 2-sided 80% CI for the difference 
Δ in Day 29 hsCRP change from Baseline between 
subjects treated with M2951+MTX and subjects 
treated with placebo + MTX will be provided. In 
addition, the change in DAS28 hsCRP from 
Baseline to Day 29 will be evaluated using the same 
approach as used for change in hsCRP. Some 
There will be 3 analyses: (1) an interim analysis (IA), triggered when 
subjects from the first 50% of the planned enrollment have reached Day 
29 of treatment and have available Day 29 hsCRP data, or have 
discontinued treatment prior to Day 29, (2) a primary analysis, triggered 
when 100% of subjects enrolled have reached Day 85 of treatment or 
have discontinued treatment prior to Day 85, and (3) a final analysis, 
triggered when 100% of subjects enrolled complete all study parts, or 
discontinue prematurely from study.
Interim Analysis
An IA will be conducted when subjects from the first 50% of the planned 
enrollment have reached Day 29 of treatment and have Day 29 data, or have 
discontinued treatment prior to Day 29. The percent change in hsCRP from 
Baseline to Day 29 will be the key endpoint evaluated at the IA. Descriptive 
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Section(s)
Previous Wording
New Wording
safety, baseline characteristics, and disposition data 
will also be summarized by treatment group at the 
time of IA.
The results of this IA will be used for internal 
decision making only and will not impact the conduct 
of the trial. See Section 6.10 for more details 
regarding limited unblinding.
The primary analysis will be performed by 
 
staff when all subjects have either completed the 
Safety Follow-Up Visit or prematurely discontinued 
from the trial and the database is locked.
statistics will be presented by treatment group. A point estimate and 2-sided 
80% CI for the difference Δ in Day 29 hsCRP change from Baseline between 
subjects treated with M2951+MTX and subjects treated with placebo + MTX 
will be provided. In addition, the change in DAS28-hsCRP from Baseline to 
Day 29 will be evaluated using the same approach as used for change in 
hsCRP. Some safety, baseline characteristics, and disposition data will also 
be summarized by treatment group at the time of IA.
The results of this IA will be used for internal decision making only and will 
not impact the conduct of the trial. See Section 6.10 for more details 
regarding limited unblinding.
re analyzed. The primary analysis will be performed by 
staff when 
all subjects have either completed the Safety Follow Up Visit or prematurely 
discontinued from the trial and the database is locked.
Primary Analysis
When the last subject reaches Day 85 of treatment or discontinues from 
treatment prematurely prior to Day 85, the protocol violations are 
determined, the SAP is signed, the database ispartially locked locked for 
the first 12-week treatment period for all randomized patients for the 
primary analysis, and the data file verified, the drug codes will be 
broken and made available for the primary data analysis. All endpoints, 
demographics and safety data will be analyzed at that time.
Final Analysis
The final analysis will occur only when the last subject completes all 
study parts, the protocol violations are determined, the database is 
locked for the final analysis, and the data file verified. Only some safety 
and key efficacy data will be summarized.
Modification of 
text to include 
open-label 
extension 
period
Section 9.2 -Subject 
Information and 
Informed Consent
A separate Subject Information Sheet and Informed 
Consent Form will be signed prior to collection of 
samples for biomarker analysis.
A separate Subject Information Sheet and Informed Consent Form will be 
signed prior to collection of samples for biomarker analysis.
A separate ICF will be signed at the End of Treatment Visit by subjects 
wishing to participate in the optional extension period.
Modification of 
text to clarify 
anonymization 
of samples
Section 9.3 -Subject 
Identification and 
Privacy
There is no time limit on the storage of blood 
samples for biomarkers after trial completion. The 
samples may be reanalyzed for newly identified 
markers or with new or improved technology. The 
samples will be destroyed or fully anonymized.
There is no time limit on theThe duration of storage of blood samples for 
biomarkers after trial completion will be according to the ICF and 
according to country regulation. The samples may be reanalyzed for 
newly identified markers or with new or improved technology. The samples 
will be destroyed or fully anonymized according to ICF and according to 
country regulation.
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the amount of 
blood drawn 
during the 
study
Appendix C - Blood 
Volumes
(see Appendix C in previous version)
(Blood samples/volumes for coagulation (only done at screening) was 
merged with Screening tests. Row for hsCRP was deleted as this is 
included in Chemistry. Volumes for Screening tests, Chemistry, 
Immunoglobulins, RF, anti-CCP, QuantiFERON-TB test, PK, and B cell 
count were corrected. Footnote specifying which immunoglobulins are 
tested was added. Additional columns for samples and volumes collected 
during Extension Period were added to reflect the additional samples 
collected during this period. Total volumes for Treatment Period and for 
Extension Period were updated in text.)
Modification of 
text to clarify
versions of 
protocol
Appendix D -
Protocol Versions 
and List of Changes
(see Appendix D in previous version)
Language was updated to “Protocol Versions” rather than Amendments for 
better clarity. Table of protocol versions and comparison tables were 
updated accordingly.
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Statistical Analysis Plan 
Clinical Trial Protocol 
Identification No. 
MS200527-0081 
Title: 
A Phase IIa Randomized, Double-Blind, Placebo-Controlled 
Trial to Evaluate the Efficacy and Safety of M2951 in Subjects 
with Rheumatoid Arthritis on Stable Methotrexate Therapy 
Trial Phase 
IIa 
Investigational Medicinal 
Product(s) 
M2951 
Clinical Trial Protocol 
Version 
02 September 2016 / Version 3.0 
Statistical Analysis Plan 
Authors 
, Biostatistician 
, Pharmacokineticist 
Statistical Analysis Plan 
Date and Version 
18 April 2017 / Version 1.0 
Statistical Analysis Plan 
Reviewers 
Merck Reviewers: 
, Lead Program Statistician 
, Lead Statistical Programmer 
, Statistical Programmer 
, Global Drug Safety 
, Medical Writer Lead 
, Medical Responsible 
, Lead Data Management 
, Data Management  
, Clinical biomarkers 
, Clinical Pharmacokineticist 
, 
 
, Clinical Trial Lead   
 
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 Reviewers: 
, Statistical Scientist 
, Lead Study Statistician 
, Global Medical Advisor 
, Medical Writer 
, Lead Statistical Programmer 
, Statistical Scientist 
, Pharmacokineticist 
, Pharmacokineticist 
 
 
 
Confidential 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies. 
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 affiliate.  
Copyright © 2017 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved. 
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2 
Table of Contents 
1 
Signature Page ......................................................................................3 
2 
Table of Contents ..................................................................................4 
3 
List of Abbreviations and Definition of Terms ....................................6 
4 
Modification History ............................................................................9 
5 
Purpose of the Statistical Analysis Plan ...............................................9 
6 
Summary of Clinical Trial Features ...................................................10 
7 
Sample Size/Randomization ...............................................................17 
8 
Overview of Planned Analyses ...........................................................18 
8.1 
Independent Monitoring Committee review .......................................18 
8.2 
Interim Analysis ..................................................................................18 
8.3 
Primary Analysis ................................................................................18 
8.4 
Final Analysis .....................................................................................18 
9 
Changes to the Planned Analyses in the Clinical Trial Protocol ........19 
10 
Protocol Deviations and Analysis Sets ...............................................20 
10.1 
Definition of Protocol Deviations and Analysis Sets .........................20 
10.2 
Definition of Analysis Sets and Subgroups ........................................21 
11 
General Specifications for Statistical Analyses ..................................24 
12 
Trial Subjects ......................................................................................31 
12.1 
Disposition of Subjects and Discontinuations ....................................31 
12.2 
Protocol Deviations ............................................................................33 
12.2.1 
Important Protocol Deviations ............................................................34 
12.2.2 
Clinically Important Protocol Deviations ...........................................34 
13 
Demographics and Other Baseline Characteristics .............................35 
13.1 
Demographics .....................................................................................35 
13.2 
Medical History ..................................................................................36 
13.3 
Other Baseline Characteristics ............................................................36 
13.3.1 
Disease history ....................................................................................36 
13.3.2 
Other ...................................................................................................37 
14 
Previous or Concomitant Medications/Procedures .............................38 
15 
Treatment Compliance and Exposure .................................................41 


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16 
Endpoint Evaluation ...........................................................................46 
16.1 
Primary Endpoint Analyses ................................................................49 
16.2 
Secondary Endpoint Analyses ............................................................51 
16.2.1 
Key secondary endpoint analysis ........................................................51 
16.2.2 
Other secondary endpoint analyses ....................................................51 
16.3 
Other Endpoint Analyses ....................................................................54 
16.3.1 
Open-label Extension Endpoint Analyses ..........................................54 
16.3.2 
Pharmacokinetic Endpoint Analyses ..................................................55 
16.3.3 
Pharmacodynamic Endpoint Analyses ...............................................56 
16.3.4 
Exploratory Endpoints ........................................................................56 
17 
Safety Evaluation ................................................................................57 
17.1 
Adverse Events ...................................................................................58 
17.1.1 
All Adverse Events .............................................................................59 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................61 
17.2.1 
Deaths .................................................................................................61 
17.2.2 
Serious Adverse Events ......................................................................62 
17.3 
Clinical Laboratory Evaluation ...........................................................62 
17.4 
Vital Signs ..........................................................................................64 
17.5 
12-Lead Electrocardiogram (ECG) .....................................................64 
17.6 
Physical Examination .........................................................................65 
17.7 
Pregnancy test .....................................................................................66 
17.8 
B cell (CD19+) count..........................................................................66 
17.9 
Urine Protein/Creatinine Ratio ...........................................................66 
17.10 
Urinalysis Microscopic Evaluation .....................................................66 
17.11 
Chest X-ray evaluations ......................................................................66 
17.12 
Other safety evaluations .....................................................................66 
18 
References ...........................................................................................67 
19 
Appendices .........................................................................................68 
19.1 
Appendix 1: HAQ-DI scoring ............................................................68 
19.2 
Appendix 2: DAS28-hsCRP formula .................................................70 
19.3 
Appendix 3: Important Protocol Deviations identified by 
programming and Clinically Important Protocol Deviations .............71 


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3 
List of Abbreviations and Definition of Terms 
 
∆ 
Difference 
ACR 
American College of Rheumatology 
ADaM 
Analysis Data Model 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANCOVA 
analysis of covariance 
anti-CCP 
anti-cyclic citrullinated peptide 
AST 
aspartate aminotransferase 
ATC 
anatomical therapeutic class 
AUC0-6h 
area under the concentration-time curve from time zero to 6 hours 
bid 
twice daily 
BLQ 
below limit of quantification 
BMI 
body mass index 
BOA 
Biostatistics Outputs Assembly 
BTK 
Bruton’s tyrosine kinase 
CFB 
change from baseline 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration 
Ctrough 
plasma concentration observed immediately before next dosing 
CSR 
Clinical Study Report 
CTP 
Clinical Trial Protocol 
CV 
coefficient of variation 
CXR 
chest X-ray 
DAS28-hsCRP 
disease activity score based on 28 joints and high-sensitivity C-reactive 
protein 
DBP 
diastolic blood pressure 
DMARD 
disease-modifying antirheumatic drug 
eCRF 
Case Report Form, electronic 
ECG 
electrocardiogram 


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ESR 
erythrocyte sedimentation rate 
EULAR 
The European League Against Rheumatism 
FSH 
follicle-stimulating hormone 
GGT 
gamma-glutamyl transferase 
GeoCV 
geometric coefficient of variation 
GeoMean 
geometric mean 
HAQ-DI 
Health Assessment Questionnaire - Disability Index 
HBsAg 
hepatitis B surface antigen 
HIV 
human immunodeficiency virus 
hsCRP 
high-sensitivity C-reactive protein 
IA 
interim analysis 
IDMC 
Independent Data Monitoring Committee 
Ig 
immunoglobulin 
IMP 
investigational medical product 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
IWRS 
Interactive Web Response System 
LOCF 
last observation carried forward 
LPLD 
last patient’s last dose  
LTBI 
latent TB infection 
MCMC 
Markov chain Monte Carlo 
MedDRA 
medical dictionary for regulatory activities 
mITT 
modified intent-to-treat  
MTX 
methotrexate 
N 
number of subjects 
NCI-CTCAE 
National Cancer Institute - Common Terminology Criteria for Adverse 
Events 
NSAID 
nonsteroidal anti-inflammatory drug 
OLE 
open-label extension 
PD 
pharmacodynamics 
PK 
pharmacokinetics 


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PT 
preferred term 
Q1 
25th percentile 
Q3 
75th percentile 
RA 
rheumatoid arthritis 
Racc(AUC0-6h) 
accumulation ratio for AUC0-6h 
Racc(Cmax) 
accumulation ratio for Cmax 
RF 
rheumatoid factor 
SAF 
safety analysis set 
SAP 
Statistical Analysis Plan 
SBP 
systolic blood pressure 
SCR 
screening analysis set 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SEM 
standard error of the mean 
SJC 
swollen joint count 
SOC 
system organ class 
TB 
Tuberculosis 
TEAE 
treatment-emergent adverse event 
TJC 
tender joint count 
tmax 
time to reach maximum plasma concentration 
ULN 
upper limit of normal 
VAS 
visual analog scale 
WHO-DD 
World Health Organization drug dictionary 


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4 
Modification History 
Unique 
Identifier for 
SAP Version 
Date of 
SAP Version 
Authors 
Changes from the 
Previous Version 
Final 1.0 
18 April 2017 
, 
 
NA – first version 
5 
Purpose of the Statistical Analysis Plan 
The purpose of this Statistical Analysis Plan (SAP) is to document technical and detailed 
specifications for analyses of data collected for protocol MS200527-0081 dated 02 September 
2016 (version 3.0). The SAP is based upon Section 8 (Statistics) of the trial protocol and is 
prepared in compliance with International Council for Harmonisation E9.  
The first version (version 1.0) of the SAP includes details for the primary and final statistical 
analyses, planned for the end of 12 weeks treatment and for the end of study, respectively.  
Results of the analyses described in this SAP will be included in the Clinical Study Report 
(CSR). Additionally, the planned analyses identified in this SAP will be included in regulatory 
submissions or future manuscripts. Any post-hoc, or unplanned analyses performed to provide 
results for inclusion in the CSR but not identified in this prospective SAP will be clearly 
identified in the CSR.  
The final clinical database cannot be locked until the final SAP has been approved and signed. 
Another SAP document (MS200527-0081_IA_IDMC_SAP_v3.0 08 Feb2017) detailed 
specifications for the Independent Data Monitoring Committee (IDMC) and Interim analyses 
(IA).  
 
 
  
 
 
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6 
Summary of Clinical Trial Features 
 
Clinical Trial Protocol Number 
MS200527-0081 
Title 
A 
Phase 
IIa 
Randomized, 
Double-Blind, 
Placebo-Controlled 
Trial 
to 
Evaluate 
the 
Efficacy and Safety of M2951 in Subjects with 
Rheumatoid Arthritis on Stable Methotrexate 
Therapy 
Trial Phase 
IIa 
IND Number 
122,963 
FDA covered trial 
No 
EudraCT Number 
2016-000064-42 
Coordinating Investigator 
 
 
 
  
Phone 
 
Fax 
 
 
Sponsor 
Merck KGaA Darmstadt, Germany   
Medical Responsible: 
 
45A Middlesex Turnpike 
Billerica, MA 01821, USA 
Telephone: 
 
Trial centers/countries 
Approximately 50 sites in 10 countries 
Planned trial period 
(first subject in-last subject out) 
July 2016 to March 2017 
Trial Registry 
Clinicaltrials.gov 
Objectives:  
Primary objective: To assess the efficacy of M2951 in subjects with active rheumatoid 
arthritis (RA) on stable methotrexate (MTX) therapy, as measured by the American College 
of Rheumatology (ACR) 20% (ACR20) response rate over a duration of 84 days. 
Key secondary objective: To assess the level of disease activity at 4 weeks in subjects with 
active RA as assessed by the percent change in high-sensitivity C-reactive protein (hsCRP) 
from Baseline to Day 29. 
Other secondary objectives: To assess the safety and tolerability of M2951 and to evaluate 
the pharmacokinetics (PK) and pharmacodynamics (PD) of M2951 in subjects with RA on 
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stable MTX therapy. 
Exploratory objectives: 
 
 
  
Open-label extension objectives: 
To evaluate the on-going safety and efficacy of M2951 in an open-label extension with 
treatment at 50 mg bid for an additional 6 months.  
Methodology: This is a Phase IIa randomized, double-blind, placebo-controlled trial in 
approximately 64 modified intent-to-treat (mITT) subjects 18 to 75 years of age with RA on 
stable MTX therapy.  
Total duration of subject participation is approximately between 5 months (20 weeks) to 
11 months (46 weeks), which includes: 
• Screening: 28 days (4 weeks) 
• Treatment: 84 days (12 weeks) 
• Optional 6-month open-label extension period (26 weeks)  
• Safety Follow-Up: 28 days (4 weeks)  
Screening will occur over Day -28 to -1 (Visit 1), during which time all Screening 
assessments must be completed and reviewed.  
On Day 1 (Visit 2), after confirmation of eligibility, assessment of RA disease activity and 
vital signs, and obtaining of required blood and urine samples, subjects will be randomly 
assigned 1:1 to receive M2951 or placebo in combinations with MTX.  
Blood and urine samples will be obtained for safety, markers of disease activity, PK, and PD 
following the schedule detailed in the Schedule of Assessments. 
 
 
  
Subjects will self-administer the Investigational Medical Product (IMP) at a set time each day 
(± 2 hours). Subjects must take their daily dose more than 1 hour prior to a meal or snack or 
more than 2 hours after a meal or snack. Clear fluids are allowed at any time. On trial visit 
days, the IMP will be administered during the trial visit, after trial visit procedures (other than 
PK/PD sampling) are completed. 
Subjects will have trial visits weekly for the first 3 weeks of treatment; bi-weekly up until 
8 weeks of treatment; a final On-Treatment Visit on Day 85, and then return for 1 Follow-Up 
Visit approximately 28 days (4 weeks) after the last dose of IMP. 
After completing the 12-week treatment period, subjects will be offered the opportunity to 
participate in an optional 6-month open-label extension period where all subjects will receive 
M2951. For subjects who choose to participate in the optional extension period, the duration 
of participation will last a total of approximately 11 months.  
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Subjects who continue to receive M2951 during the extension period will also be required to 
undergo the Safety Follow-up Visit scheduled for approximately 28 days after the last 
treatment visit. 
Planned number of subjects: A total of 64 subjects with RA. 
Primary endpoint: The primary endpoint is the ACR20 response at Day 85. 
Key secondary endpoints:  
The key secondary endpoint is the percent change in hsCRP from Baseline to Day 29. 
Other secondary endpoints (during the double-blind treatment period): 
Safety endpoints (from signing ICF until Safety Follow-Up Visit): 
• Nature, incidence, and severity of treatment-emergent adverse events 
• Changes from Baseline in vital signs and 12-lead electrocardiogram (ECG) results  
• Changes from Baseline in standard hematology and chemistry laboratory parameters 
including liver function tests, amylase/lipase, and urinalysis. 
Efficacy endpoints: 
• ACR50/ACR70 response at each time point assessed  
• Percent change in hsCRP from Baseline to Day 85 
• Change from Baseline in Disease Activity Score based on 28 joints (DAS28-hsCRP) score 
at Day 29  
• Change from Baseline in DAS28-hsCRP score at Day 85 
• Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Day 85 
• Percentage of subjects with DAS28-hsCRP < 2.6 at Day 85 
• Change from Baseline in erythrocyte sedimentation rate (ESR), anti- cyclic citrullinated 
peptide (CCP), and rheumatoid factor ([RF] at Days 29 and 85) 
• Change from Baseline to Day 85 in subject’s self-assessments including:  
- Global assessment of disease activity 
- Self-assessment of pain 
- Self-assessment of disability (Health Assessment Questionnaire – Disability Index; 
HAQ-DI) 
• Change from Baseline to Day 85 in Physician’s Global Assessment of Disease Activity. 
Pharmacokinetics: Pharmacokinetic parameters calculated for Days 1 and 29 include: 
plasma concentrations of M2951, area under the plasma concentration-time curve from time 
zero to 6 hours (AUC0-6h) after administration, maximum observed plasma concentration 
(Cmax), concentration observed immediately before next dosing (Cpre) (Day 29), time to reach 
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accumulation ratio for Cmax (Racc[Cmax]). 
Other assessments:  
Pharmacodynamics:  
• Absolute concentrations and change from Baseline in immunoglobulin (Ig) levels (IgA, 
IgM, and IgG, and subclasses) on Days 29 and 85 
• Absolute numbers and change from Baseline in B cell numbers and subsets on Day 85. 
Exploratory: 
 
  
 
 
  
Endpoints for open-label extension: 
Safety: 
• Nature, incidence and severity of TEAEs 
• Change from Baseline in vital signs and 12-lead ECG data  
• Change from Baseline in standard hematology and chemistry laboratory parameters 
including liver function tests, amylase/lipase, and urinalysis. 
Efficacy: 
• ACR50/ACR70 response at Month 6  
• Percent change in hsCRP from Baseline to Month 6 
• Change from Baseline in DAS28-hsCRP score at Month 6 
• Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Month 6 
• Percentage of subjects with DAS28-hsCRP < 2.6 at Month 6 
• Change from Baseline in ESR, anti-CCP, rheumatoid factor (at Month 6) 
• Change from Baseline to Month 6 in subject’s self-assessments including: 
• Global assessment of disease activity (VAS) 
• Self-assessment of pain (VAS) 
• Self-assessment of disability (HAQ-DI) 
Change from Baseline to Month 6 in Physician’s Global Assessment of Disease Activity 
(VAS). 
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Diagnosis and key inclusion and exclusion criteria:  
The current trial will enroll subjects who fulfill the following key inclusion criteria: 
•  Men or women 18 to 75 years of age at the time of informed consent signature 
• Confirmed diagnosis of RA according to 2010 American College of Rheumatology 
(ACR)/ The European League Against Rheumatism (EULAR) RA classification criteria of 
at least 6 months duration 
• Positive RF and/or anti-CCP (anti-cyclic citrullinated peptide) 
• Persistently active disease defined as ≥ 6 swollen joints (of 66 counted) and ≥ 6 tender 
joints (of 68 counted) 
• hsCRP ≥ 3.6 mg/L 
• Treatment for ≥ 12 weeks with 10 to 25 mg/week MTX at a stable dose for at least 
4 weeks prior to dosing with the IMP and maintained throughout the trial 
• Women of childbearing potential must use a highly effective method of contraception 
combined with one supplementary barrier method for 4 weeks prior to randomization, 
throughout the trial, and for 90 days after the last dose of IMP. For the purposes of this 
trial: 
o 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 
o The definition of highly effective contraception includes: 
 combined 
(estrogen 
and 
progestogen 
containing) 
hormonal 
contraception associated with inhibition of ovulation; oral, intravaginal 
or transdermal 
 progestogen-only hormonal contraception associated with inhibition of 
ovulation; oral, injectable, implantable 
 intrauterine device (IUD) 
 intrauterine hormone-releasing system (IUS) 
 bilateral tubal occlusion 
 vasectomized partner 
 sexual abstinence 
o Supplementary barrier methods include: 
 male or female condom with or without spermicide 
 cap, diaphragm or sponge with spermicide 


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• Women of childbearing potential must have a negative serum pregnancy test at the 
Screening Visit and a negative urine pregnancy test at Day 1/randomization before dosing. 
Subjects who fulfill any of the following key exclusion criteria should not be enrolled into 
this trial:  
• Use of oral corticosteroids > 10 mg daily prednisone equivalent, use of injectable 
corticosteroids, or change in dose of corticosteroids within 2 weeks prior to Screening or 
during Screening 
• Initiation or change in dose for nonsteroidal anti-inflammatory drugs (NSAIDs) within 
2 weeks prior to Screening 
• Treatment with tofacitinib, other BTK inhibitors, or a biologic disease-modifying 
antirheumatic drug (DMARD; eg, anti-tumor necrosis factor alpha [anti-TNF-α], 
tocilizumab 
[anti-interleukin-6 receptor], 
abatacept 
[CTLA4-Fc]), 
or 
other 
immunosuppressive drugs (sulfasalazine would be acceptable at a stable dose) other than 
methotrexate within 3 months prior to Screening or during Screening 
• Treatment with anti-CD20 therapy (eg, rituximab) within 12 months prior to Screening or 
during Screening 
• Immunologic disorder other than RA, with the exception of secondary Sjogren’s syndrome 
associated with RA, and well-controlled diabetes or thyroid disorder, or any other 
condition requiring oral, intravenous, intramuscular, or intra-articular corticosteroid 
therapy 
• Vaccination with live or live-attenuated virus vaccine within 1 month prior to Screening 
• Active, clinically significant, viral, bacterial, or fungal infection, or any major episode of 
infection requiring hospitalization or treatment with parenteral anti-infectives within 
4 weeks of Screening or during Screening, or completion of oral anti-infectives within 
2 weeks before or during Screening, or a history of recurrent infections (ie, 3 or more of 
the same type of infection in a 12-month rolling period). Vaginal candidiasis, 
onychomycosis, and genital or oral herpes simplex virus considered by the Investigator to 
be sufficiently controlled would not be exclusionary.  
• History of or positive testing for human immunodeficiency virus (HIV), hepatitis C 
antibody and/or polymerase chain reaction, hepatitis B surface antigen (HBsAg) (+) and/or 
hepatitis B core total, and/or IgM antibody (+) at Screening. 
• History of or current diagnosis of active tuberculosis (TB); undergoing treatment for latent 
TB infection (LTBI); untreated LTBI (as determined by documented results within 
3 months of the Screening Visit of a positive TB skin test with purified protein derivative 
with induration ≥ 5 mm, a positive QuantiFERON®-TB test or positive or borderline 
T-SPOT [Elispot] test); or positive QuantiFERON-TB test at Screening. Subjects with 
documented completed appropriate LTBI treatment would not be excluded and are not 
required to be tested. 
• Subjects with current household contacts with active TB will also be excluded. 


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• Indeterminate QuantiFERON-TB or T-SPOT tests may be repeated once, and will be 
considered positive if retest results are positive or indeterminate. 
• History of cancer, except adequately treated basal cell or squamous cell carcinomas of the 
skin (no more than 3 lesions requiring treatment in lifetime) or carcinoma in situ/cervical 
intraepithelial neoplasia of the uterine cervix, unless considered cured > 5 years. 
• Clinically significant abnormality on ECG, or an active infective process or any other 
clinically significant abnormality on Screening chest X-ray (CXR) taken within 4 weeks of 
the first dose, per Investigator opinion. If a CXR has been taken within the previous 
3 months and results are available and normal, the CXR does not need to be carried out  
• B cell (CD19) count < 50% of the lower limit of normal at Screening 
• Significant cytopenia including absolute neutrophil count < 1,500/ mm3, platelet count  
< 100,000/mm3, or absolute lymphocyte count < 1,000/mm3 
Investigational Medicinal Product: dose/mode of administration/dosing schedule:  
M2951 (50 mg twice daily [bid]) will be administered as 2 x 25 mg capsules bid during the 
12-week treatment period. Identical capsules filled with mannitol for placebo will be 
provided. M2951 will be administered as 2 x 25 mg tablets bid during the optional extension 
period. 
Reference therapy: dose/mode of administration/dosing schedule: Not applicable. 
Planned trial and treatment duration per subject: Total duration of subject participation is 
approximately between 5 months (20 weeks) to 11 months (46 weeks), which includes: 
• Screening: 28 days (4 weeks) 
• Treatment: 84 days (12 weeks) 
• Optional 6-month open-label extension period (26 weeks) 
• Safety Follow-Up: 28 days (4 weeks) 
After completing the 12-week treatment period, subjects will be offered the opportunity to 
participate in an optional 6-month open-label extension period with M2951. For subjects who 
choose to participate in the optional extension period, the duration of participation will last a 
total of approximately 11 months. 
Statistical methods: 
The sample size of 60 evaluable subjects was chosen to provide 80% power to demonstrate 
superiority of M2951+MTX to placebo + MTX for the primary endpoint at the 1-sided 10% 
level. Eligible subjects will be randomized 1:1 to treatment with M2951 or placebo through a 
central randomization process by an Interactive Web Response System (IWRS). 
Approximately 64 subjects will be randomized under the assumption of a 6.25% drop-out 
rate.  
There will be 3 analyses: (1) an interim analysis (IA), triggered when subjects from the first 
50% of the planned enrollment have reached Day 29 of treatment and have available Day 29 
hsCRP data, or have discontinued treatment prior to Day 29, (2) a primary analysis, triggered 


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when 100% of subjects enrolled have reached Day 85 of treatment or have discontinued 
treatment prior to Day 85, and (3) a final analysis, triggered when 100% of subjects enrolled 
complete all study parts, or discontinue prematurely from study. 
The percent change in hsCRP from Baseline to Day 29 will be the key endpoint evaluated at 
the IA. Point estimate and confidence interval (CI) estimates of the Day 29 hsCRP change 
from Baseline difference, comparing the 2 treatment groups, will be estimated for use in 
internal decision making. In addition, the change in DAS28-hsCRP from Baseline to Day 29 
will be evaluated using the same approach as used for change in hsCRP. The IA will not be 
used to alter the design of the trial. No adjustment will be made to the 1-sided Į of 10% to be 
used in the primary analysis at the end of the first treatment period (12 weeks).  
The Day 85 ACR20 proportion and a 2-sided 80% CI will be provided for each treatment 
group. The difference (ǻ) in 12-week ACR20 proportions between M2951+MTX and 
placebo + MTX, and a 2 sided 80% CI for ǻ, based on the “corrected Miettinen-Nurminen” 
method will be provided. The primary analysis will be based on the mITT Analysis Set using 
Last Observation Carried Forward for imputation of missing values and will reject the null 
hypothesis (H0): ǻ  0 if the lower limit of the CI exceeds zero.   
The Day 85 ACR50 and ACR70 proportions will be analyzed in the same way as the Day 85 
ACR20 proportions. 
Safety data will be listed and summarized using descriptive statistics. 
In addition, efficacy and safety data collected during the open-label extension period will be 
summarized. 
Pharmacokinetics 
M2951 concentrations and PK parameters will be listed and summarized by trial day.  
Pharmacodynamics 
Data on immunoglobulin levels, 
, and B cell numbers and subsets will be 
summarized in tabular and/or graphic format, as appropriate to the data. Potential PK/PD 
correlations may be explored and reported separately. 
7 
Sample Size/Randomization 
The trial is powered to demonstrate superiority of M2951 + MTX to placebo + MTX in ACR20 
response proportion after 84 days of treatment, using a test of the null hypothesis H0: ǻ  0 
based on the 2-sided 80% confidence interval (CI) for ǻ, where ǻ is the difference in Week 12 
ACR20 response proportion comparing the 2 treatment groups. The null hypothesis H0 will be 
rejected if the lower limit of the 2-sided 80% CI exceeds zero. It is assumed that the Week 12 
ACR20 response proportion in the placebo + MTX treatment group is 0.21 (1), and that the 
difference in Week 12 ACR20 response proportions between the 2 treatment groups under the 
alternative hypothesis H1: ǻ > 0 is ǻ = 0.25 (1, 2). 
If the response proportions in the 2 treatment groups are 0.46 and 0.21, respectively, under the 
alternative hypothesis, then a sample size of approximately 60 mITT subjects randomized 1:1, 
M2951+MTX:placebo+MTX, provides 80.2% power to demonstrate superiority at the 1-sided 
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10% significance level. The power calculation is based on a simulation of the 2-sided 80% CI for 
ǻ estimated using the “corrected Miettinen-Nurminen” method (3) conducted in R Cran software 
version 2.15.2 using the function PropCIs::diffscoreci (version 0.2 5, 2015).  
A total of approximately 64 subjects will be randomized to provide 60 mITT subjects in the 
presence of a 6.25% dropout rate. 
Eligible subjects will be randomized in a blinded fashion by the IWRS in a ratio of 1:1 to M2951 
dose of 50 mg bid + MTX or placebo + MTX, 
 
 
8 
Overview of Planned Analyses 
8.1 
Independent Monitoring Committee review 
An IDMC will be set up to 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. IDMC meetings will take place every 4 months or as 
requested by the IDMC members and at the IA. Details of the statistical analyses of the IDMC 
are provided in the IDMC/IA SAP and the IDMC charter. 
8.2 
Interim Analysis 
An IA will be conducted with the percent change in hsCRP from Baseline to Day 29 as key 
endpoint evaluated at the IA. Details of the statistical analyses of the IA are provided in the 
IDMC/IA SAP. 
8.3 
Primary Analysis 
When the last subject has been administered the last dose of IMP during the 12-Week treatment 
period, the protocol violations are determined, the SAP is signed and the Week 12 database is 
partially locked for the primary analysis, the drug code will be broken and made available for the 
primary data analysis. The definition and details of partial database lock for the primary analysis 
will be documented in the Data Handling Report which will be finalized before the database 
partial lock for the primary analysis. 
8.4 
Final Analysis 
The final analysis will occur only when the last subject completes all study parts (or discontinues 
study prematurely), the protocol violations are determined and the database is locked for the final 
analysis.  
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9 
Changes to the Planned Analyses in the Clinical Trial 
Protocol 
Computation of point estimates and CIs of differences from baseline in hsCRP and Disease 
Activity Score based on 28 joints and high-sensitivity C-Reactive Protein (DAS28-hsCRP)  
Details were added to complete the planned analysis of hsCRP and DAS28-hsCRP.  
In the SAP, it has been further specified that: 
• the differences in mean changes between M2951+MTX and Placebo+MTX will be considered 
for hsCRP and DAS28-hsCRP, along with the 2-sided 80% CI for the difference  
• the estimates and the CI limits will be derived using an Analysis of Covariance (ANCOVA) 
model with baseline as a covariate and treatment group as an independent variable 
• Percent Change From Baseline (CFB) of hsCRP will be provided as summary statistics 
Missing hsCRP and DAS28-hsCRP imputation 
Missing hsCRP values and DAS28-hsCRP scores will be imputed for the primary and final 
analyses:  
• Missing hsCRP values will be imputed using the same rule used for the analysis of the 
primary endpoint, ie, post-baseline Last Observation Carried Forward (LOCF) 
• Missing components of DAS28-hsCRP will be imputed using the same rule as the primary 
endpoint, i.e., post-baseline Last Observation Carried Forward (LOCF) 
Imputation of hsCRP and DAS28-hsCRP is not applicable for open-label extension (OLE) 
period, only for 12-week treatment period. 
 
 
 
 
 
 
 
OLE PD endpoints 
The Schedule of Assessments table in protocol specifies immunoglobulin and B cells and 
subtypes to be collected during the optional OLE period.  A description of the analysis of these 
data is missing from the “Endpoints for Open-label Extension” section of the protocol. A 
separate analysis set has been added here in Section 10.2. 
CTCAE Grades for Relevant Laboratory Parameters 
The Grade 1 definitions for the laboratory parameters AST, ALT, bilirubin, amylase, lipase, and 
creatinine in Table 3 in the protocol were cited incorrectly.  For these parameters, Grade 1 will 
be defined as in CTCAE, version 4.03.  In fact, all laboratory abnormalities will be graded as 
specified in CTCAE, version 4.03; Table 3 of the protocol will not be used. 
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PK statistical presentation 
The protocol specified that M2951 concentrations and PK parameters would be described with 
standard error of mean and 25th and 75th percentile. For this study, M2951 concentrations and PK 
parameters will be summarized as described in Specific rules for PK parameters, Section 11. 
Also specified in the protocol was an additional descriptive statistics table for BLQ PK values set 
to missing, this will not be presented for this study. 
 
Change of IA trigger 
The protocol mentioned that IA would be conducted when subjects from the first 50% of the 
planned enrollment (ie 32 subjects) have reached Day 29 of treatment and have Day 29 data, or 
have discontinued treatment prior to Day 29. The trigger has been updated and the change from 
protocol is detailed in IDMC/IA SAP. 
 
OLE extension endpoints 
For the final analysis, in addition to the ACR50 and ACR70, the ACR20 will be also analyzed as 
an open-label extension endpoint. 
 
OLE mITT definition 
The definition of OLE mITT set has been updated. It will include all subjects who received at 
least 1 dose of M2951 during open-label extension period and have at least 1 available efficacy 
evaluation at a time point after first dose in open-label extension period, instead of 1 available 
ACR20 evaluation.  
  
10 
Protocol Deviations and Analysis Sets 
10.1 
Definition of Protocol Deviations and Analysis Sets 
No per Protocol analysis is planned. 
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
subject's rights, safety, or well-being.  
The following important deviations will be identified and confirmed prior to or at the Data 
Review Meeting, which will occur before the database lock. The outcome of the Data Review 
Meeting will document the important protocol deviations as well as the finalization of the 
analysis population in a memo.  
• Subjects that are dosed on the study despite not satisfying the inclusion criteria 
• Subjects that develop withdrawal criteria whilst on the study but are not withdrawn 
• Subjects that receive the wrong treatment or an incorrect dose 
• Subjects that receive an excluded concomitant medication 
• Deviation from Good Clinical Practice 


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• Inclusion and exclusion criteria violations 
• Other 
violations/events 
that 
may 
have 
a 
relevant 
influence 
on 
the 
pharmacokinetic/pharmacodynamic (PK/PD) analysis (eg, adverse events (AEs), vomiting, 
sample processing errors, inaccurate dosing, etc.) 
Any important protocol deviations that lead to the exclusion of a subject from an analysis set will 
be considered clinically important (see Section 10.2). 
All important protocol deviations should be documented in Clinical Data Interchange Standards 
Consortium Study Data Tabulation Model (SDTM) (or Analysis Data Model (ADaM) for those 
derived by programming) whether identified through sites monitoring, medical review and/or 
programming based on the inclusion/exclusion criteria presented in the protocol. Important 
protocol deviations to be identified by programming as well as all clinically important protocol 
deviations are listed and described in Appendix 3. 
10.2 
Definition of Analysis Sets and Subgroups 
Screening Analysis Set (SCR) 
The SCR includes all subjects who signed the informed consent.  
Safety Analysis Set (SAF) 
The SAF will include all subjects who received at least 1 dose of M2951 or placebo. The SAF 
will be used for all demographic/baseline characteristics and safety analyses.  
 
Analyses performed on the SAF will consider subjects as treated. Subjects will be allocated to 
active arm if at least one dose of M2951 was taken during first 12-week treatment period. 
The OLE SAF will include all subjects who received at least 1 dose of M2951 during the OLE 
period. The OLE SAF will be used for all safety analyses at the time of the final analysis. 
mITT Analysis Set  
The mITT Analysis Set will include all subjects who received at least 1 dose of M2951 or 
placebo and have at least 1 available ACR20 evaluation at a time point postdose. The mITT 
Analysis Set will be used for the analysis of all efficacy endpoints. Subjects will be analyzed as 
randomized. 
 
The OLE mITT Analysis Set will include all subjects who received at least 1 dose of M2951 
during OLE period and have at least 1 available efficacy evaluation (ACR components, ESR, 
anti-CCP, RF) at a time point after first dose in OLE period. The OLE mITT Analysis Set will be 
used for the analysis of efficacy endpoints at the time of the final analysis. 


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Pharmacokinetic Analysis Set 
The PK Analysis Set will include all subjects who receive at least 1 dose of M2951 and have at 
least 1 quantifiable M2951 plasma concentration at a scheduled PK time point postdose without 
any important deviations or events that may impact the quality of the data or alter the evaluation 
of the PK. The PK Analysis Set will be used for all PK analyses. Subjects who receive placebo 
will not be included. 
Pharmacodynamic Analysis Set 
The PD Analysis Set will include all subjects who receive at least 1 dose of M2951 or placebo 
and have at least 1 measured PD endpoint, not including 
, at a scheduled PD 
time point after first dose without deviations or important events affecting PD, and who provide 
evaluable PD data. All PD analyses, not including 
, will be based on this analysis 
set. 
 
Deviations, or changes to the procedures or events that may have a relevant influence on the PK 
may also influence PD analysis or impact the quality of the PD data and may lead to exclusion 
from the PD Analysis Set. Please see examples of deviations or events listed in Section 12.2.2. 
In the case subjects or data are excluded from the PD analysis set, their PD data will be listed in 
the CSR and flagged. 
 
The OLE PD Analysis Set will include all subjects who receive at least 1 dose of M2951 during 
OLE period and have at least 1 available PD endpoint at a time point after first dose in OLE 
period. All PD analyses, not including 
, will be based on this OLE PD Analysis 
Set at time of final analysis. 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
Randomized Analysis Set 
The randomized analysis set will include all randomized subjects. This set will be used to 
provide a listing for checking whether randomization occurred as planned. 
 
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The “as-treated” principle will be applied to all evaluations, except those based on the mITT 
Analysis Set, ie, subjects who receive a treatment other than the one assigned by randomization 
will be analyzed by the actual treatment received. The use of the analysis sets in the different 
analyses is summarized in the following table:  
Table 1: Summary of analyses by sets 
Analyses 
SCR 
SAF 
OLE 
SAF 
mITT 
Analysis 
Set 
OLE 
mITT 
Analysis 
Set 
PK 
Analysis 
Set 
PD 
Analysis 
Set 
OLE PD 
Analysis 
Set 
 
 
Randomized 
Analysis Set 
Subject Disposition 
status 
9 
 
 
 
 
 
 
 
 
 
Analysis sets 
9 
 
 
 
 
 
 
 
 
 
Subject disposition 
by visit 
 
 
 
 
 
 
 
 
 
9 
Important Protocol 
Deviations 
 
 
 
 
 
 
 
 
 
9 
Demographic and 
Baseline 
Assessments 
 
9 
 
 
 
 
 
 
 
 
Prior Medications 
 
9 
 
 
 
 
 
 
 
 
Concomitant 
Medications 
 
9 
9 
 
 
 
 
 
 
 
Concurrent 
procedures 
 
9 
9 
 
 
 
 
 
 
 
Compliance and 
Exposure 
 
9 
9 
 
 
 
 
 
 
 
Safety Analysis 
 
9 
9 
 
 
 
 
 
 
 
Primary Efficacy 
Analysis 
 
 
 
9 
 
 
 
 
 
 
Secondary Efficacy 
Analysis 
 
 
 
9 
 
 
 
 
 
 
OLE Efficacy 
Analysis 
 
 
 
 
9 
 
 
 
 
 
PK Analysis 
 
 
 
 
 
9 
 
 
 
 
PD Analysis 
 
 
 
 
 
 
9 
9 
 
 
Randomization 
listing 
 
 
 
 
 
 
 
 
 
9 
 
Subgroup analysis: 
Subgroup analyses will be performed on randomized subjects with either:  
• hsCRP at screening  3.6 mg/L  
• hsCRP at baseline  3.6 mg/L 
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• hsCRP at screening  5 mg/L  
• hsCRP at baseline  5 mg/L  
 
Details of these subgroup analyses can be found in Table 14 of Section 16.  
11 
General Specifications for Statistical Analyses 
All statistical analyses will be performed by 
. 
Treatment groups and IMP: 
Treatment groups are defined as placebo + MTX and M2951 + MTX groups, except for the 
analyses including both the first 12-week treatment period and OLE period data, which will be 
summarized according to treatment groups ‘Placebo/M2951 + MTX’ and ‘M2951 + MTX’. 
Unless otherwise indicated, all analyses will be presented separately for the two treatment 
groups. The IMPs are placebo and M2951. 
Presentation of Tables/Figures 
For the primary analysis at the end of first 12-week treatment period, drug code will be broken 
and tables and figures will be produced using true treatment groups and their true labels (ie, 
‘Placebo’, ‘M2951 50 mg BID’). For the final analysis, tables and figures will be produced using 
true treatment groups and the following labels: ‘Placebo/M2951 50 mg BID’ and ‘M2951 50 mg 
BID/M2951 50 mg BID’.  
Tables and figures will be sorted by treatment group (in order of ‘Placebo’ and ‘M2951 50 mg 
BID’, or ‘Placebo/M2951 50 mg BID’ and ‘M2951 50 mg BID/M2951 50 mg BID’ for final 
analysis) and chronological scheduled time point (where applicable).  
Presentation of Listings: 
All data recorded during the trial will be presented in individual data listings. All listings are 
sorted by treatment group (in order of ‘Placebo’ and ‘M2951 50 mg BID’, or ‘Placebo/M2951 
50 mg BID’ and ‘M2951 50 mg BID/M2951 50 mg BID’ for final analysis), subject, and 
scheduled time point (where applicable), if not otherwise stated.   
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Data handling for the planned analysis: 
For the primary analysis, data will be handled as follows:  
• Data from OLE, or safety follow-up posterior to OLE, will be excluded from the primary 
analysis. This exclusion will be performed at the ADaM level; no selection will be 
performed, neither at the data management level, nor at the SDTM level.  
• As the database lock for the primary analysis will be based on data up to and including 
the last patient’s last dose of IMP (LPLD) during 12-Week treatment period, all data 
from screening to LPLD during the 12-Week treatment period for all subjects will be 
locked and available in the database for the primary analysis. 
• A cut-off date will be applied at the SDTM level: all data posterior to LPLD during 12-
Week treatment period will be removed from the database. Details on the implementation 
of this cut-off date are available in the document named SDTM Cut-off date 
implementation rules_BTKi(M2951)-Compound_v2.0.docx 
• For all subjects, data during the 12-week treatment period up to and including the LPLD 
will be included for the primary analysis except for the safety follow-up data. All safety 
follow-up data will be reported for the mITT population at the final analysis stage.  
• Data selection for the primary and final analyses will be identified at the ADaM level 
first before any statistical calculations can start. Therefore, the data handlings described 
in all tables in the following sections of this SAP will depend on data selected in the 
ADaM level. 
 
For the final analysis, data will be presented on subjects who agreed to participate in OLE.  
Presentation of continuous and qualitative variables: 
Continuous variables will be summarized using descriptive statistics, ie  
• number of subjects (N) 
• number and percentage of non-missing values 
• number and percentage of missing values  
• mean, standard deviation (SD) 
• median, 25th Percentile - 75th Percentile (Q1-Q3) 
• minimum and maximum 
For both continuous and qualitative variables, percentages such as 0% or 100% should be 
reported with the same format used for the column, together with the count of observations. For 
example, if the count of observations is zero, then display ‘0 (  0.0)’; if the count of observations 
represents 100%,  then display ‘xx (100.0)’. 
Qualitative variables will be summarized by counts and percentages.  Unless otherwise stated, 
the calculation of proportions will be based on the number of subjects in the analysis set of 
interest. Therefore counts of missing observations will be included in the denominator and 
presented as a separate category. 


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In case the analysis refers only to certain visits, percentages will be based on the number of 
subjects in the analysis set of interest, unless otherwise specified. Total of missing and non-
missing observations at each time-point will reflect the population still in the trial at that time. 
For example, if a subject is still in the trial at the time-point but with missing data, it should be 
counted in the number of missing observations.  
Pharmacodynamic endpoints will be reported as described above for presentation of continuous 
and qualitative variables. 
Specific rules for PK concentrations and PK parameters  
Plasma concentrations of M2951 will be presented descriptively by study day and nominal time 
point for the PK analysis set including number of subjects (N), number of observations (n), 
mean, SD, coefficient of variation (CV%) median, minimum, and maximum. The below limit of 
quantification (BLQ) PK concentration values will be set to zero prior to computing descriptive 
statistics of PK concentrations. Missing concentrations will be omitted from the calculation of 
descriptive statistics. 
Individual plasma and mean concentration-time plots will be provided using a linear and semi-
logarithmic scale. 
Descriptive statistics for PK parameters (see Section 16.3.2 for calculations) will be summarized 
by study day (N, n, arithmetic mean, SD of the arithmetic mean, CV%, median, minimum, 
maximum geometric mean [GeoMean], geometric coefficient of variation [GeoCV%], and the 
95% CI for the GeoMean). For tmax, only n, minimum, median, and maximum will be reported. 
For calculation and presentation of PK descriptive statistics, and the inferential statistical 
analysis, values as presented in the data listings will be used as the source data. Minimum, 
maximum, mean, GeoMean, median, Q1, Q3, and 95% CI for mean or GeoMean will be 
presented to the same significant figure precision as listed data. Standard deviation will be 
presented to 1 significant figure more than the precision of the data listed. The CV% and 
GeoCV% will always be reported to 1 decimal place. Derived parameters will be reported to 3 
significant figures, except for parameters that are taken directly from concentration data which 
will be reported using similar precision to those from which they were derived or elapsed 
sampling times which will be reported as 2 decimal places. 
Definition of baseline: 
For the purpose of statistical analysis, baseline is defined as the last non-missing measurement 
prior to the first dose of study drug as described in the following table:  


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Table 2: Definition of baseline 
Randomized 
Time Period
Baseline
Placebo+MTX 
First 12-week treatment period 
Last non-missing measurement prior 
to first dose of study drug of the 
12-week treatment period 
OLE Period 
Last non-missing measurement prior 
to the first dose of M2951 of the OLE 
period 
M2951+MTX 
First 12-week treatment period 
Last non-missing measurement prior 
to first dose of study drug of the 
12-week treatment period 
OLE Period 
Last non-missing measurement prior 
to first dose of study drug of the 
12-week treatment period 
Definition of CFB:  
CFB and percent CFB will be computed as follows:  
• CFB = visit value – baseline value 
• Percent CFB = 100 * (visit value – baseline value) / baseline value 
Definition of duration: 
Unless otherwise specified, duration will be calculated as the difference between start and stop 
date + 1 (e.g. duration of AE (days) = AE start date – AE stop date + 1). Unless otherwise 
specified, missing dates will not be imputed. 
The time since an event will be calculated as: 
• date of event minus reference date +1 (eg days in study at onset of AE = AE start date - date 
of randomization + 1) if date of event is equal or greater than reference date 
• date of event minus reference date (eg days in study at onset of AE = AE start date - date of 
randomization) otherwise 
Conversion factors: 
The following conversion factors will be used to convert days into months or years: 1 month = 
30.4375 days, 1 year = 365.25 days. For time windows calculation, 1 month is expressed as 30 
days. 
Definition of Body Mass Index (BMI) (kg/m²): 
BMI will be computed as weight / (height²), where weight is expressed in kg and height in m.  
Handling of missing data: 
The Table 3 summarizes how missing data will be handled for each ACR component and 
DAS28-hsCRP:  


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Table 3: Missing data handling of ACR and DAS28-hsCRP 
Period 
covered 
Parameter 
Methods of imputation 
12-Week 
treatment 
period 
ACR 
1. LOCF-NR (Primary analysis): 
a. Imputation of each component using LOCF 
b. Derivation of ACR (responder/non-responder) 
c. If the subject discontinues from treatment, the 
subject will be considered as non-responder for 
all visits after discontinuation 
2. Non-responder imputation (sensitivity analysis) 
a. Derivation of ACR (responder/non-responder) using 
observed ACR components 
b. If the ACR is missing, then the ACR will be 
assigned as non-responder 
3. Other sensitivity analysis (see Table 13) 
DAS28-hsCRP 
LOCF:  
a. Imputation on each component using LOCF 
b. Derivation of DAS28-hsCRP at each timepoint 
OLE period
ACR 
No imputation 
DAS28-hsCRP 
No imputation 
 
Unless otherwise specified, missing data will not be replaced.  
In all subject data listings, imputed values will be presented. In all listings imputed information 
will be flagged. Non imputed partial dates will be presented in a format such as “_____YYYY”. 
Where imputation is defined, an imputed date with flag (ie, D for day, M for month) will be 
reported. 
Missing statistics, eg when they cannot be calculated, should be presented as ‘nd’ (denoting “not 
done”). For example, if n=1, the measure of variability (SD) cannot be computed and should be 
presented as ‘nd’. 
In case of zero records, an empty output with 0 occurrences, or a sentence mentioning that there 
are no data, will be presented. For tables of AEs and Deaths (outputs required for EudraCT 
and/or clinicaltrial.gov), if there are no observations, the output must contain the first line 
‘Subject with…’ or ‘Subject who died’ displayed with 0 occurrence. 


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If the System Organ Class (SOC) or Anatomical Therapeutic Class (ATC) term is missing/not 
coded yet, then ‘Uncoded SOC’ (or ‘Uncoded ATC’) will be indicated at the ADaM level. When 
a Preferred Term (PT) is missing, it will be set to ‘Uncoded PT: verbatim text’. 
Treatment day: 
Treatment day is defined as relative day to the start date of treatment. Treatment day will be 
calculated accordingly, ie: 
• For primary analysis, treatment day 1 is defined as the date of first administration of any 
IMP. 
• For final analysis, treatment day 1 is defined as the first administration of M2951: 
o For subjects who switch from placebo to M2951, the treatment day 1 will be 
defined as the first administration of M2951 in OLE period 
o For subjects who have taken M2951 during 12-Week treatment period and 
continue with the same treatment during OLE, the treatment day 1 will be defined 
as the first administration of M2951 during 12-Week treatment period   
 
The day before is defined as Treatment day –1 (no Treatment day 0 is defined). 
Repeated and unscheduled measurements: 
Data collected at unscheduled visits will be included and analyzed for safety analyses in the 
same fashion as the data collected at scheduled visits. Unscheduled measurements will also be 
used for shift tables.  
Gap between 12-Week treatment period and OLE period 
Subjects with a gap strictly greater than 4 weeks between 12-Week treatment period and OLE 
period will be analyzed the same way as subjects without a gap.  Specific data listings on safety 
data (AEs and all laboratory data) will be produced for these subjects for the final analysis. 
 
Time windows 
As a measurement may have been performed out of window, data will be re-allocated according 
to time windows defined in Table 4, so that each measurement is allocated to the closest 
timepoint. In case of a gap between 12-Week treatment period and OLE, time windows 
allocation will be handled case by case at the time of statistical analysis. 
 
For efficacy and safety analyses, each measurement will be assigned an analysis visit number 
first according to Table 4. The analysis visit will then be used for all missing data imputations, 
analysis variable derivations, statistical calculations and presentations. For patient data listings 
by timepoint, the visit as collected in the database as well as the analysis visit will be displayed. 


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Table 4: Time windows 
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Software: 
Non-compartmental computation of PK parameters will be performed using Phoenix® 
WinNonlin® Version 6.4, or higher (
 
). Graphics may be prepared with SAS Version 9.4, or higher; SigmaPlot® 12.5, or higher 
(
); or Phoenix WinNonlin 6.4, or higher. 
All other statistical analyses will be performed using SAS® (
 
). 
PPD
PPD
PPD


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12 
Trial Subjects 
The subsections in this section include specifications for reporting subject disposition and 
treatment/trial discontinuations. Additionally procedures for reporting protocol deviations are 
provided. 
12.1 
Disposition of Subjects and Discontinuations 
A table on screened subjects describing the number and percent of subjects in each of following 
disposition categories will be produced by treatment group: 


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Table 5: Disposition 
 
Primary 
analysis 
Final 
analysis 
Total number of screened subjects, ie subjects that gave informed consent 
(overall summary only) 
 
 
Number of subjects who discontinued prior to randomization and reason 
(overall summary only) 
 
 
Number of randomized subjects 
 
 
Number of randomized subjects who did not start treatment 
 
 
Number of randomized subjects who completed 12-week double-blind 
treatment period 
 
 
Number of randomized subjects who permanently discontinued treatment 
during 12-week double-blind treatment period and reason 
 
 
Number of randomized subjects who discontinued from trial after 
randomization during 12-week double-blind treatment period and reason 
 
 
Number of randomized subjects who declined to participate in OLE and 
discontinued from trial after completion of 12-week double-blind treatment 
period during safety follow-up and reason 
 
 
Number of randomized subjects who declined to participate in OLE and 
completed safety follow-up period according to protocol 
 
 
Number of randomized subjects who agreed to participate in OLE period 
 
 
Number of randomized subjects with a gap > 4 weeks between double-blind 
period and OLE period 
 
 
Number of randomized subjects who completed the OLE period 
 
 
Number of randomized subjects who permanently discontinued treatment 
during OLE period and reason 
 
 
Number of randomized subjects who discontinued from trial after 
randomization during OLE period and reason 
 
 
Number of randomized subjects who completed safety follow-up after OLE 
according to protocol 
 
 
Number of randomized subjects who discontinued from trial after completion 
of OLE period during safety follow-up and reason 
 
 
For the primary analysis, a table of randomized subjects not treated as randomized, including 
reason for not being treated as randomized will be produced by randomized treatment group. 


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A table based on screened subjects, describing the number and percent of subjects in each 
analysis set by treatment group, will be produced: 
Table 6: Analysis sets 
 
Primary 
analysis 
Final 
analysis 
Number of screened subjects 
9 
9 
Number of randomized subjects 
9 
9 
Number of subjects included in the SAF 
9 
9 
Number of subjects included in the OLE SAF 
 
9 
Number of subjects included in the PK Analysis Set 
9 
9 
Number of subjects included in the PD Analysis Set 
9 
9 
Number of subjects included in the OLE PD Analysis Set 
 
9 
Number of subjects included in the 
 
9 
9 
Number of subjects included in the mITT Analysis Set 
9 
9 
Number of subjects included in the OLE mITT Analysis Set 
 
9 
A table based on screened subjects, describing the number and percent of subjects in each region 
(eg Europe, European Economic Area (as required by EudraCT) and North America), country 
within region and site, by analysis set, will be produced. 
A table based on randomized subjects with patients still on trial at each visit will be also 
produced. This table will also include the number of patients who discontinued before each visit. 
Corresponding individual listings will be prepared. Discontinued subjects (from treatment or 
study) will be listed with their reason for withdrawal (from treatment or study). Additionally, a 
listing of the subjects screened but not randomized will be produced with the reason for not 
being randomized. A listing of randomized subjects with subject number, randomization date, 
and randomized treatment group, ordered by randomization number within randomization 
stratum, will be produced for the purpose of assessing whether randomization was conducted as 
planned. 
The list of re-screened subjects and corresponding subject identifiers will be provided. These 
subjects’ identifiers will be listed. Only the second subject identifier will be used in statistical 
descriptions and analyses, while the first identifier will not be considered/excluded from the 
disposition counts. 
12.2 
Protocol Deviations 
The Table 7 summarizes how protocol deviations will be handled for both primary and final 
analysis:  
CCI


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Table 7: Protocol deviations 
Analysis 
Period covered 
for protocol 
deviations 
reporting
Treatment Group 
Observation 
Period 
Analysis Set 
Primary 
analysis 
12-Week 
treatment period 
Placebo or 
M2951 50 mg 
BID 
First dose of 12-
Week treatment 
period up to first 
dose of OLE, or 
last observed dose 
during the 12-
Week treatment 
period if subject 
either prematurely 
discontinues from 
treatment or 
declines to 
participate in OLE
Randomized 
Final 
analysis 
OLE 
Placebo/M2951 
50 mg BID 
First dose of OLE 
to last observed 
dose 
Randomized and 
entered into OLE 
12-Week 
treatment period 
+ OLE 
M2951 50 mg 
BID/M2951 50 
mg BID 
First dose to last 
observed dose 
Randomized and 
entered into OLE 
12.2.1 
Important Protocol Deviations 
The following summary tables and listings of important protocol deviations will be provided 
(separately for pre-/post inclusion deviations): 
• Table providing frequency for each type of important protocol deviation 
• Listing of important protocol deviations 
12.2.2 
Clinically Important Protocol Deviations 
Clinically important protocol deviations, as defined in Section 10.1 and Section 10.2, will be 
summarized and listed. 
Deviations, or changes to the procedures or events that may have a relevant influence on the 
PK/PD analysis or impact the quality of the PK/PD data may lead to exclusion from the PK/PD 
analysis sets. Examples include, but may not be limited to, the following: 


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o Adverse events, vomiting, diarrhea etc. 
o Vomiting following oral dosing (these instances will be discussed on a 
case-by-case basis) 
o Sample processing errors that may lead to inaccurate bioanalytical results 
o Inaccurate dosing or dosing errors 
o Concomitant medication violations (see Section 6.5.2. of the protocol) 
In the case of a deviation or event that may affect PK, PK data collected during the affected 
study day will be excluded from the study results after consultation and agreement with Sponsor 
or sponsor representative. Other changes to the procedures or events which do not impact the 
quality of the PK data will not be considered clinically important protocol deviations. A common 
example of a protocol deviation that is not clinically important is a missed PK blood sample or 
deviations from PK blood collection times, with the requirement that the actual time of collection 
is recorded. An exception to a PK blood sample deviation defined as not clinically important is 
the predose sample which will be considered a deviation if it is not collected predose, and the 
6 hour sample if missing or collected 10 minutes outside the scheduled window. 
If subjects or select M2951 concentrations are excluded from the PK analysis set, the excluded 
PK data will be listed in the CSR and flagged. 
13 
Demographics and Other Baseline Characteristics 
Demographics and baseline characteristics will only be summarized for the primary analysis. 
Demographics and baseline characteristics will be summarized on SAF and presented by 
treatment group and overall. All data will be listed on SAF. 
13.1 
Demographics 
• Demographic characteristics  
- Sex: male, female  
- Race: White, Black or African American, Asian, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Other 
- Ethnicity: Hispanic or Latino, Not Hispanic or Latino 
- Age (years) at informed consent: summary statistics  
- Age categories :  
o < 65 years, ≥ 65 years 
• Geographic Region (eg Europe, North America) 
• European Economic Area (Yes/No) 
Specifications for computation: 
• Age (years):  


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- (date of given informed consent - date of birth + 1) / 365.25 
- In case of missing day for at least one date, but month and year available for both dates:  
For the derivation of age, the day of informed consent and the day of birth will be set to 1 
and the formula above will be used 
- In case of missing month for at least one date, but year available for both dates:  
For the derivation of age, the day and the month of informed consent and the day and 
month of birth will be set to 1 and the formula above will be used 
• Site codes will be used for the determination of the subject’s geographic region and European 
Economic Area membership. 
13.2 
Medical History 
The medical history will only be summarized for the primary analysis. 
The medical history will be summarized using Medical Dictionary for Regulatory Activities 
(MedDRA), current version, PT as event category and MedDRA SOC body term as Body 
System category. The MedDRA version used will be indicated in footnote. Medical history will 
be tabulated by SOC and PT. SOC and PT will be alphabetically sorted. Medical history will be 
also listed.    
13.3 
Other Baseline Characteristics 
13.3.1 
Disease history 
Information on RA baseline disease characteristics collected during screening will only be 
summarized for the primary analysis. 
Information on RA baseline disease characteristics collected during screening will be 
summarized in total and by treatment arm. Descriptive statistics will be presented for:  
• Time (months) since confirmed diagnosis of RA according to 2010 ACR/The EULAR RA 
classification criteria. Time will be computed as (Date of Informed Consent Signature – Date 
of confirmed diagnosis of RA) / 30.4375. If the date of confirmed diagnosis of RA is entirely 
missing, then time since confirmed diagnosis of RA will not be computed. In case of partial 
missing date of confirmed diagnosis of RA, this date will be imputed as follows:  
o If only the day is missing, then it will be replaced by the first day of the month 
o If both day and month are missing, then it will be replaced by the first of January 
• The count of Tender Joint Count 68 (TJC68) 
• The count of Swollen Joint Count 66 (SJC66) 


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• Physician’s Global Assessment of Disease Activity using horizontal Visual Analog Scale 
(VAS) in mm 
• Subject’s Global Assessment of Disease Activity using horizontal VAS in mm 
• Subject’s Assessment of Pain using horizontal VAS in mm 
• Subject’s Assessment of Physical Function as measured by HAQ-DI will be derived 
(Appendix 1: HAQ-DI scoring) and described overall and by dimensions (dressing and 
grooming, getting up, eating, walking, hygiene, reach, grip, activities) 
• hsCRP (mg/L) as a continuous variable and by category (normal/high based on central 
normal laboratory ranges) 
• ESR (mm/Hr) as a continuous variable and by category (low/normal/high based on local 
normal ranges collected in eCRF) 
• Acute-phase reactant (at least one test result is needed for the classification): normal hsCRP 
and normal ESR, abnormal hsCRP or abnormal ESR. Abnormal refers to either low or high 
normal range classification. 
• RF (expressed in kU/L) as a continuous variable and classified as negative (≤ Upper Limit of 
Normal [ULN]) and positive (> ULN) 
• Anti-CCP antibodies classified as a continuous variable and as negative (≤ ULN) and 
positive (> ULN) 
• Serology (at least one test result is needed for the classification): negative RF and negative 
anti-CCP (≤ ULN), low-positive RF or low-positive anti-CCP (> ULN, ≤ 3*ULN), high-
positive RF or high positive anti-CCP (> 3*ULN) 
• DAS28-hsCRP, derived using formula presented in Appendix 2, summarized as a continuous 
variable and by disease activity category (< 2.6 [remission], ≥ 2.6 to ≤ 3.2 [low], > 3.2 to ≤ 
5.1 [moderate] and > 5.1 [high]). 
13.3.2 
Other 
Physical examination will only be summarized for the primary analysis. 
Descriptive statistics will be presented for physical examination as continuous variables: height 
(cm), weight (kg) and BMI (kg/m²). 


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14 
Previous or Concomitant Medications/Procedures 
Medications/procedures will be presented according to Table 8: 
Table 8: Data handling for medications/procedures 
Analysis 
Period covered 
Treatment 
groups
Data 
summarized
Analysis sets 
Primary 
analysis 
12-Week 
treatment period 
Placebo or 
M2951 50 mg 
BID 
Previous 
medications + 
concomitant 
medications
SAF 
Final analysis 
OLE 
Placebo/M2951 
50 mg BID 
Concomitant 
medications only 
OLE SAF 
12-Week 
treatment period 
+ OLE 
M2951 50 mg 
BID/M2951 50 
mg BID 
Concomitant 
medications only 
OLE SAF 


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The definition of previous or concomitant medication is presented in Table 9: 
Table 9: Definition of previous/concomitant medication 
Analysis 
Period 
covered 
Treatment 
groups 
Definition 
Primary 
analysis 
12-Week 
treatment 
period 
Placebo or 
M2951 50 mg 
BID 
Previous medications are medications, other than trial 
medications, which either:  
1. started and stopped before first administration of 
any IMP (Placebo or M2951).  
2. started prior to the first administration of IMP 
(Placebo or M2951) and are taken by subjects on 
or after the first administration of IMP.                  
Concomitant medications are medications, other than 
IMPs, which either: 
1. started on or after the first administration of any 
IMP (Placebo or M2951).  
2. started prior to the first administration of IMP 
(Placebo or M2951) and are taken by subjects on 
or after the first administration of IMP.                  
Final 
analysis 
 
OLE 
 
Placebo/M2951 
50 mg BID 
Concomitant medications are medications, other than 
IMPs, which either:  
1. started on or after the first administration of 
M2951 during OLE. 
2. started prior the first administration of M2951 
during OLE and are taken by subjects on or after 
the first administration of M2951 during OLE. 
12-Week 
treatment 
period + 
OLE 
M2951 50 mg 
BID/M2951 50 
mg BID 
Concomitant medications are medications, other than 
IMPs, which either:  
1. started on or after the first administration of 
M2951 during 12-Week treatment period. 
2. started prior the first administration of M2951 
during 12-Week treatment period and are taken 
by subjects on or after the first administration of 
M2951 during 12-Week treatment period. 


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Partial dates will be handled as follows:  
• For previous medications, in case the date values will not allow a medication to be 
unequivocally allocated to previous medication, the medication will be considered as 
previous medication. 
• For concomitant medications, in case the date values will not allow a medication to be 
unequivocally allocated to concomitant medication, the medication will be considered as 
concomitant medication. 
The ATC-2nd level and PT will be tabulated as given from the World Health Organization Drug 
Dictionary (WHO-DD) current version. In case multiple ATCs are assigned to a drug, all ATC-
2nd level will be used for reporting.  
The number and proportion of subjects with previous or concomitant medications (previous 
medications will not be summarized for final analysis) will be separately summarized by 
treatment group and will be presented by descending frequency of ATC 2nd level term and then 
by descending frequency of PT in total column. If multiple ATCs/PTs have the same frequency, 
they will be sorted alphabetically. The WHO-DD version used will be indicated in footnote.  
Previous or concomitant medications will be also listed.  
All concurrent procedures, which were undertaken any time on trial, will be summarized. 
Concurrent procedures will be classified by medical review. Number of subjects with concurrent 
procedures (prior, on or after the first day of IMP) overall and by type of procedure (as classified 
by medical review) will be summarized by treatment group. 
Concurrent procedures will be also listed.  


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15 
Treatment Compliance and Exposure 
Exposure 
Exposure will be separately analyzed for the 12-week treatment period, for the OLE period and 
overall (ie 12-Week treatment period + OLE).  
Exposure for 12-week treatment period will only be presented for primary analysis, whereas 
exposure for OLE period and overall exposure will only be presented for final analysis. 
The Table 10 summarizes how exposure time will be computed:  
Table 10: Exposure time 
Analysis 
Period covered 
Treatment 
groups
Exposure time 
Analysis sets 
Primary 
analysis 
12-Week 
treatment period 
Placebo or 
M2951 50 mg 
BID 
From first dose 
of any IMP 
during 12-Week 
treatment period 
to last observed 
dose of 12-Week 
treatment period 
SAF 
Final analysis 
OLE 
Placebo/M2951 
50 mg BID 
From first dose 
of M2951 to last 
dose of M2951 
during OLE
OLE SAF 
12-Week 
treatment period 
+ OLE 
M2951 50 mg 
BID/M2951 50 
mg BID 
From the first 
dose of M2951 
during 12-Week 
treatment period 
to the last dose of 
M2951 during 
OLE 
OLE SAF 
12-week treatment period 
Exposure for the 12-week treatment period will be presented on SAF. 


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For the 12-week treatment period, subjects will receive 50 mg bid M2951 or placebo 
administered as 2 matching oral capsules twice daily for 84 days. Each treatment kit contains 
enough medication for administration for 1 week + 2 days (ie 36 capsules). On trial visit days, 
subjects will be given treatment kits containing the number of capsules needed up to next 
planned trial visit. Subjects will self-administer IMP in a blinded manner at a set time each day 
(± 2 hours) as two matching capsules bid (morning and evening) for 12 weeks: 
• Subjects randomized to placebo arm will take four placebo capsules filled with mannitol  
• Subjects randomized to M2951 arm will take four capsules filled with 25 mg of M2951. 
On trial visit days, IMP will be administered during the trial visit after the scheduled trial visit 
procedures (other than post treatment PK/PD sampling) are completed. Exposure time in weeks 
will be calculated according to the following formula:  
exposure weeks = date of last dose - date of first dose + 1/7 
First dose refers to the first administration of any IMP in 12-week treatment period. 
Exposure time will be presented by summary statistics and according to the following categories:  
• ≤ 1 week  
• > 1 to 2 weeks  
• > 2 to 4 weeks  
• > 4 to 8 weeks  
• > 8 weeks 
The cumulative actual dose (mg) per subject for the 12-week treatment period will also be 
summarized for the active treatment group. The cumulative actual dose is defined as the sum of 
the total dose levels that the subject received between first and last treatment dose: number of 
ingested capsules * 25mg. The number of ingested capsules will be computed as the difference 
between the dispensed amount of capsules and the returned amount of capsules. Cumulative 
actual dose cannot be calculated for placebo treatment group. 
Study drug administrations will also be listed by treatment group, and subject, with start/end 
dates of administration, and reason for dose change or no dose (if applicable).  


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OLE period 
Exposure for the OLE period will only be presented on patients from OLE SAF who switch from 
Placebo to M2951 50 mg BID. 
After completing the treatment period, subjects will be offered the opportunity to participate in 
an optional 6-month M2951 extension period on Week 12 (Visit 8). Subjects who received 
M2951 during the treatment period will continue with the same dose of M2951 (in tablet 
formulation). All subjects in the placebo group during the treatment period will discontinue 
placebo and start treatment with 50 mg bid M2951 tablets on Day 1 of OLE. On trial visit days, 
the IMP will be administered during the trial visit after the scheduled trial visit procedures are 
completed. 
Subjects will take 2 matching oral tablets twice daily for 6 months. Subjects will self-administer 
the IMP at a set time each day (± 2 hours). 
Exposure time in weeks will be calculated according to the following formula:  
exposure weeks = date of last dose - date of first dose + 1/7 
First dose refers to the first administration of M2951 in OLE period. 
Exposure time will be presented by summary statistics and according to the following categories:  
• ≤ 4 weeks  
• > 4 to 8 weeks  
• > 8 to 12 weeks  
• > 12 to 16 weeks  
• > 16 weeks 
The cumulative actual dose (mg) per subject for the OLE period will also be summarized for 
both treatment groups. It is defined as for the 12-week treatment period.   
Overall 
Overall exposure will be presented on OLE SAF only for subjects who received M2951 during 
the 12-week treatment period and continue with the same dose of M2951 during OLE period.  
Exposure time in weeks will be calculated according to the following formula:  
exposure weeks = date of last dose - date of first dose + 1/7 


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First dose refers to the first administration of M2951 in the study. 
Exposure time will be presented by summary statistics and according to the following categories:  
• ≤ 6 weeks  
• > 6 to 12 weeks  
• > 12 to 18 weeks  
• > 18 to 24 weeks  
• > 24 weeks 
The cumulative actual dose (mg) per subject will be computed as well. It is defined as for the 12-
week treatment period or OLE period. 
Study drug administrations will also be listed by treatment group, and subject, with start/end 
dates of administration and reason for dose change (if applicable).  
Compliance 
Compliance will be separately analyzed for the 12-week treatment period, the OLE period and 
overall, in the same manner as exposure was analyzed (see Table 10).  
For each analysis, a listing of kit number with date of dispense, number of ingested and returned 
capsules/tablets will also be provided. 
12-week treatment period 
Compliance for the 12-week treatment period will be presented on SAF. 
For the 12-week treatment period, compliance with treatment is defined as the number of 
capsules taken during a period divided by the number of capsules that should have been taken 
during that period, multiplied by 100 to yield a percentage, ie: 
compliance for X weeks of treatment =  
100*(

36 ∗ −number of returned capsules for X_wk period 
4 ∗number of days between first intake and last intake of X_wk period ) 
Compliance with treatment and the number of ingested capsules will be tabulated overall (ie 
from first intake to last intake of 12-week treatment period).  


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OLE period 
Compliance for the OLE period will be presented on OLE SAF. 
For the OLE period, compliance with treatment is defined using the same formula as for the 12-
week treatment period, replacing capsules with tablets. 
Compliance with treatment and the number of ingested tablets will be tabulated overall (ie from 
first intake to last intake during OLE period).  
Overall 
Overall compliance will be presented on OLE SAF only for subjects who received M2951 during 
the 12-week treatment period and continue with the same dose of M2951 during OLE period.  
Overall compliance with treatment is defined using the same formula as for the 12-week 
treatment period, replacing capsules with capsules/tablets. 
Compliance with treatment and the number of ingested capsules/tablets will be tabulated overall 
(ie from first intake to last intake of the study).  


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16 
Endpoint Evaluation 
For all efficacy endpoints, data selection for primary and final analyses will be handled as 
indicated in the Table 11: 
Table 11 : Data handling for efficacy analysis 
Analysis 
Population 
Period covered 
Treatment groups 
Data to be 
analyzed 
Primary analysis 
mITT Analysis Set 
12-Week treatment 
period until start of 
OLE or 
discontinuation of 
treatment prior to 
OLE, whichever is 
applicable 
Placebo or M2951 50 
mg BID 
All data collected 
during the 12-
Week treatment 
period up to start 
of OLE if 
applicable 
Final analysis 
OLE mITT Analysis 
set 
OLE period only 
Placebo/M2951 50 mg 
BID only 
Data from OLE 
period only, or 
posterior to OLE 
(Safety follow-up / 
End of Study) 
Both 12-Week 
treatment period 
and OLE period 
M2951 50 mg 
BID/M2951 50 mg 
BID only 
Data from both 
periods (12-Week 
treatment and OLE 
period), ie all data 
collected 
throughout the 
study  
 
The Table 12  summarizes the analyses of efficacy endpoints:  
Table 12 : Summary of efficacy endpoints for the primary analysis 
Analysis 
Endpoint 
Method 
Missing Data Handling 
Primary 
endpoint 
ACR20 at Week 
12/Day 84  
(1) Primary: Computation of response 
rate, point estimate and 2-sided 80% 
CI for ∆ based on the “corrected 
Miettinen-Nurminen” method 
(2) Supportive**: logistic regression with 
treatment and baseline hsCRP as 
covariates 
Primary: LOCF-NR (Table 3) 
Sensitivity: See Table 13 
Key 
secondary 
endpoint 
hsCRP CFB at 
Week 4/Day 28 and 
Week 12/Day 84 
(1) Primary: ANCOVA model 
(2) Supportive: Hodges-Lehmann 
estimation for 80% CI  
Primary: LOCF 


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Analysis 
Endpoint 
Method 
Missing Data Handling 
Other 
secondary 
endpoints 
ACR20 response at 
each visit  
(1) Primary: Computation of response 
rate, point estimate and 2-sided 80% 
CI for ∆ based on the “corrected 
Miettinen-Nurminen” method 
(2) Supportive: logistic regression with 
treatment and baseline hsCRP as 
covariates 
Primary: LOCF-NR (Table 3) 
Sensitivity: See Table 13 
ACR50/ACR70 
response at each 
visit 
(1) Primary: Computation of response 
rate, point estimate and 2-sided 80% 
CI for ∆ based on the “corrected 
Miettinen-Nurminen” method 
(2) Supportive: logistic regression with 
treatment and baseline hsCRP as 
covariate 
Primary: LOCF-NR (Table 3) 
Sensitivity: See Table 13 
CFB and percent 
CFB at each visit for 
each ACR 
component, ESR, 
anti-CCP, RF 
Summary Statistics  
As observed 
CFB in 
DAS28-hsCRP 
score at Week 
4/Day 28, and Week 
12/Day 84 
(1) Primary : ANCOVA model 
(2) Supportive:  Hodges-Lehmann 
estimation for 80% CI  and ANCOVA 
model with baseline hsCRP as 
covariate 
Primary: LOCF of each 
component prior to DAS28 
calculation 
Percentage of 
subjects with 
DAS28-hsCRP < 
3.2 (well-controlled 
disease) at Week 
12/Day  84 
(1) Primary: Computation of response 
rate, point estimate and 2-sided 80% 
CI for ∆ based on the “corrected 
Miettinen-Nurminen” method 
(2) Supportive: logistic regression with 
treatment and baseline hsCRP as 
covariate 
Primary: LOCF-NR (Table 3) 
 
Percentage of 
subjects with 
DAS28-hsCRP < 
2.6 at Week 12 / 
Day 84 
(1) Primary: Computation of response 
rate, point estimate and 2-sided 80% 
CI for ∆ based on the “corrected 
Miettinen-Nurminen” method 
(2) Supportive: logistic regression with 
treatment and baseline hsCRP as 
covariate 
Primary: LOCF-NR (Table 3) 
 
** All supportive analysis will be based on the primary missing data imputation method. No sensitivity analysis of 
missing data imputation will be performed for all supportive analyses. 


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The Table 13 summarizes the sensitivity analyses to be performed on missing data imputations: 
Table 13 : Sensitivity analysis for the primary analysis 
Endpoint 
Method 
ACR Response 
Non-responder imputation (NR): ACR20 response rate will be evaluated 
on mITT analysis set. Subjects with missing ACR score will be considered 
as non-responders. 
Completely Missing at Random pattern (MCAR): ACR20 response rate 
will be evaluated as observed without any LOCF imputation on mITT 
analysis set. 
Missing At Random pattern (MAR): ACR20 will be imputed using 
multiple imputations process using MI SAS procedure as follows:  
1. Monotone missing data structure will be created as follows: 
intermediate (non-monotone) missing data will be multiply imputed 
using the Markov chain Monte Carlo (MCMC) method and 
assuming MAR and multivariate normality. Transformation of data 
will only be used if there is a clear deviation from normality. The 
SAS procedure PROC MI with the MCMC option will be used with 
seed number=20170524. The number of burn-in iterations will be 
set to 200, which is the default value. Nevertheless, if diagnosis 
plots show that the convergence has not yet occurred, this will be 
adjusted.  
2. Then, each component will be imputed with treatment group, 
hsCRP at baseline and data at previous visit from all ACR20 
components as covariates.  
3. Imputation will be repeated 1000 times. The ACR20 will then be 
calculated for each of the multiply imputed data sets from the 
imputed 
components. 
Results 
will 
be 
combined 
using 
MIANALYZE SAS procedure with the Rubin’s rules. 
Missing Not At Random pattern (MNAR): ACR20 will be imputed using 
multiple imputations process with MI SAS procedure for the MNAR 
pattern, using controlled-arm data with the MNAR statement from SAS MI 
procedure. 
 


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Subgroup analyses will be performed on the randomized subjects with either:  
• hsCRP at screening ≥ 3.6 mg/L  
• hsCRP at baseline ≥ 3.6 mg/L  
• hsCRP at screening ≥ 5 mg/L  
• hsCRP at baseline ≥ 5 mg/L  
The Table 14 summarizes the analyses to be performed for each subgroup: 
Table 14 : Subgroup analysis for the primary analysis 
Endpoint 
Method 
Missing Data Handling 
ACR20/ACR50/ACR70 
response at each visit 
Primary: Computation of response rate, point 
estimate and 2-sided 80% CI for ∆ based on the 
“corrected Miettinen-Nurminen” method 
Primary: LOCF-NR (Table 3) 
 
CFB in hsCRP and 
DAS28-hsCRP score at 
Week 4/Day 28 and 
Week 12/Day 84 
Primary : ANCOVA model 
Supportive:  Hodges-Lehmann estimation for 
80% CI, only if the assumption of normality is 
violated 
Primary and supportive: LOCF of 
each component prior to DAS28 
calculation 
 
Percentage of subjects 
with DAS28-hsCRP < 
3.2 (well-controlled 
disease) at Week 
12/Day 84 
Primary: Computation of response rate, point 
estimate and 2-sided 80% CI for ∆ based on the 
“corrected Miettinen-Nurminen” method 
Primary: LOCF-NR (Table 3) 
 
Percentage of subjects 
with DAS28-hsCRP < 
2.6 at Week 12 / Day 
84 
Primary: Computation of response rate, point 
estimate and 2-sided 80% CI for ∆ based on the 
“corrected Miettinen-Nurminen” method 
Primary: LOCF-NR (Table 3) 
 
 
16.1 
Primary Endpoint Analyses 
The primary endpoint, ACR20 response rate at Week 12, will be presented on the mITT Analysis 
Set. 
The ACR20 is a primary efficacy measure for which, at Week 12, a subject must have at least 
20% improvement in the following ACR Core Set values. 
• TJC (being the number of joints assessed as “Pain/Tender only” or “Pain/Tender and 
Swollen” among the 68 joint count) and 
• SJC (being the sum of joints assessed as “Swollen only” or “Pain/Tender and Swollen” 
among the 66 joint count) and 
• An improvement of at least 20% in at least 3 of the following 5 assessments: 
- Subject’s Global Assessment of Disease Activity  
- Subject’s Assessment of Pain 


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- Subject’s Assessment of Physical Function as measured by the HAQ-DI 
- Physician’s Global Assessment of Disease Activity 
- Acute phase reactant as measured by hsCRP. 
In this trial, ACR20 response calculations will use the HAQ-DI for the subject’s assessment of 
physical function and hsCRP as the measure of acute phase reactant. 
Improvement of at least 20% of these assessments is defined as follows: 
• TJC (68 joint count): a decrease of at least 20% of the number of tender joint compared to 
baseline 
• SJC (66 joint count): a decrease of at least 20% of the number of swollen joint compared to 
baseline  
• Subject’s Global Assessment of Disease Activity: a decrease of at least 20% on the VAS 
compared to baseline. 
• Subject’s Assessment of Pain: a decrease of at least 20% on the VAS compared to baseline. 
• Subject’s Assessment of Physical Function: a decrease of at least 20% of the HAQ-DI score 
compared to baseline. 
• Physician’s Global Assessment of Disease Activity: a decrease of at least 20% on the VAS 
compared to baseline 
• Acute phase reactant: a decrease of at least 20% of hsCRP measurement compared to baseline 
The hypotheses tested are as follows: 
• H0: Difference in ACR20 response rates at Week 12 (M2951 versus placebo) ≤ 0. 
• H1: Difference in ACR20 response rates at Week 12 (M2951 versus placebo) > 0. 
Tests will be based on the 2-sided 80% CI for ∆.  
The Week 12 ACR20 proportion and a 2-sided 80% CI will be provided for each treatment 
group. The difference ∆ in ACR20 proportions between M2951 + MTX and placebo + MTX, 
and a 2-sided 80% CI for ∆, based on the “corrected Miettinen-Nurminen” method (3) - method 
of Mee interval corrected with Miettinen and Nurminen factor n/(n-1), n being the total number 
of evaluable randomized subjects - will be provided.  
The 2-sided 80% CI for ∆ based on the “corrected Miettinen-Nurminen” method will be 
computed with SAS® FREQ procedure, using RISKDIFF and CL=MN statements. 
The primary analysis will be based on the mITT Analysis Set using post baseline LOCF for 
imputation of missing values for the ACR components. If a subject discontinued prior to Week 
12, then the subject will be considered as ACR20 non-responder. The null hypothesis H0: ∆ ≤ 0 
will be rejected at the 1-sided 0.10 level if the lower limit of the 2-sided 80% CI exceeds zero.  


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The primary analysis will be repeated for subjects with baseline hsCRP ≥3.6mg/L, as detailed in 
Table 14. 
Additional sensitivity analyses will be performed on ACR20 response as described in Table 13. 
16.2 
Secondary Endpoint Analyses 
16.2.1 
Key secondary endpoint analysis 
The key secondary endpoint is the change in hsCRP from Baseline to Week 4 and will be 
presented on the mITT Analysis Set. 
Descriptive statistics will be presented by treatment group for CFB as well as percent CFB of 
hsCRP. A point estimate and 2-sided 80% CI for the difference ∆ in Week 4 hsCRP mean CFB 
between subjects treated with M2951 + MTX and subjects treated with placebo + MTX 
(reference) will be provided.  
Point estimate and its CI limits will be estimated with SAS® GLM procedure using LSMEANS 
statement. The ANCOVA will include baseline as a covariate and treatment group as an 
independent variable. A sensitivity analysis will be performed using a non-parametric method. 
The Hodges-Lehmann difference median estimate and 80% CI will be calculated with SAS® 
NPAR1WAY procedure using HL statement. Asymptotic and exact CIs will be computed. 
Assumptions for the ANCOVA models:  
Validity of the model will be verified as follows:  
• The homogeneity of variances between treatment groups will be checked using the Levene’s 
test. A scatter plot of residuals versus fitted values will be also performed. 
• In order to assess the independence of error terms, a residual lag plot will be performed, ie 
constructed by plotting residual (i) against residual (i-1).  
• A scatter plot of the response variable against the covariate, using separate symbols for each 
treatment group will be performed to verify the presence of linear relationship between the 
covariate and the response variable, and that all treatment regression lines have the same slope. 
• Homogeneity of regression slopes will be verified by first running the model with the 
interaction between the covariate and the treatment group. This assumption will be validated 
if this interaction is not significant. If this assumption is verified, then the interaction will be 
removed from the model. 
• Normality of residuals will be checked by computing Skewness and Kurtosis, which should 
fall within the interval [-2;2]. Normal QQ-plot of residuals will be performed as well. 
16.2.2 
Other secondary endpoint analyses 
The following efficacy endpoint analyses will be performed for the primary analysis and 
presented on the mITT Analysis Set: 


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• ACR20 response at each visit 
• ACR50/ACR70 response at each visit  
• Change and percent change in hsCRP from Baseline to Week 12 
• CFB in DAS28-hsCRP score at Week 4 and Week 12  
• Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Week 12 
• Percentage of subjects with DAS28-hsCRP < 2.6 at Week 12 
• CFB in ESR, anti-CCP, RF (at Week 4 and Week 12) 
• CFB to Week 12 in subject’s self-assessments including: 
- Global assessment of disease activity (VAS) 
- Self-assessment of pain (VAS) 
- Self-assessment of disability (HAQ-DI) 
• CFB to Week 12 in Physician’s Global Assessment of Disease Activity (VAS). 
The Week 12 hsCRP CFB will be analyzed in the same way as the Week 4 hsCRP CFB, ie 
descriptive statistics, ANCOVA model and sensitivity analysis using Hodges-Lehmann 
difference median estimate and 80% CI. This analysis will also be applied to DAS28-hsCRP 
score CFB at Week 4 and Week 12. The DAS28-hsCRP will be derived using the formula 
presented in Appendix 2.  
ACR50 and ACR70 are defined in the same way as the ACR20 using at least 50% and 
70% improvement, respectively. The ACR50 and ACR70 proportions will be analyzed in the 
same way as the Week 12 ACR20 proportions.  
This analysis will also be applied to Week 12 “DAS28-hsCRP < 3.2” proportion and Week 12 
“DAS28-hsCRP < 2.6” proportion, but without the sensitivity analysis. 
Proportions of ACR20/50/70, “DAS28-hsCRP < 3.2” and “DAS28-hsCRP < 2.6” will also be 
presented by treatment group and time point as observed, ie without any imputation. 
Descriptive statistics  
Descriptive statistics will be tabulated by treatment group and time point for the following 
continuous variables, both absolute value and CFB. The summary statistics will be provided as 
observed without imputation of missing data.  
• DAS28-hsCRP score 
• hsCRP (CFB and percent CFB) 
• ESR  
• anti-CCP  
• RF 


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• TJC68 (CFB and percent CFB) 
• SJC66 (CFB and percent CFB) 
• subject’s global assessment of disease activity (CFB and percent CFB) 
• subject’s assessment of pain (CFB and percent CFB) 
• subject’s self-assessment of disability (HAQ-DI) (CFB and percent CFB) 
• Physician’s Global Assessment of Disease Activity (CFB and percent CFB) 
Each of the following parameters will be also displayed by categories. The number and 
percentage of subjects at Week 4 and Week 12 will be computed and a shift table from baseline 
to Week 4 and Week 12 respectively will be provided. For all shift tables, data will be 
summarized as observed, ie no imputation on missing data. The following parameters will be 
presented into categories:  
• hsCRP (mg/L) by category (normal/high based on central normal laboratory ranges) 
• DAS28-hsCRP, derived using the formula presented in Appendix 2, summarized by disease 
activity category (< 2.6 [remission], ≥ 2.6 to ≤ 3.2 [low], > 3.2 to ≤ 5.1 [moderate] and > 5.1 
[high]). 
• ESR (mm/Hr) by category (low/normal/high based on local normal ranges collected in 
eCRF) 
• Acute-phase reactant (at least one test result is needed for the classification): normal hsCRP 
and normal ESR, abnormal hsCRP or abnormal ESR. Abnormal refers to either below or 
above the normal range classification. 
• RF (expressed in kU/L) classified as negative (≤ ULN) and positive (> ULN) 
• anti-CCP classified as negative (≤ ULN) and positive (> ULN) 
• Serology (at least one test result is needed for the classification): negative RF and negative 
anti-CCP (≤ ULN), low-positive RF or low-positive anti-CCP (> ULN, ≤ 3*ULN), high-
positive RF or high positive anti-CCP (> 3*ULN) 
Box plots will be performed for each ACR component and DAS28 at each timepoint. Both 
treatment groups will be presented in the same graph. One plot will present the CFB and another 
plot for the percent CFB).  Data will be displayed as observed, ie without any imputation. 
Line plots will be generated for ACR response at each visit over time for both primary and final 
analysis as follows: 
• For the primary analysis, both treatment groups will be displayed. 
• For the final analysis, only the M2951 50 mg BID/ M2951 50 mg BID subjects will be 
presented.  
• Data will be presented using the LOCF-NR method, as for the primary endpoint.   


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16.3 
Other Endpoint Analyses 
16.3.1 
Open-label Extension Endpoint Analyses 
Descriptive statistics will be provided for data observed in the OLE period, and no imputation of 
missing data will be performed:  
• Continuous endpoints: summary statistics will be provided for each group. 
• Categorical endpoints: number and frequency of subjects in each category will be reported for 
each group. 
The following efficacy endpoint analyses will be performed for the final analysis and presented 
on the OLE mITT Analysis Set: 
• ACR20/ACR50/ACR70 response at Month 6 
• Absolute value, CFB and percent CFB in hsCRP at Month 6 
• Absolute value, CFB in DAS28-hsCRP score at Month 6 
• Percentage of subjects with DAS28-hsCRP < 3.2 (well-controlled disease) at Month 6 
• Percentage of subjects with DAS28-hsCRP < 2.6 at Month 6 
• Absolute value, CFB in ESR, anti-CCP, RF at Month 6 
• Absolute value, CFB and percent CFB in TJC68, SJC66 at Month 6 
• Absolute value, CFB and percent CFB to Month 6 in subject’s self-assessments including: 
- Global assessment of disease activity (VAS) 
- Self-assessment of pain (VAS) 
- Self-assessment of disability (HAQ-DI) 
• Absolute value, CFB and percent CFB to Month 6 in Physician’s Global Assessment of 
Disease Activity (VAS). 
Each of the following parameters will be also displayed into categories. The number and 
percentage of subjects at Month 6 will be computed and a shift table from baseline to Month 6 
will be provided. For all shift tables, data will be summarized as observed, ie no imputation on 
missing data. The following parameters will be presented into categories: 
• hsCRP (mg/L) by category (normal/high based on central normal laboratory ranges) 
• DAS28-hsCRP, derived using formula presented in Appendix 2, summarized by disease 
activity category (< 2.6 [remission], ≥ 2.6 to ≤ 3.2 [low], > 3.2 to ≤ 5.1 [moderate] and > 5.1 
[high]). 
• ESR (mm/Hr) by category (low/normal/high based on local normal ranges collected in 
eCRF) 


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• Acute-phase reactant (at least one test result is needed for the classification): normal hsCRP 
and normal ESR, abnormal hsCRP or abnormal ESR. Abnormal refers to either low or high 
normal range classification. 
• RF (expressed in kU/L) classified as negative ( ULN) and positive (> ULN) 
• anti-CCP classified as negative ( ULN) and positive (> ULN) 
• Serology (at least one test result is needed for the classification): negative RF and negative 
anti-CCP (ULN), low-positive RF or low-positive anti-CCP (> ULN,  3*ULN), high-
positive RF or high positive anti-CCP (> 3*ULN) 
16.3.2 
Pharmacokinetic Endpoint Analyses 
Analysis of the PK of M2951 and the associated figures will be the responsibility of the clinical 
pharmacokineticist at 
. The PK summaries and data listings 
as well as the statistical analysis of the PK parameters will be the responsibility of the study 
biostatistician at 
. 
For the PK analysis, predose sample M2951 concentrations that are BLQ will be assigned a 
numerical value of zero. On Day 1, any missing predose value will also be assigned a numerical 
value of zero for the calculation of AUC. Any anomalous concentration values observed at 
predose will be identified in the CSR. All postdose BLQ concentrations will be set to ‘zero’ in all 
cases. Graphical displays of mean (± SD for linear profiles only) plasma concentration-time 
profiles will be presented on linear and semi-logarithmic scales by dose level with Day 1 and 
Day 29 data on the same plot.  
Non-compartmental computation of M2951 PK parameters will be performed. Pharmacokinetic 
parameters will be evaluated and listed for all patients who provide sufficient concentration-time 
data.  
Individual PK parameters will be calculated using actual elapsed time from dose with a 
maximum of 14 significant digits in the time data (or using scheduled time if actual time is not 
available). The predose sample will be considered as if it had been taken simultaneously with the 
administration of IMP.  
For each subject in the PK analysis set the following PK parameters will be calculated for 
M2951 on Day 1 and Day 29 following the morning dose on Days 1 and 29: 
AUC0-6h 
Area under the plasma concentration-time curve from time zero to 6 hours after 
morning dosing, calculated according to the mixed log linear trapezoidal rule (ie, 
linear up/log down). Units: h*ng/mL. 
Cmax 
Maximum plasma concentration observed after morning dose, obtained directly 
from the observed concentration versus time data. Units: ng/mL. 
PPD
PPD


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tmax 
Time to reach maximum plasma concentration, obtained directly from the 
observed concentration versus time data. Units: h. 
Ctrough 
the concentration observed immediately before next dosing (Day 29 only). Units: 
ng/mL. 
Racc(AUC0-6h) 
Accumulation 
ratio 
for 
AUC, 
calculated 
as 
ratio 
of 
AUC’s:  
AUC0-6h, Day29/AUC0-6h, Day1.   
Racc(Cmax) 
Accumulation ratio for Cmax, calculated as ratio of Cmax’s:  Cmax, Day29/Cmax, Day1.  
16.3.3 
Pharmacodynamic Endpoint Analyses 
Absolute B cell numbers and subtypes (mature-naïve, non-switched, immature/transitional, 
memory), are assessed at screening and Days 1, 29, and 85 (end of treatment), prior to the 
morning dose in the 12-week treatment period. In addition absolute B cell numbers and subtypes 
will be assessed in the optional OLE period at Month 3, Month 6, and at the End of Trial Visit. 
Immunoglobulin levels (IgA, IgM, and IgG and subclasses) will be assessed at screening, Day 57 
and Day 85 (end of treatment) in the treatment period, and at Month 3 and Month 6 visits in the 
OLE period.  
Absolute B cell, B cell subtypes, and immunoglobulin levels (observed, change from baseline, 
and percent change from baseline values) will be summarized using the relevant PD analysis set. 
Descriptive statistics for these variables (mean, SD, CV%, median, minimum/maximum, Q1 and 
Q3 percentile, and interquartile range) will be presented. 
The mean (SD) absolute value for each treatment group will be plotted versus time point for 
B cell, B cell subsets (mature-naïve, non-switched, immature/transitional, memory), and IgM, 
IgA, IgG immunoglobulin levels and IgG subclasses IgG1-IgG4. Similar plots of the mean (SD) 
percent change from baseline for each treatment group versus time point will be generated for 
B cell and B cell subtypes (mature-naïve, non-switched, immature/transitional, memory), NK 
cell, T cell, T cell subtypes (CD4 and CD8) and IgM, IgA, and IgG (and IgG subclasses) 
immunoglobulin levels. 
16.3.4 
Exploratory Endpoints 
 
 
  
 
 
 
   
 
CCI


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17 
Safety Evaluation 
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as AEs, laboratory tests and vital signs.  
CCI
CCI


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For all safety endpoints, data selection for primary and final analyses will be handled as 
indicated in the Table 15: 
Table 15 : Data handling for safety analysis 
Analysis 
Population 
Period covered 
Treatment groups 
Data to be 
analyzed 
Primary analysis 
Safety Analysis Set 
12-Week treatment 
period until start of 
OLE or 
discontinuation of 
treatment prior to 
OLE, whichever is 
applicable 
Placebo or M2951 
50 mg BID 
All Data collected 
during the 12-Week 
treatment period up 
to start of OLE if 
applicable 
Final analysis 
OLE Safety Analysis 
set 
OLE period only 
Placebo/M2951 50 
mg BID only 
Data from OLE 
period only, or 
posterior to OLE 
(Safety follow-up / 
End of Study) 
Both 12-Week 
treatment period and 
OLE period 
M2951 50 mg 
BID/M2951 50 mg 
BID only 
Data from both 
periods (12-Week 
treatment and OLE 
period), ie all data 
collected 
throughout the 
study  
17.1 
Adverse Events 
All analyses described in Section 17.1 will be based on treatment-emergent adverse events 
(TEAEs) if not otherwise specified. 


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TEAEs will be defined according to Table 16.  
Table 16: Definition of TEAE  
Primary analysis 
TEAEs will be defined as AEs starting on or after first treatment 
administration of any IMP (placebo or M2951) until first dose of 
M2951 during OLE (or until the end of study if the patient 
declined to participate in OLE period). 
 
Only AEs from 12-Week treatment period will be considered. 
Final analysis 
• For subjects who switch from placebo to M2951 50 mg 
BID, TEAEs will be defined as AEs starting on or after 
first treatment administration of M2951 50 mg BID during 
OLE until the end of study.  
Only AEs from OLE period will be considered. 
• For patients who continue with M2951 50 mg BID during 
OLE, TEAEs will be defined as AEs starting on or after 
first treatment administration of M2951 during 12-Week 
double blind treatment period.  
AEs from both periods (12-Week treatment and OLE) will 
be considered. 
Incomplete AE-related dates will be handled as follows: 
• In case the onset date is missing completely or missing partially but the onset month and year, 
or the onset year are equal to the start of IMP then the onset date will be replaced by the 
minimum of start of IMP and AE resolution date.  
• In all other cases the missing onset day or missing onset month will be replaced by 1. 
• Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of subject's death. In the latter case, the date of death 
will be used to impute the incomplete stop date.  
• Further information collected after the cut-off for an analysis (such as a fatal outcome) may be 
extracted from the Safety data base and presented separately in the CSR. 
17.1.1 
All Adverse Events 
AEs will be coded according to the latest MedDRA version available at the time of analysis. The 
severity of AEs will be graded using National Cancer Institute - Common Terminology Criteria 
for Adverse Events (NCI-CTCAE version 4.03) toxicity grades. AEs with missing classification 
concerning IMP relationship will be considered related to the IMP.  


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All AEs recorded during the course of the trial (ie assessed from signature of informed consent 
until the end of the Follow-up/End of Trial visit) will be coded according to the MedDRA and 
assigned to a SOC and PT.  
The number and percentage of subjects experiencing at least one TEAE will be summarized 
according to MedDRA SOCs and PTs by treatment group, relationship to IMP, and severity. If a 
subject experiences more than one occurrence of the same TEAE during the trial, the subject will 
only be counted once for that treatment (the worst severity and the worst relationship to trial 
treatment will be tabulated).  
In case a subject had events with missing and non-missing grades, the maximum of the non-
missing grades will be displayed. 
A TEAE summary table will include a row for the overall frequency of TEAEs of the following 
types:  
• Any TEAE 
• IMP related TEAE 
• Serious TEAE 
• IMP related serious TEAE 
• TEAE with severe intensity (NCI-CTCAE grade ≥ 3, NCI-CTCAE grade ≥ 4) 
• IMP related TEAE with severe intensity (NCI-CTCAE grade ≥ 3, NCI-CTCAE grade ≥ 4) 
• TEAE leading to death 
• IMP related TEAE leading to death  
A separate TEAE summary table will present the following:  
• TEAE leading to interruption of IMP  
• IMP related TEAE leading to interruption of IMP 
• TEAE leading to withdrawal of IMP 
• IMP related TEAE leading to withdrawal of IMP  
• TEAE leading to dose reduction  
• IMP related TEAE leading to dose reduction    
• TEAE leading to study termination  
• IMP related TEAE leading to study termination 


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The TEAE tables to be prepared are listed below.  
 
Overall 
frequency 
By primary 
SOC and PT 
By PT 
only 
TEAE overview summary
X
NA
NA
TEAE leading to discontinuation of IMP/study/dose 
reduction of IMP overview summary 
X 
NA 
NA 
TEAE by SOC and PT
X
X
TEAE by PT
X
X
IMP related TEAE by SOC and PT
X
X
Serious TEAE by SOC and PT
X
X
IMP related serious TEAE by SOC and PT
X
X
Non-serious TEAE by SOC and PT*
X
TEAE by worst grade, SOC and PT
X
IMP related TEAE by worst grade, SOC and PT
X
TEAE leading to death by SOC and PT
X
X
IMP related TEAE leading to death by SOC and PT
X
X
TEAE leading to withdrawal of IMP by SOC and PT 
X 
X 
TEAE leading to study termination 
X 
X 
*A table with all AEs will be first provided and then only AEs exceeding a frequency of 5% in at least one of the 
treatment groups (> 5%), by SOC and PT will be provided. 
Group/SOC terms will be sorted alphabetically. PTs within each group/SOC will be sorted by 
active dose descending frequency, and alphabetically if multiple PTs have the same frequency.  
Pre-treatment and TEAEs will be listed separately by treatment group and subject. Specific data 
listings of pre-treatment AEs and TEAEs will be performed for subjects with a gap > 4 weeks 
between 12-Week treatment period and OLE period. 
A listing of TEAEs leading to withdrawal of IMP, a listing of TEAEs leading to study 
termination, if any, will be provided. 
Exposure adjusted incidence rates are calculated as number of subjects with AE divided by the 
sum of the individual times of all subjects in the safety population from start of treatment to first 
onset of AE. The incidence rate multiplied with 1000 would give the number of AEs expected in 
1000 subjects within 1 time unit (for example 1 year). The exposure adjusted incidence rates of 
TEAEs will be presented by SOC and PT. 
17.2 
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events 
17.2.1 
Deaths 
A summary of deaths will be provided including (clinicaltrials.gov requirement): 
• Number and percentage of (all) deaths 
• Number and percentage of the primary cause of death (categories: disease progression, 
adverse event, unknown, other)  


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The tabulation of TEAEs leading to death is described in Section 17.1.1. A listing of deaths, if 
any, will be provided.  
In case there is no death in the trial, only the summary of death required by clinicaltrials.gov will 
be performed, neither tabulation of TEAE leading to death will be edited, nor the listing of death. 
17.2.2 
Serious Adverse Events 
The tabulation of serious TEAEs is described in Section 17.1.1. A subject listing of serious 
TEAEs will be provided. 
17.3 
Clinical Laboratory Evaluation 
The following laboratory parameters will be measured during the trial as part of the safety 
evaluation: 
• Hematology 
• Biochemistry 
• Urinalysis 
• Coagulation 
The clinical laboratory safety tests to be measured in this trial are provided in the protocol (refer 
to Section 7.4.3 Table 4 of the Clinical Trial Protocol [CTP]). 
Continuous protocol-specified clinical laboratory findings (hematology, biochemistry, urinalysis, 
coagulation) will be summarized by treatment using descriptive statistics (see Section 11). The 
statistics will be presented for baseline, each time point during the study, and CFB to each time 
point, when applicable. 
Laboratory results will be classified according to NCI-CTCAE Version 4.03 as provided by the 
central laboratory. In case a laboratory parameter has bi-directional toxicities (eg Potassium) 
both directions will be presented for the given parameter (ie Potassium Low and Potassium 
High). On-treatment values are results of assessments done from the first IMP administration on 
Day 1. Laboratory results containing a modifier such as “<” or “>=” will be handled case by case 
for summary statistics and will be reported as collected in the database in subject data listings. 
A shift table of baseline versus post-baseline based on the worst NCI-CTCAE grade will be 
presented by treatment group for hematology and biochemistry.  
Additional laboratory results that are neither classified in protocol nor part of NCI-CTCAE will 
be presented according to the categories based on normal ranges: below normal limits (Low), 
within normal limits (Normal), and above normal limits (High). Classification into categories 
will be presented in subject data listings only. 


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Boxplots of the laboratory values (by treatment arm) by time point will be provided for: 
• Hemoglobin 
• Absolute reticulocyte count 
• White blood cell count 
• Absolute neutrophil count  
• Absolute lymphocyte count 
• Platelet count 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Gamma-glutamyl transferase (GGT) 
• Total bilirubin 
• Amylase 
• Lipase 
• Creatinine 
• Blood urea nitrogen (BUN) 
Boxplots for laboratory parameters where toxicity grades are defined based on the ratio of the 
parameter values and the ULN will not be displayed using the unit of measurement but instead 
using the ratio of the measured value over ULN. This comprises the following parameters:  
• ALT 
• AST 
• GGT 
• Total bilirubin 
• Creatinine 
• Amylase 
• Lipase 




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• Pulse rate interval (msec) 
• QRS (msec) 
• QT (msec) 
• Fridericia corrected QT (QTcF) (msec). 
QTcF values will be categorized according to their calculated values into the categories 
• ≤ 430 msec, 
• > 430 – 450 msec, 
• > 450 – 480 msec, 
• > 480 – 500 msec,  
• > 500 msec 
and categorized according to their CFB into the categories 
• ≤ 30 msec, 
• > 30 – 60 msec, 
• > 60 msec. 
The ECG outlier values will also be tabulated. The categories described above will be 
summarized by treatment group in frequency tables using number and percentage of subjects.  
A listing of ECG quantitative values, morphological and rhythm results will be produced.  
A shift table of rhythm results, from baseline to end of treatment, of the number and percentage 
of subjects for each category (Sinus rhythm, Atrial fibrillation, Other, Missing and Total) will be 
provided. This table will only be performed for the primary analysis. 
A shift table of morphological assessments, from baseline to end of observation, of the number 
and percentage of subjects for each interpretation category (Normal, Abnormal, Missing, and 
Total) will also be provided, the end of observation referring to the last available observation of 
the 12-week treatment period for the primary analysis and the last available observation of the 
study for the final analysis. 
17.6 
Physical Examination 
No summary table will be provided since physical examination findings during screening will be 
recorded as medical history events and findings during the trial as AEs. 


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17.7 
Pregnancy test 
Results of pregnancy test (serum and urine beta human chorionic gonadotropin for women only) 
will be listed. 
17.8 
B cell (CD19+) count 
B cell (CD19+) count data will be listed by treatment group and time point (where applicable). 
17.9 
Urine Protein/Creatinine Ratio 
Urine Protein/Creatinine Ratio data will be listed by treatment group and time point (where 
applicable). 
17.10 
Urinalysis Microscopic Evaluation 
Urinalysis Microscopic Evaluation data will be listed by treatment group and time point (where 
applicable). 
17.11 
Chest X-ray evaluations 
CXR evaluations will be listed and tabulated by treatment group using the number and 
percentage of subjects for each interpretation category (Normal, Abnormal Not Clinically 
Significant, Clinically Significant, and Abnormal Overall).  
17.12 
Other safety evaluations 
Other characteristics like viral serology, Quantiferon TB test, thyroid-stimulating hormone and 
prior surgeries will be listed only.  
 
 
 
 
 


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18 
References 
(1) Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to 
anti-tumor necrosis factor therapy. Arthritis Rheum. 2006; 54(9):2793-806. 
(2) Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK 
inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate 
in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. 
Arthritis Rheum. 2012; 64(4):970-81. 
(3) Miettinen OS, Nurminen M. Comparative analysis of two rates. Stat Med. 1985; 4(2):213-26. 
(4) US Department of Health and Human Services. Common Terminology Criteria for Adverse 
Events Version 4.0. 2009 (v4.03: June 14, 2010). 
(5) Anderson J, Caplan L, Yazdany J, et al. Rheumatoid Arthritis Disease Activity Measures: 
American College of Rheumatology Recommendations for Use in Clinical Practice. Arthritis 
Care & Research. 2012; 64(5):640-47. 
(6) Stanford Patient Education Research Center Website [internet]. 2016. [cited 2016 April 14]. 
Available from: http://patienteducation.stanford.edu/research/haq20.html 






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19.2 
Appendix 2: DAS28-hsCRP formula 
As per CTP Section 7.3.1.3, the DAS28-hsCRP will be computed according to below formula: 
DAS28-hsCRP=0.56*√(TJC28)+0.28*√(SJC28) + 0.014*GH +0.36*ln(hsCRP+1) +0.96 
Where,  
• TJC28=28 Tender Joint Counts (14 joints on each side of the subject’s body: 2 shoulders, 2 
elbows, 2 wrists, 10 metacarpophalangeal joints, 2 interphalangeal joints of the thumb, 8 
proximal interphalangeal joints, and 2 knees) 
• SJC28=28 Swollen Joint Counts (same joints used as for TJC28) 
• ln(hsCRP)=natural logarithm of hsCRP 
• GH=the General Health component of the DAS (ie Subject’s Global Assessment of Disease 
Activity).


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19.3 
Appendix 3: Important Protocol Deviations identified by programming and Clinically 
Important Protocol Deviations 
 
Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV01 
Age < 18 or > 75 at 
trial entry 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #1 
If calculated age at informed 
consent is <18 or >75 years, or 
if corresponding inclusion 
criterion is ticked No. 
PDEV02 
No diagnosis of RA > 
6 months’ duration at  
Screening 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #2 
If no diagnosis of RA or time 
between diagnosis of RA and 
Screening Visit is less than 6 
months or corresponding 
inclusion criterion is ticked No. 
PDEV03 
Negative RF and 
negative anti-CCP 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #3 
If RF (IgG-RF, IgM-RF, IgA-
RF) is classified as negative 
(≤ULN) and  
Anti-CCP classified as negative 
(≤ULN)  at the Screening visit 
or corresponding inclusion 
criterion is ticked No. 
PDEV04 
Absence of 
persistently active 
disease 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #4 
If subject has less than 6 
swollen joints (of 66 counted) or 
less than 6 tender joints (of 68 
counted) at Screening Visit or 
corresponding inclusion 
criterion is ticked No.  


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Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV05 
hsCRP < 3.6 mg/L 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #5 
If hsCRP < 3.6 mg/L at 
Screening Visit or 
corresponding inclusion 
criterion is ticked No. 
PDEV06 
Treatment for less than 
12 weeks with 10 to 
25 mg/week MTX 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #6 
If no relevant previous 
medication is reported in the 
eCRF as MTX, or a relevant 
medication reported with a 
duration less than 12 weeks or a 
dose not included between 10 
and 25 mg, or corresponding 
inclusion criterion is ticked No. 
PDEV07 
Women of 
childbearing potential 
do not agree to use 
highly effective 
methods of 
contraception  
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #7 
If corresponding inclusion 
criterion is ticked No. 
PDEV08 
Males do not agree to 
use or to have their 
female partners use 
highly effective 
contraception 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #8 
If corresponding inclusion 
criterion is ticked No. 


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Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV09 
Women of 
childbearing potential 
do not have negative 
serum pregnancy test 
at screening or 
negative urine 
pregnancy test at Day 
1 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria #9 
If women have a positive serum 
pregnancy test at Screening visit 
or a positive urine pregnancy 
test at Day 1 before 
randomization and dosing, or 
corresponding inclusion 
criterion is ticked No. 
PDEV10 
History of vaccination 
not compliant  
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria 
#10 
If identified by medical review 
or corresponding inclusion 
criterion is ticked No. 
PDEV11 
Informed consent not 
signed  
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Inclusion criteria 
#11 
If missing date of informed 
consent, or corresponding 
inclusion criterion is ticked No. 
PDEV12 
Use or change in dose 
of corticosteroids 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #1 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV13 
Initiation or change in 
dose for nonsteroidal 
anti-inflammatory 
drugs  
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #2 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV14 
Treatment with 
tofacitinib, other BTK 
inhibitors, or a 
biologic DMARD, or 
other 
immunosuppressive 
drugs other than MTX  
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #3 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 


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Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV15 
Treatment with anti-
CD20 therapy (eg, 
rituximab) 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #4 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV16 
Immunologic disorder 
other than RA 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #5 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV17 
Vaccination with live 
or live attenuated virus 
vaccine 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #6 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV18 
Severe drug allergy or 
history of anaphylaxis 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #7 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV19 
Significant viral, 
bacterial or fungal 
infection 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #8 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV20 
History of or positive 
HIV, hepatitis C, 
hepatitis B and/or IgM 
antibody 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria #9 If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV21 
History of or current 
diagnosis of active TB 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#10 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV22 
History of 
splenectomy or any 
major surgery  
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#11 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 


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Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV23 
History of any 
myocardial infarction 
or cerebrovascular 
event 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#12 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV24 
Anticoagulation or 
antiplatelet therapy 
other than daily aspirin 
for cardioprotection 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#13 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV25 
Fish oil 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#14 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV26 
History of cancer 
unless considered 
cured > 5 years 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#15 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV27 
Breastfeeding/lactating 
or pregnant women 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#16 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV28 
Clinically significant 
abnormality on ECG 
or an active infective 
process or any other 
clinically significant 
abnormality on CXR, 
per Investigator 
opinion 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#17 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 


M2951 
 
 
 
 
 
Phase IIa in Rheumatoid Arthritis 
 
MS200527-0081  
 
 
 
 
 
18 April 2017 / Version 1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
76/78 
 
 
Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV29 
Estimated glomerular 
filtration rate by the 4-
variable Modification 
of Diet in Renal 
Disease of < 45 
mL/min/1.73 m2 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#18 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV30 
TSH < 0.01 or ≥ 7.1 
mIU/L at Screening 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#19 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV31 
Clinically significant 
laboratory abnormality 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#20 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV32 
B cell (CD19) count < 
50% of the lower limit 
of normal 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#21 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV33 
Significant cytopenia 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#22 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV34 
Participation in any 
investigational drug 
trial 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#23 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 


M2951 
 
 
 
 
 
Phase IIa in Rheumatoid Arthritis 
 
MS200527-0081  
 
 
 
 
 
18 April 2017 / Version 1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
77/78 
 
 
Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV35 
Subjects receiving 
medications, herbal 
supplements, or food 
known to be moderate 
or strong inhibitors of 
CYP3A or drugs 
mainly metabolized by 
CYP3A (see Section 
6.5.2 of CTP) 
Yes 
Yes 
Eligibility 
and Entry 
Criteria 
Exclusion criteria 
#24 
If identified by medical review 
or corresponding exclusion 
criterion is ticked Yes. 
PDEV36 
Concurrent treatment 
with a non-permitted 
drug or procedure 
(refer to section 6.5.2 
of CTP). 
Yes 
case by 
case basis 
 
 
If identified by medical review. 
PDEV37 
Incorrect treatment 
group IP dispensed to 
subject   
Yes 
case by 
case basis 
IP 
Compliance
 
If randomized treatment is 
different from actual treatment 
PDEV38 
Non-compliant with IP 
usage  
Yes 
case by 
case basis 
IP 
Compliance
 
Check if <80% of >120% 
PDEV39 
IP not taken in 
compliance with 
protocol  eg, at the 
appropriate times, 
during/timed with 
meals/snacks 
case by 
case basis 
case by 
case basis 
IP 
Compliance
 
From monitoring log/Medical 
Review 
PDEV40 
Subject did not sign 
ICF and was enrolled  
Yes 
Yes 
Informed 
Consent 
Criteria 
 
ICF date is greater than 
randomization date 


M2951 
 
 
 
 
 
Phase IIa in Rheumatoid Arthritis 
 
MS200527-0081  
 
 
 
 
 
18 April 2017 / Version 1.0 
 
 
C O N F I D E N T I A L 
I N F O R M A T I O N 
78/78 
 
 
Protocol 
Deviation 
number 
Protocol Deviation 
Important Clinically 
Important 
Type 
criteria 
Inclusion/Exclusion 
criteria number 
Check 
PDEV41 
Subject used 
prohibited 
medication(s)   
case by 
case basis 
case by 
case basis 
Other 
Criteria 
 
Medical review 
PDEV42 
Lab safety and/or PK 
samples not drawn 
according to protocol 
requirements  
case by 
case basis 
case by 
case basis 
Laboratory 
Assessment 
Criteria 
 
Monitoring deviation log, 
Medical review