Clinical trial NCT02960438
Conditions: Rheumatoid Arthritis
Keywords: E6011 rheumatoid arthritis
Sponsor: Eisai Co., Ltd.
Start date: 2016-10-20; Completion date: 2019-09-17
Enrollment: 273 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison study in rheumatoid arthritis participants inadequately responding to methotrexate.

Detailed description:

Arms: arm 1: In the Treatment Phase, E6011 100 mg will be subcutaneously administered at Weeks 0, 1, and 2, and then every 2 weeks up to Week 22. In the Extension Phase, E6011 200 mg will be subcutaneously administered every 2 weeks until Week 102. arm 2: In the Treatment Phase, E6011 200 mg will be subcutaneously administered at Weeks 0, 1, and 2, and then every 2 weeks up to Week 22. In the Extension Phase, E6011 200 mg will be subcutaneously administered every 2 weeks until Week 102. arm 3: In the Treatment Phase, E6011 400 mg will be subcutaneously administered at Weeks 0, 1, 2, 4, 6, 8, and 10, and then E6011 200 mg will be subcutaneously administered every 2 weeks up to Week 22. In the Extension Phase, E6011 200 mg will be subcutaneously administered every 2 weeks until Week 102. arm 4: In the Treatment Phase, placebo will be subcutaneously administered at Weeks 0, 1, and 2, and then every 2 weeks up to Week 22. In the Extension Phase, E6011 200 mg will be subcutaneously administered every 2 weeks until Week 102.
Interventions: intervention 1: E6011 intervention 2: Placebo
Intervention descriptions: intervention 1: subcutaneous administration intervention 2: subcutaneous administration

Protocol documents:
SAP_002.pdf: 
Statistical Analysis Plan 
E6011-J081-201 
 
 
Eisai 
FINAL Version 1.0 
Confidential 
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STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E6011-J081-201 
Study Protocol 
Title: 
A Dose Response Study of E6011 in Subjects With Rheumatoid 
Arthritis Inadequately Responding to Methotrexate 
Date: 
24 Mar 2020 
Version: 
Final Version 1.0 (Extension Phase) 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................8 
3.1 
Study Objectives ......................................................................................................8 
3.1.1 
Primary Objectives ......................................................................................8 
3.1.2 
Secondary Objectives...................................................................................8 
3.1.3 
Exploratory Objective .................................................................................8 
3.2 
Overall Study Design and Plan ................................................................................8 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................9 
5 
STATISTICAL METHODS ..............................................................................................9 
5.1 
Study Endpoints .....................................................................................................10 
5.1.1 
Primary Endpoint ......................................................................................10 
5.1.2 
Secondary Endpoints .................................................................................10 
5.2 
Study Subjects ........................................................................................................11 
5.2.1 
Definitions of Analysis Sets .......................................................................11 
5.2.2 
Subject Disposition.....................................................................................12 
5.2.3 
Protocol Deviations ....................................................................................12 
5.2.4 
Demographic and Other Baseline Characteristics ..................................12 
5.2.5 
Prior and Concomitant Therapy ..............................................................15 
5.2.6 
Treatment Compliance ..............................................................................15 
5.3 
Data Analysis General Considerations ..................................................................15 
5.3.1 
Pooling of Centers ......................................................................................15 
5.3.2 
Adjustments for Covariates ......................................................................15 
5.3.3 
Multiple Comparisons/Multiplicity ..........................................................15 
5.3.4 
Examination of Subgroups ........................................................................16 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers ................................16 
5.3.6 
Other Considerations.................................................................................17 
5.3.6.1 
Total number of joints ........................................................................17 
5.3.6.2 
HAQ subcategory score .................................................................17 
5.4 
Efficacy Analyses ..................................................................................................17 
5.4.1 
Primary Efficacy Analyses ........................................................................17 
5.4.2 
Secondary Efficacy Analyses ....................................................................17 
5.4.3 
Other Efficacy Analyses ............................................................................18 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................18 
5.5.1 
Pharmacokinetic Analyses ........................................................................18 
Serum E6011 Concentration ..................................................................................18 
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5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ......................................................................................................19 
5.5.2.1 
Pharmacodynamic, Pharmacogenomic Analyses ..............................19 
5.5.2.2 
Other Biomarker Analyses..............................................................19 
5.5.2.3 
Immunogenicity Analyses ...............................................................19 
5.6 
Safety Analyses ......................................................................................................20 
5.6.1 
Extent of Exposure .....................................................................................20 
5.6.2 
Adverse Events ...........................................................................................20 
5.6.3 
Laboratory Values .....................................................................................21 
5.6.4 
Vital Signs ...................................................................................................22 
5.6.5 
Electrocardiograms....................................................................................22 
5.6.6 
Other Safety Analyses................................................................................22 
5.6.6.1 
Chest X-Ray ......................................................................................22 
5.6.6.2 
Neurological findings .......................................................................23 
5.6.6.3 
Blood CD4 positive cell counts ........................................................23 
5.7 
Other Analyses .......................................................................................................23 
5.7.1 
Anti-JCV Antibody Test............................................................................23 
5.8 
Exploratory Analyses .............................................................................................23 
6 
INTERIM ANALYSES ...................................................................................................23 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................24 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................24 
8.1 
Baseline, Time Windows for statistical analyses ...................................................24 
8.1.1 
Definition of baseline value .......................................................................24 
8.1.2 
Definition of change from baseline and percent change from 
baseline ........................................................................................................24 
8.1.3 
Time windows .............................................................................................24 
8.2 
Pharmacokinetic data handling ..............................................................................29 
8.2.1 
Lower Limit of Quantification of E6011 Serum Concentration ............29 
8.2.2 
BLQ Handling for Developing Concentration–Time Profiles ...............29 
8.2.3 
BLQ Handling for Developing Tables .....................................................29 
8.2.4 
Handling of anomalous concentration values .........................................29 
8.2.5 
General Rules for Presentation of Drug Concentrations .......................30 
8.3 
Imputation rule for partial date ..............................................................................30 
8.3.1 
Date of Diagnosis ........................................................................................30 
8.3.2 
Medication ..................................................................................................30 
8.3.3 
Adverse Events ...........................................................................................31 
8.4 
Decimal places .......................................................................................................32 
8.5 
TNF Agent .............................................................................................................32 
9 
PROGRAMMING SPECIFICATIONS ..........................................................................33 
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10 STATISTICAL SOFTWARE ..........................................................................................33 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................33 
12 REFERENCES ................................................................................................................33 
13 APPENDICES .................................................................................................................34 
13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 ................................................................................34 
13.2 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .....36 
 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE 
adverse event 
ATC 
anatomical therapeutic class 
ANCOVA 
analysis of covariance 
Ang2 
angiopoietin 2 
ATC 
anatomical therapeutic class 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
Blood pressure 
CCP 
cyclic citrullinated peptide 
CDAI 
clinical disease activity index 
CI 
confidence interval 
CRF 
case report form 
CRP 
C-reactive Protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAS28 
disease activity score in 28 joints, 
DP 
Decimal places 
EGF 
epidermal growth factor 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
European League Against Rheumatism 
FAS 
full analysis set 
γ-GTP 
γ-glutamine transpeptidase 
HAQ 
Health Assessment Questionnaire 
HAQ-DI 
Health Assessment Questionnare Disability Index 
IL 
Interleukin 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
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Abbreviation 
Term 
LRG1 
leucine-rich alpha-2 glycoprotein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
matrix metalloproteinase 
mTSS 
modified total sharp score 
MTX 
Methotrexate 
NCI 
National Cancer Institute 
NRI 
non-responder imputation 
OC 
observed cases 
PD 
pharmacodynamics 
PK 
Pharmacokinetic 
PPS 
per protocol set 
PT 
preferred term 
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDAI 
simple disease activity index 
SI 
Système International 
SJC 
swollen joint counts 
SJC28 
swollen joint counts in 28 joints 
SJC66 
swollen joint counts in 66 joints 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TJC 
tender joint counts 
TJC28 
tender joint counts in 68 joints 
TJC68 
tender joint counts in 28 joints 
TLG 
tables, listings, and graphs 
TNF-RI 
tumor necrosis factor receptor-I 
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Abbreviation 
Term 
TRACP-5b 
tartrate resistant acid phosphatase 5b 
VAS 
visual analog scale 
VCAM-1 
vascular cell adhesion molecule-1 
VEGF 
vascular endothelial growth factor 
WHO DD 
World Health Organization Drug Dictionary 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E6011-
J081-201. Since the Version 6 of the protocol defined that it was unnecessary to conduct 
assessments other than safety assessment, all the efficacy analysis will be conducted until 
Week 84, that is the latest Visit of ongoing subjects at the time of amendment of the protocol. 
Statistical methods of Extension Phase are provided in this document. 
 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
• 
To evaluate the efficacy of E6011 compared with placebo by ACR20 response rate at 
Week 12 as a primary endpoint 
• 
To evaluate the safety and tolerability of E6011 
 
3.1.2 
Secondary Objectives 
• 
To evaluate the effect of E6011 on suppressing radiographic progression of joint 
destruction at Week 24 
• 
To evaluate the pharmacokinetics (PK) and immunogenicity of E6011 
 
3.1.3 
Exploratory Objective 
• 
To explore the PK/pharmacodynamics (PD) and biomarkers of E6011 
 
3.2 
Overall Study Design and Plan 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison study.  The following 4 treatment groups are selected for the study: E6011 
100 mg, 200 mg, 400 mg, and placebo.  In the E6011 100 mg, 200 mg, and placebo groups, 
subjects will receive 100 mg, 200 mg, or placebo at Weeks 0, 1, 2, and every 2 weeks 
subsequently.  In the E6011 400 mg group, subjects will receive 400 mg at Weeks 0, 1, 2, 4, 
6, 8, 10 and then 200 mg every 2 weeks subsequently. 
The study consists of Screening, Observation, Treatment, Extension, and Follow-up Phases. 
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Undergoing screening assessments within 42 days prior to the study treatment, subjects with 
the certain eligibility confirmed in the Observation Phase will be allocated into any of the 
100 mg, 200 mg, 400 mg, or placebo groups at a 1:2:2:2 ratio through dynamic allocation 
using the following factors: C- reactive protein (CRP) level at Screening,  Rheumatoid 
Arthritis (RA) Duration, and Prior Use of Biologics Treatment. 
In the Treatment Phase (24 weeks), subjects will receive either E6011 or placebo at Weeks 0, 
1, 2, and every 2 weeks until Week 22 in a double-blind manner. 
Subjects who complete evaluations at Week 24 of the Treatment Phase will enter the 
Extension Phase.  The Extension Phase is up to Week 104 from the starting of the study 
treatment, and subjects will receive an open-label E6011 200 mg every 2 weeks until 
Week 102.  When subjects insufficiently respond to the treatment or when their disease 
relapses in the Extension Phase (show no improvement from Observation Phase in both of 
tender joint counts (TJC) and swollen joint counts (SJC) at 2 consecutive assessments with 
an interval of ≥1 week), a dose escalation will be allowed. 
Follow-up investigations will be conducted on-site 28 days after the completion of the study 
or the discontinuation of the treatment, and either an on-site or telephone-interview 
investigation will be conducted 70 days after the last dosing. 
 
4 
DETERMINATION OF SAMPLE SIZE 
The sample size was based on an expected ACR20 response rate of 30% at Week 12 in the 
placebo group and at least 60% in both of the E6011 200 mg and 400 mg groups, as per 
previous Study 103 and the results from other drugs for treatment of RA.  Although multiplicity 
adjustment using Hochberg method will be carried out in the primary analysis, sample size was 
calculated at a 1-sided significance level of α=0.0125 (α=0.025/2) conservatively.  The sample 
sizes of 50 for E6011 200 mg, 400 mg, and placebo will have 91% power to detect a difference 
in response rate of 35% between placebo and each E6011 group and will have 79% power to 
detect a difference in response rate of 30% based on a chi-square test.   
 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. 
 
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5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
• 
ACR20 response rate at Week 12 
The ACR20 response is defined as if the following 3 criteria (ACR components) are met: 
1. Greater than or equal to 20% reduction from baseline in the TJC in 68 joints (TJC68)  
2. Greater than or equal to 20% reduction from baseline in the SJC in 66 joints (SJC66)  
3. Greater than or equal to 20% reduction from baseline in at least 3 of the following 
5 assessments: 
- 
Physician's Global Assessment of Disease Activity (VAS)  
- 
Patient's Global Assessment of Disease Activity (VAS) 
- 
Patient's Assessment of Pain (VAS) 
- 
HAQ-DI 
- 
CRP 
 
5.1.2 
Secondary Endpoints 
• ACR20, ACR50, and ACR70 response rate at each visit (excluding ACR20 at Week 12) 
• Values and change from baseline in ACR components (TJC, SJC, VAS [patient's 
assessment of pain, patient's global assessment of disease activity and physician's global 
assessment of disease activity], functional assessment by subjects [HAQ-DI], and 
CRP∙ESR), DAS28-ESR, DAS28-CRP, SDAI, and CDAI at each visit 
• EULAR response criteria at each visit; subjects will be classified based on DAS28-ESR 
or DAS28-CRP 
• DAS28-ESR, DAS28-CRP, SDAI, CDAI, and Boolean remission rates at each visit 
• Values and change from baseline in modified total sharp score (mTSS) at each visit 
The ACR50 response is defined similar to the ACR20 with a 50% reduction. 
The ACR70 response is defined similar to the ACR20 with a 70% reduction. 
The DAS28-CRP calculates on the following formula, and disease activity is categorized as 
High at > 4.1, Moderate at > 2.7 and ≤4.1, Low at <= 2.7, and Remission at <= 2.3. 
0.56 × sqrt{TJC in 28 joints (TJC28)} + 0.28×sqrt{SJC in 28 joints (SJC28)} + 0.36 
× ln{CRP (mg/dL) × 10 + 1} + 0.014 × Patient's Global Assessment of Disease 
Activity (VAS) (mm) + 0.96 
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The DAS28-ESR will be calculated on the following formula, and disease activity is 
categorized as High at > 5.1, Moderate at > 3.2 and <= 5.1, Low at <= 3.2, and Remission at 
< 2.6. 
0.56 × sqrt{TJC28}+ 0.28 × sqrt{SJC28}+0.70×ln{ESR (mm/h)}+0.014 × Patient's 
Global Assessment of Disease Activity (VAS) (mm) 
EULAR Response Criteria: 
Present DAS28 
DAS28 change from baseline 
<–1.2 
>= –1.2 and <–0.6 
>= –0.6 
(missing included) 
Low 
Good response 
Moderate response 
No response 
Moderate 
Moderate response 
Moderate response 
No response 
High 
Moderate response 
No response 
No response 
 
The CDAI will be calculated on the following formula, and disease activity is categorized as  
High at > 22, Moderate at >10 and <= 22, Low at <= 10, and Remission at <= 2.8. 
SJC28+ TJC28 
+ Patient's Global Assessment of Disease Activity (VAS) (mm)/10 
+ Physician's Global Assessment of Disease Activity (VAS) (mm)/10 
The SDAI will be calculated on the following formula, and disease activity is categorized as  
High at > 26, Moderate at > 11 and <= 26, Low at <= 11, and Remission at <= 3.3. 
SJC28+ TJC28 
+ Patient's Global Assessment of Disease Activity (VAS) (mm)/10 
+ Physician's Global Assessment of Disease Activity (VAS) (mm)/10 + CRP (mg/dL) 
The Boolean remission is defined as satisfied all of the following conditions: 
1. TJC68 <= 1 
2. SJC66 <= 1 
3. CRP (mg/dL) <= 1 
4. Disease activity assessments VAS (mm) by subjects <= 10 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Definition of analysis sets are as follows: 
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• 
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 
dose of study drug after 24 weeks to 104 weeks and had at least 1 postdose efficacy 
measurement after 24 weeks to 104 weeks 
• 
The Safety Analysis Set is the group of subjects who received at least 1 dose of study 
drug after 24 weeks to 104 weeks and had at least 1 postdose safety assessment after 24 
weeks to 104 weeks 
The number of subjects randomized, the number and the percentage of subjects included in 
each analysis set, and the number and the percentage of subjects excluded from each analysis 
set will be presented by treatment group and overall. 
 
5.2.2 
Subject Disposition 
The number and percentage of subjects who completed extension phase and discontinued the 
study, and reasons for discontinuation will be summarized for each treatment group and overall. 
 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock.  The protocol 
deviations identified according to the criteria at study entry and during treatment will not be 
included in tables, listings, and graphs (TLGs) covered by SAP, but presented in the clinical 
study report (CSR). 
 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group and overall using descriptive statistics.   
Continuous demographic and baseline variables include: 
 Age (year) 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2) at Screening 
 Rheumatoid Arthritis (RA) Duration (years) 
 Dose of MTX (mg/week) 
 Serum Rheumatoid Factor (RF) Concentration (IU/mL) 
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 Serum Anti-Cyclic Citrullinated Peptide (CCP) Antibody Concentration (U/mL) 
 Oral Steroid*1 (mg/day) 
 ACR Components 
- 
TJC68 at Baseline 
- 
SJC66 at Baseline 
- 
TJC28 at Baseline 
- 
SJC28 at Baseline 
- 
CRP (mg/dL) at Screening 
- 
CRP (mg/dL) at Baseline 
- 
ESR (mm/h) at Baseline 
- 
Physician's Global Assessment of Disease Activity (VAS) (mm) at Baseline  
- 
Patient's Global Assessment of Disease Activity (VAS) (mm) at Baseline  
- 
Patient's Assessment of Pain (VAS) (mm) at Baseline  
- 
HAQ-DI at Baseline 
 DAS28-CRP at Baseline 
 DAS28-ESR at Baseline 
 CDAI at Baseline 
 SDAI at Baseline 
 Joint Space Narrowing at Baseline 
 Number of Bone Erosions at Baseline 
 mTSS at Baseline 
 mTSS divided by RA Duration (/year) 
 
Categorical variables include: 
 Age group (18<= <35, 35<= <50, 50<= <75) 
 Sex (Male, Female) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Race (White, Black or African American, Japanese, Chinese, Other Asian, American 
Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Other) 
 RA Duration (< 5 years, 5 years <=) 
 RA Duration (< 1 year, 1 year <= < 5 years, 5 years  <= < 10 years, 10 years <= < 15 
years, >= 15 years) 
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 Smoking History (Current, Former, Never) 
 Current Medical Conditions (Yes, No) 
 Prior Use of Biologics Treatment (Yes - TNF*2/Non-TNF, No) 
 Drug experience of MTX (Yes, No) 
 Dose of MTX (< 6 mg/week, 6 mg/week <= < 12 mg/week, >= 12 mg/week) 
 Drug experience of DMARDs within 12 weeks before informed consent except MTX 
(Yes - 1/2/…, No) 
 Continuation of Steroid 
 Serum RF Concentration (Seropositive - High Positive/Low Positive, Seronegative)*3 
 Anti-CCP Antibody (Seropositive - High Positive/Low Positive, Seronegative)*4 
 Classification of Global Functional Status in RA 
 DAS28-CRP Category (High: >4.1, Moderate: 2.7 < <= 4.1, Low: <= 2.7) 
 DAS28-ESR Category (High: >5.1, Moderate: 3.2 < <= 5.1, Low: <= 3.2) 
 CDAI (High: > 22, Moderate: 10 < <= 22, Low: <= 10) 
 SDAI (High: > 26, Moderate: 11 < <= 26, Low: <= 11) 
 CRP level at Screening (< 0.6mg/dL, >= 0.6mg/dL) 
 CRP level at Baseline (< 0.6mg/dL, >= 0.6mg/dL) 
 ESR level at Baseline (< 28mm/h, >= 28mm/h) 
*1 Prednisone-equivalent dose 
*2 Refer section 8.5 “TNF agent” 
*3 Categories of Serum RF Concentration are derives as follows: 
 
Seropositive:  > 15 (IU/mL) 
 
 
High Positive:  < 45 (IU/mL) 
 
 
Low Positive:  15 <=  <= 45 (IU/mL) 
 
Seronegative:  <= 15 (IU/mL) 
*4 Categories of Anti-CCP Antibody are derives as follows: 
 
Seropositive:  >= 4.5 (U/mL) 
 
 
High Positive:  < 13.5 (U/mL) 
 
 
Low Positive:  4.5 < <= 13.5 (U/mL) 
 
Seronegative:  < 4.5 (U/mL) 
 
Subject data listings will be provided. 
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MEDICAL HISTORY 
A subject data listing will be provided. 
 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the case report form (CRF) will be coded 
to an 11-digit code using the World Health Organization Drug Dictionary (WHO DD) 
version (Mar2016 or later).  The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the FAS by treatment group, Anatomical 
Therapeutic Chemical (ATC) class, and WHO DD preferred term.  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug.  A subject data listing of all medications will be provided. 
 
5.2.6 
Treatment Compliance 
Treatment compliance will be described in section 5.6.1. 
 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers 
Subjects from all centers will be pooled for all analyses. 
 
5.3.2 
Adjustments for Covariates 
No covariates are planned for analyses for extension phase. 
 
5.3.3 
Multiple Comparisons/Multiplicity 
No multiplicity are planned for analyses for extension phase. 
 
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5.3.4 
Examination of Subgroups 
No subgroup analyses are planned for analyses for extension phase. 
 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
For the efficacy analyses, approaches to handling missing data for continuous variables, except 
mTSS, will be the observed cases (OC) method and the last observation carried forward 
(LOCF) method; binary variables and EULAR response criteria will be the observed cases 
(OC) method, the last observation carried forward (LOCF) method and the non-responder 
imputation (NRI) method as each visit. 
mTSS value at Week 24, Week 52 and Week 76 will be extrapolated from values of baseline 
and values of postbaseline, which will be used in summary statistics. The linear extrapolation 
method will be used for analysis of the structural progression endpoint (van der Heijde mTSS) 
to impute missing data at time points when analyses are conducted (including the analyses at 
Week 24, Week 52 and Week 76).  For patients who discontinue the study or the study 
treatment or for patients who miss a radiograph for any reason, baseline data and the most 
recent radiographic data prior to discontinuation or the missed radiograph, adjusted for time, 
will be used for linear extrapolation to impute missing data at subsequent time points. All 
patients originally randomized to placebo will be switched to active treatment at Week 24; 
Missing postbaseline values will be imputed only if both a baseline value and a postbaseline 
value from another time point are available, as long as the patient was on the same treatment 
at each applicable time point. 
Calculation for value of mTSS extrapolation will be derived by follow formula: 
• 
Week 24 = (Postbaseline) + ( Postbaseline – Baseline ) * ( ( 24 – ( Study Day of 
Postbaseline / 7 ) / Study Day of Postbaseline / 7 ) 
• 
Week 52 = (Postbaseline) + ( Postbaseline – Baseline ) * ( ( 52 – ( Study Day of 
Postbaseline / 7 ) / Study Day of Postbaseline / 7 ) 
• 
Week 76 = (Postbaseline) + ( Postbaseline – Baseline ) * ( ( 76 – ( Study Day of 
Postbaseline / 7 ) / Study Day of Postbaseline / 7 ) 
 
The two individual components of mTSS (Erosion and joint space narrowing [JSN] score) will 
be analyzed in the same way as the mTSS. 
For the safety analyses for continuous value, descriptive statistics are used OC method and 
LOCF method, this is applied only the last observation of each phase, in tables and figures. 
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In the cases of laboratory result contains less (or more) than quantitation limit value is treated 
as:  
a. zero, when less than quantitation limit value, 
b. quantitation limit value, when more than quantitation limit value. 
In the cases of pharmacokinetic data, refer “8.2 Convention for Pharmacokinetic data 
handling”. 
 
5.3.6 
Other Considerations 
5.3.6.1 
Total number of joints 
For the calculation of the total number of joints that are tender/swollen, if any joints are not 
evaluable, the score is prorated by taking the number of joints that are tender/swollen divided 
by the number of evaluable joints and multiplied by the target number of joints, rounded to 
nearest integer. If assessment of joints are “Not Done”, the joints will be handled as tender and 
swollen.  
5.3.6.2 
HAQ subcategory score 
The HAQ-DI is composed of 20 items in 8 categories (Dressing and Grooming, Arising, 
Eating, Walking, Hygiene, Reach, Grip, Activities).  To calculate the HAQ-DI, the highest 
sub-category score determines the value for each category, there must be responses in at least 
6 of the 8 categories or else a HAQ-DI cannot be computed. The category scores are then 
averaged into an overall HAQ-DI. 
HAQ-DI = (Amount of score with all categories) / (Number of categories scored) 
 
5.4 
Efficacy Analyses 
The FAS will be used for the efficacy analyses. 
 
5.4.1 
Primary Efficacy Analyses 
No primary efficacy analyses are planned for analyses for extension phase. 
 
5.4.2 
Secondary Efficacy Analyses 
For each component of ACR (TJC, SJC, VAS [patient's assessment of pain, patient's global 
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assessment of disease activity and physician's global assessment of disease activity], 
functional assessment by subjects (HAQ) and CRP∙ESR), DAS28-ESR, DAS28- CRP, 
SDAI, and CDAI in each visit, the values and the changes from baseline will be summarized 
by treatment group.  
For mTSS, values and changes from baseline will be summarized by treatment group. For 
DAS28-ESR and DAS28-CRP, frequency and percentage of each classification (no response, 
moderate response, good response) by EULAR response criteria will be summarized by 
treatment group and visit in a shift table.  For DAS28-ESR, DAS28-CRP, SDAI and CDAI, 
frequency and percentage of each category (Remission, Low, Moderate, High) will be 
summarized by treatment group and visit in a shift table. 
The mean change from baseline of ACR components, DAS28-CRP, DAS28-ESR, CDAI and 
SDAI - visit will be displayed by treatment group. ACR response rate - visit will be 
displayed by treatment group.  Cumulative probability of the change from baseline in mTSS 
will be displayed at week 52 and Week 76. 
All efficacy endpoints for the treated subjects will be listed. 
 
5.4.3 
Other Efficacy Analyses 
No other efficacy analyses are planned for this study. 
 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
Serum E6011 Concentration 
Serum PK samples for PK analyses will be collected on Week 0 (predose), Week 1 (predose), 
Week 2 (predose), Week 4 (predose), Week 8 (predose), Week 12 (predose) , Week 16 
(predose), Week 20 (predose), Week 24 (predose) to Week 104 (predose) by 4 Weeks. 
The Safety Analysis Set will be used for PK analyses. 
<Table> 
No Tables are planned for analyses for extension phase. 
<Listing> 
Actual sampling time and serum concentrations of E6011 for each subject will be listed. 
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<Figure> 
No figures are planned for analyses for extension phase. 
 
5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
5.5.2.1 
Pharmacodynamic, Pharmacogenomic Analyses 
No Pharmacodynamic and Pharmacogenomic analyses are planned for this study. 
 
5.5.2.2 
Other Biomarker Analyses 
All biomarker analyses will be performed using the Full Analysis Set.   
For the Extension Phase, summary statistics for serum RF concentration, serum anti-CCP 
antibody concentration, and serum matrix metalloproteinase-3 concentration, serum tartrate 
resistant acid phosphatase 5b (TRACP-5b) concentration, serum cytokine concentration, 
serum leucine-rich alpha-2 glycoprotein 1 (LRG1) concentration, serum angiopoietin 2 (Ang2) 
concentration, Vectra™ DA and it’s component (vascular cell adhesion molecule-1 (VCAM-
1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF)-A, interleukin 
(IL)-6, tumor necrosis factor receptor-I (TNF-RI), serum matrix metalloproteinase-1, serum 
matrix metalloproteinase-3, YKL-40, leptin, resistin, SA and CRP) value, change from 
baseline and percent change from baseline, by treatment group and time point, will be 
calculated.  Exploratory investigations of the relationship between efficacy and biomarkers 
will be conducted. The analysis plan for CX3CR1 is out of scope of this document. All other 
biomarkers will be collected on baseline and postbaseline, referring section 8.1.3 “Time 
window”. 
Subject data listings will be provided. 
 
5.5.2.3 
Immunogenicity Analyses 
All immunogenicity analyses will be performed using the Safety Analysis Set.   
The percentage and frequency of occurrences will be calculated for serum anti-E6011 
antibodies and E6011-induced anti-E6011 antibodies by treatment group and time point.  If 
anti-E6011 antibody develops, the frequency and percentage of any anti-E6011 antibody 
neutralization activity and isotypes will be calculated. 
These are analyzed by Week 84. 
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Subject data listings will be provided. 
 
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, n, 
mean, SD, median, minimum, maximum for continuous variables; n [%] for categorical 
variables). Safety variables include treatment-emergent adverse events (TEAEs), clinical 
laboratory parameters, vital signs, 12-lead ECG results, chest x-ray, neurological findings, and 
blood CD4 positive cell count. Day 1 for all safety analyses will be defined as the date of the 
first dose of study drug. 
 
5.6.1 
Extent of Exposure 
The extent of exposure to study drug will be characterized by duration of exposure, number of 
injection dose and study medication compliance for each treatment group.  Definition of 
analysis items are as follows: 
 Duration of exposure (weeks) = (Date of Last Dose - Date of First Dose + 14 ) / 7 
 Number of Injection = Count of records with non-zero treatment 
 Study Medication Compliance (%) = Number of Injection / Number of Expected 
Injection * 100 
Subject data listings will be provided. 
 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 19.1 or higher) lower level 
term (LLT) closest to the verbatim term. The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database. A treatment-emergent adverse 
event (TEAE) is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
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Only those AEs that are treatment-emergent will be included in summary tables. 
A subject will be counted only once within an SOC and PT, even if the subject experienced 
more than 1 TEAE within a specific SOC and PT.   
The TEAEs will be summarized by treatment group and E6011 overall.  The incidence of 
follow TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC 
and PT: 
• 
TEAEs 
• 
TEAEs by maximum intensity 
• 
Serious TEAEs 
• 
TEAEs leading to study drug withdrawn 
• 
TEAEs leading to interruption of study drug 
• 
TEAEs leading to reduction from study drug 
• 
Treatment Related, TEAEs 
• 
Treatment Related, TEAEs by maximum grade 
• 
Treatment Related, Serious TEAEs 
• 
Treatment Related, TEAEs leading to study drug withdrawn 
• 
Treatment Related, TEAEs leading to interruption of study drug 
• 
Treatment Related, TEAEs leading to reduction from study drug 
In the analysis, the AEs emerged until 70 days after the last dose are intended 
Subject data listings of All AEs, SAEs, AEs leading to death, leading to study drug withdrawn 
or leading to interruption from study drug will be provided.  
 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units. For quantitative 
parameters listed in protocol Section 9.5.1.5.3, the actual value and the change from baseline 
to each postbaseline visit will be summarized by visit and treatment group using descriptive 
statistics.  Qualitative parameters listed in protocol Section 9.5.1.5.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
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range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will be used to compare 
the baseline LNH classification to the LNH classification for the highest and lowest value 
during the study. 
The Sponsor’s Grading for Laboratory Values using CTCAE v4.0 presents the criteria that will 
be used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV is defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject will be counted once in the laboratory parameter high 
and in the laboratory parameter low categories, as applicable. 
Laboratory results versus visit by treatment group will be displayed using box-plot. 
Subject data listings of Laboratory test results and TEMAV will be provided. 
 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (systolic and diastolic BP, pulse, temperature, 
and weight) and changes from baseline will be presented by visit and treatment group. 
Subject data listings will be provided. 
 
5.6.5 
Electrocardiograms 
Shift tables will be presented changes from baseline in 12-lead ECG interpretation 
(normal/abnormal, not clinically significant/abnormal, not clinically significant) by visit and 
treatment group. 
Subject data listings will be provided. 
 
5.6.6 
Other Safety Analyses 
5.6.6.1 
Chest X-Ray 
Shift tables will be presented changes from baseline in chest x-ray (normal/abnormal, not 
clinically significant/abnormal, not clinically significant) by visit and treatment group. 
Subject data listings will be provided. 
 
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5.6.6.2 
Neurological findings 
Descriptive statistics for neurological findings will be presented by visit and treatment group. 
Subject data listings will be provided. 
 
5.6.6.3 
Blood CD4 positive cell counts 
For Blood CD4 positive cell counts, the actual value and the change from baseline to each 
postbaseline visit will be summarized by visit and treatment group using descriptive statistics. 
Blood CD4 positive cell counts will be assigned a low/normal/high (LNH) classification 
according to whether the value was below (L), within (N), or above (H) the it’s reference range. 
Within-treatment comparisons will be based shift tables that compare the baseline LNH 
classification to the LNH classification at each postbaseline visit. 
Subject data listings will be provided. 
 
5.7 
Other Analyses 
5.7.1 
Anti-JCV Antibody Test 
Anti-JCV antibody test result (positive or negative) is judged according to the results of 
screen assay and inhibition assay. 
Subject data listings will be provided. 
 
5.8 
Exploratory Analyses 
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriate titled and labeled as exploratory and will be clearly distinguished 
from planned analyses when results are reported in the Clinical Study Report. 
 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
 
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7 
CHANGES IN THE PLANNED ANALYSES 
Changes in the planned analyses for protocol are as follows: 
• 
Based on the protocol amendment Version 6, all efficacy results will be summarized until 
week 84. 
• 
Regarding the PK analysis for extension phase, only listing will be created. 
 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Baseline, Time Windows for statistical analyses 
8.1.1 
Definition of baseline value 
The baseline value was defined as the most recent value reported just before first dosing. 
 
8.1.2 
Definition of change from baseline and percent change from baseline 
Change from baseline is defined as postbaseline value minus baseline value.  Percent change 
from baseline is defined as follows: 
% Change from baseline = (Change from baseline/Baseline) * 100 
For any Baseline value of 0, the subject’s corresponding percent change from baseline will 
not be included in the summary statistics table. 
 
8.1.3 
Time windows 
Time windows are defined as Table 8.1 to Table 8.8 for each assessment.  Observation that has 
the most recent date-time on base date-time is adopted if plural observations exist in the time 
window.  Observation recorded later is adopted if they recorded in that same period. 
Table 8.1  Definition of time windows and calculated visits for vital signs and Serum E6011 
concentration 
Visit 
Base date 
Time windows 
Week 1 (Day 8) 
Date of first drug 
administration + 7 days 
Base date - 3 days <=   < Base date + 3 
days 
Week 2 (Day 15) 
Date of first drug 
administration + 14 days 
Base date - 4 days <=   < Base date + 7 
days 
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Week 4 (Day 29) 
Date of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 
104 by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 
14 days 
 
Table 8.2  Definition of time windows and calculated visits for Physical findings, 
administration site finding 
Visit 
Base date 
Time windows 
Week 1 (Day 8) 
Date of first drug 
administration + 7 days 
Base date - 3 days <=   < Base date + 3 
days 
Week 2 (Day 15) 
Date of first drug 
administration + 14 days 
Base date - 4 days <=   < Base date + 7 
days 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 12 
by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 24 - Week 
36 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 52 - Week 
88 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 168 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.3  Definition of time windows and calculated visits for Joint assessment, ESR, VAS, 
HAQ, Laboratory tests (include Hematology, blood chemistry, urinalysis, RF, anti-CCP 
antibody and matrix metalloproteinase -3) 
Visit 
Base date 
Time windows 
Week 2 (Day 15) 
Date of first drug 
administration + 14 days 
Base date - 4 days <=   < Base date + 7 
days 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
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Visit 
Base date 
Time windows 
Week 8 - Week 
104 by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.4  Definition of time windows and calculated visits for 12-lead ECG, Chest x-ray, 
Pregnancy test, Blood CD4 positive cells 
Visit 
Base date 
Time windows 
Week 12 - Week 
24 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 76 
Date-time of first drug 
administration + 532 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.5  Definition of time windows and calculated visits for body weight, Autoantibody 
Visit 
Base date 
Time windows 
Week 12 - Week 
36 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date – 14 days <=   < Base date + 
14 days 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.6  Definition of time windows and calculated visits for Neurological findings, 
Vasculitis marker tests 
Visit 
Base date 
Time windows 
Week 12 - Week 
36 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
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Week 52 - Week 
88 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.7  Definition of time windows and calculated visits for Serum KL-6, β D glucan, Serum 
TRACP-5b concentration, Vectra™ DA 
Visit 
Base date 
Time windows 
Week 12 - Week 
24 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.8  Definition of time windows and calculated visits for Serum anti-E6011 antibody 
Visit 
Base date 
Time windows 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 
104 by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.9  Definition of time windows and calculated visits for Serum cytokine concentration, 
LRG1, Ang2 
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Visit 
Base date 
Time windows 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 12 - Week 
24 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.10  Definition of time windows and calculated visits for Anti-JCV antibody test 
Visit 
Base date 
Time windows 
Week 24 
Date-time of first drug 
administration + 168 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 76 
Date-time of first drug 
administration + 532 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.11  Definition of time windows and calculated visits for Virus test, Syphilis test, 
Tuberculosis test 
Visit 
Base date 
Time windows 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 14 days <=   < Base date + 14 
days 
Week 104 
Date-time of first drug 
administration + 728 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
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Table 8.12  Definition of time windows and calculated visits for Joint x-ray 
Visit 
Base date 
Time windows 
Week 0 
Date-time of first drug 
administration 
Base date <= 28 days 
Week 24 
Date-time of first drug 
administration + 168 
days 
28 days < <= Base date + 28 days 
Week 52 
Date of first drug 
administration + 334 
days 
Base date - 28 days <=   < Base date + 28 
days 
Week 76 
Date-time of first drug 
administration + 532 
days 
Base date - 28 days <=   < Base date + 28 
days 
 
8.2 
 Pharmacokinetic data handling 
8.2.1 
Lower Limit of Quantification of E6011 Serum Concentration 
The LLOQ of E6011 serum concentration is 0.1 µg/mL.  
 
8.2.2 
BLQ Handling for Developing Concentration–Time Profiles 
When developing individual concentration-time profiles, BLQ values will be handled 
according to 302-104.00-MNL for non-compartmental pharmacokinetic analysis.  
 
8.2.3 
BLQ Handling for Developing Tables 
When developing tables, BLQ values will be handled according to 302-104.00-MNL for non-
compartmental pharmacokinetic analysis.  
 
8.2.4 
Handling of anomalous concentration values 
Handling anomalous concentration values will follow the 302-104.00-MNL for non-
compartmental pharmacokinetic analysis. 
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8.2.5 
General Rules for Presentation of Drug Concentrations 
When presenting individual/raw (raw, hereafter) values and summary statistics,  the following 
rule will be applied:  for drug concentrations, all summary statistics (mean, median, geometric 
mean, standard deviation (SD)  and coefficient variation (CV) ) will have 3 significant digits.   
 
8.3 
Imputation rule for partial date 
8.3.1 
Date of Diagnosis 
Imputation rule for date of diagnosis is as follows:  
• 
Complete date:  Date as reported on CRF. 
• 
Year and Month are not missing but Day is missing:  Year and Month as reported on 
CRF, Date as 15th 
• 
Year is not missing but Month and Day are missing:  Year as reported on CRF, Month 
and Day as July 1st. 
• 
Year is missing or Date is completely missing:  Missing 
 
8.3.2 
Medication 
Imputation rule for medication start date is as follows: 
• 
Complete date:  Date as reported on CRF 
• 
Year and Month are not missing but Day is missing:  Year and Month as reported on 
CRF, Day as 1st 
• 
Year is not missing but Month and Day are missing:  Year as reported on CRF, Month 
and Day as January 1st 
• 
Year is missing or Start Date is completely missing:  Missing 
Imputation rule for medication end date is as follows: 
• 
Complete date:  Date as reported on CRF 
• 
Year and Month are not missing but Day is missing:  Date of death or Year and Month 
as reported on CRF, last day of the reported month, which is earlier 
• 
Year is not missing but Month and Day are missing:  Year as reported on CRF, Month 
and Day as December 31st 
• 
Year is missing or Start Date is completely missing:  Missing 
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8.3.3 
Adverse Events 
Imputation rule for adverse event start date is as follows: 
• 
Year and Month are not missing but Day is missing 
 Year and Month are the same as year and month of the earliest among non-missing 
values of first dosing date of study Treatment and imputed AE end date:  The 
earliest among non-missing values of first dosing date of study Treatment and 
imputed AE end date 
 Year and Month are not the same as year and month of the earliest among non-
missing values of first dosing date of study Treatment and imputed AE end date:  
Year and Month as reported on CRF, Day as 1st 
• 
Year is not missing but Month and Day are missing 
 Year is the same as year of the earliest among non-missing values of first dosing 
date of study Treatment and imputed AE end date:  The earliest among non-missing 
values of first dosing date of study Treatment and imputed AE end date 
 Year is not the same as year of the earliest among non-missing values of first dosing 
date of study Treatment and imputed AE end date:  Year as reported on CRF, Month 
and Day as January 1st 
• 
Completely missing:  First dosing date or imputed AE end date, which is earlier 
Imputation rule for adverse event end date is as follows: 
• 
Outcome is ‘fatal’ and End Date is not complete date:  Date of death 
• 
Outcome is ‘fatal’ and End Date is complete date 
 different from the date of death:  Confirm to CDM 
 same as the date of death:  Date of death 
• 
Outcome is not ‘fatal’ and date of death is not missing 
 Year and Month are the same as the year and month of date of death:  Date of death 
 Year and Month are not the same as the year and month of date of death:  Year and 
Month as reported on CRF, Day as the last day of the month 
 Year is the same as the year of date of death:  Date of death 
 Year is not the same as the year of date of death:  Year as reported on CRF, Month 
and Day as December 31st 
 Completely missing:  Date of death 
• 
Outcome is not ‘fatal’ and date of death is missing  
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 Year and Month are not missing but Day is missing:  Year and Month as reported on 
CRF, Day as the last day of the month 
 Year is not missing but Month and Day are missing, and Year is before the Year of 
date of discontinuation from study:  Year as reported on CRF, Month and Day as 
December 31st 
 Year is not missing but Month and Day are missing, and Year is same as the Year of 
date of discontinuation from study:  Date of discontinuation from study 
• 
Outcome is marked ‘Recovered’ or ‘Recovered with sequelae’:  Date of discontinuation 
from study 
• 
Outcome is missing or is ‘Not recovered’, ‘Recovering’ or ‘Unknown’, or Year is 
missing or Start Date is completely missing:  Missing 
• 
Year, Month and Day are all missing and date of death is not missing:  Date of death 
 
8.4 
Decimal places 
Decimal places (DP) for descriptive statistics, except PK analysis, is defined as follows: 
• 
Mean:  Significant digits + 1 
• 
SD:  Significant digits + 2 
• 
Median:  Significant digits + 1 
• 
Min, Max:  Significant digits 
• 
Percentage of frequency:  fixed one decimal place 
Significant digits for the derived parameter is defined as follows: 
• 
TJC68, SJC66, TJC28, SJC28:  Integer 
• 
DAS28-CRP, DAS28-ESR, CDAI, SDAI, Calcium Corrected:  2 DP 
• 
HAQ-DI:  1 DP 
DP for the other calculated result is defined as follows: 
• 
Confidence Interval:  fixed  2 DP 
• 
Pvalue:  fixed 3 DP(truncated below 4 DP) , except < 0.001.  When < 0.001, as is. 
Summary of change from baseline is based on significant digits of each parameter, and percent 
change from baseline is defined as 1 DP. 
8.5 
TNF Agent 
Medications as TNF agent are extracted at ATC4 Code = L04AB. 
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9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS version 9.3 or later. 
 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
 
12 REFERENCES 
Not applicable. 
 
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13 APPENDICES 
13.1 National Institute for Health: Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 
National Cancer Institute (NCI) CTCAE version 4.0 May 2009 is available online at: 
https://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.0_2009-05-29_QuickReference_5x7.pdf 
CTCAE grades for selected laboratory parameters are listed in the table below, where ULN is the upper limit of normal and LLN is 
the lower limit of normal. 
Lab Parameter 
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hematology 
Hemoglobin (low) 
< LLN - 100 (g/L) 
< 100 - 80 (g/L) 
< 80 - 65 (g/L) 
 
Death 
Hemoglobin (high)  
Increase in > 0 - 20 (g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >20 - 40 (g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in > 40 (g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
 
 
Platelet Count (PLT) (low) 
< LLN - 75.0 (10^9/L) 
< 75.0 - 50.0 (10^9/L) 
< 50.0 - 25.0 (10^9/L) 
< 25.0 (10^9/L) 
 
White Blood Cell Count  
(WBC) (low) 
< LLN - 3.0 (10^9/L) 
< 3.0 - 2.0 (10^9/L) 
< 2.0 - 1.0 (10^9/L) 
< 1.0 (10^9/L) 
 
White Blood Cell Count  
(WBC) (high) 
 
 
> 100 (10^9/L) 
 
Death 
Lymphocytes (low) 
< LLN - 0.8 (10^9/L) 
< 0.8 - 0.5 (10^9/L) 
< 0.5 - 0.2 (10^9/L) 
< 0.2 (10^9/L) 
 
Lymphocytes (high) 
 
> 4 - 20 (10^9/L) 
> 20 (10^9/L) 
 
 
Neutrophils (low) 
< LLN - 1.5 (10^9/L) 
< 1.5 - 1 (10^9/L) 
< 1 - 0.5 (10^9/L) 
< 0.5 (10^9/L) 
 
Blood Chemistry 
Albumin (low) 
< LLN - 3 (g/dL) ; 
< LLN - 30 (g/L) 
< 3 - 2 (g/dL) ; 
< 30 - 20 (g/L) 
< LLN - 2 (g/dL) ; 
< 20 (g/L) 
 
Death 
Alkaline Phosphatase (high) 
> ULN - 3.0 x ULN  
> 3.0 - 5.0 x ULN  
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
 
Alanine Aminotransferase  
(high) 
> ULN - 3.0 x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
 
Amylase (high) 
> ULN - 1.5 x ULN 
> 1.5 - 2.0 x ULN 
> 2.0 - 5.0 x ULN 
> 5.0 x ULN 
 
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Lab Parameter 
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Aspartate Aminotransferase  
(high) 
> ULN - 3.0 x ULN  
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN  
> 20.0 x ULN 
 
Total Bilirubin (high) 
> ULN – 1.5 x ULN  
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x ULN 
> 10.0 x ULN 
 
Corrected Calcium*, serum-
low (hypocalcemia) 
< LLN - 2.0 (mmol/L) ; 
< LLN - 8.0 (mg/dL) 
< 2 - 1.75 (mmol/L) ; 
< 8.0  - 7.0 (mg/dL) 
< 1.75 - 1.5 (mmol/L) ; 
< 7.0 - 6.0 (mg/dL) 
< 1.5 (mmol/L) ; 
< 6.0 (mg/dL) 
Death 
Corrected Calcium*, serum-
high (hypercalcemia) 
> ULN – 2.9 (mmol/L) ; 
> ULN – 11.5 (mg/dL) 
> 2.9 – 3.1 (mmol/L) ; 
> 11.5 – 12.5 (mg/dL) 
> 3.1 – 3.4 (mmol/L) ; 
> 12.5 – 13.5 (mg/dL) 
> 3.4 (mmol/L) ; 
> 13.5 (mg/dL) 
Death 
Cholesterol (high) 
> ULN - 300 (mg/dL) ; 
> ULN - 7.75 (mmol/L) 
> 300 - 400 (mg/dL) ; 
> 7.75 - 10.34 (mmol/L) 
> 400 - 500 (mg/dL) ; 
> 10.34 - 12.92 (mmol/L) 
> 500 (mg/dL) ; 
> 12.92 (mmol/L) 
 
Creatinine (high) 
> 1 - 1.5 x baseline ; 
> ULN - 1.5 x ULN 
> 1.5 - 3.0 x baseline ; 
> 1.5 - 3.0 x ULN 
> 3.0 x baseline ; 
> 3.0 - 6.0 x ULN 
> 6.0 x ULN 
 
Gammaglutamyltransferase 
(high) 
> ULN - 3.0 x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
 
Glucose, serum-low  
(hypoglycemia) 
< LLN - 55 (mg/dL) ;  
< LLN - 3.0 (mmol/L) 
< 55 - 40 (mg/dL) ;  
< 3.0 - 2.2 (mmol/L) 
< 40 - 30 mg/dL ;  
< 2.2 - 1.7 mmol/L 
< 30 mg/dL ; 
< 1.7 mmol/L 
Death 
Glucose, serum-high  
(hyperglycemia) 
> ULN - 160 (mg/dL) ; 
> ULN - 8.9 (mmol/L) 
> 160 - 250 (mg/dL) ; 
> 8.9 - 13.9 (mmol/L) 
> 250 - 500 (mg/dL) ; 
> 13.9 - 27.8 (mmol/L) 
> 500 (mg/dL) ;  
> 27.8 (mmol/L) 
Death 
Phosphate, serum-low  
(hypophosphatemia) 
< LLN - 2.5 mg/dL;  
< LLN - 0.8 mmol/L 
< 2.5 - 2.0 mg/dL;  
< 0.8 - 0.6 mmol/L 
< 2.0 - 1.0 mg/dL;  
< 0.6 - 0.3 mmol/L 
< 1.0 mg/dL;  
< 0.3 mmol/L; 
Death 
Potassium, serum-low  
(hypokalemia) 
< LLN - 3.0 mmol/L 
 
< 3.0 - 2.5 mmol/L 
< 2.5 mmol/L 
Death 
Potassium, serum-high  
(hyperkalemia) 
> ULN - 5.5 mmol/L 
> 5.5 - 6.0 mmol/L 
> 6.0 - 7.0 mmol/L 
> 7.0 mmol/L 
Death 
Sodium (Hyponatremia) (low) 
< LLN - 130 mmol/L 
 
< 130 - 120 mmol/L 
< 120 mmol/L; 
Death 
Sodium (Hypernatremia) 
(high) 
> ULN - 150 mmol/L 
> 150 - 155 mmol/L 
> 155 - 160 mmol/L 
> 160 mmol/L; 
Death 
Triglyceride 
(hypertriglyceridemia) (high) 
150 - 300 (mg/dL) ;  
1.71 - 3.42 (mmol/L) 
> 300 - 500 (mg/dL) ;  
> 3.42 - 5.7 (mmol/L) 
> 500 - 1000 (mg/dL) ; 
> 5.7 - 11.4 (mmol/L) 
> 1000 (mg/dL) ; 
> 11.4 (mmol/L) 
Death 
Uric 
Acid 
(hyperuricemia) 
(high) 
> ULN - 10 (mg/dL) ; 
> ULN - 0.59 (mmol/L) 
 
 
> 10 (mg/dL) ; 
> 0.59 (mmol/L) 
Death 
Urinalysis 
Protein 
1+ 
2+ or higher 
 
 
 
Other 
Blood CD4 Positive Cell  
Counts 
< LLN - 0.5 (10^9/L) 
< 0.5 - 0.2 (10^9/L) 
< 0.2 - 0.05 (10^9/L) 
< 0.05 (10^9/L) 
 
* Corrected serum calcium by albumin should be referred. If serum albumin is <4.0 g/dL, the corrected calcium will be calculated using the following formula: 
Corrected calcium (mg/dL) = Total calcium (mg/dL) – 0.8 x [Albumin (g/dL) – 4] 
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As to Alkaline Phosphatase and γ-GTP, criteria for Grade 2 is changed from ULN x 2.5 (in the CTCAE) to ULN x 3.0. 
 
13.2 Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results 
Except for phosphate, a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or higher.  For 
phosphate, a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 3 or higher. 
 
 
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PPD
PPD
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PPD
PPD
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Prot_000.pdf: 
 
Eisai Co., Ltd. 
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Date: 25 Mar 2019 version 6.0 
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Page 1 of 76 
 
1 
TITLE PAGE 
 
Clinical Study Protocol 
Study Protocol 
Number: 
E6011-J081-201 
Study Protocol 
Title: 
A Dose Response Study of E6011 in Subjects With Rheumatoid 
Arthritis Inadequately Responding to Methotrexate 
Sponsor: 
Eisai Co., Ltd. 
4-6-10 Koishikawa, Bunkyo-Ku, Tokyo 112-8088, Japan 
Investigational 
Product Name: 
E6011 
Indication: 
Rheumatoid arthritis (RA) patients inadequately responding to 
methotrexate (MTX) 
Phase: 
2 
Approval Date: 
V1.0 
31 Aug 2016 
 
V2.0 
13 Oct 2016 
 
V3.0 
23 Feb 2017 
 
V4.0 
24 Apr 2017 
 
V5.0 
31 Aug 2018 
 
V6.0 
25 Mar 2019 
GCP Statement: 
This study is to be performed in full compliance with Good Clinical 
Practice (GCP) and regulations.  All required study documentation 
will be archived as required by regulatory authorities. 
Confidentiality 
Statement: 
This document is confidential.  It contains proprietary information 
of Eisai (the sponsor).  Any viewing or disclosure of such 
information that is not authorized in writing by the sponsor is 
strictly prohibited.  Such information may be used solely for the 
purpose of reviewing or performing this study. 
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2 
CLINICAL PROTOCOL SYNOPSIS 
Compound No.:  E6011 
Name of Active Ingredient: To be determined   
Study Protocol Title 
A Dose Response Study of E6011 in Subjects With Rheumatoid Arthritis Inadequately Responding to 
Methotrexate 
Study Regions (Countries) or Sites 
Japan 
Study Period and Phase of Development 
October 2016 to February 2020 (planned)  
Phase 2 
Objectives 
To conduct the following assessments on repeated subcutaneous administrations of E6011 in 
rheumatoid arthritis (RA) patients inadequately responding to methotrexate (MTX): 
<Primary objectives> 
• 
To evaluate the efficacy of E6011 compared with placebo by using ACR20 response rate at 
Week 12 as a primary endpoint 
• 
To evaluate the safety and tolerability of E6011 
<Secondary objectives> 
• 
To evaluate the effect of E6011 on suppressing radiographic progression of joint destruction at 
Week 24 
• 
To evaluate the pharmacokinetics (PK) and immunogenicity of E6011 
<Exploratory objective> 
• 
To explore the PK/pharmacodynamics (PD) and biomarkers of E6011 
Study Design 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group comparison 
study.  The following 4 treatment groups are selected for the study: E6011 100 mg, 200 mg, 400 mg, 
and placebo.  In the E6011 100 mg, 200 mg, and placebo groups, subjects will receive the study 
treatment (100 mg, 200 mg, or placebo, respectively) at Weeks 0, 1, 2, and then every 2 weeks.  In 
the E6011 400 mg group, subjects will receive 400 mg at Weeks 0, 1, 2, 4, 6, 8, 10 and then 200 mg 
every 2 weeks. 
The study consists of Screening, Observation, Treatment, Extension, and Follow-up Phases. 
After undergoing screening assessments within 42 days prior to the study treatment, subjects with the 
certain eligibility confirmed in the Observation Phase will be allocated to any of the E6011 100 mg, 
200 mg, 400 mg, or placebo groups at a 1:2:2:2 ratio through dynamic allocation using the following 
factors: C-reactive protein (CRP) level at the Screening Phase, disease duration, and history of 
biologics treatment. 
In the Treatment Phase (24 weeks), subjects will receive either E6011 or placebo at Weeks 0, 1, 2, 
and every 2 weeks until Week 22 in a double-blind manner.  
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Subjects who complete evaluations at Week 24 of the Treatment Phase will enter the Extension 
Phase.  The Extension Phase is up to 104 weeks after the start of the study treatment, and subjects 
will receive an open-label E6011 200 mg every 2 weeks until Week 102.  If the investigator or 
subinvestigator judges that the response to treatment is insufficient in the Extension Phase, 
administration of E6011 400 mg every 2 weeks will also be allowed (reduction of the dose back to 
200 mg after an increase to 400 mg will also be allowed). 
If subjects complete or discontinue the study, a follow-up visit should be conducted 28 days after the 
completion or discontinuation of the study, and a follow-up visit or telephone interview should be 
conducted 70 days after the last dosing.  
An overview of the study design is presented below. 
Observation 
Phase 
Primary endpoint 
 
 
Screening 
Phase 
Treatment Phase 
(Double-blind) 
Extension Phase 
(Open label) 
Days –42 to –1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 0 1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 24 26 28 30 32 ……… 
104 
 
*: If the investigator or subinvestigator judges that response to treatment is insufficient during the 
Extension Phase, administration of E6011 400 mg every 2 weeks will also be allowed. 
In addition, if subjects complete or discontinue the study, a follow-up visit should be conducted 
28 days after the completion or discontinuation of the study, and a follow-up visit or telephone 
interview should be conducted 70 days after the last dosing. 
Number of Subjects 
A total of 175 subjects (25 for the 100 mg group, 50 for the 200 mg group, 50 for the 400 mg group, 
and 50 for the placebo group) 
400 mg 
200 mg 
200 mg* 
200 mg* 
200 mg* 
200 mg* 
Placebo group 
100 mg group 
200 mg group 
400 mg group 
Placebo 
200 mg 
100 mg 
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Inclusion Criteria 
Subjects must meet all of the following criteria to participate in this study: 
1. Aged ≥18 and <75 years old at the time of written informed consent 
2. RA patients who meet the 1987 ACR criteria or 2010 ACR/EULAR criteria ≥12 weeks before 
written informed consent 
3. Received MTX treatment at 6 to 16 mg/week for ≥12 weeks before screening and presented 
≥6 tender joints (out of 68 joints) and ≥6 swollen joints (out of 66 joints) in the Screening and 
Observation Phases 
4. Able to continue a stable dose regimen of MTX at 6 to 16 mg/week from 4 weeks or more 
before starting the study treatment until completion of the Extension Phase (or until study 
discontinuation) 
5. For patients with a history of biologics treatment for RA Note, the following criteria should be 
fulfilled. 
(Note: This includes those treated in clinical studies) 
• 
The history of biologics treatment for RA with any of adalimumab, infliximab, golimumab, 
certolizumab pegol, etanercept, tocilizumab, and abatacept (including biosimilars). 
• 
No biologics treatment for RA within 12 weeks prior to the study treatment 
6. CRP level ≥0.6 mg/dL or erythrocyte sedimentation rate (ESR) ≥28 mm/hr in the Screening 
Phase 
7. Erosions at ≥3 sites in radiographic joint image in the Screening Phase, or those with erosions at 
≥1 site and either positive for rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) 
antibody in the Screening Phase 
8. Weighs ≥30 kg and ≤100 kg in the Screening Phase 
9. Has voluntarily consented, in writing, to participate in this study.  If a subject is below the age of 
20, written consent should be obtained from a legally acceptable representative. 
10. Has been thoroughly briefed on the requirements of the study, can understand, and is willing and 
able to comply with all aspects of the protocol 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Any history or complication of inflammatory arthritic disorder Note other than RA and Sjogren’s 
syndrome  
(Note: Such as arthritis associated with viral infection, systemic lupus erythematosus, mixed 
connective tissue disease, dermatomyositis/polymyositis, scleroderma, rheumatic polymyalgia, 
psoriatic arthritis, and arthritis occurring in patients under 16 years of age) 
2. Class IV in the Criteria for Functional Status in RA (the ACR 1991 Revised Criteria) in the 
Screening Phase 
3. Received biologics treatment for RA but discontinued it because of inadequate response 
4. Received disease-modifying antirheumatic drugs (DMARDs) other than MTX within 4 weeks 
before staring the study treatment 
5. Received reflunomid or tofacitinib within 12 weeks before starting the study treatment 
6. Received corticosteroids equivalent to >10 mg/day of prednisolone within 4 weeks before 
starting the study treatment 
7. Received corticosteroids (intraarticular, intramuscular, or intravenous), intraarticular injection of 
sodium hyaluronate (including sodium hyaluronate crosslinked polymer and sodium hyaluronate 
crosslinked polymer crosslinked with vinylsulfone), intraarticular injection of local anesthesia 
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agent, or an analgesic other than NSAIDs (oral, suppository, and topical) within 4 weeks before 
starting the study treatment 
8. Treatment with MTX, folic acid, corticosteroids (equivalent to ≤10 mg/day of prednisolone, 
taken orally or by suppository) or herbal medicine indicated for RA was started, or dose regimen 
was modified within 4 weeks before starting the study treatment (however, if MTX dose was 
increased or decreased beyond 4 mg at one time, MTX should be used at a stable regimen for 
8 weeks before starting the study treatment). 
9. Underwent arthrocentesis/drainage within 4 weeks before starting the study treatment or 
cytapheresis therapy within 8 weeks before starting the study treatment 
10. Underwent surgical operation on the joint (including synovectomy and repair of tendon rupture) 
which is evaluated in this study within 8 weeks before informed consent 
11. Received cyclophosphamide, cyclosporin (except for eye drop solution), azathioprine, or 
denosumab within 52 weeks before starting the study treatment 
12. Received immunoglobulin preparations or blood products within 24 weeks before starting the 
study treatment 
13. Received a live vaccine within 12 weeks before starting the study treatment, or is planning to 
receive one 
14. Any current clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, or renal 
disease) that could affect the subject’s safety or interfere with the conduct of study in the opinion 
of the investigator or subinvestigator 
15. Any current uncontrolled disorders such as acute cardiac infarction, unstable angina, brain 
infarct, or symptomatic intracerebral hemorrhage 
16. Severe or uncontrolled diabetes 
17. History of severe allergy (shock or anaphylactoid symptoms) 
18. History or current clinical condition of malignant tumor, lymphoma, leukemia, or 
lymphoproliferative disease, except for skin carcinoma (epithelial carcinoma or basal cell 
carcinoma) and cervix carcinoma which have been completely excised and without metastasis or 
recurrence for more than 5 years before informed consent 
19. Immunodeficiency or history of human immunodeficiency virus (HIV) infection 
20. Infection requiring hospitalization or intravenous administration of antibiotics within 4 weeks 
before starting the study treatment or disease requiring administration of antivirus drugs (e.g., 
herpes zoster) within 4 weeks before starting the study treatment 
21. History of tuberculosis or current active tuberculosis 
22. History of clinically important vasculitis 
23. Tested positive for any of the following in the Screening Phase: HIV, hepatitis B virus surface 
antigen (HBs antigen), hepatitis B virus surface antibody (HBs antibody), hepatitis B virus core 
antibody (HBc antibody), hepatitis B virus DNA (HBV DNA), hepatitis C virus antibody (HCV 
antibody), human T-lymphotrophic virus type I antibody (HTLV-1 antibody), or syphilis (except 
if positive for the HBs antibody only, and it is clear that this is due to hepatitis B vaccination. In 
case of positive RPR and negative TP antibody results in the syphilis tests, the positive result is 
not considered valid if a false positivity is confirmed by repeated TP antibody negative results of 
other syphilis tests performed 21 days or more later).  For subjects who are negative for both 
HBs antigen and HBV-DNA quantitative test and positive for either or both of anti-HBc 
antibody and anti-HBs antibody, their study participation is allowed if the investigator or 
subinvestigator takes a proper measure such as HBV-DNA monitoring based on the “Guideline 
for measures against hepatitis B caused by immunosuppression and chemotherapy.” 
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24. Positive in tuberculosis test (QuantiFERON®TB Gold Test or T-SPOT®.TB Test) in the 
Screening Phase.  For those whose results are “hold” (indeterminable) in repeated tests, their 
study participation is only allowed if they start receiving a prophylactic treatment with isoniazid 
(in principle, 300 mg/day [5 mg/kg/day in case of low weight] for approximately 9 months) 
≥21 days before starting the study treatment. 
25. Findings indicating a history of tuberculosis on chest x-ray in the Screening Phase 
26. Neurological findings such as motor paralysis, visual impairment, or language disorder in the 
Screening Phase 
27. Blood CD4-positive cell count <200 /μL or white blood cell count <3,000 /μL in the Screening 
Phase 
28. Any of the following laboratory abnormalities in the Screening Phase 
• 
Hemoglobin: 
<8.0 g/dL 
• 
Neutrophil count: <1,500/μL  
• 
Platelet: 
<100,000/μL 
• 
AST or ALT: 
>3× the upper limit of normal (ULN) 
• 
Serum creatinine: 
>1.5 mg/dL 
• 
Serum KL-6: 
>ULN 
• 
β-D glucan: 
>ULN 
29. Demonstrated prolonged QTcF interval (>450 ms) in repeated ECG examinations 
30. Women of childbearing potential who have a positive pregnancy test in the Screening or 
Observation Phase or of breastfeeding 
31. Women of childbearing potential who: 
• 
Had unprotected sexual intercourse within 30 days before study entry and who do not agree to 
use a highly effective method of contraception (e.g., total abstinence, an intrauterine device 
[IUD], a double-barrier method [such as condom plus diaphragm with spermicide], an oral 
contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the 
entire study period or for 70 days after the last dosing. 
• 
Are currently abstinent, and do not agree to use a double-barrier method (condom plus 
diaphragm with spermicide) during the study period or for 70 days after the last dosing. 
• 
Are using oral contraceptives but are not on a stable dose of the same oral contraceptives for at 
least 4 weeks before study treatment, or who do not agree to use the same oral contraceptives 
during the study or for 70 days after the last dosing. 
• 
All women will be considered to be of childbearing potential unless they are postmenopausal 
[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other 
known or suspected cause] or have been sterilized surgically [i.e., either of bilateral tubal 
ligation, total hysterectomy, or bilateral oophorectomy was performed at least 1 month before 
study treatment]). 
32. Men who have not had a successful vasectomy (without confirmed azoospermia) and their 
female partners do not meet any of the criteria above (however, study entry is allowed if the 
female partner is not of childbearing potential or practicing highly effective contraception 
throughout the study period or for 70 days after the last dosing).  No sperm donation is allowed 
during the study period or for 70 days after the last dosing. 
33. Scheduled for surgery during the study 
34. Currently enrolled in another clinical study, or used any investigational drug or device within 
28 days (or 5× the half-life, whichever is longer) before informed consent 
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35. Has been treated with E6011 or any unapproved biologics for RA 
36. Use of a psychotropic agent as recreational purpose other than therapeutic purpose 
37. Any history of a medical condition or a concomitant medical condition that in the opinion of the 
investigator or subinvestigator would compromise the subject’s ability to safely complete the 
study 
Study Treatments 
Treatment Phase: In the E6011 100 mg, 200 mg, or placebo group, subjects will receive each dose at 
Weeks 0, 1, 2 and then every 2 weeks up to Week 22 by repeated subcutaneous administration.  In the 
E6011 400 mg group, subjects will receive 400 mg at Weeks 0, 1, 2, 4, 6, 8, 10 and then 200 mg 
every 2 weeks up to Week 22 by repeated subcutaneous administration. 
Extension Phase: E6011 200 mg will be subcutaneously administered every 2 weeks until Week 102.  
When subjects insufficiently respond to the treatment, repeated subcutaneous administration (400 mg 
of E6011 every 2 weeks) will be allowed. 
The study drug containing E6011 50 mg, 100 mg, or placebo in 1 vial (1 mL) will be used in the 
study.  In the Treatment Phase, 4 mL will be subcutaneously administered in Weeks 0 to 10, and 
2 mL will be subcutaneously administered in Weeks 12 to 22.  In the Extension Phase, 2 mL will be 
administered subcutaneously for the 200 mg dosing and 4 mL will be administered subcutaneously 
for the 400 mg dosing.  
In the 2 mL administration, subjects will receive study drug subcutaneously in 2 separate sites, 1 mL 
each, from the following sites: right or left upper arm, right or left abdomen, or right or left thigh.  In 
the 4 mL administration, subjects will receive study drug subcutaneously in 4 separate sites, 1 mL 
each.  However, 2 mL of the study drug may be given subcutaneously in 1 site only if the investigator 
or subinvestigator judges that the study drug can be administered properly. 
Duration of Treatment 
Treatment Phase: 
24 weeks 
Extension Phase: 
80 weeks 
Concomitant Drug/Therapy 
<Prohibited Concomitant Drugs and Therapies> 
The concomitant use of the following drugs or therapies is prohibited until completion of the 
Extension Phase (or until study discontinuation). 
• 
DMARDs (except MTX)  
• 
Biologics (adalimumab, infliximab, golimumab, certolizumab pegol, etanercept, tocilizumab, 
abatacept, etc.), including biosimilars 
• 
Intraarterial, intramuscular, or intravenous injection of corticosteroids 
• 
Intraarticular injection of sodium hyaluronate (including sodium hyaluronate crosslinked 
polymer and sodium hyaluronate crosslinked polymer crosslinked with vinylsulfone) or local 
anesthetic agent 
• 
Arthrocentesis/drainage 
• 
Cytapheresis 
• 
Any analgesic other than NSAIDs (oral, suppository, or topical) 
• 
Cyclophosphamide, cyclosporin (with the exception of eye drops), azathioprine, or denosumab 
• 
Immunoglobulin preparations or blood products 
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• 
Live vaccines 
• 
Activated form folic acid, over-the-counter medications containing folic acid as main 
component 
• 
Other investigational drugs or investigational devices  
• 
Surgical operations on arthritic disorder  
< Restricted Concomitant Drugs >  
• 
MTX and folic acid should be continued at a stable dose regimen up to completion of the 
Extension Phase (or until study discontinuation).  However, if an adverse event associated 
with MTX is noted during the Extension Phase, dose reduction or interruption is 
permitted. If the event disappears after dose reduction or interruption, the dose can be 
increased to the previous level. 
• 
Corticosteroids (equivalent to ≤10 mg/day of prednisolone, taken orally or by suppository) and 
herbal medicine indicated for RA are allowed under restricted conditions, but the dose regimen 
should not to be modified up to Week 24 (or until study discontinuation).  Between Week 24 
and Week104, the regimen should not be modified except for the following cases: dose 
reduction, dose interruption, dose increase following the dose reduction (up to the initial dose 
level), and restarting administration after interruption. 
• 
NSAIDs (oral, suppository, or topical) may be taken concomitantly but are prohibited between 
the night before the day of efficacy assessments and the end of the assessments. 
• 
After the date Version 6 of the protocol is approved by IRB, dose reduction, dose interruption, 
dose increase following the dose reduction (up to the initial dose level), and restarting 
administration after interruption will be allowed for MTX, folic acid, corticosteroids, or herbal 
medicine indicated for RA). There will be no restrictions in using NSAIDs (oral, suppository, 
or topical). 
Assessments 
After the date Version 6 of the protocol is approved by IRB, it is unnecessary to conduct assessments 
other than <safety>. 
< Efficacy > 
Number of tender joints, number of swollen joints, visual analog scale (VAS; patient’s pain 
assessment and patient’s disease activity global assessment, and physician’s disease activity global 
assessment), patient’s physical function assessment (health assessment questionnaire [HAQ]), CRP, 
ESR, and joint x-ray 
< Safety > 
Safety will be assessed based on all adverse events (AEs) observed, regular monitoring of clinical 
laboratory tests (including vasculitis marker tests), vital signs, chest x-ray, standard 12-lead 
electrocardiograms, physical findings, injection site findings, and neurological findings. 
< Pharmacokinetics > 
Serum E6011 concentration 
< Biomarkers > 
Serum total fractalkine (FKN) concentration, serum RF concentration, serum anti-CCP antibody 
concentration, serum matrix metalloproteinase (MMP)-3 concentration, serum tartrate resistant acid 
phosphatase (TRACP) -5b concentration, serum cytokine concentration (granulocyte macrophage 
colony-stimulating factor [GM-CSF], interferon-γ [IFN-γ], interleukin [IL]-1β, IL-6, TNFα, etc.), 
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serum leucine-rich alpha-2 glycoprotein 1 (LRG1) concentration, serum angiopoietin 2 (Ang2) 
concentration, Vectra™ DA, immunocytes such as blood CX3CR1-positive cells 
< Immunogenicity > 
Serum anti-E6011 antibody 
Bioanalytical Methods 
Serum E6011 concentration, serum total FKN concentration, serum RF concentration, serum anti-
CCP antibody concentration, serum MMP-3 concentration, serum TRACP-5b concentration, serum 
cytokine concentration, serum LRG1 concentration, serum Ang2 concentration, Vectra™ DA, and 
serum anti-E6011 antibody will be determined using validated assay methods.  Immunocytes such as 
blood CX3CR1-positive cells will be analyzed. 
Statistical Methods 
The statistical analyses in the Treatment Phase will be performed after the database in the Treatment 
Phase is locked and the treatment is unblinded, and then final statistical analyses will be performed 
by using all data after the database throughout the study period is locked.   
The details will be described separately in the Statistical Analysis Plans. The Statistical Analysis 
Plans for the Treatment Phase and the entire study (the Treatment and Extension Phases) will be 
finalized before each database lock.   
< Primary Endpoint > 
• 
ACR20 response rate at Week 12 
< Secondary Endpoints > 
• 
ACR20, ACR50, and ACR70 response rates at each evaluation time point (excluding ACR20 
response rate at Week12) 
• 
Values and changes from baseline in ACR components (number of tender joints, number of 
swollen joints, VAS [patient’s pain assessment and patient’s disease activity global assessment, 
and physician’s disease activity global assessment], patient’s physical function assessment 
[HAQ], and CRP/ESR), DAS28-ESR, DAS28-CRP, simple disease activity index (SDAI), and 
clinical disease activity index (CDAI) at each evaluation time point 
• 
EULAR response classification and disease activity classification based on DAS28-ESR and 
DAS28-CRP at each evaluation time point 
• 
Remission rates calculated based on remission criteria (DAS28-ESR, DAS28-CRP, SDAI, 
CDAI, and Boolean) at each evaluation time point 
• 
Values and changes from baseline in modified total sharp score (mTSS) at each evaluation 
time point 
< Analysis Sets > 
• 
The Full Analysis Set (FAS) is the group of randomized subjects who received the study drug 
and had at least 1 evaluable postdose primary efficacy data. 
• 
The Per Protocol Set (PPS) is the group of subjects who sufficiently complied with the 
protocol.  Details of the PPS criteria will be determined before database lock and treatment 
unblinding and will be specified in the Statistical Analysis Plan. 
• 
The Safety Analysis Set is the group of subjects who received at least 1 dose of study drug and 
had at least 1 evaluable postdose safety data. 
< Efficacy Analyses > 
The primary efficacy analysis set is FAS. 
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Analyses for the Primary Endpoint 
ACR20 response rate at Week 12 will be analyzed using a logistic regression model with CRP level 
at the Screening Phase, disease duration and history of biologics treatment as covariates, for the 
comparison between placebo and either E6011 200 mg or 400 mg. Overall significance level is 
α=0.025 (one-sided).  The Hochberg method will be used to adjust the multiplicity.  Subjects with 
missing primary efficacy endpoint due to early discontinuation or other reasons will be considered 
nonresponders. In case that the number of subjects in each category of covariates is very small, 
integration of the categories will be planned.  ACR20 response rate and its 2-sided 95% confidence 
interval for each treatment group will be calculated.  The difference in ACR20 response rate between 
each of E6011 doses and placebo and its 2-sided 95% confidence interval will also be calculated.  
Subgroup analyses or sensitivity analyses will be conducted as needed. 
In addition, the following analyses will be conducted for ACR20 response rate at Week 12. 
• 
To compare ACR20 response between E6011 100 mg and placebo by using a logistic 
regression model (CRP level at the Screening Phase, disease duration and history of biologics 
treatment as covariates).  The difference in ACR20 response rate between E6011 100 mg and 
placebo and its 2-sided 95% confidence interval will also be calculated. 
• 
To estimate the dose-response relationship using a statistical model, such as Emax model, if 
appropriate 
Analyses for the Secondary Endpoints 
The multiplicity adjustment will not be considered for secondary efficacy analyses. 
For ACR20 (excluding Week 12), ACR50, and ACR70 response rates at each evaluation time point, 
similar analyses to primary analyses will be conducted. 
For each component of ACR (number of tender joints, number of swollen joints, VAS [patient’s pain 
assessment and patient’s disease activity global assessment, and physician’s disease activity global 
assessment], patient’s physical function assessment [HAQ], and CRP/ESR), DAS28-ESR, DAS28-
CRP, SDAI, and CDAI, summary statistics (mean, standard deviation, median, and range) for values 
and changes from the baseline will be calculated by treatment group and evaluation point.  The 
changes from baseline will also be analyzed by using ANCOVA with baseline value, CRP level at the 
Screening Phase, disease duration and history of biologics treatment as covariates.  The significance 
level for comparisons between placebo and each treatment group with E6011 (100 mg, 200 mg, and 
400 mg) is α=0.05 (2-sided). 
For mTSS, summary statistics for values and change from baseline will be calculated by treatment 
group and evaluation time point.  The changes from baseline will be analyzed by using ANCOVA in 
the same manner as above. 
For EULAR response classification and disease activity classification based on DAS28-ESR and 
DAS28-CRP, shift tables will be created by treatment group and evaluation time point. 
For remission rates in DAS28-ESR, DAS28-CRP, SDAI, CDAI, and Boolean, similar analyses to 
primary analyses will be conducted. 
< Pharmacokinetic Analyses > 
For the Treatment Phase, summary statistics for serum E6011 concentrations at each specified time 
point will be calculated by treatment group.  Serum E6011 concentration-time profiles will be plotted.  
Population pharmacokinetic analyses will be conducted.  Data from other studies will be integrated as 
necessary.  E6011 concentration data will be used to build PK models.  The models may be used to 
explore the relationship between PK and covariates.  The relationship between serum E6011 
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concentrations and biomarkers and/or efficacy will also be explored through population PK/PD 
modeling.  For population PK analyses, the details will be described in the separately prepared 
analysis plan and its report, and the results will not be included in the clinical study report.   
< Biomarkers > 
For the Treatment Phase, summary statistics for values, and changes and percent changes from 
baseline of serum RF concentration, serum anti-CCP antibody concentration, and serum MMP-3 
concentration, serum TRACP-5b concentration, serum cytokine concentration, serum LRG1 
concentration, serum Ang2 concentration, Vectra™ DA and its components (VCAM-1, epidermal 
growth factor [EGF], vascular endothelial growth factor [VEGF]-A, IL-6, tumor necrosis factor 
receptor-I [TNF-RI], MMP-1, MMP-3, YKL-40, leptin, resistin, serum amyloid A [SAA], and CRP), 
by treatment group and evaluation time point, will be calculated.  Exploratory investigations of the 
relationship between efficacy and biomarkers will be conducted.  Details and results of analyses of 
immunocytes such as blood CX3CR1-positive cells will be provided in a separate report, and will not 
be included in the clinical study report.   
< Immunogenicity > 
All immunogenicity analyses will be performed using the Safety Analysis Set.  The percentage and 
frequency of occurrences will be calculated for serum anti-E6011 antibodies by treatment group and 
evaluation time point.  If anti-E6011 antibody develops, the frequency and percentage of any anti-
E6011 antibody neutralization activity and isotypes will be calculated. 
< Safety Analyses > 
All safety analyses will be performed on the Safety Analysis Set.  For the Treatment Phase, summary 
statistics for safety data, presented by treatment group, will be calculated on an “as treated” basis (n, 
mean, standard deviation, median, minimum, maximum for continuous variables; n and percentage 
for categorical variables).  Safety variables include adverse events, clinical laboratory parameters, 
vital signs, standard 12-lead ECG results, chest x-ray, neurological findings, and blood CD4-positive 
cell count.  
• 
Incidence (%) of adverse events occurring postdose will be calculated by treatment group 
• 
For clinical laboratory parameters, vital signs, and blood CD4-positive cell counts, summary 
statistics for each value and change from baseline will be calculated by treatment group 
• 
For standard 12-lead ECG, chest x-ray, and neurological findings, the frequency and 
percentage of abnormal findings will also be calculated by treatment group 
 
As to the Extension Phase, similar analyses to those described above in the Treatment Phase will be 
conducted for efficacy, pharmacokinetics (except for population PK and PK/PD analyses), biomarker, 
immunogenicity, and safety endpoints by treatment group of the Treatment Phase. 
Interim Analyses 
No interim analysis is planned for this study. 
Sample Size Rationale 
ACR20 response rate at Week 12 was assumed to be 30% in the placebo group and at least 60% in 
both of the E6011 200 mg and 400 mg groups, on the basis of the previous E6011-J081-103 study 
and the results from other drugs for treatment of RA.  Although multiplicity will be considered by 
using the Hochberg method in the primary analysis, sample size was conservatively calculated at a 1-
sided significance level of α=0.0125 (α=0.025/2).  The sample sizes of 50 for the E6011 200 mg, 
400 mg, and placebo groups will have 91% power to detect a difference in response rate of 35% 
between placebo and each E6011 group and will have 79% power to detect a difference in response 
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rate of 30% based on a chi-square test.  The sample size of 25 for the E6011 100 mg group was 
determined for the purpose of estimating the dose-response curve. 
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3 
TABLE OF CONTENTS 
1 
TITLE PAGE .....................................................................................................................1 
2 
CLINICAL PROTOCOL SYNOPSIS ...............................................................................2 
3 
TABLE OF CONTENTS .................................................................................................13 
4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................17 
5 
ETHICS............................................................................................................................19 
5.1 
Institutional Review Boards/Independent Ethics Committees ..............................19 
5.2 
Ethical Conduct of the Study .................................................................................19 
5.3 
Subject Information and Informed Consent ...........................................................19 
6 
INVESTIGATORS AND STUDY PERSONNEL ..........................................................20 
7 
INTRODUCTION ...........................................................................................................20 
8 
STUDY OBJECTIVES ....................................................................................................22 
8.1 
Primary Objectives.................................................................................................22 
8.2 
Secondary Objectives.............................................................................................22 
8.3 
Exploratory Objective ............................................................................................22 
9 
INVESTIGATIONAL PLAN ..........................................................................................22 
9.1 
Overall Study Design and Plan ..............................................................................22 
9.1.1 
Screening Phase ...........................................................................................24 
9.1.2 
Observation Phase (Day 1: Predose)............................................................24 
9.1.3 
Treatment Phase ...........................................................................................24 
9.1.4 
Extension Phase ...........................................................................................24 
9.1.5 
Follow-up Phase...........................................................................................25 
9.2 
Discussion of Study Design, Including Choice of Control Groups .......................25 
9.3 
Selection of Study Population ................................................................................26 
9.3.1 
Inclusion Criteria .........................................................................................26 
9.3.2 
Exclusion Criteria ........................................................................................27 
9.3.3 
Removal of Subjects From Therapy or Assessment ....................................30 
9.4 
Treatments..............................................................................................................30 
9.4.1 
Treatments Administered .............................................................................30 
9.4.2 
Identity of Investigational Products .............................................................32 
9.4.2.1 
Chemical Name and Structural Formula of E6011 ..............................33 
9.4.2.2 
Comparator Drug .................................................................................33 
9.4.2.3 
Labeling for Study Drug ......................................................................33 
9.4.2.4 
Storage Conditions ...............................................................................33 
9.4.3 
Method of Assigning Subjects to Treatment Groups ...................................34 
9.4.4 
Selection of Doses in the Study ...................................................................34 
9.4.5 
Selection and Timing of Dose for Each Subject ..........................................35 
9.4.6 
Blinding........................................................................................................35 
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9.4.7 
Prior and Concomitant Therapy ...................................................................36 
9.4.7.1 
Prohibited Concomitant Therapies and Drugs .....................................37 
9.4.7.1.1 
Prohibited Concomitant Therapies and Drugs ...............................37 
9.4.7.1.2 
Restricted Concomitant Therapies and Drugs ...............................37 
9.4.8 
Treatment Compliance .................................................................................38 
9.4.9 
Drug Supplies and Accountability ...............................................................38 
9.5 
Study Assessments .................................................................................................39 
9.5.1 
Assessments .................................................................................................39 
9.5.1.1 
Demography .........................................................................................39 
9.5.1.2 
Assessments in the Screening and Observation Phases .......................39 
9.5.1.2.1 
Smoking History, Medical History/Complications, and 
Physical Examinations ...................................................................39 
9.5.1.2.2 
Prior Medications ...........................................................................39 
9.5.1.2.3 
Disease Characteristics of RA .......................................................39 
9.5.1.2.4 
Other Assessments .........................................................................39 
9.5.1.3 
Efficacy Assessments...........................................................................40 
9.5.1.3.1 
Assessment of Tender and Swollen Joint Counts ..........................40 
9.5.1.3.2 
Assessment Using Visual Analog Scale (VAS).............................40 
9.5.1.3.3 
Assessment Using Health Assessment Questionnaire (HAQ) .......41 
9.5.1.3.4 
Assessment of Erythrocyte Sedimentation Rate (ESR) .................41 
9.5.1.3.5 
Assessment of C-reactive protein (CRP) .......................................41 
9.5.1.3.6 
Assessment of Joint X-ray .............................................................41 
9.5.1.4 
Pharmacokinetic, Pharmacogenomic, Biomarker, and 
Immunogenicity Assessments ..............................................................42 
9.5.1.4.1 
Pharmacokinetic Assessments .......................................................42 
9.5.1.4.2 
Pharmacogenomic Assessments ....................................................42 
9.5.1.4.3 
Assessments of Biomarkers ...........................................................42 
9.5.1.4.4 
Immunogenicity Assessments ........................................................43 
9.5.1.5 
Safety Assessments ..............................................................................43 
9.5.1.5.1 
Adverse Events and Events Associated with Special Situations ...44 
9.5.1.5.2 
Serious Adverse Events and Events Associated with Special 
Situations........................................................................................45 
9.5.1.5.3 
Laboratory Measurements .............................................................46 
9.5.1.5.4 
Vital Signs and Weight Measurements ..........................................47 
9.5.1.5.5 
Physical Examinations ...................................................................47 
9.5.1.5.6 
Electrocardiograms ........................................................................48 
9.5.1.5.7 
Other Safety Assessments ..............................................................48 
9.5.1.6 
Other Assessments ...............................................................................49 
9.5.2 
Schedule of Procedures/Assessments ..........................................................49 
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9.5.2.1 
Study Schedule.....................................................................................49 
9.5.2.2 
Volume of Blood Samples ...................................................................55 
9.5.3 
Appropriateness of Measurements ...............................................................56 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events 
Associated with Special Situations ..............................................................58 
9.5.4.1 
Reporting of Serious Adverse Events ..................................................58 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through 
Breastfeeding .......................................................................................58 
9.5.4.3 
Reporting of Events Associated with Special Situations .....................59 
9.5.4.3.1 
Reporting of Adverse Events Associated With Study Drug 
Overdose, Misuse, Abuse, or Medication Error ............................59 
9.5.4.4 
Expedited Reporting ............................................................................59 
9.5.4.5 
Breaking the Blind ...............................................................................60 
9.5.4.6 
Regulatory Reporting of Adverse Events ............................................60 
9.5.5 
Completion/Discontinuation of Subjects .....................................................60 
9.5.6 
Abuse or Diversion of Study Drug ..............................................................61 
9.5.7 
Confirmation of Medical Care by Another Physician .................................61 
9.6 
Data Quality Assurance .........................................................................................61 
9.6.1 
Data Collection ............................................................................................61 
9.6.2 
Clinical Data Management ..........................................................................62 
9.7 
Statistical Methods .................................................................................................62 
9.7.1 
Statistical and Analytical Plans ....................................................................62 
9.7.1.1 
Study Endpoints ...................................................................................62 
9.7.1.1.1 
Primary Endpoint ...........................................................................62 
9.7.1.1.2 
Secondary Endpoints .....................................................................63 
9.7.1.2 
Definitions of Analysis Sets.................................................................64 
9.7.1.3 
Subject Disposition ..............................................................................64 
9.7.1.4 
Demographic and Other Baseline Characteristics ...............................64 
9.7.1.5 
Prior and Concomitant Therapy ...........................................................65 
9.7.1.6 
Efficacy Analyses ................................................................................65 
9.7.1.6.1 
Primary Efficacy Analysis .............................................................65 
9.7.1.6.2 
Secondary Efficacy Analyses ........................................................65 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses ...................................................................66 
9.7.1.7.1 
Pharmacokinetic and Pharmacodynamic Analyses .......................66 
9.7.1.7.2 
Pharmacogenomic, Biomarker, and Immunogenicity Analyses ..66 
9.7.1.8 
Safety Analyses ....................................................................................67 
9.7.1.8.1 
Extent of Exposure .........................................................................67 
9.7.1.8.2 
Adverse Events ..............................................................................67 
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9.7.1.8.3 
Laboratory Values ..........................................................................68 
9.7.1.8.4 
Vital Signs ......................................................................................68 
9.7.1.8.5 
Electrocardiograms ........................................................................68 
9.7.1.8.6 
Other Safety Analyses....................................................................68 
9.7.1.9 
Extension Phase Analyses....................................................................69 
9.7.2 
Determination of Sample Size .....................................................................69 
9.7.3 
Interim Analysis ...........................................................................................69 
9.7.4 
Other Statistical/Analytical Issues ...............................................................69 
9.7.5 
Procedure for Revising the Statistical Analysis Plan ...................................69 
10 REFERENCE LIST .........................................................................................................70 
11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE PROCEDURES) .......72 
11.1 
Changes to the Protocol .........................................................................................72 
11.2 
Adherence to the Protocol ......................................................................................72 
11.3 
Monitoring Procedures...........................................................................................72 
11.4 
Recording of Data ..................................................................................................73 
11.5 
Identification of Source Data .................................................................................73 
11.6 
Retention of Records..............................................................................................73 
11.7 
Auditing Procedures and Inspection ......................................................................74 
11.8 
Handling of Study Drug .........................................................................................74 
11.9 
Publication of Results ............................................................................................74 
11.10 Disclosure and Confidentiality ..............................................................................75 
11.11 Discontinuation of Study .......................................................................................75 
11.12 Subject Insurance and Indemnity ...........................................................................75 
12 APPENDICES .................................................................................................................76 
 
LIST OF IN-TEXT TABLES 
Table 1 
Dose and Administration of the Study Drug ..............................................32 
Table 2 
Study Drugs ...............................................................................................33 
Table 3 
Clinical Laboratory Tests ...........................................................................47 
Table 4 
Schedule of Procedures/Assessments in Study E6011-J081-201 ..............51 
Table 5 
Volume of Blood Samples .........................................................................56 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design ..............................................................................................23 
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4 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
ADL 
activities of daily living 
ANCOVA 
analysis of covariance 
Ang2 
angiopoietin 2 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase (SGPT) 
AST 
aspartate aminotransferase (SGOT) 
ATC 
anatomical therapeutic chemical 
BUN 
blood urea nitrogen 
CCP 
cyclic citrullinated peptide 
CDAI 
clinical disease activity index 
CH50 
50% hemolytic unit of complement 
CRA 
clinical research associate 
CRO 
contract research organization 
CRP 
C-reactive protein 
CTCAE 
common terminology criteria for adverse events 
CX3CR1 
CX3C motif chemokine receptor 1 (receptor of fractalkine) 
DAS 
disease activity score 
DNA 
deoxyribonucleic acid 
DMARDs 
disease-modifying antirheumatic drugs 
EGF 
epidermal growth factor 
ESR 
erythrocyte sedimentation rate 
EULAR 
European League Against Rheumatism 
FAS 
full analysis set 
FKN 
fractalkine 
γ-GTP 
γ-glutamine transpeptidase 
GCP 
good clinical practice 
GM-CSF 
granulocyte macrophage colony-stimulating factor 
HAQ 
health assessment questionnaire 
HbA1c 
hemoglobin A1c 
HBc 
hepatitis B virus core 
HBs 
hepatitis B virus surface 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIV 
human immunodeficiency virus 
HTLV-1 
human T cell lymphotropic virus-1 
ICAM-1 
intercellular adhesion molecule-1 
ICH 
International Conference on Harmonisation 
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Abbreviation 
Term 
IFN-γ 
interferon-γ 
IgG 
immunoglobulin G 
IL 
interleukin 
IVRS/IWRS 
interactive voice/web response systems 
LDH 
lactate dehydrogenase 
LRG1 
leucine-rich alpha-2 glycoprotein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
matrix metalloproteinase 
MRI 
magnetic resonance imaging system 
mTSS 
modified total sharp score 
MTX 
methotrexate 
NSAIDs 
nonsteroidal antiinflammatory drug 
PD 
pharmacodynamics 
PK 
pharmacokinetics 
PML 
progressive multifocal leukoencephalopathy 
PPS 
per protocol set 
PT 
preferred term 
QOL 
quality of life 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
SAA 
serum amyloid A 
SDAI 
simple disease activity index 
SOC 
system organ class 
SOP 
standard operating procedures 
TEAE 
treatment emergent adverse events 
TNFα 
tumor necrosis factor α 
TNF-RI 
tumor necrosis factor receptor-I 
TRACP-5b 
tartrate resistant acid phosphatase 5b 
VAS 
visual analog scale 
VCAM-1 
vascular cell adhesion molecule-1 
VEGF 
vascular endothelial growth factor 
WHO DD 
World Health Organization Drug Dictionary 
 
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5 
ETHICS 
5.1 
Institutional Review Boards/Independent Ethics Committees 
The protocol, informed consent form (ICF), and appropriate related documents must be 
reviewed and approved by an Institutional Review Board (IRB) constituted and functioning 
in accordance with Good Clinical Practice (GCP).  Any protocol amendment or revision to 
the ICF will be resubmitted to the IRB for review and approval, except for changes involving 
only logistical or administrative aspects of the study (eg, change in CRA[s], change of 
telephone number[s]).  Documentation of IRB compliance with the GCP regarding 
constitution and review conduct will be provided to the sponsor. 
A signed letter of study approval from the IRB chairman must be sent to the head of the 
medical institution before study start and such documents must be sent to the sponsor before 
the release of any study drug to the site by the sponsor or its designee.  If the IRB decides to 
suspend or terminate the study, the head of the medical institution will immediately send the 
notice of study suspension or termination to the sponsor. 
In accordance with GCP, study progress is to be reported to IRB annually (or as required) by 
the investigator via the head of the medical institution.  The sponsor will submit periodic 
reports and inform the IRB via the investigator and the head of the medical institution of any 
reportable adverse events (AEs) per GCP and local IRB standard operating procedures.  
Upon completion of the study, the investigator will provide the IRB and the sponsor with a 
brief report of the outcome of the study via the head of the medical institution. 
5.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with standard operating procedures of the 
sponsor (or designee), which are designed to ensure adherence to the following: 
• 
Principles of the World Medical Association Declaration of Helsinki (Ethical Principles 
for Medical Research Involving Human Subjects) 
• 
GCP 
• 
Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 
145, 1960) 
5.3 
Subject Information and Informed Consent 
As part of administering the informed consent document, the investigator or subinvestigator 
must explain to each subject (or guardian/legally acceptable representative) the nature of the 
study, its purpose, the procedures involved, the expected duration, the potential clinical risks 
and benefits involved, any potential discomfort, potential alternative procedure(s) or 
course(s) of treatment available to the subject, and the extent of maintaining confidentiality 
of the subject’s records.  Each subject must be informed that participation in the study is 
voluntary, that he/she may reject the participation or withdraw from the study at any time, 
and that the rejection or withdrawal of consent will not affect his/her subsequent medical 
treatment or relationship with the treating physician. 
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This informed consent should be given by means of a standard written statement, written in 
nontechnical language.  The subject (or the subject’s legally acceptable representative) 
should understand the statement before signing and dating it and will be given a copy of the 
signed document.  The subject will be asked to sign an ICF before any study-specific 
procedures are performed.  No subject can enter the study before his/her informed consent 
has been obtained. 
An unsigned copy of an IRB-approved ICF must be prepared in accordance with GCP and all 
applicable local regulations.  Each subject must sign an approved ICF before study 
participation.  The form must be signed and dated by the investigator or subinvestigator (and 
clinical research coordinator, if required).  The original, signed ICF for each subject will be 
verified by the sponsor and kept on file according to local procedures at the site.  The subject 
(or the subject’s legally acceptable representative) should be informed in a timely manner if 
new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study.  The communication of this information should be 
documented. 
6 
INVESTIGATORS AND STUDY PERSONNEL 
This study will be conducted by qualified investigators selected by the sponsor (Eisai) at 
approximately 100 investigational sites in Japan. 
The name and telephone and fax numbers of the medical monitor and other contact personnel 
at the sponsor are listed in Appendix 2. 
7 
INTRODUCTION 
Rheumatoid arthritis (RA) is an autoimmune disease characterized by the inflammation of 
synovium in a joint.  Its major clinical symptoms are pain and swelling of joints of limbs.  
Progressed inflammation of synovium causes joint destruction, which leads to impaired 
activity of daily living (ADL) and eventually lowers quality of life (QOL).  Joint dysfunction 
may be reversible after treatment in many cases at the onset, but it often becomes irreversible 
after the development of joint destruction.  In addition, prolonged disease increases the 
incidence of complications such as interstitial pneumonia and secondary amyloidosis.  As a 
result, RA patients are considered to have a shorter life expectancy than healthy adult people 
by approximately 10 years due to events including cardiovascular system associated with 
infection and inflammation as well as dysfunction caused by joint destruction (Tanaka Y, 
2011; Miyasaka N, 2013).  
Estimated prevalence of RA is approximately 1% of the world population, of which 600,000 
to 700,000 are Japanese.  Patients most commonly affected are women in their 40s to 50s, 
who are in their most productive years. This causes significant psychological, social, and 
financial burdens to their family in addition to their own physical difficulties (Ochi T, et al., 
2004). 
Disease-modifying antirheumatic drugs (DMARDs) have been mainly used to treat RA 
patients, with methotrexate (MTX) being the standard medication.  However, some patients 
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do not sufficiently benefit from DMARD therapy as they experience adverse reactions, or do 
not adequately respond to DMARDs (Kremer JM, 2001).  
There are several reports indicate that the emergence of biologics such as anti-TNF agents 
can improve clinical symptoms, prevent joint destruction progression, and improve impaired 
physical function in patients who do not adequately respond to DMARD therapy (Maini R, et 
al., 1999; Nishimoto N, et al., 2007; Takeuchi T, et al., 2013).  Meanwhile, the remission rate 
is approximately 20% to 40% after biologics treatment (Takeuchi T, 2010) and there are 
patients who are unable to continue the treatment due to the adverse reactions.  Thus, medical 
needs are not fully satisfied and development of highly effective and safer drugs with a new 
mechanism of action is eagerly anticipated. 
E6011 is the world’s first humanized fractalkine (FKN) monoclonal antibody (mAb).  The 
antibody was created in KAN Research Institute, Inc., a research subsidiary of Eisai Co., Ltd.  
FKN is thought to have both chemotaxis and adhesive effects to leukocytes and to play an 
important role on cell invasions in inflamed tissues (Imai T, et al., 2005).  E6011 inhibited 
human FKN-induced chemotaxis of human fractalkine receptor (CX3CR1) expressing mouse 
B lymphocyte precursor cells, in vitro.  In a collagen-induced arthritis (CIA) model in mice, a 
widely used animal model for RA, administrations of FKN monoclonal antibodies against 
mouse FKN showed amelioration of the status of RA.  CX3CR1 and FKN are reported to be 
strongly expressed in the synovium of patients with RA (Nanki T, et al., 2002) and the 
relationship with RA is suggested.  FKN is reported to be involved in the differentiation of 
osteoclast (Koizumi K, et al., 2009); thus, E6011 is also expected to have an inhibitory effect 
against the structural damage of joints through inhibition of bone absorption in RA. 
A Phase 1 clinical study of single intravenous (IV) administration of E6011 in healthy adults 
(E6011-J081-001, hereinafter called Study 001) and a Phase 1 clinical study of single 
subcutaneous (SC) administration of E6011 in healthy adults (E6011-J081-002, hereinafter 
called Study 002) have been completed. In Study 001 (IV: 0.0006 to 10 mg/kg) and Study 
002 (SC: 50 to 400 mg), adverse events which could affect safety and tolerability have not 
been observed in any dose group. 
In a Phase 1/2 clinical study of repeated subcutaneous administrations of E6011 in RA 
subjects (E6011-J081-103, hereinafter called Study 103), we evaluated the safety and 
tolerability of E6011 at repeated subcutaneous administrations of 100 mg, 200 mg, and 
400 mg as primary objective.  Analysis of 12-week dosing presented no concerns about the 
safety and tolerability in RA subjects who repeatedly received E6011 at 100 to 400 mg and 
the clinical symptoms of RA tended to be improved in exploratory efficacy evaluations.  In 
consideration of current situation where an RA medication with novel mechanism of action 
in terms of safety and efficacy is desired and E6011 is highly expected to provide benefits to 
RA patients as a novel therapeutic agent, a double-blind, placebo-controlled, parallel-group 
comparison study was planned to assess the dose response of the efficacy and safety of 
E6011. 
The last subject entered the Extension Phase (open-label) in March 2018, and all subjects had 
completed 52 weeks of treatment with E6011 by March 2019. Consequently, it was 
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considered unnecessary to conduct any non-safety assessments after March 2019, and the 
protocol will be revised to Version 6. 
8 
STUDY OBJECTIVES 
The following assessments will be conducted on repeated subcutaneous administrations of 
E6011 in RA patients inadequately responding to MTX. 
8.1 
Primary Objectives 
• 
To evaluate the efficacy of E6011 compared with placebo by ACR20 response rate at 
Week 12 as a primary endpoint 
• 
To evaluate the safety and tolerability of E6011 
8.2 
Secondary Objectives 
• 
To evaluate the effect of E6011 on suppressing radiographic progression of joint 
destruction at Week 24 
• 
To evaluate the PK and immunogenicity of E6011 
8.3 
Exploratory Objective 
• 
To explore the PK/pharmacodynamics (PD) and biomarkers of E6011 
9 
INVESTIGATIONAL PLAN 
9.1 
Overall Study Design and Plan 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison study.  The following 4 treatment groups are selected for the study: E6011 
100 mg, 200 mg, 400 mg, and placebo.  In the E6011 100 mg, 200 mg, and placebo groups, 
subjects will receive the study treatment (100 mg, 200 mg, or placebo, respectively) at 
Weeks 0, 1, 2, and then every 2 weeks.  In the E6011 400 mg group, subjects will receive 
400 mg at Weeks 0, 1, 2, 4, 6, 8, 10 and then 200 mg every 2 weeks. 
The study consists of Screening, Observation, Treatment, Extension, and Follow-up Phases. 
Screening assessments will be performed within 42 days prior to the study treatment, and 
subjects with the certain eligibility confirmed in the Observation Phase will be allocated to 
any of the E6011 100 mg, 200 mg, 400 mg, or placebo groups at a 1:2:2:2 ratio through 
dynamic allocation using the following factors: C-reactive protein (CRP) level at the 
Screening Phase, disease duration and history of biologics treatment. 
In the Treatment Phase (24 weeks), subjects will receive either E6011 or placebo at Weeks 0, 
1, 2, and every 2 weeks until Week 22 in a double-blind manner. 
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Subjects who complete evaluations at Week 24 of the Treatment Phase will enter the 
Extension Phase.  The Extension Phase is up to 104 weeks after the start of the study 
treatment, and subjects will receive an open-label E6011 200 mg every 2 weeks until 
Week 102.  If the investigator or subinvestigator judges that the response to treatment is 
insufficient in the Extension Phase, administration of E6011 400 mg every 2 weeks will also 
be allowed (reduction of the dose back to 200 mg after an increase to 400 mg will also be 
allowed). 
If subjects complete or discontinue the study, a follow-up visit should be conducted 28 days 
after the completion or discontinuation of the study, and a follow-up visit or telephone 
interview should be conducted 70 days after the last dosing. 
An overview of the study design is presented in Figure 1. 
Observation 
Phase 
Primary endpoint 
 
 
Screening 
Phase 
Treatment Phase 
(Double-blind) 
Extension Phase 
(Open label) 
Days –42 to –1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 0 1 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 24 26 28 30 32 ……… 
104 
 
Figure 1 
Study Design 
*: If the investigator or subinvestigator judges that response to treatment is insufficient during the 
Extension Phase, administration of E6011 400 mg every 2 weeks will also be allowed. 
In addition, if subjects complete or discontinue the study, a follow-up visit should be conducted 
28 days after the completion or discontinuation of the study, and a follow-up visit or telephone 
interview should be conducted 70 days after the last dosing. 
 
400 mg 
200 mg 
200 mg*  
200 mg* 
200 mg* 
200 mg* 
Placebo group 
100 mg group 
200 mg group 
400 mg group 
Placebo 
200 mg 
100 mg 
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9.1.1 
Screening Phase 
Subjects must be fully informed of the nature of the study and written informed consent must 
be obtained prior to the start of any assessment/evaluation for this study.  The procedure for 
obtaining informed consent is described in Section 5.3. 
Subjects who submitted informed consent will undergo screening evaluations between  
Day –42 and Day –1 to confirm that each subject meets all the inclusion criteria and none of 
the exclusion criteria.   
Results of the screening assessments will be recorded in the CRF.  If a subject is judged 
ineligible to enroll the study, the reason should also be recorded in the CRF. 
For subjects who require prophylactic treatments with isoniazid based on the results of the 
tuberculosis test at the Screening Phase, the prophylactic treatments are needed for at least 21 
days before starting the study treatment, so the duration of the Screening Phase may be 
extended until 21 days from the start of isoniazid administrations.  If a patient requires 
another syphilis test based on the result in the Screening Phase, reexamination has to be 
performed after an interval of 21 days or longer during the Screening Phase. The Screening 
Phase can be extended until the reexamination result is obtained.   
9.1.2 
Observation Phase (Day 1: Predose) 
Subjects who complete the assessments in the Screening and Observation Phases and meet 
the criteria for inclusion/exclusion (Sections 9.3.1 and 9.3.2) will start the Treatment Phase. 
9.1.3 
Treatment Phase 
Subjects with confirmed eligibility in the Observation Phase to enter the study will be 
randomized to E6011 100 mg, 200 mg, 400 mg, or placebo group at a 1:2:2:2 ratio through 
dynamic allocation using the following factors: CRP level at the Screening Phase, disease 
duration and history of biologics treatment.  Subjects will receive either E6011 or placebo at 
Weeks 0, 1, 2, and then every 2 weeks until Week 22 in a double-blind manner. 
9.1.4 
Extension Phase 
Subjects who complete evaluations at Week 24 of the Treatment Phase will enter the 
Extension Phase.  The investigator or subinvestigator must confirm that all data through 
Week 24 of the Treatment Phase (the double-blind part) are completely entered into CRFs by 
Week 26, when the initial assessments in the Extension Phase will be performed.  Each 
subject’s assigned treatment group will be blinded until the database of the Treatment Phase 
is fixed. 
The Extension Phase is up to 104 weeks after the start of the study treatment, and subjects 
will receive an open-label E6011 200 mg every 2 weeks until Week 102.  If the investigator 
or subinvestigator judges that the response to treatment is insufficient in the Extension Phase, 
administration of E6011 400 mg every 2 weeks will also be allowed (reduction of the dose 
back to 200 mg after an increase to 400 mg will also be allowed). 
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9.1.5 
Follow-up Phase 
If subjects complete or discontinue the study, a follow-up visit should be conducted 28 days 
after the completion or discontinuation of the study, and a follow-up visit or telephone 
interview should be conducted 70 days after the last dosing. 
9.2 
Discussion of Study Design, Including Choice of Control Groups 
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison, dose-response study with a primary objective to evaluate the efficacy and safety 
of repeated subcutaneous administrations of E6011 in RA subjects who inadequately respond 
to a treatment with MTX. 
In all of the recommendations of the European League Against Rheumatism (EULAR) (Josef 
SS, et al., 2013), the guideline of the American College of Rheumatology (ACR) (Singh JA, 
et al., 2016), and “the guideline for the use of TNF inhibitors” of the Japan College of 
Rheumatology, a basic treatment for RA is the one with low molecular weight DMARDs, 
particularly MTX, a standard therapeutic drug, and biologics are considered as a secondary 
option when patients inadequately respond to MTX.  For a clinical study of E6011, we 
consider it appropriate to target those who inadequately respond to MTX (a standard 
therapeutic drug for RA) as subjects. 
Randomization will be used for avoiding bias in assigning subjects to treatment groups, and 
making the distributions of subject characteristics (such as demographics and other baseline 
characteristics), known and unknown, of treatment groups be similar, as well as improving 
the validity of statistical comparison among groups.  Blinding will be also employed to avoid 
the occurrence of bias in data collections or evaluation of endpoints.  In this study, placebo 
will be used as a comparator drug and subjects will be randomized to treatment groups 
through dynamic allocation using the following factors with a potential impact on efficacy 
evaluations: CRP level at the Screening Phase, disease duration and history of biologics 
treatment. 
All of the EULAR recommendations (Josef SS, et al., 2013), the ACR guideline (Singh JA, 
et al., 2016), and the guideline for the use of TNF inhibitors of the Japan College of 
Rheumatology indicate that drug therapies for RA should be reviewed every 3 or 6 months.  
“The Guideline for the clinical evaluation of antirheumatic drugs” also describes that “the 
duration of Phase 3 study should be determined according to the properties of an 
investigational drug and should be approximately 12 weeks in general or up to 6 months as 
needed”.  In fact, many clinical studies in RA patients are designed to have a primary 
evaluation time point at Week 12 or 24. 
Since the result from Study 103 suggested the efficacy of E6011 in its 12-week treatment 
period, the primary endpoint of this study is determined to be ACR20 response rate at 
Week 12.  E6011 is expected to have an inhibitory effect against the structural damage of 
joints through inhibition of bone absorption in RA.  Therefore, modified Total Sharp Score 
(mTSS), a measure for joint destruction progression, is also evaluated in this study.  “The 
Guideline for the clinical evaluation of antirheumatic drugs” and clinical study data of 
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similar drugs to E6011 indicate that at least 24 weeks is required for mTSS evaluation; thus, 
the double-blind part of this study is designed to be 24 weeks. 
Subjects who complete the double-blind part for 24 weeks will be able to proceed to the 
Extension Phase, where E6011 200 mg may be administered every 2 weeks up to Week 104 
in an open-label manner.  Our target is patients who inadequately respond to MTX, a 
standard therapeutic agent for RA.  Therefore, we consider that the study design where 
subjects can continue E6011 treatment is useful from the perspective of patient benefit.   
Furthermore, if the subjects insufficiently respond to the treatment in the Extension Phase, 
the design also allows for administration of E6011 400 mg every 2 weeks 
The Follow-up Phase was set to be 70 days after the last dose of the study drug, which is 
approximately 5 times of the longest half-life of E6011 in the previous clinical data. 
9.3 
Selection of Study Population 
Subjects who meet all of the inclusion criteria and do not meet any of the exclusion criteria 
will be eligible to receive study drug. 
9.3.1 
Inclusion Criteria 
Subjects must meet all of the following criteria to participate in this study: 
1. Aged ≥18 and <75 years old at the time of written informed consent 
2. RA patients who meet the 1987 ACR criteria or 2010 ACR/EULAR criteria ≥12 weeks 
before written informed consent 
3. Received MTX treatment at 6 to 16 mg/week for ≥12 weeks before screening and 
presented ≥6 tender joints (out of 68 joints) and ≥6 swollen joints (out of 66 joints) in the 
Screening and Observation Phases 
4. Able to continue a stable dose regimen of MTX at 6 to 16 mg/week from 4 weeks or 
more before starting the study treatment until completion of the Extension Phase (or until 
study discontinuation) 
5. For patients with a history of biologics treatment for RANote, the following criteria should 
be fulfilled.  
(Note: This includes those treated in clinical studies) 
• 
The history of biologics treatment for RA with any of adalimumab, infliximab, 
golimumab, certolizumab pegol, etanercept, tocilizumab, and abatacept (including 
biosimilars). 
• 
No biologics treatment for RA within 12 weeks prior to the study treatment 
6. CRP level ≥0.6 mg/dL or erythrocyte sedimentation rate (ESR) ≥28 mm/hr in the 
Screening Phase 
7. Erosions at ≥3 sites in radiographic joint image in the Screening Phase, or those with 
erosions at ≥1 site and either positive for rheumatoid factor (RF) or anti-cyclic 
citrullinated peptide (CCP) antibody in the Screening Phase 
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8. Weighs ≥30 kg and ≤100 kg in the Screening Phase 
9. Has voluntarily consented, in writing, to participate in this study.  If a subject is below 
the age of 20, a legally acceptable representative should provide written consent 
10. Has been thoroughly briefed on the requirements of the study, can understand, and is 
willing and able to comply with all aspects of the protocol 
9.3.2 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from this study: 
1. Any history or complication of inflammatory arthritic disorderNote other than RA and 
Sjogren’s syndrome 
(Note: This includes arthritis associated with viral infection, systemic lupus 
erythematosus, mixed connective tissue disease, dermatomyositis/polymyositis, 
scleroderma, rheumatic polymyalgia, psoriatic arthritis, and arthritis occurring under 16 
years of age) 
2. Class IV in the Criteria for Functional Status in RA (the ACR 1991 Revised Criteria) in 
the Screening Phase 
3. Received biologics treatment for RA but discontinued it because of inadequate response 
4. Received disease-modifying antirheumatic drugs (DMARDs) other than MTX within 4 
weeks before staring the study treatment 
5. Received reflunomid or tofacitinib within 12 weeks before starting the study treatment 
6. Received corticosteroids equivalent to >10 mg/day of prednisolone within 4 weeks before 
starting the study treatment 
7. Received corticosteroids (intraarticular, intramuscular, or intravenous), intraarticular 
injection of sodium hyaluronate (including sodium hyaluronate crosslinked polymer and 
sodium hyaluronate crosslinked polymer crosslinked with vinylsulfone), intraarticular 
injection of local anesthesia agent, or an analgesic other than NSAIDs (oral, suppository, 
and topical) within 4 weeks before starting the study treatment 
8. Treatment with MTX, folic acid, corticosteroids (equivalent to ≤10 mg/day of 
prednisolone, taken orally or by suppository) or herbal medicine indicated for RA was 
started, or dose regimen was modified within 4 weeks before starting the study treatment 
(however, if MTX dose was increased or decreased beyond 4 mg at one time, MTX 
should be used at a stable regimen for 8 weeks before starting the study treatment). 
9. Underwent arthrocentesis/drainage within 4 weeks before starting the study treatment or 
cytapheresis therapy within 8 weeks before starting the study treatment 
10. Underwent surgical operation on the joint (including synovectomy and repair of tendon 
rupture) which is evaluated in this study within 8 weeks before informed consent 
11. Received cyclophosphamide, cyclosporin (except for eye drop solution), azathioprine, or 
denosumab within 52 weeks before starting the study treatment 
12. Received immunoglobulin preparations or blood products within 24 weeks before starting 
the study treatment 
13. Received a live vaccine within 12 weeks before starting the study treatment, or is 
planning to receive one 
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14. Any current clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, or 
renal disease) that could affect the subject’s safety or interfere with the conduct of study 
in the opinion of the investigator or subinvestigator 
15. Any current uncontrolled disorders such as acute cardiac infarction, unstable angina, 
brain infarct, or symptomatic intracerebral hemorrhage 
16. Severe or uncontrolled diabetes 
17. History of severe allergy (shock or anaphylactoid symptoms) 
18. History or current clinical condition of malignant tumor, lymphoma, leukemia, or 
lymphoproliferative disease, except for skin carcinoma (epithelial carcinoma or basal cell 
carcinoma) and cervix carcinoma which have been completely excised and without 
metastasis or recurrence for more than 5 years before informed consent 
19. Immunodeficiency or history of human immunodeficiency virus (HIV) infection 
20. Infection requiring hospitalization or intravenous administration of antibiotics within 4 
weeks before starting the study treatment or disease requiring administration of antivirus 
drugs (e.g., herpes zoster) within 4 weeks before starting the study treatment 
21. History of tuberculosis or current active tuberculosis 
22. History of clinically important vasculitis 
23. Tested positive for any of the following in the Screening Phase: HIV, hepatitis B virus 
surface antigen (HBs antigen), hepatitis B virus surface antibody (HBs antibody), 
hepatitis B virus core antibody (HBc antibody), hepatitis B virus DNA (HBV DNA), 
hepatitis C virus antibody (HCV antibody), human T-lymphotrophic virus type I antibody 
(HTLV-1 antibody), or syphilis (except if positive for the HBs antibody only, and it is 
clear that this is due to hepatitis B vaccination. In case of positive RPR and negative TP 
antibody results in the syphilis test, the positive result is not considered valid if a false 
positivity is confirmed by repeated TP antibody negative results of other syphilis tests 
performed 21 days or more later).  For subjects who are negative for both HBs antigen 
and HBV-DNA quantitative test and positive for either or both of anti-HBc antibody and 
anti-HBs antibody, their study participation is allowed if the investigator or 
subinvestigator takes a proper measure such as HBV-DNA monitoring based on the 
“Guideline for measures against hepatitis B caused by immunosuppression and 
chemotherapy.” 
24. Positive in tuberculosis test (QuantiFERON®TB Gold Test or T-SPOT®.TB Test) in the 
Screening Phase.  For those whose results are “hold” (indeterminable) in repeated tests, 
their study participation is only allowed if they start receiving a prophylactic treatment 
with isoniazid (in principle, 300 mg/day [5 mg/kg/day in case of low weight] for 
approximately 9 months) ≥21 days before starting the study treatment. 
25. Findings indicating a history of tuberculosis on chest x-ray in the Screening Phase 
26. Neurological findings such as motor paralysis, visual impairment, or language disorder in 
the Screening Phase 
27. Blood CD4-positive cell count <200 /μL or white blood cell count <3,000 /μL in the 
Screening Phase 
28. Any of the following laboratory abnormalities in the Screening Phase 
• 
Hemoglobin: 
<8.0 g/dL 
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• 
Neutrophil count: 
<1,500 /μL  
• 
Platelet: 
<100,000 /μL 
• 
AST or ALT: 
>3× the upper limit of normal (ULN) 
• 
Serum creatinine: 
>1.5 mg/dL 
• 
Serum KL-6: 
>ULN 
• 
β-D glucan: 
>ULN 
29. Demonstrated prolonged QTcF interval (>450 ms) in repeated ECG examinations 
30. Women of childbearing potential who have a positive pregnancy test in the Screening or 
Observation Phase or of breastfeeding 
31. Women of childbearing potential who: 
• 
Had unprotected sexual intercourse within 30 days before study entry and who do not 
agree to use a highly effective method of contraception (e.g., total abstinence, an 
intrauterine device [IUD], a double-barrier method [such as condom plus diaphragm 
with spermicide], an oral contraceptive, or have a vasectomized partner with 
confirmed azoospermia) throughout the entire study period or for 70 days after the 
last dosing. 
• 
Are currently abstinent, and do not agree to use a double-barrier method (condom 
plus diaphragm with spermicide) during the study period or for 70 days after the last 
dosing. 
• 
Are using oral contraceptives but are not on a stable dose of the same oral 
contraceptives for at least 4 weeks before study treatment, or who do not agree to use 
the same oral contraceptives during the study or for 70 days after the last dosing.  
• 
All women will be considered to be of childbearing potential unless they are 
postmenopausal [amenorrheic for at least 12 consecutive months, in the appropriate 
age group, and without other known or suspected cause] or have been sterilized 
surgically [i.e., either of bilateral tubal ligation, total hysterectomy, or bilateral 
oophorectomy was performed at least 1 month before dosing of study drug]). 
32. Men who have not had a successful vasectomy (without confirmed azoospermia) and 
their female partners do not meet any of the criteria above (however, study entry is 
allowed if the female partner is not of childbearing potential or practicing highly effective 
contraception throughout the study period or for 70 days after the last dosing).  No sperm 
donation is allowed during the study period or for 70 days after the last dosing. 
33. Scheduled for surgery during the study 
34. Currently enrolled in another clinical study or used any investigational drug or device 
within 28 days (or 5× the half-life, whichever is longer) before informed consent 
35. Has been treated with E6011 or any unapproved biologics for RA. 
36. Use of a psychotropic agent as recreational purpose other than therapeutic purpose 
37. Any history of a medical condition or a concomitant medical condition that in the opinion 
of the investigator or subinvestigator would compromise the subject’s ability to safely 
complete the study 
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9.3.3 
Removal of Subjects From Therapy or Assessment 
The investigator or subinvestigator may withdraw the subject from the study at any time for 
safety or administrative reasons.  The subject may stop study drug or withdraw from the 
study at any time for any reason. 
All subjects who discontinue the study should be followed for procedures/assessments at 
discontinuation as specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, 
Table 4; also see Section 9.5.5 “Completion/Discontinuation of Subjects” for more 
information).  
A subject will be withdrawn from the study under any of the following circumstances. 
1. Occurrence of AE that made it difficult to continue the study 
2. Subject is pregnant. 
3. Subject's ineligibility is confirmed. 
4. Concomitant medication or therapy cannot be continued in accordance with the protocol. 
5. Required surgical operation on arthritic disorder 
6. Diagnosed with malignant tumor 
7. Tested positive in tuberculosis test (QuantiFERON TB® Gold Test or T-SPOT®.TB Test)   
8. Tested positive for any of the following: HIV, HBs antigen, HBV DNA, HCV antibody, 
HTLV-1 antibody, or syphilis (except if false positive for the syphilis test) 
9. When the investigator or subinvestigator judges that efficacy of E6011 is insufficient, 
after the date Version 6 of the protocol was approved by IRB 
10. When the investigator or subinvestigator judges that there are other effective treatment 
options available besides continuing this study, after the date Version 6 of the protocol 
was approved by IRB 
Withdrawal from the study will be considered if a subject skips 3 consecutive 
administrations. 
9.4 
Treatments 
9.4.1 
Treatments Administered 
Treatment Phase:  In the E6011 100 mg, 200 mg, or placebo groups, subjects will receive 
each dose at Weeks 0, 1, 2 and then every 2 weeks up to Week 22 by 
repeated subcutaneous administration.  In the E6011 400 mg group, 
subjects will receive 400 mg at Weeks 0, 1, 2, 4, 6, 8, 10 and then 200 mg 
every 2 weeks up to Week 22 by repeated subcutaneous administration. 
Extension Phase:  Subjects will receive E6011 200 mg every 2 weeks from Week 24 to 
Week 102 by repeated subcutaneous administration. When subjects 
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insufficiently respond to the treatment, repeated subcutaneous 
administration (400 mg of E6011 every 2 weeks) will be allowed. 
The study drug contains E6011 50 mg, 100 mg, or placebo in 1 vial (1 mL).  In the Treatment 
Phase, 4 mL will be subcutaneously administered in Weeks 0 to 10, and 2 mL will be 
subcutaneously administered in Weeks 12 to 22.  In the Extension Phase, 2 mL will be 
subcutaneously administered for the 200 mg dosing and 4 mL will be subcutaneously 
administered for the 400 mg dosing. 
In the 2 mL administration, subjects will receive study drug subcutaneously in 2 separate 
sites, 1 mL each, from the following sites: right or left upper arm, right or left abdomen, or 
right or left thigh.  In the 4 mL administration, subjects will receive study drug 
subcutaneously in 4 separate sites, 1 mL each.  However, 2 mL of the study drug may be 
given subcutaneously in 1 site only if the investigator or subinvestigator judges that the study 
drug can be administered properly. 
The dose and administration method for the study drug is described in Table 1. 
Study drug will be administered upon completion of all the planned assessments (except for 
findings on injection sites) on the day of study drug administration.  On the first and second 
administrations of the study drug in both the Treatment and Extension Phases (i.e., Weeks 0, 
1, 24, and 26), subjects are required to stay at the site for at least 60 minutes after dosing to 
confirm its safety before being discharged. 
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Table 1 
Dose and Administration of the Study Drug 
Phase 
Dose 
Dosage Volume 
Dosage and Injection Site 
Treatment Phase: 
Weeks 0 to 10 
(Double-blind)  
100 mg 
200 mg 
400 mg 
or 
placebo 
4 mL 
(4 vialsb) 
Study drug will be given subcutaneously in 4 
separate sites, 1.0 mL each, among the 
following sites: right or left upper arm, right or 
left abdomen, or right or left thigh.   
(The study drug may be given subcutaneously in 
2 separate sites, 2 mL each, only if the 
investigator or subinvestigator judges that the 
study drug can be administered properly.) 
Treatment Phase: 
Weeks 12 to 22 
(Double-blind)  
100 mg 
200 mg 
or 
placebo 
2 mL 
(2 vialsc) 
Study drug will be given subcutaneously in 2 
separate sites, 1.0 mL each, among the 
following sites: right or left upper arm, right or 
left abdomen, or right or left thigh.   
Extension Phase: 
Weeks 24 to 102 
(Open label) 
200 mg 
2 mL 
(2 vialsd) 
Study drug will be given subcutaneously in 2 
separate sites, 1.0 mL each, among the 
following sites: right or left upper arm, right or 
left abdomen, or right or left thigh.  
 (2 mL of the study drug may be given 
subcutaneously in 1 site only if the investigator 
or subinvestigator judges that the study drug can 
be administered properly.) 
400 mga 
4 mL 
(4 vialse) 
Study drug will be given subcutaneously in 4 
separate sites, 1.0 mL each, among the 
following sites: right or left upper arm, right or 
left abdomen, or right or left thigh.   
(The study drug may be given subcutaneously in 
2 separate sites, 2 mL each, only if the 
investigator or subinvestigator judges that the 
study drug can be administered properly.) 
a: When subjects insufficiently respond to the treatment, repeated subcutaneous administration (400 mg of 
E6011 every 2 weeks) will be allowed. 
b: 2×50 mg/mL vial and 2×0 mg/mL vial for 100 mg administration, 4×50 mg/mL vial for 200 mg 
administration, 4×100 mg/mL vial for 400 mg administration, and 4×0 mg/mL vial for placebo 
c: 2×50 mg/mL vial for 100 mg administration, 2×100 mg/mL vial for 200 mg administration, and 2×0 mg/mL 
vial for placebo 
d: 2×100 mg/mL vial for 200 mg administration 
e: 4×100 mg/mL vial for 400 mg administration 
 
9.4.2 
Identity of Investigational Products 
The study drugs for this study are provided in Table 2.   
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Study drugs will be packed as per the study design and provided by the sponsor.  Details of 
labeling and package of the study drugs are shown in Appendix 5. 
Table 2 
Study Drugs 
Study Drug 
Dosage Form and Strength 
E6011 
Aqueous solution containing 50 mg or 100 mg E6011 in a vial (1 mL) 
Placebo 
Aqueous solution containing no E6011 in a vial (1 mL) 
Storage Condition:  2 to 8 °C, protected from light. 
Manufacturer:  Eisai Co., Ltd. 
The study drugs for the Treatment Phase (double-blind) will be provided in small boxes 
packed in 2 large boxes, one containing small boxes for 5 administrations (Weeks 0 to 6) and 
the other containing small boxes for 8 administrations (Weeks 8 to 22).  
The study drugs for the Extension Phase (100 mg E6011 in 1 mL vial) will be provided in 
boxes containing 10 vials each. 
9.4.2.1 
Chemical Name and Structural Formula of E6011 
• 
Test drug code:   
E6011 
• 
Generic name:   
To be determined 
• 
Chemical name:   
IgG2 
• 
Molecular weight:   147 kDa 
• 
Structural formula:  glycoprotein with immunoglobulin structure having 2 heavy chains 
(445 amino acids/chain) 
 
linked by disulfide bonds to 2 light chains (214 amino acids/chain) 
9.4.2.2 
Comparator Drug 
Placebo 
9.4.2.3 
Labeling for Study Drug 
The following information has to be provided: 
• 
Statement to the effect “For clinical study use only” 
• 
Name and address of the sponsor 
• 
Chemical name and Identification number 
• 
Manufacturing number or symbol 
• 
Storage conditions 
9.4.2.4 
Storage Conditions 
Study drug will be stored in accordance with the specified storage conditions.  The study 
drug manager (or designee) will monitor the temperature at the storage location to ensure that 
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the study drug is maintained within an established temperature range.  The study drug 
manager (or designee) is responsible for ensuring that the temperature is monitored 
throughout the study period and that records are maintained; the temperature should be 
monitored continuously by using an in-house validated data acquisition system, by using an 
automatic temperature recording device or by manual means, such that minimum and 
maximum thermometric values over a specific time period can be recorded and retrieved as 
required. 
9.4.3 
Method of Assigning Subjects to Treatment Groups 
Subjects will be assigned to treatment groups through dynamic allocation algorithm that will 
be prepared by an independent enrollment center. 
After screening assessments are performed within 42 days before starting the study 
treatment, eligible subjects will be randomized to E6011 100 mg, 200 mg, 400 mg, or 
placebo at a 1:2:2:2 ratio through dynamic allocation using the following factors: CRP level 
at the Screening Phase, disease duration and history of biologics treatment.   
Randomization will be performed centrally by an interactive web response system (IWRS).  
The person responsible for randomization will generate the list of randomized drug numbers.  
At screening, the investigator or designee will access the IWRS to register the subject 
information.  The independent enrollment center will confirm the eligibility of the subject, 
assign each subject to a treatment group by using dynamic allocation algorithm, and inform 
the drug number to the investigator or subinvestigator via email.  Upon completing all the 
planned assessments at the Observation Phase, the investigator or subinvestigator will 
prescribe the study drug for the eligible subject based on the drug number specified by the 
independent enrollment center. 
9.4.4 
Selection of Doses in the Study 
In the Treatment Phase (12 weeks) of Study 103, 21 of 37 subjects (56.8%) experienced 
adverse events (AEs).  AEs occurring in 2 or more subjects were injection site erythema, 
nasopharyngitis, headache, and oropharyngeal pain.  As a dose-dependent increase in the 
incidence of adverse reactions or occurrence of events to be concerned related to E6011 were 
not observed in Study 103, we consider that subcutaneous administration of E6011 is 
generally safe and tolerated in RA subjects at a dose up to 400 mg every 2 weeks.  Regarding 
the efficacy, although Study 103 was an open-label study without a placebo control, the 
clinical symptoms of RA tended to improve in all of the E6011 100 mg, 200 mg, and 400 mg 
groups in evaluations up to Week 12.   
The relationship between E6011 and its target membrane-bound FKN was investigated based 
on PK/PD analysis using serum E6011 and total FKN concentrations (sum of free FKN and 
E6011-FKN complex) in Study 001 and Study 002.  Based on the result, the share of 
membrane-bound FKN for E6011 at Week 12 was estimated to be 98.9% and 99.6% in the 
E6011 100 mg and 200 mg groups in Study 103, respectively.  It is reported that the share of 
membrane-bound FKN for biologics commercially available as RA drugs and given at 
clinically recommended dose was estimated to be approximately 99.5% (Tani K, et al, 2013).  
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Thus sufficient share of membrane-bound FKN and improvement of clinical symptoms can 
be expected with E6011 200 mg, and we determined that the administration of 200 mg every 
2 weeks is appropriate as a central dose.  We also set the dose of 400 mg as a high-dose level, 
since earlier achievement of sufficient share of membrane-bound FKN and improvement of 
clinical symptoms may be expected in that dose.  However, since 400 mg administration 
requires 4 subcutaneous administrations (or 2 subcutaneous administrations of 2 mL each), 
evaluations with 400 mg administrations are limited to 12 weeks (for the primary evaluation 
period) to reduce the burden on the subjects (particularly those who are given placebo for 24 
weeks) and the subjects will receive 200 mg (central dose) subcutaneously in 2 separate sites 
from Week 12 onward. 
“The guideline for the clinical evaluation of antirheumatic drugs” recommends a Phase 2b 
study include placebo and 3 doses of active drug.  To collect data on the dose response and 
safety of E6011 with the widest possible dose range, we consider it appropriate to set the 
following 3 active drug groups: E6011 200 mg as a central dose group; E6011 100 mg as a 
low-dose group; and E6011 400 mg as initial dose administered until Week 10 and 200 mg 
after Week 12 as a high-dose group.  E6011 100 mg is only set as a dose for evaluation of the 
dose response and not for evaluation of the efficacy compared with placebo. 
In the Extension Phase, subjects will receive 200 mg administrations of E6011 (central dose) 
every 2 weeks. However, when subjects insufficiently respond to the treatment (E6011 200 
mg every 2 weeks), dose escalation will be allowed (E6011 400 mg every 2 weeks). 
E6011 is to be administered at Weeks 0, 1, 2, and then every 2 weeks because a loading 
administration 1 week after the first administration led to the prompt achievement of steady 
state in PK in Study 103. 
9.4.5 
Selection and Timing of Dose for Each Subject 
Please refer to Section 9.4.1 “Treatments Administered”. 
Study drugs can be administered regardless of the meal time.  Study drugs must be 
administered upon completion of all the planned assessments (except for findings on 
injection site) on the day. 
9.4.6 
Blinding 
During the double-blind part, subjects and all personnel involved in the conduct of study and 
evaluations, including investigators, subinvestigators, and clinical research associates 
(CRAs), will be blinded to the treatment codes.  Randomization data will be kept strictly 
confidential, filed securely by the sponsor or CRO and accessible only to authorized persons 
(e.g., Eisai Global Safety) until the time of unblinding, per standard operating procedures 
(SOP). 
Although the Extension Phase is an open-label part, each subject’s assigned treatment group 
will be blinded to subjects and any personnel involved in the conduct of study or evaluations, 
including investigators, subinvestigators, and CRAs, until the database of the Treatment 
Phase is fixed. 
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The bioanalytical laboratory and the immunogenicity assay laboratory will report the results 
to the sponsor after unblinding.  
Joint x-ray images will be directly sent to the institute of joint x-ray central evaluation and 
evaluated in a blinded manner so as to maintain the blindness.  After unblinding, the sponsor 
will obtain the evaluation results of those joint x-ray images captured by Week 24. 
• 
Key code and emergency key code 
After study drug randomization (and prior to delivering the assigned study drug to the site), 
the person responsible for randomization will immediately seal the key codes and keep them 
until unblinding.  The emergency key code will be prepared to assure the subjects’ safety.  
After study drug randomization (and prior to delivering the assigned study drug to the site), 
the person responsible for randomization will immediately seal the emergency key code for 
each subject (per drug number) and the emergency key code center will store them until 
unblinding.  Only in the case of a medical emergency where information about the assigned 
study drug is needed (including regulatory requirements) for appropriate treatment of the 
subject or ensuring the subject’s safety, the emergency key code for the subject may be 
broken (opened). 
At unblinding, the person responsible for randomization will verify that all the emergency 
key codes are maintained for blinding, except those broken (opened) according to the 
prescribed procedure.  
• 
Sealing boxes of study drugs at collection by the sponsor 
The study drug manager (or designee) must check the number of all opened and unused study 
drugs and seal (stamp or sign) the opened box containing unused study drugs at collection by 
the sponsor. 
• 
Procedures for unblinding 
After database lock, the sponsor will ask the person responsible for randomization for 
unblinding, and the person responsible for randomization will break (open) the key code. 
9.4.7 
Prior and Concomitant Therapy 
Any medication (including over-the-counter medications) or therapy administered to the 
subject between the date of informed consent (12 weeks prior to the consent for DMARDs) 
and the follow-up assessments (28 days after discontinuation or completion of study) will be 
recorded in the CRF.  All prior biologics for RA will be recorded regardless of the timing of 
dosing.  The investigator or subinvestigator will record any concomitant medication/therapy 
associated with the occurrence of AEs in the CRF.  However, medications, test agents, 
solvents or fluid infusions used as pretreatment for surgery, examination, or drug 
administration will not be considered concomitant drugs.   
For prior and concomitant medications indicated above, the name, administration route, dose 
(medications for RA and folic acid only [not for NSAIDs]), treatment start date (or timing of 
treatment initiation), treatment end date, reason for use, and reason for withdrawal (biologics 
for RA only) will be recorded in the CRF.  For concomitant therapy, the name, treatment 
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start date (or timing of treatment initiation) and treatment end date, and reason for 
concomitant use will be recorded in the CRF. 
9.4.7.1 
Prohibited Concomitant Therapies and Drugs 
9.4.7.1.1 
PROHIBITED CONCOMITANT THERAPIES AND DRUGS 
The concomitant use of the following drugs or therapies is prohibited until completion of the 
Extension Phase (or until study discontinuation).  
• 
DMARDs (except MTX) 
• 
Biologics (adalimumab, infliximab, golimumab, certolizumab pegol, etanercept, 
tocilizumab, abatacept, etc.), including biosimilars 
• 
Intraarticular, intramuscular, or intravenous injection of corticosteroids  
• 
Intraarticular injection of sodium hyaluronate (including sodium hyaluronate crosslinked 
polymer and sodium hyaluronate crosslinked polymer crosslinked with vinylsulfone) or 
intraarticular injection of local anesthetic agent  
• 
Arthrocentesis/drainage 
• 
Cytapheresis 
• 
Any analgesics other than NSAIDs (oral, suppository, or topical) 
• 
Cyclophosphamide, cyclosporin (with the exception of eye-drops), azathioprine, or 
denosumab 
• 
Immunoglobulin preparations or blood products 
• 
Live vaccines 
• 
Folic acid preparation or over-the-counter medications containing folic acid as main 
component 
• 
Other investigational drugs or medical devices 
• 
Surgical operations on arthritic disorder 
 
9.4.7.1.2 
RESTRICTED CONCOMITANT THERAPIES AND DRUGS 
• 
MTX and folic acid should be used as a stable dose regimen up to completion of the 
Extension Phase (or until study discontinuation).  However, if an adverse event 
associated with MTX is noted, dose reduction or interruption is permitted. If the event 
disappears after dose reduction or interruption, the dose can be increased to the previous 
level. 
• 
Corticosteroids (equivalent to ≤10 mg/day of prednisolone, taken orally or by 
suppository) and herbal medicine indicated for RA are allowed under restricted 
conditions, but the dose regimen should not to be modified up to Week 24 (or until study 
discontinuation).  Between Week 24 and Week 104, the regimen should not be modified 
except for the following cases: dose reduction, dose interruption, dose increase following 
the dose reduction (up to the initial dose level), and restarting administration after 
interruption. 
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• 
NSAIDs (oral, suppository, or topical) may be taken concomitantly but are prohibited 
between the night before the day of efficacy assessments and the end of the assessments. 
• 
After the date Version 6 of the protocol is approved by IRB, it is unnecessary to record 
concomitant medications/therapies in the CRF. 
9.4.8 
Treatment Compliance 
The investigator, subinvestigator, or clinical research coordinator will record the time and 
status of study drug administrations in the CRF throughout the study period.  If a subject 
cannot complete the entire dose, the reason for incomplete dosing will be recorded in the 
CRF.  CRAs will review treatment compliance during site visits and at the completion of the 
study. 
9.4.9 
Drug Supplies and Accountability 
The study drug manager (or designee) will be responsible for the accountability of all study 
drugs (dispensing, inventory, and record keeping) following the instructions for handling of 
study drugs provided by the sponsor and adherence to GCP guidelines as well as other 
regulatory requirements. 
Under no circumstances will the investigator or subinvestigator allow the study drugs to be 
used other than as directed by this protocol.  Study drugs will not be dispensed to any 
individual who is not enrolled in the study.   
The study drug manager (or designee) must keep accurate and timely records of the number 
of all study drugs received, the number of study drugs prescribed, the number of study 
prescribed to subject but not used (unused drug 1), the number of study drugs dispensed to 
investigational site but not prescribed to subject (unused drug 2) and the number of study 
drugs returned to the sponsor (total of unused drugs 1 and 2), and where applicable (if study 
drugs are discarded at the site).  This includes, but may not be limited to: (a) documentation 
of receipt of study drugs, (b) study drugs dispensing/return reconciliation log per subject, (c) 
drug accountability log, (d) documentation of returns to the sponsor, and (e) certificates of 
destruction for any destruction of study drugs that occurs at the site.   
The drug accountability logs must be made available, upon request, for review by a CRA or 
inspection by a representative of a health authority.  The study drug manager (or designee) 
must check the quantity of all unused study drugs, exchange the study drug return form for 
the study drug recovery form with the sponsor, and return all unused study drugs to the 
sponsor. Unused study drugs that are to be returned from the site will be collected directly by 
CRA and will be returned to the sponsor’s designated depot(s). 
Drug accountability will be reviewed by CRA throughout the study period (during site visits, 
at the completion of the study, etc.). 
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9.5 
Study Assessments 
9.5.1 
Assessments 
9.5.1.1 
Demography 
Demographic information of subjects will be collected during the Screening Phase.  
Demographic information includes date of birth, sex, and race/ethnicity.  In addition to these, 
subject identification code and date of obtaining written informed consent will be also 
documented in the CRF. 
9.5.1.2 
Assessments in the Screening and Observation Phases 
9.5.1.2.1 
SMOKING HISTORY, MEDICAL HISTORY/COMPLICATIONS, AND PHYSICAL 
EXAMINATIONS 
Smoking history, medical history (including surgeries), and comorbidities will be assessed 
during the Screening Phase, and smoking history, surgical history for RA or comorbidities, 
and medical history concerning the exclusion criteria 15, 16, 18, 20, and 26 will be recorded 
in the CRF.  
Physical examinations will be performed at the time points specified in the Schedule of 
Procedures/Assessments (Section 9.5.2.1, Table 4).  The results of the physical examination 
will be recorded in the medical chart at the site.  If changes in physical findings from 
screening meet the definition of an AE, the AE will be recorded in the CRF. 
9.5.1.2.2 
PRIOR MEDICATIONS 
For treatment drugs for RA and folic acid, all biologics for RA and medications other than 
biologics for RA administered after informed consent (12 weeks prior to the enrollment for 
DMARDs) should be recorded in the CRF, with the name, administration route, dose (only 
treatment drugs for RA and folic acid except for NSAIDs), treatment start date (or timing of 
treatment initiation), treatment end date, and reason for discontinuation (biologics for RA 
only) detailed. 
9.5.1.2.3 
DISEASE CHARACTERISTICS OF RA 
• 
Time of Diagnosis 
• 
Classification of Functional Status in RA (ACR 1991 Revised Criteria) 
• 
Number of tender joints and number of swollen joints  
• 
CRP and ESR 
• 
Joint x-ray image (number of bone erosions) 
• 
RF or anticyclic citrullinated peptide (anti-CCP) antibody (positive/negative) 
9.5.1.2.4 
OTHER ASSESSMENTS 
• 
Height and weight 
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• 
Virus tests: HIV, HBs antigen, HBs antibody, HBc antibody, HBV-DNA, HCV antibody, 
and HTLV-1 antibody 
• 
Syphilis testing  
• 
Tuberculosis test (QuantiFERON TB® Gold Test or T-SPOT®.TB Test) 
Assays will be performed at the same laboratory where clinical laboratory tests are conducted 
(except for QuantiFERON TB® Gold Test or when T-SPOT®.TB Test is performed at the 
study institution), and test results will be recorded as a source document at the investigational 
site.  Samples will be handled according to the separately prescribed procedures. 
9.5.1.3 
Efficacy Assessments 
After the date Version 6 of the protocol is approved by IRB, it is unnecessary to conduct 
assessments for efficacy. 
9.5.1.3.1 
ASSESSMENT OF TENDER AND SWOLLEN JOINT COUNTS 
The number of tender joints and the number of swollen joints will be evaluated during the 
Screening and Observation Phases, Treatment Phase (Weeks 2, 4, 8, 12, 16, 20, and 24), 
Extension Phase (up to Week 104, every 4 weeks), and at discontinuation.  As a general rule, 
assessments will be performed by the same investigator or subinvestigator at each site. 
A total of 68 joints will be examined for tenderness by applying pressure to the joint or by 
moving joints.  Tender joints will be marked with tick or cross in corresponding frames of 
the Assessment Sheet for Tender and Swollen Joint Counts (Appendix 7).   A total of 66 
joints (minus 2 hip joints) will be examined for swollen joints.  Swollen joints will be marked 
with open circles in corresponding frames of the Assessment Sheet for Tender and Swollen 
Joint Counts (Appendix 7).  If assessment cannot be made because the subject had a joint 
replacement procedure or due to any other reasons, a filled square will be entered. 
9.5.1.3.2 
ASSESSMENT USING VISUAL ANALOG SCALE (VAS) 
Subjects will be evaluated using a visual analog scale (VAS) during the Observation Phase, 
Treatment Phase (Weeks 2, 4, 8, 12, 16, 20, and 24), Extension Phase (every 4 weeks up to 
Week 104), and at discontinuation.  As a general rule, assessments will be performed by the 
same investigator or subinvestigator at each site. 
For physician’s disease activity assessment, disease activity of the subject will be evaluated 
and the result will be entered by the physician on a score sheet, “Physician’s disease activity 
assessment form” (Appendix 8), by placing a mark on a 100 mm analog scale. 
For patient’s pain assessment, the degree of pain associated with RA will be indicated by the 
subject on a score sheet, “Patient’s pain/disease activity assessment form patient” (Appendix 
9), by placing a mark on a 100 mm analog scale.   
For patient’s disease activity assessment, the degree of disease activity of RA will be 
indicated by the subject on a score sheet, “Patient’s pain/disease activity assessment form 
(Appendix 9), by placing a mark on a 100 mm analog scale. 
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Patient’s pain/disease activity assessments (except for those at discontinuation) must be 
performed prior to any evaluations and tests by the investigator or subinvestigator at the time 
point, so that any influence on the subject’s evaluation can be avoided. 
The investigator, subinvestigator, or clinical research coordinator will read the scale on the 
assessment form and enter the result on the assessment form and the CRF. 
9.5.1.3.3 
ASSESSMENT USING HEALTH ASSESSMENT QUESTIONNAIRE (HAQ) 
Subjects will be evaluated using the health assessment questionnaire (HAQ) during the 
Observation Phase, Treatment Phase (Weeks 2, 4, 8, 12, 16, 20, and 24), Extension Phase (up 
to Week 104, every 4 weeks), and at discontinuation.  
Physical function will be self-evaluated by the subject using a Health assessment 
questionnaire (HAQ) (Appendix 10).  The assessment will be made based on the activities 
capable without any aids or devices.  The assessments (except for that at discontinuation) 
must be performed prior to any evaluations and tests by the investigator or subinvestigator at 
the time point, so that any influence on the subject’s evaluation can be avoided.  The 
investigator or subinvestigator will verify the report by the subject for its accuracy and 
consistency before releasing the subject.  The result of the completed HAQ will be 
documented in the CRF by the investigator, subinvestigator, or clinical research coordinator.  
This assessment is made based on the activities at each evaluation time point, and the results 
will not be compared with previous data. 
9.5.1.3.4 
ASSESSMENT OF ERYTHROCYTE SEDIMENTATION RATE (ESR) 
Erythrocyte sedimentation rate (ESR) of each subject will be measured during the Screening 
Phase, Observation Phase, Treatment Phase (Weeks 2, 4, 8, 12, 16, 20, and 24), Extension 
Phase (up to Week 104, every 4 weeks), and at discontinuation, and the result will be 
recorded in the CRF. 
9.5.1.3.5 
ASSESSMENT OF C-REACTIVE PROTEIN (CRP) 
CRP of each subject will be measured as part of blood biochemical tests during the Screening 
Phase, Observation Phase, Treatment Phase (Weeks 2, 4, 8, 12, 16, 20, and 24), Extension 
Phase (every 4 weeks up to Week 104), and at discontinuation.  
9.5.1.3.6 
ASSESSMENT OF JOINT X-RAY 
Joint x-ray images will be captured in the Screening Phase, Treatment Phase (Week 24), 
Extension Phase (Weeks 52, 76, and 104), and at discontinuation.  
Joint x-ray images will be sent to the institute of joint x-ray central evaluation with subject 
identification number.  The institute will evaluate the images, and the evaluation results of 
joint x-ray images captured by Week 24 will be submitted to the sponsor after unblinding.  
Joint x-ray images will be evaluated according to the separately prescribed procedures.   
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9.5.1.4 
Pharmacokinetic, Pharmacogenomic, Biomarker, and Immunogenicity 
Assessments 
After the date Version 6 of the protocol is approved by IRB, it is unnecessary to conduct 
assessments for pharmacokinetic, pharmacogenomic, biomarker, and immunogenicity. 
However, pharmacokinetic and immunogenicity assessments will be conducted at 
discontinuation. 
9.5.1.4.1 
PHARMACOKINETIC ASSESSMENTS 
Serum E6011 Concentration 
Blood samples will be collected for measuring serum E6011 concentrations at the time points 
specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).  Serum 
E6011 concentrations will be measured at the bioanalytical laboratory using a validated, 
specific, and selective analytical method.  Planned blood volume for these measurements is 
provided in Table 5 (Section 9.5.2.2).  Samples will be handled according to the separately 
prescribed procedures. 
9.5.1.4.2 
PHARMACOGENOMIC ASSESSMENTS 
Not applicable. 
9.5.1.4.3 
ASSESSMENTS OF BIOMARKERS 
Serum Total FKN Concentration 
Blood samples will be collected for measuring serum total FKN concentrations at the time 
points specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).  
Planned blood volume for these analyses is provided in Table 5 (Section 9.5.2.2).   Samples 
will be handled according to the separately prescribed procedures.  Measurements will be 
conducted at the biomarker assay laboratory. 
Serum Concentrations of RF, Anti-CCP, and MMP-3 
Blood samples will be collected for measuring serum concentrations of rheumatoid factor 
(RF), anticyclic citrullinated peptide (anti-CCP) antibody, and matrix metalloproteinase 
(MMP)-3 at the time points specified in the Schedule of Procedures/Assessments (Section 
9.5.2.1, Table 4).  Planned blood volume for these measurements is provided in Table 5 
(Section 9.5.2.2).  Samples will be handled according to the separately prescribed 
procedures.  Measurements will be conducted at the biomarker assay laboratory. 
Serum Concentrations of Cytokines, LRG1, and Ang2 
Blood samples will be collected for measuring serum concentrations of cytokines 
(granulocyte macrophage colony-stimulating factor [GM-CSF], interferon-γ [IFN-γ], 
interleukin [IL]-1β, IL-6, TNFα, etc.), leucine-rich alpha-2 glycoprotein 1 (LRG1), and 
angiopoietin 2 (Ang2) at the time points specified in the Schedule of Procedures/Assessments 
(Section 9.5.2.1, Table 4).  Planned blood volume for these measurements is provided in 
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Table 5 (Section 9.5.2.2).  Samples will be handled according to the separately prescribed 
procedures.  Measurements will be conducted at the biomarker assay laboratory. 
Serum TRACP-5b Concentration 
Blood samples will be collected for measuring serum concentrations of tartrate resistant acid 
phosphatase (TRACP)-5b at the time points specified in the Schedule of 
Procedures/Assessments (Section 9.5.2.1, Table 4).  Planned blood volume for these 
measurements is provided in Table 5 (Section 9.5.2.2).  Samples will be handled according to 
the separately prescribed procedures.  Measurements will be conducted at the biomarker 
assay laboratory. 
Measurement of Immunocytes Such as Blood CX3CR1-positive Cells 
Blood samples will be collected for measuring immunocytes such as blood CX3CR1-positive 
cells at the time points specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, 
Table 4).  Planned blood volume for these measurements is provided in Table 5 
(Section 9.5.2.2).  Samples will be handled according to the separately prescribed 
procedures.  Measurements will be conducted at the biomarker assay laboratory.  
Vectra™ DA 
Blood samples will be collected for Vectra™ DA, assay kit for biomarkers including 
VCAM-1, epidermal growth factor [EGF], vascular endothelial growth factor [VEGF]-A, 
IL-6, tumor necrosis factor receptor-I [TNF-RI], MMP-1, MMP-3, YKL-40, leptin, resistin, 
serum amyloid A [SAA], and CRP at the time points specified in the Schedule of 
Procedures/Assessments (Section 9.5.2.1, Table 4).  Planned blood volume for these 
measurements is provided in Table 5 (Section 9.5.2.2).  Samples will be handled according to 
the separately prescribed procedures.  Measurements will be conducted at the biomarker 
assay laboratory. 
9.5.1.4.4 
IMMUNOGENICITY ASSESSMENTS 
Serum Anti-E6011 Antibody 
Blood samples will be collected for measuring of serum anti-E6011 antibodies at the time 
points specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).  The 
presence or absence of serum anti-E6011 antibody will be assessed at the immunogenicity 
assay laboratory using a validated, specific, and selective analytical method.  When anti-
E6011 antibodies are observed, the neutralization activity and isotypes of the anti-E6011 
antibody will be evaluated.  Planned blood volume for these measurements is provided in 
Table 5 (Section 9.5.2.2).  Samples will be handled according to the separately prescribed 
procedures. 
9.5.1.5 
Safety Assessments 
Safety assessments will consist of the following, as specified in the Schedule of 
Procedures/Assessments (Section 9.5.2.1, Table 4). 
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All AEs observed; regular monitoring of clinical laboratory tests (including vasculitis marker 
tests), vital signs, chest x-ray, standard 12-lead electrocardiograms, physical findings, 
injection site findings, and neurological findings. 
9.5.1.5.1 
ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered an investigational product.  An AE does not necessarily 
have a causal relationship with the medicinal product.  For this study, the study drugs are 
E6011 and placebo.  
The criteria for identifying AEs in this study are: 
• 
Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
whether or not considered related to the investigational product (Note:  Every sign or 
symptom should not be listed as a separate AE if the applicable disease [diagnosis] is 
being reported as an AE) 
• 
Any new disease or exacerbation of an existing disease 
• 
Any deterioration in nonprotocol-required measurements of a laboratory value or other 
clinical test (eg, ECG or x-ray) that results in symptoms, a change in treatment, or 
discontinuation of study drug 
• 
Recurrence of an intermittent medical condition (eg, headache) not present pretreatment 
(Baseline) 
• 
An abnormal laboratory test result should be considered an AE if the identified laboratory 
abnormality leads to any type of intervention, withdrawal of study drug, or withholding 
of study drug, whether prescribed in the protocol or not 
However, worsening of the primary disease (RA) is not considered an AE unless the 
symptom aggravated unexpectedly (slight change of RA condition is captured under efficacy 
assessments as disease progression rather than as an AE). 
It is the responsibility of the investigator to review all laboratory findings in all subjects and 
determine if they constitute an AE.   
All AEs observed during the study will be reported on the CRF.  All AEs, regardless of 
relationship to study drug or procedure, must be collected during the time the subject signed 
the informed consent and 70 days after the subject’s last dose.  Subjects who failed screening 
in Screening or Observation Phase primarily due to AE(s), such AE(s) and seriousness must 
be recorded in the CRF. 
Any laboratory abnormality considered to constitute an AE will be reported on the CRF.  
Abnormal laboratory values are listed as separate AEs if they are considered to be part of the 
clinical syndrome that is being reported as an AE.  Medical and scientific judgment is 
exercised in deciding whether an isolated laboratory abnormality is classified as an AE. 
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All AEs must be followed for 70 days after the subject’s last dose, or until resolution, 
whichever comes first.  However, all SAEs must be followed until resolution or, if resolution 
is unlikely, to stabilization.   
Every effort must be made by the investigator to categorize each AE according to its severity 
and its relationship to the study treatment. 
Assessing Severity of Adverse Events 
Adverse events will be graded on a 5-point scale according to Common Terminology Criteria 
for Adverse Event (CTCAE v4.0).  Investigators will report CTCAE grades for all AEs for 
increasing severity.   
As to ALP and γ-GTP, criteria for Grade 2 will be changed from ULN×2.5 (in the CTCAE) 
to ULN×3.0. 
Assessing Relationship to Study Treatment 
Items to be considered when assessing the relationship of an AE to the study treatment are: 
• 
Temporal relationship of the onset of the event to the initiation of the study treatment 
• 
The course of the event, especially the effect of discontinuation of study treatment or 
reintroduction of study treatment, as applicable 
• 
Whether the event is known to be associated with the study treatment or with other 
similar treatments 
• 
The presence of risk factors in the study subject known to increase the occurrence of the 
event 
• 
The presence of nonstudy, treatment-related factors that are known to be associated with 
the occurrence of the event 
Classification of Causality 
Not related 
A causal relationship between the study drug and the AE is not a 
reasonable possibility. 
Related 
A causal relationship between the study drug and the AE is a reasonable 
possibility. 
9.5.1.5.2 
SERIOUS ADVERSE EVENTS AND EVENTS ASSOCIATED WITH SPECIAL SITUATIONS 
A serious adverse event (SAE) is any untoward medical occurrence that at any dose: 
• 
Results in death 
• 
Is life-threatening (ie, the subject was at immediate risk of death from the adverse event 
as it occurred; this does not include an event that, had it occurred in a more severe form 
or was allowed to continue, might have caused death) 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
Results in persistent or significant disability/incapacity 
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• 
Is a congenital anomaly/birth defect (in the child of a subject who was exposed to the 
study drug) 
Other important medical events that may not be immediately life-threatening or result in 
death or hospitalization but, when based on appropriate medical judgment, may jeopardize 
the subject or may require intervention to prevent one of the outcomes in the definition of 
SAE listed above should also be considered SAEs.  Medical and scientific judgment should 
be exercised in deciding whether expedited reporting is appropriate in such situations.  
In addition to the above, events associated with special situations include pregnancy or 
exposure to study drug through breastfeeding; AEs associated with study drug overdose, 
misuse, abuse, or medication error.  These events associated with special situations are to be 
captured using the SAE procedures (see Section 9.5.4.2 and Section 9.5.4.3) but are to be 
considered as SAEs only if they meet one of the above criteria.  All AEs associated with 
special situations are to be reported on the CRF whether or not they meet the criteria for 
SAEs.   
All SAEs must be followed to resolution or, if resolution is unlikely, to stabilization. 
The following hospitalizations are not considered to be SAEs because there is no “adverse 
event” (ie, there is no untoward medical occurrence) associated with the hospitalization: 
• 
Hospitalizations for respite care  
• 
Planned hospitalizations required by the protocol 
• 
Hospitalization planned before informed consent (where the condition requiring the 
hospitalization has not changed after study drug administration) 
• 
Hospitalization for administration of study drug or insertion of access for administration 
of study drug 
• 
Hospitalization for routine maintenance of a device (eg, battery replacement) that is in 
place before study entry 
9.5.1.5.3 
LABORATORY MEASUREMENTS 
Clinical laboratory tests to be performed, including hematology, chemistry, and urinalysis, 
are summarized in Table 3.  The Schedule of Procedures/Assessments (Section 9.5.2.1, 
Table 4) shows the visits and time points at which blood for clinical laboratory tests and 
urine for urinalysis will be collected in the study. 
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Table 3 
Clinical Laboratory Tests 
Category 
Parameters 
Hematology 
WBC count, RBC count, hemoglobin, hematocrit, platelets, and 
differential of WBC (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils) 
Blood chemistry 
 
 Liver function tests 
Total bilirubin, aspartate aminotransferase, alanine 
aminotransferase, alkaline phosphatase, gamma glutamyl 
transpeptidase  
 Renal function tests 
Blood urea nitrogen, creatinine 
 Other 
Glucose, HbA1c, albumin, total cholesterol, HDL cholesterol, LDL 
cholesterol, triglycerides, amylase, inorganic phosphorus, LDH, 
creatine kinase, total protein, uric acid, sodium, potassium, 
chloride, calcium, CRP, KL-6, β-D-glucan 
Urinalysis 
pH, protein, glucose, urobilinogen, ketones, occult blood, specific 
gravity, amylase 
Other 
 
 
Vasculitis marker 
Serum complement titer (CH50), soluble intercellular adhesion 
molecule (ICAM)-1, soluble vascular cell adhesion molecule 
(VCAM)-1, soluble E-selectin, thrombomodulin, D-dimer 
 
Autoantibody 
Antinuclear antibody, anti-DNA antibody 
CRP = C-reactive protein, HDL cholesterol = high-density lipoprotein cholesterol, LDH = lactate dehydrogenase, 
LDL cholesterol = low-density lipoprotein cholesterol, RBC = red blood cell, WBC = white blood cell 
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol (see Section 9.5.1.5.1) and the CRF Completion Guidelines.   In these instances, the 
AE corresponding to the laboratory abnormality will be recorded in the CRF. 
9.5.1.5.4 
VITAL SIGNS AND WEIGHT MEASUREMENTS 
Measurement of vital signs (i.e., systolic and diastolic blood pressure [mmHg], pulse [beats 
per minute], body temperature [in centigrade], and weight [kg)) will be performed at the 
visits specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4) by 
using prespecified methods and recorded in the CRF.  Blood pressure and pulse will be 
measured in the sitting or supine position after a rest for 5 minutes.  All blood pressure 
measurements should be performed on the same arm, and body temperature should be 
measured by axillary thermometer. 
If blood sampling is planned at the same timeframe and vital signs are measured after blood 
collection, measurement of vital signs must be carried out after sufficient time to avoid 
potential influence of blood collection on vital signs. 
9.5.1.5.5 
PHYSICAL EXAMINATIONS 
Physical examinations will be performed at the visits specified in the Schedule of 
Procedures/Assessments (Section 9.5.2.1, Table 4).  Physical examination results will be 
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recorded in the medical chart at the site.  Changes from screening physical examination 
findings that meet the definition of an AE will be recorded in the CRF. 
9.5.1.5.6 
ELECTROCARDIOGRAMS 
Electrocardiograms will be obtained at the visits specified in the Schedule of 
Procedures/Assessments (Section 9.5.2.1, Table 4).  Standard 12-lead ECG recordings will 
be used.  Subjects must be in the supine position for 5 minutes prior to ECG.  The 
investigator or subinvestigator records the results (abnormal or normal) in the CRF.  If blood 
sampling is planned at the same timeframe and ECG is performed after blood collection, 
ECG must be carried out after sufficient time to avoid potential influence of blood collection 
on ECG. 
An ECG abnormality may meet the criteria of an AE as described in this protocol 
(Section 9.5.1.5.1) and the CRF Completion Guidelines.  In these instances, the ECG 
abnormality will be recorded as an AE in the CRF. 
For ECG abnormalities meeting the criteria of an SAE (Section 9.5.1.5.2), the investigator 
must report the sponsor using the SAE form (with the ECG report) via fax, or other means of 
transmission (see “Reporting of Serious Adverse Events”). 
9.5.1.5.7 
OTHER SAFETY ASSESSMENTS 
Chest x-ray 
Chest x-rays (frontal view and lateral view) will be assessed at the time points specified in 
the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).  The investigator or 
subinvestigator will determine whether findings are normal or abnormal, and record the 
results in the CRF.  For any abnormalities meeting the criteria of an AE as defined in this 
protocol (Section 9.5.1.5.1), they should be recorded as an AE in the CRF. 
When a subject who was previously ineligible for this study is enrolled after obtaining 
informed consent again, chest x-ray results which were assessed within 12 weeks before the 
start of study drug administration can be used as screening data, only if the chest x-ray was 
examined for the purpose of this study following the previous informed consent. 
Pregnancy test 
For female subjects of childbearing potential, blood test (quantitative, the central laboratory) 
will be performed at the Screening Phase, Weeks 12, 24, 52, 76, 104, and at discontinuation, 
and on-site test will be performed during the Observation Phase.  All the test results will be 
recorded in the medical chart at the site. 
Injection site findings 
Drug injection sites will be examined on each subject at the time points specified in the 
Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).  The results will be recorded 
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in the medical chart at the site.  Any abnormal findings should be recorded as an AE in the 
CRF. 
Neurological findings 
Subjects will be examined for the presence or absence of neurological findings at time points 
specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4), by using the 
Neurological finding checklist (see Appendix 11), and the results will be recorded in the 
CRF.  If any abnormal neurological findings are suspected anytime at the scheduled or 
unscheduled time points, the subject must be examined by using the Neurological finding 
checklist.  If any abnormal findings appear after administration of the study drug, the sponsor 
must be notified immediately using the Neurological finding report form (Appendix 12) sent 
by fax, etc. and the subject must be examined by a neurologist.  Head MRI (T1-weighted 
image, FLAIR image and diffusion-weighted image) must be performed within 2 weeks and 
the copies of the images must be submitted to the sponsor.  The sponsor must immediately 
transmit any pertinent information to the progressive multifocal leukoencephalopathy (PML) 
evaluation expert, who will advise on whether the treatment should be continued on the 
subject or not.  The study drug administration must be suspended until the evaluation by the 
PML evaluation expert is completed.  Such events should be recorded in the CRF as AEs. 
Blood CD4-positive cell counts 
Blood samples will be collected to measure blood CD4-positive cell counts at the time points 
specified in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).  Planned 
blood volume for these measurements is provided in Table 5 (Section 9.5.2.2). 
The clinical laboratory facility will report the results to the investigational site and the 
sponsor, and the results will be stored as source document at the site.  Samples will be 
handled according to the separately prescribed procedures. 
9.5.1.6 
Other Assessments 
Anti-JC virus antibody test 
Anti-JC virus (JCV) antibody test will be performed at the time points specified in the 
Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4).   Samples will be handled 
according to the separately prescribed procedures. 
9.5.2 
Schedule of Procedures/Assessments  
9.5.2.1 
Study Schedule 
Table 4 presents the schedule of procedures/assessments for this study. 
Each assessment will be performed within 3 days before or after the scheduled date during 
Weeks 1 to 12 or within 7 days before or after the scheduled date after Week 14 using 
Week 0 as a reference point.  In the Follow-up Phase, each assessment will be performed 
within 7 days before or after the scheduled date (“within 7 days after the scheduled date” for 
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the assessments at “70 days after the last dosing”).  However, the interval between study 
treatments should be at least 3 days until 2 weeks after the start of study treatment, and at 
least 6 days after 4 weeks have elapsed since the start of study treatment. If any scheduled 
assessment or administration of the study drug cannot perform within the above period, each 
assessment will still be performed, but administration of the study drug will be skipped.  
After the date Version 6 of the protocol is approved by IRB, it is unnecessary to conduct 
"tender and swollen joint counts/ESR", "VAS/HAQ", "RF/anti-CCP antibody/MMP-3", 
"serum E6011 concentration", "serum anti-E6011 antibody", "serum total FKN 
concentration", "cytokines/LRG1/Ang2", "TRACP-5b", "CX3CR1-positive cell count", or 
"Vectra™ DA". However, assessments of "serum E6011 concentration" and "serum anti-
E6011 antibody" will be conducted at discontinuation. 
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Table 4 
Schedule of Procedures/Assessments in Study E6011-J081-201 
Phase 
Screen 
-ing 
Obser 
-vation 
Treatment 
       Time postdose 
 
Assessment 
Day –42 
to 
Day –1 
W0 
W1 
W2 
W4 
W6 
W8 
W10 
W12 
Day 1 
Day 8 
±3 days 
Day 15 
±3 days 
Day 29 
±3 days 
Day 43 
±3 days 
Day 57 
±3 days 
Day 71 
±3 days 
Day 85 
±3 days 
Pre 
Dosing 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, complication 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
 
Study drug administrationa 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prior treatment / 
concomitant medication or 
therapy 
 
Vital signs 
X 
X 
 
X 
X 
X 
 
X 
 
X 
Height / body weightb 
 Xb 
 
 
 
 
 
 
 
 
X 
Physical findings, injection 
site findingc 
X 
X 
 
X 
X 
X 
 
X 
 
X 
Standard 12-lead ECG 
X 
 
 
 
 
 
 
 
X 
Chest x-ray 
X 
 
 
 
 
 
 
 
 
X 
Pregnancy testd 
X 
Xd 
 
 
 
 
 
 
 
X 
Neurological findingse 
X 
 
 
 
 
 
 
 
 
X 
Anti-JCV antibody test 
X 
 
 
 
 
 
 
 
 
 
Blood CD4-positive cells 
X 
 
 
 
 
 
 
 
 
X 
Viral test, syphilis test, TB 
test 
X 
 
 
 
 
 
 
 
 
 
Number of tender / 
swollen joints, ESR 
X 
X 
 
 
X 
X 
 
X 
 
X 
VAS, HAQ 
 
X 
 
 
X 
X 
 
X 
 
X 
Joint x-ray 
X 
 
 
 
 
 
 
 
 
 
Hematology, blood 
chemistry, urinalysis, RF, 
anti-CCP antibody, 
MMP-3 
X 
X 
 
 
X 
X 
 
X 
 
X 
Autoantibody 
 
X 
 
 
 
 
 
 
 
X 
serum KL-6, β-D glucan  
X 
 
 
 
 
 
 
 
 
X 
Vasculitis marker tests 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
 
Serum E6011 
concentration 
 
X 
 
X 
X 
X 
 
X 
 
X 
Serum anti-E6011 
antibody 
 
X 
 
 
 
X 
 
X 
 
X 
Serum total FKN 
 
X 
 
 
 
 
 
 
 
 
Serum cytokine 
concentration, LRG1, 
Ang2 
 
X 
 
 
 
X 
 
 
 
X 
Serum TRACP-5b 
concentration 
 
X 
 
 
 
 
 
 
 
X 
Immunocytes such as 
blood CX3CR1-positive 
cells 
 
X 
 
 
X 
X 
 
 
 
X 
Vectra™ DA 
 
X 
 
 
 
 
 
 
 
X 
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Table 4  Schedule of Procedures/Assessments in Study E6011-J081-201 
(continued) 
Phase 
Treatment 
               Time postdose
 
Assessment 
W14 
±7 days 
W16 
±7 days 
W18 
±7 days 
W20 
±7 days 
W22 
±7 days 
W24 
±7 days 
Informed consent 
 
 
 
 
 
 
Demographics, medical history, 
complication 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
Study drug administrationa,f 
X 
X 
X 
X 
X 
Xg 
Prior treatment / concomitant 
medication or therapy 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
X 
 
X 
Height / body weightb 
 
 
 
 
 
X 
Physical findings, injection site 
findingc 
 
 
 
 
 
X 
Standard 12-lead ECG 
 
 
 
 
 
X 
Chest x-ray 
 
 
 
 
 
X 
Pregnancy testd 
 
 
 
 
 
X 
Neurological findingse 
 
 
 
 
 
X 
Anti-JCV antibody test 
 
 
 
 
 
X 
Blood CD4-positive cells 
 
 
 
 
 
X 
Viral test, syphilis test, TB test 
 
 
 
 
 
 
Number of tender / swollen joints, 
ESR 
 
X 
 
X 
 
X 
VAS, HAQ 
 
X 
 
X 
 
X 
Joint x-ray 
 
 
 
 
 
X 
Hematology, blood chemistry, 
urinalysis, RF, anti-CCP antibody, 
MMP-3 
 
X 
 
X 
 
X 
Autoantibody 
 
 
 
 
 
X 
Serum KL-6, β-D glucan 
 
 
 
 
 
X 
Vasculitis marker tests 
 
 
 
 
 
X 
Adverse events 
 
 
 
 
 
 
 
Serum E6011 concentration 
 
X 
 
X 
 
X 
Serum anti-E6011 antibody 
 
X 
 
X 
 
X 
Serum total FKN 
 
 
 
 
 
 
Serum cytokine concentration, LRG1, 
Ang2 
 
 
 
 
 
X 
Serum TRACP-5b concentration 
 
 
 
 
 
X 
Immunocytes such as blood CX3CR1-
positive cells 
 
 
 
 
 
X 
Vectra™ DA 
 
 
 
 
 
X 
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Table 4  Schedule of Procedures/Assessments in Study E6011-J081-201 
(continued) 
Phase 
Extension 
               Time postdose
 
Assessment 
W26 
±7 
days 
W28 
±7 
days 
W30 
±7 
days 
W32 
±7 
days 
W34 
±7 
days 
W36 
±7 
days 
W38 
±7 
days 
W40 
±7 
days 
W42 
±7 
days 
W44 
±7 
days 
W46 
±7 
days 
W48 
±7 
days 
W50 
±7 
days 
W52 
±7 
days 
Informed consent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, complication 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administrationa,f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Prior treatment / 
concomitant medication or 
therapy 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Height / body weightb 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 Xb 
Physical findings, injection 
site findingc 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Standard 12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Chest x-ray 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Pregnancy testd 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Neurological findingse 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Anti-JCV antibody test 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood CD4-positive cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Viral test, syphilis test, TB 
test 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Number of tender / swollen 
joints, ESR 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
VAS, HAQ 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Joint x-ray 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematology, blood 
chemistry, urinalysis, RF, 
anti-CCP antibody,  
MMP-3 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Autoantibody 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Serum KL-6, β-D glucan 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vasculitis marker tests 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Adverse events 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum E6011 concentration 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum anti-E6011 antibody 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Serum total FKN 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum cytokine 
concentration, LRG1, 
Ang2 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Serum TRACP-5b 
concentration 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Immunocytes such as 
blood CX3CR1-positive 
cells 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Vectra™ DA 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
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Table 4  Schedule of Procedures/Assessments in Study E6011-J081-201 
(continued) 
Phase 
Extension 
Treatment/
Extension 
Follow-up 
               Time postdose
 
Assessment 
W52+2nh 
±7 days 
W52+4ni 
±7 days 
W64 
W88 
±7 days 
W76 
±7 days 
W100 
±7 days 
W104 
±7 days 
Discont. 
28 days after 
completion or 
discount. 
70 days after 
the last dosing 
Informed consent 
 
 
 
 
 
 
 
 
 
Demographics, medical 
history, complication 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
 
 
 
 
 
 
 
 
Study drug administrationa,f 
X 
X 
X 
X 
X 
 
 
 
 
Prior treatment / concomitant 
medication or therapy 
 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
 
Height / body weightb 
 
 
 
 
 
X 
X 
X 
 
Physical findings, injection site 
findingc 
 
 
X 
X 
 
X 
X 
X 
 
Standard 12-lead ECG 
 
 
 
X 
 
X 
X 
 
 
Chest x-ray 
 
 
 
X 
 
X 
X 
 
 
Pregnancy testd 
 
 
 
X 
 
X 
X 
 
 
Neurological findingse 
 
 
X 
X 
 
X 
X 
 
 
Anti-JCV antibody test 
 
 
 
X 
 
X 
X 
 
 
Blood CD4-positive cells 
 
 
 
X 
 
X 
X 
 
 
Viral test, syphilis test, TB test 
 
 
 
 
 
X 
X 
 
 
Number of tender / swollen 
jointsl, ESRl 
 
 
X 
X 
X 
X 
X 
X 
 
 
VASl, HAQl 
 
X 
X 
X 
X 
X 
X 
 
 
Joint x-rayl 
 
 
 
X 
 
X 
X 
 
 
Hematology, blood chemistry, 
urinalysis, RFl, anti-CCP 
antibodyl, MMP-3l 
 
X 
X 
X 
X 
X 
X 
X 
 
Autoantibody 
 
 
 
 
 
X 
X 
 
 
Serum KL-6, β-D glucan 
 
 
 
 
 
X 
X 
 
 
Vasculitis marker tests 
 
 
X 
X 
 
X 
X 
 
 
Adverse events 
 
Serum E6011 concentrationl 
 
X 
X 
X 
X 
X 
X 
 
 
Serum anti-E6011 antibodyl 
 
X 
X 
X 
X 
X 
X 
 
 
Serum total FKNl 
 
 
 
 
 
 
 
 
 
Serum cytokine concentrationl, 
LRG1l, Ang2l 
 
 
 
 
 
X 
X 
 
 
Serum TRACP-5b 
concentrationl 
 
 
 
 
 
X 
X 
 
 
Immunocytes such as blood 
CX3CR1-positive cellsl 
 
 
 
 
 
 
Xj 
 
Xk 
Vectra™ DAl 
 
 
 
 
 
X 
X 
 
 
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a. 
Study drug will be administered upon completion of all the planned investigations (except for injection site findings) on 
the day. 
b. 
To measure height only at the Screening Phase and W52. 
c. 
To examine injection site findings after study drug administration. 
d. 
To perform pregnancy test in women of childbearing potential. On-site test conducted at the Observation Phase only. 
e. 
If any postdose abnormality is observed in neurological examination, head MRI (T1-weighted image, FLAIR image, 
diffusion-weighted image) will be performed within 2 weeks along with consultation to a neurologist. 
f. 
The interval between study treatments is at least 7 days (at least 6 days between treatments) 
g. 
Administration of study drug at Week 24 is done in an open-label manner. 
h. 
W52+2n: W54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98, 102 
i. 
W52+4n: W56, 60, 68, 72, 80, 84, 92, 96 
j. 
Basically performed at study discontinuation, and a missing value is permissible only when collection of the sample is 
difficult due to abrupt discontinuation. 
k. 
Will only be conducted if blood sample is judged to be feasible at the visit. 
l. 
After the date Version 6 of the protocol is approved by IRB, applicable assessments will not be conducte. However, 
assessments of serum E6011 concentration and serum anti-E6011 antibody will be conducted at discontinuation. 
9.5.2.2 
Volume of Blood Samples 
Table 5 shows the frequency of blood samplings and volume of blood samples obtained 
throughout the study period.  If any deviation from reference range or any finding for which 
the investigator or subinvestigator considers it necessary to confirm the subject’s safety, the 
required volume of blood samples may increase from the specified volumes tabulated below.  
As it is unnecessary to conduct non-safety assessments after the date Version 6 of the 
protocol is approved by IRB, the volume of blood samples may be lower in applicable 
subjects. 
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Table 5 
Volume of Blood Samples 
Test item 
Volume per 
sampling 
Screening 
Phase 
Observation
Phase 
Treatment 
Phase 
Extension 
Phase 
Follow-up 
Phase 
Days –42 
to –1 
Predose of 
Day 1 
Weeks 1  
to 24 
Weeks 26 
to 104 
Viral test, syphilis test, TB test 
26 mL 
once 
 
 
twice 
 
Erythrocyte sedimentation rate 
2 mL 
once 
once 
7 times 
20 times 
 
Hematology 
2 mL 
once 
once 
7 times 
20 times 
once 
Blood chemistry 
10 mL 
once 
once 
7 times 
20 times 
once 
Pregnancy test 
(once)a 
 
(twice)a 
(3 times)a 
 
Serum KL-6 
(once)a 
 
(twice)a 
(twice)a 
 
Anti-JCV antibody test 
3 mL 
once 
 
once 
3 times 
 
Blood CD4-positive cells 
2 mL 
once 
 
twice 
3 times 
 
RF, anti-CCP antibody, MMP-3 
4 mL 
once 
once 
7 times 
20 times 
once 
Autoantibody 
3 mL 
 
once 
twice 
3 times 
 
Serum TRACP-5b concentration 
 
(once)a 
(twice)a 
(twice)a 
 
β-D glucan 
3 mL 
once 
 
twice 
twice 
 
Vasculitis marker tests 
5.8 mL 
 
once 
twice 
6 times 
 
Serum E6011 concentration 
2 or 5 mL 
 
onceb 
8 timesb 
20 timesb 
 
Serum anti-E6011 antibody 
 
onceb 
6 timesb 
20 timesb 
 
Serum total FKN 
 
(once)a 
 
 
 
Serum cytokine concentration, 
serum LRG1, and Ang2 
5 mL 
 
once 
3 times 
twice 
 
Vectra™ DA 
 
(once)a 
(twice)a 
(twice)a 
 
Immunocytes such as blood  
CX3CR1-positive cells 
5 mL 
 
once 
4 times 
oncec 
Onced 
Total volume of blood samples 
Each Phase 
52.0 mL 
41.8 mL 
225.6 mL 
591.8 mL 
16 mL 
Screening to Week 24 
319.4 mL 
 
Screening to Week 104 
911.2 mL 
 
Screening to the Follow-up Phase 
932.2 mL 
a:  Blood collections for these items (inside the brackets) are included in those for the items just above. 
b:  The volume of blood sample is 5 mL at the time point for assessing both serum E6011 concentration and 
serum anti-E6011 antibody and 2 mL at the time point for assessing serum E6011 concentration only. 
c:  Twice for subjects who discontinue treatment later than Week 52 
d:  Will only be conducted if blood collection is judged to be feasible at the visit.  
9.5.3 
Appropriateness of Measurements 
Efficacy endpoints of this study are set as follows: 
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ACR20 response rate, ACR50 response rate, ACR70 response rate, DAS 28-ESR, DAS28-
CRP, HAQ, simple disease activity index (SDAI), clinical disease activity index (CDAI), 
Boolean remission rate, and mTSS. 
According to “The Guideline for the clinical evaluation of antirheumatic drugs”,  it is 
recommended that the improvement in ACR20 be set as a primary endpoint and the 
improvement in ACR50 and ACR70 as secondary ones.  Therefore, we consider it 
appropriate to set ACR20 response rate, which is a world standard, as the primary endpoint.  
In addition, evaluation on DAS28 and comprehensive approaches with more strict measures 
than ACR20, such as ACR50, ACR70, SDAI, CDAI, and remission criteria are required, 
given the recent progress of RA diagnosis and treatment system.  For assessment of the 
progression of joint destruction, mTSS by the modified Sharp method using radiography has 
been verified globally. 
The safety assessments to be performed in this study, including hematology, blood 
chemistry, urinalysis, and assessment of AEs, are standard evaluations to ensure subject 
safety.  Potential risks of vasculitis and PML are set as important safety evaluation items, and 
the following assessments will be conducted. 
1. Potential risk of vasculitis 
It is expected that E6011 acts on FKN, which is strongly expressed in vascular endothelial 
cells in inflammatory diseases.  Although there have been no findings suggestive of vasculitis 
in nonclinical or clinical studies reported so far, vasculitis markers will be measured in this 
study to investigate the potential risk of vasculitis. 
2. Potential risk of PML 
PML has been recognized as a potential rare complication in patients with multiple sclerosis 
or Crohn’s disease being treated with natalizumab (humanized anti-α4-integrin monoclonal 
antibody) (FDA Drug Safety Communication).  The pathogenesis of PML remains unclear; 
however, it is believed that α4-integrin might be involved.  Although there have been no 
findings suggestive of PML in clinical studies reported so far, the mechanism of action of 
E6011 is to neutralize FKN, and reports that α4-integrin activity is intensified by interaction 
between FKN and CX3CR1 (Goda S, et al., 2000) suggest that an indirect effect of E6011 on 
α4-integrin cannot be entirely ruled out.  Considering the potential risk of PML, subjects with 
blood CD4-positive cell count <200 /μL or white blood cell count <3,000 μL or subjects with 
neurological findings will be excluded in this study.  Periodic neurological examinations will 
be conducted during the study, and PML evaluation expert will be appointed for enabling 
investigators to obtain advice on diagnosis and treatment of PML; in case neurological 
findings are observed after starting the study drug administration, the subject must receive a 
medical examination by a neurologist, have a head MRI examination within 2 weeks, and 
interrupt the study drug administrations until completion of evaluation by the PML expert.  
In addition, after the completion or discontinuation of the study, follow-up investigations on 
event of PML or death by phone or other means will be planned in every 6 months for 2 
years from the last dose of the study drug.  The pathogenesis of PML is not completely 
understood; however, it is believed that latent JCV being reactivated due to reduced cellular 
immunity results in nerve damage (Practice Guideline of Progressive Multifocal 
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Leukoencephalopathy); therefore, anti-JCV antibody will be assayed and the data will be 
collected in this study. 
9.5.4 
Reporting of Serious Adverse Events, Pregnancy, and Events Associated 
with Special Situations 
9.5.4.1 
Reporting of Serious Adverse Events 
All serious adverse events (SAEs), regardless of their relationship to study treatment, must be 
reported as soon as possible but no later than 1 business day from the date the 
investigator becomes aware of the event.  In addition, the investigator must report to 
the sponsor on a completed SAE form as soon as possible. 
Serious adverse events, regardless of causality assessment, must be collected through the 
study and for 70 days after the subject’s last dose.  All SAEs must be followed to resolution 
or, if resolution is unlikely, to stabilization.  Any SAE judged by the investigator to be 
related to the study treatment or any protocol-required procedure should be reported to the 
sponsor regardless of the length of time that has passed since study completion. 
Contact information of urgent safety issues is provided in Appendix 2. 
It is very important that the SAE report form be filled out as completely as possible at the 
time of the initial report.  This includes the investigator’s assessment of causality. 
Any follow-up information received on SAEs should be forwarded within 1 business day of 
its receipt.  If the follow-up information changes the investigator’s assessment of causality, 
this should also be noted on the follow-up SAE form. 
Preliminary SAE reports should be followed as soon as possible by detailed descriptions 
including copies of hospital case reports, autopsy reports, and other documents requested by 
the sponsor. 
9.5.4.2 
Reporting of Pregnancy and Exposure to Study Drug Through Breastfeeding 
Any pregnancy in which the estimated date of conception is either before the last visit or 
within 70 days of last study treatment, or any exposure to study drug through breastfeeding 
during study treatment or within 70 days of last study treatment, must be reported. 
If an adverse outcome of a pregnancy is suspected to be related to study drug exposure, this 
should be reported regardless of the length of time that has passed since the exposure to study 
treatment. 
A congenital anomaly, death during perinatal period, an induced abortion, or a spontaneous 
abortion are considered to be an SAE and should be reported in the same time frame and in 
the same format as all other SAEs (see Section 9.5.4.1” Reporting of Serious Adverse 
Events”). 
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Pregnancies or exposure to study drug through breastfeeding must be reported by fax or 
email as soon as possible but no later than 1 business day from the date the investigator 
becomes aware of the pregnancy.  The contact information for the reporting of pregnancies 
and exposure to study drug through breastfeeding is provided in Section 9.5.4.1.  The 
pregnancy report form (Appendix 13) must be used for reporting.  All pregnancies must be 
followed to outcome.  The outcome of the pregnancy must be reported by the pregnancy 
outcome report form (Appendix 14) as soon as possible but no later than 1 business day from 
the date the investigator becomes aware of the outcome. 
A subject who becomes pregnant must be withdrawn from the study.  
9.5.4.3 
Reporting of Events Associated with Special Situations 
9.5.4.3.1 
REPORTING OF ADVERSE EVENTS ASSOCIATED WITH STUDY DRUG OVERDOSE, 
MISUSE, ABUSE, OR MEDICATION ERROR 
Adverse events associated with study drug overdose, misuse, abuse, and medication error 
refer to AEs associated with uses of the study drug outside of that specified by the protocol.  
Overdose, misuse, abuse, and medication error are defined as follows:  
Overdose 
Accidental or intentional use of the study drug in an amount higher 
than the protocol-defined dose. 
Misuse 
Intentional and inappropriate use of study drug not in accordance with 
the protocol 
Abuse 
Sporadic or persistent intentional excessive use of study drug 
accompanied by harmful physical or psychological effects 
Medication error 
Any unintentional event that causes or leads to inappropriate study 
drug use or subject harm while the study drug is in the control of site 
personnel or the subject.  
All AEs associated with overdose, misuse, abuse, or medication error should be captured on 
the Adverse Event CRF and also reported using the procedures detailed in Reporting of 
Serious Adverse Events (Section 9.5.4.1) even if the AEs do not meet serious criteria.  Abuse 
is always to be captured as an AE.  If the AE associated with an overdose, misuse, abuse, or 
medication error does not meet serious criteria, it must still be reported using the SAE form 
and in an expedited manner but should be noted as nonserious on the SAE form and the 
Adverse Event CRF. 
9.5.4.4 
Expedited Reporting 
The sponsor must inform investigators and the head of the medical institution and regulatory 
authorities of reportable events, in compliance with applicable regulatory requirements, on an 
expedited basis.  For this reason, it is imperative that sites provide complete SAE information 
in the manner described above (see Section 9.5.4.1”Reporting of Serious Adverse Events”). 
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9.5.4.5 
Breaking the Blind 
In the case of a medical emergency where the appropriate treatment of the subject requires 
knowledge of the study treatment given, the investigator may break the randomization code 
for an individual subject.  In all such cases, the AE necessitating the emergency blind break 
will be handled as an SAE in accordance with the procedures indicated above (see 
Section 9.5.4.1”Reporting of Serious Adverse Events”).  Any broken code will be clearly 
justified and documented.  The sponsor must be notified immediately of the blind break. 
Procedures for emergency blind break are as follows.  
Procedures for emergency blind break 
1. The investigator or the sponsor will request the emergency code center to break the 
subject’s emergency unblinding code. 
2. The emergency code center will obtain the necessary information (investigational site 
/department, name of person requesting blind break, drug number, study title, and the 
person to contact when returning the information) from the person requesting code 
breaking (the investigator or the sponsor). 
3. If unblinding is judged appropriate, the emergency code center will unblinding the 
emergency code for the subject and promptly inform the result to the person to contact 
(the investigator or the sponsor). 
4. When the unblinding request is made by an investigator, the emergency code center will 
promptly notify the sponsor of the necessary information obtained by the investigator and 
the result of unblinding.  
5. When the unblinding request is made by the sponsor, the sponsor will notify the 
investigator of the reason, course, and result of the unblinding.  
Contact information of the emergency code center is provided in Appendix 2. 
9.5.4.6 
Regulatory Reporting of Adverse Events 
Adverse events will be reported to regulatory authorities in compliance with local law and 
established guidance.  The format of these reports will be dictated by the local requirements. 
9.5.5 
Completion/Discontinuation of Subjects 
A subject may elect to discontinue the study at any time for any reason.  All subjects who 
discontinue the study are to complete the study’s early discontinuation procedures indicated 
in the Schedule of Procedures/Assessments (Section 9.5.2.1, Table 4). 
The investigator will promptly explain to the subject involved that the study will be 
discontinued for that subject and provide appropriate medical treatment and other necessary 
measures for the subject.  A subject who has ceased to return for visits will be followed up by 
mail, phone, or other means to gather information such as the reason for failure to return, the 
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status of treatment compliance, the presence or absence of AEs, and clinical courses of signs 
and symptoms.   
Subjects who discontinue early from the study will be discontinued for 1 of these primary 
reasons: AE(s), lost to follow-up, subject choice, inadequate therapeutic effect, progression 
of disease, withdrawal of consent, pregnancy, study terminated by sponsor, or other.  In 
addition to the primary reason, the subject may indicate 1 or more secondary reason(s) for 
discontinuation.  Study disposition information will be collected on the CRF. 
9.5.6 
Abuse or Diversion of Study Drug 
Not applicable. 
9.5.7 
Confirmation of Medical Care by Another Physician 
The investigator, subinvestigator, or clinical research coordinator will instruct subjects to 
inform site personnel when they are planning to receive medical care by another physician.  
At each visit, the investigator will ask the subject whether he/she has received medical care 
by another physician since the last visit or is planning to do so in the future.  When the 
subject is going to receive medical care by another physician, the investigator or 
subinvestigator, with the consent of the subject, will inform the other physician that the 
subject is participating in the clinical study. 
9.6 
Data Quality Assurance 
This study will be organized, performed, and reported in compliance with the protocol, 
SOPs, working practice documents, and applicable regulations and guidelines.   
9.6.1 
Data Collection 
Data required by the protocol will be collected on the CRFs and entered into a validated data 
management system that is compliant with all regulatory requirements.  As defined by GCP, 
the CRF is a printed, optical, or electronic document designed to record all of the protocol-
required information to be reported to the sponsor on each study subject. 
Data collection on the CRF must follow the instructions described in the CRF Completion 
Guidelines.  The investigator has ultimate responsibility for the collection and reporting of all 
clinical data entered on the CRF.  The investigator must sign the completed CRF to attest to 
its accuracy, authenticity, and completeness. 
Completed, original CRFs are the sole property of Eisai and should not be made available in 
any form to third parties without written permission from Eisai, except for authorized 
representatives of Eisai or appropriate regulatory authorities. 
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9.6.2 
Clinical Data Management 
All software applications used in the collection of data will be properly validated following 
standard computer system validation that is compliant with all regulatory requirements.  All 
data, both CRF and external data (eg, laboratory data), will be entered into a clinical system. 
9.7 
Statistical Methods 
Statistical analyses will be performed by using SAS or other validated statistical software as 
needed after unblinding. In this study, the statistical analysis in the Treatment Phase will be 
performed after the database in the Treatment Phase is locked and the data is unblinded, and 
then final analysis will be performed by using all data after the database throughout the study 
period is locked.  The details will be described separately in the Statistical Analysis Plan 
(SAP). SAP for the Treatment Phase and the entire study (the Treatment and Extension 
Phases) will be finalized before each database lock. 
9.7.1 
Statistical and Analytical Plans 
The statistical analyses of study data are described in this section.  Analyses in the Treatment 
Phase are mainly described in the following sections to Section 9.7.1.8, while analyses in the 
Extension Phase are described in Section 9.7.1.9. 
9.7.1.1 
Study Endpoints 
9.7.1.1.1 
PRIMARY ENDPOINT 
• 
ACR20 response rate at Week 12 
ACR20 response rate: A subject is defined as ACR20 responder if all of the following 3 
criteria are met, and ACR 20 response rate refers to the percentage of subjects with ACR20 
response: 
1. Greater than or equal to 20% reduction from baseline in the tender joint counts (out of 68 
joints) 
2. Greater than or equal to 20% reduction from baseline in the swollen joint counts (out of 
66 joints) 
3. Greater than or equal to 20% reduction from baseline in at least 3 of the following 
5 assessments: 
- 
Physician’s disease activity assessment 
- 
Patient’s disease activity assessment 
- 
Patient’s pain assessment 
- 
HAQ 
- 
CRP 
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9.7.1.1.2 
SECONDARY ENDPOINTS 
• 
ACR20, ACR50, and ACR70 response rates at each evaluation time point (excluding 
ACR20 response rate at Week 12) 
• 
Values and change from baseline in ACR components (number of tender joints, number 
of swollen joints, VAS [Patient’s pain assessments/disease activity global assessments 
and physician’s disease activity global assessment], patient’s physical function 
assessment [HAQ], and CRP/ESR), DAS28-ESR, DAS28-CRP, SDAI, and CDAI at each 
evaluation time point 
• 
EULAR response criteria and disease activity classification based on DAS28-ESR or 
DAS28-CRP at each evaluation time point 
• 
Remission rate calculated based on each remission criterion (DAS28-ESR, DAS28-CRP, 
SDAI, CDAI, and Boolean) at each evaluation time point 
• 
Values and change from baseline in mTSS at each evaluation time point 
The ACR50 response rate is defined similarly to the ACR20 response rate, except for a 50% 
reduction as threshold. 
The ACR70 response rate is defined similarly to the ACR20 response rate, except for a 70% 
reduction as threshold. 
DAS28-CRP: This will be calculated on the following formula, and disease activity is 
categorized as High at >4.1, Moderate at >2.7 and ≤4.1, Low at ≤2.7, and Remission at <2.3. 
0.56×√[Number of tender joints (28 joints)]+0.28×√[Number of swollen joints (28 
joints)]+0.36×ln (CRP×10+1)+0.014×Patient’s disease activity assessments + 0.96 
DAS28-ESR: This will be calculated on the following formula, and disease activity is 
categorized as High at >5.1, Moderate at >3.2 and ≤5.1, Low at ≤3.2, and Remission at <2.6. 
0.56×√[Number of tender joints (28 joints)]+ 0.28×√[Number of swollen joints (28 
joints)]+0.70×ln (ESR)+0.014×Patient’s disease activity assessments 
EULAR Response Criteria: 
Present DAS28 
DAS28 reduction from baseline 
<–1.2 
≥–1.2 and <–0.6 
≥–0.6 
(missing included) 
Low 
Good response 
Moderate response 
No response 
Moderate 
Moderate response 
Moderate response 
No response 
High 
Moderate response 
No response 
No response 
 
The CDAI will be calculated on the following formula, and disease activity is categorized as  
High at >22, Moderate at >10 and ≤22, Low at ≤10, and Remission at ≤2.8. 
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Number of swollen joints (28 joints) +Number of tender joints (28 joints) 
+ Patient’s disease activity assessments/10 
+ Physician’s disease activity assessment/10 
SDAI: This will be calculated on the following formula, and disease activity is categorized as  
High at >26, Moderate at >11 and ≤26, Low at ≤11, and Remission at ≤3.3. 
Number of swollen joints (28 joints) +Number of tender joints (28 joints) 
+ Patient’s disease activity assessments/10 
+ Physician’s disease activity assessment/10+CRP 
Boolean remission: A subject is judged to have Boolean remission if all of the following 
conditions are satisfied: 
1. Tender joint counts (out of 68 joints) ≤1 
2. Swollen joint counts (out of 66 joints) ≤1 
3. CRP ≤1 
4. Patient’s disease activity assessment ≤10 
 
9.7.1.2 
Definitions of Analysis Sets 
The Full Analysis Set (FAS) is the group of randomized subjects who received the study 
drug and had at least 1 evaluable postdose primary efficacy measurement. 
The Per Protocol Analysis Set (PPS) is the group of subjects who sufficiently complied with 
the protocol.  Details of the PPS criteria will be determined before database lock and 
unblinding and will be specified in the Statistical Analysis Plan.  
The Safety Analysis Set is the group of subjects who received the study drug and had at least 
1 evaluable postdose safety assessment. 
9.7.1.3 
Subject Disposition 
The number of subjects who provided signed informed consent, and who failed screening 
along with the reason for such screen failure will be summarized.   
The number of randomized subjects, subjects who are treated/not treated (after 
randomization), completed/discontinued the study, and the reason for the discontinuation will 
be summarized for each treatment group and the overall subjects. 
9.7.1.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group and the overall subjects.  Continuous variables include 
age, RA duration; categorical variables include sex, race, etc. 
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9.7.1.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the CRF will be coded to an 11-digit code 
using the World Health Organization Drug Dictionary (WHO DD).  The number 
(percentage) of subjects who took prior and concomitant medications will be summarized on 
the FAS by treatment group, Anatomical Therapeutic Chemical (ATC) class, and WHO DD 
preferred term.  Prior medications will be defined as medications that stopped before the first 
dose of study drug.  Concomitant medications will be defined as medications that (1) started 
before the first dose of study drug and were continuing at the time of the first dose of study 
drug, or (2) started on or after the date of the first dose of study drug.  All medications will be 
presented in subject data listings. 
9.7.1.6 
Efficacy Analyses 
The FAS will be used as the primary population for the efficacy analyses, while the PPS will 
be used as a supportive population for the efficacy analyses. 
9.7.1.6.1 
PRIMARY EFFICACY ANALYSIS 
ACR20 response rate at Week 12 will be analyzed using a logistic regression model with 
CRP level at the Screening Phase, disease duration and history of biologics treatment as 
covariates, for the comparison between placebo and either E6011 200 mg or 400 mg.  
Overall significance level is α=0.025 (one-sided). The Hochberg method will be used to 
adjust the multiplicity.  Subjects with missing primary efficacy endpoint due to early 
discontinuation or other reasons will be considered nonresponders.  In case that the number 
of subjects in each category of covariates is very small, integration of the categories will be 
planned.  ACR20 response rate and its 2-sided 95% confidence interval for each treatment 
group will be calculated.  The difference in ACR20 response rate between each of E6011 
doses and placebo and its 2-sided 95% confidence interval will also be calculated.  Subgroup 
analyses or sensitivity analyses will be conducted as needed. 
In addition, the following analyses will be conducted for ACR20 response rate at Week 12. 
• 
To compare ACR20 response between E6011 100 mg and placebo using a logistic 
regression model with CRP level at the Screening Phase, disease duration and history of 
biologics treatment as covariates. The difference in ACR20 response rate between E6011 
100 mg and placebo and its 2-sided 95% confidence interval will also be calculated. 
• 
To estimate the dose-response relationship using a statistical model, such as Emax model, 
if appropriate. 
9.7.1.6.2 
SECONDARY EFFICACY ANALYSES 
The multiplicity adjustment will not be considered for secondary efficacy analyses. 
For ACR20 (excluding Week 12), ACR50, and ACR70 response rates at each time 
evaluation time point, similar analyses to primary analyses will be conducted. 
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For each component of ACR (number of tender joints, number of swollen joints, VAS 
[patient’s pain assessment and patient’s disease activity global assessment, and physician’s 
disease activity global assessment], patient’s physical function assessment [HAQ] and 
CRP/ESR), DAS28-ESR, DAS28-CRP, SDAI, and CDAI in each evaluation time point, 
summary statistics (mean, standard deviation, median, and range) for the values and the 
changes from baseline will be calculated by treatment group and evaluation time point.  The 
changes from baseline will also be analyzed using ANCOVA with baseline value, CRP level 
at the Screening Phase, disease duration and history of biologics treatment as covariates.  The 
significance level for comparisons between placebo and each treatment group with E6011 
(100 mg, 200 mg, and 400 mg) is α=0.05 (2-sided). 
For mTSS, summary statistics for values and change from baseline will be calculated by 
treatment group and evaluation time point.  The changes from baseline will be analyzed 
using ANCOVA in the same manner as above. 
For EULAR response classification and disease activity classification based on DAS28-ESR 
and DAS28-CRP, shift tables will be created by treatment group and evaluation time point. 
For remission rates calculated based on remission criteria (DAS28-ESR, DAS28-CRP, 
SDAI, CDAI, and Boolean), similar analyses to primary analyses will be conducted. 
9.7.1.7 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
9.7.1.7.1 
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES 
For the Treatment Phase, summary statistics for serum E6011 concentrations will be 
calculated by treatment group and evaluation time point.  Serum E6011 concentration-time 
profiles will be plotted.   
Population pharmacokinetic analyses will be conducted.  Data from other studies will be 
integrated as necessary.  Serum E6011 concentration data will be used to build PK models.  
The models may be used to explore the relationship between PK and covariates.  The 
relationship between serum E6011 concentrations and biomarkers and/or efficacy will also 
be investigated through population PK/PD modeling.  For population PK analyses, the details 
will be described in the separately prepared analysis plan and its report, and the results will 
not be included in the clinical study report. 
9.7.1.7.2 
PHARMACOGENOMIC, BIOMARKER, AND IMMUNOGENICITY ANALYSES 
Pharmacogenomic Analyses 
Not applicable. 
Biomarker Analyses 
For the Treatment Phase, summary statistics for serum RF concentration, serum anti-CCP 
antibody concentration, and serum MMP-3 concentration, serum TRACP-5b concentration, 
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serum cytokine concentration, serum LRG1 concentration, serum Ang2 concentration, 
Vectra™ DA and its component (VCAM-1, EGF, VEGF-A, IL-6, TNF-RI, MMP-1, MMP-3, 
YKL-40, leptin, resistin, SA and CRP) value, change from baseline and percent change from 
baseline, by treatment group and evaluation time point, will be calculated.  Exploratory 
investigations of the relationship between efficacy and biomarkers will be conducted.  
Details and results of analyses of immunocytes such as blood CX3CR1-positive cells will be 
provided in a separate report, and will not be included in the clinical study report.   
Immunogenicity Analyses 
All immunogenicity analyses will be performed using the Safety Analysis Set.   
The percentage and frequency of occurrences will be calculated for serum anti-E6011 
antibodies by treatment group and evaluation time point.  If anti-E6011 antibody develops, 
the frequency and percentage of any anti-E6011 antibody neutralization activity and isotypes 
will be calculated. 
9.7.1.8 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set.  For the Treatment Phase, 
summary statistics for safety data, presented by treatment group, will be calculated on an “as 
treated” basis (e.g., n, mean, standard deviation, median, minimum, maximum for continuous 
variables; n and percentage for categorical variables).  Safety variables include AEs, clinical 
laboratory parameters, vital signs, 12-lead ECG results, chest x-ray, neurological findings, 
and blood CD4-positive cell count.  In safety analysis, the date of starting study treatment is 
treated as Day 1. 
9.7.1.8.1 
EXTENT OF EXPOSURE 
The duration of exposure to study drug will be characterized by treatment group using 
summary statistics. 
9.7.1.8.2 
ADVERSE EVENTS 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA).  Adverse events will be coded to the MedDRA (Version 19.0 or higher) lower 
level term (LLT) closest to the verbatim term.  The linked MedDRA preferred term (PT) and 
primary system organ class (SOC) are also captured in the database. 
A treatment-emergent adverse event (TEAE) is defined as an AE that emerges during 
treatment, having been absent at pretreatment (Baseline) or  
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or  
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
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Only those AEs that are treatment-emergent will be included in summary tables.  All AEs, 
treatment-emergent or otherwise, will be presented in subject data listings. 
The TEAEs will be summarized by treatment group.  The incidence of TEAEs will be 
reported as the number (percentage) of subjects with TEAEs by SOC and PT.  A subject will 
be counted only once within an SOC and PT, even if the subject experienced more than 1 
TEAE within a specific SOC and PT.  The number (percentage) of subjects with TEAEs will 
also be summarized by highest CTCAE grade. 
The number (percentage) of subjects with TEAEs will also be summarized by relationship to 
study drug (Yes [related] and No [not related]).  
The number (percentage) of subjects with treatment-related TEAEs will be summarized by 
SOC and PT.  Treatment-related TEAEs include those events considered by the investigator 
to be related to study treatment.  The number (percentage) of subjects with treatment-related 
TEAEs will also be summarized by highest CTCAE grade. 
9.7.1.8.3 
LABORATORY VALUES 
Laboratory results will be summarized using Système International (SI) units.  For 
continuous variables, summary statistics for the actual value and the change from baseline 
will be summarized by visit.   
For ordinal classification parameters, laboratory test results will be assigned a 
low/normal/high (LNH) classification according to whether the value was below (L), within 
(N), or above (H) the laboratory parameter’s reference range.  The number (percentage) of 
subjects by LNH will be summarized on shift tables (the baseline vs. each postbaseline visit) 
by treatment group.  Similar shift tables will also compare the baseline LNH classification to 
the LNH classification for the highest and lowest value after starting the study drug 
administration. 
9.7.1.8.4 
VITAL SIGNS 
Summary statistics for values and changes from baseline of vital sign parameters (i.e., 
systolic and diastolic BP, pulse, temperature, and weight) will be calculated by evaluation 
time point and treatment group. 
9.7.1.8.5 
ELECTROCARDIOGRAMS 
The number and percentages of subjects with normal/abnormal findings in 12-lead ECG will 
be summarized on shift tables by treatment group. 
9.7.1.8.6 
OTHER SAFETY ANALYSES 
Chest x-ray 
The number and percentages of subjects with normal/abnormal findings in chest x-ray will be 
summarized on shift tables by treatment group. 
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Neurological findings  
The number and percentages of subjects with normal/abnormal findings in neurological 
examination will be summarized on shift tables by treatment group. 
Blood CD4-positive cell counts 
For Blood CD4-positive cell counts, summary statistics for the actual value and the change 
from baseline will be calculated by evaluation time point and treatment group.  Blood CD4-
positive cell counts will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the reference range, and 
summarized on shift tables by treatment group.  
9.7.1.9 
Extension Phase Analyses 
Similar analyses to those described in the above sections for the Treatment Phase will be 
conducted for efficacy, pharmacokinetics (except for population PK and PK/PD analyses), 
biomarker, immunogenicity, and safety endpoints by treatment group of the Treatment Phase. 
9.7.2 
Determination of Sample Size 
The sample size is based on an expected ACR20 response rate of 30% at Week 12 in the 
placebo group and at least 60% in both of the E6011 200 mg and 400 mg groups, as per 
results of Study 103 and studies of similar drugs.  Although multiplicity adjustment using the 
Hochberg method will be carried out in the primary analysis, sample size was conservatively 
calculated at a 1-sided significance level of α=0.0125 (α=0.025/2).  The sample sizes of 50 
for E6011 200 mg, 400 mg, and placebo will have 91% power to detect a difference in 
response rate of 35% between placebo and each E6011 group and will have 79% power to 
detect a difference in response rate of 30% based on a chi-square test.   
The sample size of 25 for E6011 100 mg was set for the purpose of estimating the dose-
response curve. 
9.7.3 
Interim Analysis 
No interim analysis is planned for this study. 
9.7.4 
Other Statistical/Analytical Issues 
Not applicable. 
9.7.5 
Procedure for Revising the Statistical Analysis Plan 
If the SAP needs to be revised after the study starts, the sponsor will determine how the 
revision impacts the study and how the revision should be implemented.  The details of the 
revision will be documented and described in the clinical study report. 
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10 REFERENCE LIST 
FDA Drug Safety Communication: New risk factor for Progressive Multifocal 
Leukoencephalopathy (PML) associated with Tysabri (natalizumab). Safety Announcement. 
01-20-2012 http://www.fda.gov/Drugs/DrugSafety/ucm288186.htm 
Goda S, Imai T, Yoshie O, Yoneda O, Inoue H, Nagano, et al. CX3C-chemokine, fractalkine-
enhanced adhesion of THP-1 cells to endothelial cells through integrin-dependent and -
independent mechanisms. J Immunol. 2000; 164(6);4313-20. 
Imai T, Nishimura M, Nanki T, Umehara H. Fractalkine and inflammatory disease [in 
Japanese]. Jpn. J. Clin. Immunol. 2005;28(3):131-9.  
Josef SS, Robert L, Ferdinand CB, Maya B, Gerd B, Maxime D, et al. EULAR 
recommendations for the management of rheumatoid arthritis with synthetic and biological 
disease-modifying antirheumatic drugs: 2013 update 
Joseph R. Berger, Sidney A. Houff & Eugene O. Major. Monoclonal antibodies and 
progressive multifocal leukoencephalopathy. mAbs. 2009 Nov;1 (6): 583–9 
Koizumi K, Saitoh Y, Minami T, Takeno N, Tsuneyama K, Miyahara T, et al. Role of 
CX3CR1/fractalkine in osteoclast differentiation and bone resorption. J Immunol. 2009; 
183(12): 7825-31. 
Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid 
arthritis. Ann Intern Med. 2001;134:695–706. 
Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab 
(chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in 
rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III 
trial. Lancet. 1999;354(9194):1932–9 
Miyasaka N. Paradigm shift and future perspectives in rheumatoid arthritis [in Japanese]. 
Nihon Rinsho. 2013:71;1141–6. 
Nanki T, Imai T, Nagasaka K, Urasaki Y, Nonomura Y, Taniguchi K, et al. Migration of 
CX3CR1-Positive T Cells Producing Type 1 Cytokines and Cytotoxic Molecules into the 
Synovium of Patients With Rheumatoid Arthritis. Arthritis Rheum. 2002; 46(11):2878-83. 
Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Study of 
active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): 
evidence of clinical and radiographic benefit from an x ray reader-blinded randomised 
controlled trial of tocilizumab. Ann Rheum Dis. 2007;66(9):1162–7 
Ochi T, Yamamoto K, Ryu J. Diagnosis and Treatment Guidelines for Rheumatoid Arthritis 
based on EBM (revised) 2004 [in Japanese]. Japan Rheumatism Foundation. 
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Research group of Prion disease and slow virus infection, Ministry of Health, Labour and 
Welfare Sciences Research Grant, Research Committee on Epidemiology of Intractable 
Diseases. “Clinical Guideline 2013: Progressive Multifocal Leukoencephalopathy (PML)”  
[in Japanese]. 
Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, et al. 2015 American 
College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis 
Rheumatol. 2016 Jan;68(1):1-26. 
Takeuchi T. Rheumatoid arthritis: progress in diagnosis and treatment, Differential diagnosis 
of arthritis [in Japanese]. Nihon Naika Gakkai Zasshi. 2010:99;2392–400. 
Takeuchi T, Yamanaka H, Ishiguro N, Miyasaka N, Mukai M, Matsubara T, et al. 
Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of 
joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study. 
Ann Rheum Dis. 2014;73(3):536-43. 
Tanaka Y. Paradigm shift of diagnosis and treatment of rheumatoid arthritis [in Japanese]. 
Nihon Naika Gakkai Zasshi. 2011:100;1978–86.  
Tani K, Takayanagi R, Yokoyama H, Yamada Y. Theoretical analysis of efficacy of 
biological agent for rheumatoid arthritis based on target molecular binding occupancy: 
Rheumatol Int. 2013:33(7);1791-5 
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11 PROCEDURES AND INSTRUCTIONS (ADMINISTRATIVE 
PROCEDURES) 
11.1 Changes to the Protocol 
Any change to the protocol requires a written protocol amendment or administrative change 
that must be approved by the sponsor before implementation.   
Amendments specifically affecting the safety of subjects, the scope of the investigation, or 
the scientific quality of the study require additional approval by the applicable IRBs.  These 
requirements should in no way prevent any immediate action from being taken by the 
investigator, or by the sponsor, in the interest of preserving the safety of all subjects included 
in the study.  If the investigator determines that an immediate change to or deviation from the 
protocol is necessary for safety reasons to eliminate an immediate hazard to the subjects, the 
sponsor and the IRB for the site must be notified immediately.  The sponsor must notify the 
regulatory authority as required per local regulations. 
Protocol amendments that affect only administrative aspects of the study may not require 
submission to health or regulatory authority or the IRB.  In these cases, the sponsor may be 
required to send a letter to the IRB and the Competent Authorities detailing such changes. 
11.2 Adherence to the Protocol 
The investigators and subinvestigators will conduct the study in strict accordance with the 
protocol. 
11.3 Monitoring Procedures 
The sponsor’s/CRO’s CRA will maintain contact with the investigator and designated staff 
by telephone, letter, or email between study visits.  Monitoring visits to each site will be 
conducted by the assigned CRA as described in the monitoring plan.  The investigator will 
allow the CRA to inspect the clinical, laboratory, and pharmacy facilities to assure 
compliance with GCP and local regulatory requirements.  The CRFs and subject’s 
corresponding original medical records (source documents) are to be fully available for 
review by the sponsor’s representatives at regular intervals.  These reviews verify adherence 
to study protocol and data accuracy in accordance with local regulations.  All records at the 
site are subject to inspection by the local auditing agency and to IRB review. 
In accordance with the GCP, source documents include, but are not limited to, the following: 
• 
Clinic, office, or hospital charts 
• 
Copies or transcribed health care provider notes that have been certified for accuracy 
after production 
• 
Recorded data from automated instruments such as IVRS/IWRS, x-rays, and other 
imaging reports (eg, sonograms, CT scans, magnetic resonance images, radioactive 
images, ECGs, rhythm strips, EEGs, polysomnographs, pulmonary function tests) 
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regardless of how these images are stored, including microfiche and photographic 
negatives 
• 
Pain, quality of life, or medical history questionnaires completed by subjects 
• 
Records of telephone contacts 
• 
Diaries or evaluation checklists 
• 
Drug distribution and accountability logs maintained in pharmacies or by research 
personnel 
• 
Laboratory results and other laboratory test outputs (eg, urine pregnancy test result 
documentation and urine dip-sticks) 
• 
Correspondence regarding a study subject’s treatment between physicians or memoranda 
sent to the IRBs 
• 
CRF components (eg, questionnaires) that are completed directly by subjects and serve as 
their own source 
11.4 Recording of Data 
A CRF is required and must be completed for each subject by qualified and authorized 
personnel.  All data on the CRF must reflect the corresponding source document, except 
when a section of the CRF itself is used as the source document.  Any correction to entries 
made on the CRF must be documented in a valid audit trail where the correction is dated, the 
individual making the correct is identified, the reason for the change is stated, and the 
original data are not obscured.  Only data required by the protocol for the purposes of the 
study should be collected. 
The investigator must sign each CRF.  The investigator will report the CRFs to the sponsor 
and retain a copy of the CRFs. 
11.5 Identification of Source Data 
All data to be recorded in the CRF must reflect the corresponding source documents.  For the 
following items, the data recorded directly in the CRF are to be considered source data: 
• 
Status of study treatment (eg, reasons for discontinuation of study treatment, reasons of 
the dose change) 
• 
Reason for providing prior/concomitant therapy (including nonpharmacotherapies) 
• 
Information on study discontinuation (eg, no visit to an investigational site) 
• 
Information on AE (eg, severity, causal relationship to the study drug, outcome) 
11.6 Retention of Records 
The circumstances of completion or termination of the study notwithstanding, the head of the 
medical institution is responsible for retaining all study documents, including but not limited 
to the protocol, copies of CRFs, the Investigator's Brochure, and regulatory agency 
registration documents (eg, ICFs, and IRB correspondence).  In addition, the sponsor will 
send a list of treatment codes by study subject to the investigator after the clinical database 
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for this study has been locked.  The site should plan to retain study documents, as directed by 
the sponsor, for at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 3 years have elapsed since the formal discontinuation of clinical 
development of the investigational product.  As this investigational product is expected to be 
designated as a biological product, the site must preserve name and address of a subject, date 
of drug administration, and lot number for at least 10 years after the last drug administration 
to identify individuals. 
It is requested that at the completion of the required retention period, the site contact the 
sponsor, allowing the sponsor the option of permanently retaining the study records. 
11.7 Auditing Procedures and Inspection 
In addition to routine monitoring procedures, the sponsor’s Clinical Quality Assurance 
department conducts audits of clinical research activities in accordance with the sponsor’s 
SOPs to evaluate compliance with the principles of GCP and all applicable local regulations.   
11.8 Handling of Study Drug 
All study drug will be supplied to the investigator (or a designated pharmacist/or designee) 
by the sponsor.  Drug supplies must be kept in an appropriate secure area (eg, locked cabinet) 
and stored according to the conditions specified on the drug labels.  The investigator (or a 
designated pharmacist/or designee) must maintain an accurate record of the shipment and 
dispensing of the study drug in a drug accountability ledger, a copy of which must be given 
to the sponsor at the end of the study.  An accurate record of the date and amount of study 
drug dispensed to each subject must be available for inspection at any time.  The CRA will 
visit the site and review these documents along with all other study conduct documents at 
appropriate intervals once study drug has been received by the site. 
All drug supplies are to be used only for this study and not for any other purpose.  The 
investigator (or site personnel) must not destroy any drug labels or any partly used or unused 
drug supply before approval to do so by the sponsor.  At the conclusion of the study and as 
appropriate during the study, the investigator (or a designated pharmacist/or designee) will 
return all unused drug and a copy of the completed drug disposition form (if requested) to the 
sponsor. 
11.9 Publication of Results 
All manuscripts, abstracts, or other modes of presentation arising from the results of the 
study must be reviewed and approved in writing by the sponsor in advance of submission 
pursuant.  The review is aimed at protecting the sponsor's proprietary information existing 
either at the date of the commencement of the study or generated during the study. 
The detailed obligations regarding the publication of any data, material results, or other 
information generated or created in relation to the study shall be set out in the agreement 
between the head of the medical institution and the sponsor. 
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11.10 Disclosure and Confidentiality 
The contents of this protocol and any amendments and results obtained during the study 
should be kept confidential by the investigator, the subinvestigator, the clinical research 
coordinator, and the IRB and will not be disclosed in whole or in part to others, or used for 
any purpose other than reviewing or performing the study, without the written consent of the 
sponsor.  No data collected as part of this study will be used in any written work, including 
publications, without the written consent of the sponsor.  These obligations of confidentiality 
and non-use shall in no way diminish such obligations as set forth in either the 
Confidentiality Agreement or Clinical Trial Agreement executed between the head of the 
medical institution and the sponsor. 
All persons assisting in the performance of this study must be bound by the obligations of 
confidentiality and non-use set forth in either the Confidentiality Agreement or Clinical Trial 
Agreement executed between the head of the medical institution and the sponsor. 
11.11 Discontinuation of Study 
The sponsor reserves the right to discontinue the study for medical reasons or any other 
reason at any time.  If a study is prematurely terminated or suspended, the sponsor will 
promptly inform the investigators, heads of the medical institutions, and regulatory 
authorities of the termination or suspension and the reason(s) for the termination or 
suspension.  The IRB will also be informed promptly and provided the reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). 
The investigator reserves the right to discontinue the study should his/her judgment so 
dictate.  If the investigator terminates or suspends a study without prior agreement of the 
sponsor, the investigator should inform the head of the medical institution where applicable, 
and the investigator/ the head of the medical institution should promptly inform the sponsor 
and the IRB and provide the sponsor and the IRB with a detailed written explanation of the 
termination or suspension.  Study records must be retained as noted above. 
If no subjects are enrolled in an investigational site for 3 months or more from the initiation 
of the recruits at the site, discontinuation of contract with the site will be considered. 
11.12 Subject Insurance and Indemnity 
The sponsor will provide insurance for any subjects participating in the study in accordance 
with all applicable laws and regulations. 
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12 APPENDICES 
Appendix 1 
Investigational sites and investigators 
Appendix 2 
Study administrative structure 
Appendix 3 
ACR 1987 revised criteria for the classification of rheumatoid arthritis, and 
the 2010 ACR/EULAR classification criteria for rheumatoid arthritis 
Appendix 4 
Classification of functional capacity in rheumatoid arthritis (ACR 1991 
revised criteria) 
Appendix 5 
Identification, package, and labeling of investigational products 
Appendix 6 
List of prohibited/restricted concomitant drugs 
Appendix 7 
Assessment sheet for tender and swollen joint counts (sample) 
Appendix 8 
Physician’s disease activity assessment form (sample) 
Appendix 9 
Patient’s pain/disease activity assessment form (Sample) 
Appendix 10 
Health assessment questionnaire (Sample) 
Appendix 11 
Neurological finding checklist 
Appendix 12 
Neurological finding report form 
Appendix 13 
The pregnancy report form 
Appendix 14 
The pregnancy outcome report form 
Appendix 15 
Information on unauthorized medical devices (blood collection tube, etc.) in 
Japan 
 
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E6011-J081-201 
1 
Overview of Protocol Amendment between Ver. 1 and Ver. 2 
A Dose Response Study of E6011 in Subjects with Rheumatoid Arthritis Inadequately Responding to Methotrexate 
(The parts of change: underline) 
Protocol body 
Pertinent page 
Before Amendment (Ver.1, August 31, 2016) 
After Amendment (Ver. 2, October 13, 2016) 
Reason for Amendment 
P38, 9.5.1.5.7 OTHER 
SAFETY 
ASSESSMENTS 
Pregnancy test 
For female subjects of childbearing 
potential, blood test (quantitative, the 
central laboratory) will be performed at 
the Screening Phase, Weeks 12, 24, 52, 
76, 104, and at discontinuation, and 
urinalysis test (qualitative, on-site) will 
be performed during the Observation 
Phase. 
For female subjects of childbearing potential, blood test 
(quantitative, the central laboratory) will be performed 
at the Screening Phase, Weeks 12, 24, 52, 76, 104, and 
at discontinuation, and on-site test will be performed 
during the Observation Phase. All the test results will be 
recorded in the medical charts at the site. 
For on-site pregnancy 
test during the 
Observation Phase, 
either urine tests 
(qualitative) or blood 
tests (quantitative) can 
be performed. 
P44, 9.5.2.2 Table 5 
Volume of Blood 
Samples 
See below. 
The volume of blood 
samples for anti-JCV 
antibody was changed 
(decreased). 
correction 
Eisai
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Page 77 of 217


E6011-J081-201 
 
 
 
 
 
 
 
 
2 
(Before) Table 1 
Volume of Blood Samples 
Test item 
Volume per 
sampling 
Screening 
Phase 
Observation
Phase 
Treatment 
Phase 
Extension 
Phase 
Follow-up 
Phase 
Days –42 
to –1 
Predose of 
Day 1 
Weeks 1  
to 24 
Weeks 26 
to 104 
Viral test, syphilis test, TB test 
26 mL 
once 
 
 
twice 
 
Erythrocyte sedimentation rate 
2 mL 
once 
once 
7 times 
20 times 
 
Hematology 
2 mL 
once 
once 
7 times 
20 times 
once 
Blood chemistry 
10 mL 
once 
once 
7 times 
20 times 
once 
Pregnancy test 
(once)a 
(once)a 
(twice)a 
(3 times)a 
 
Serum KL-6 
(once)a 
 
(twice)a 
(twice)a 
 
Anti-JCV antibody test 
3.5 mL 
once 
 
once 
3 times 
 
Blood CD4-positive cells 
2 mL 
once 
 
twice 
3 times 
 
RF, anti-CCP antibody, MMP-3 
4 mL 
once 
once 
7 times 
20 times 
once 
Autoantibody 
3 mL 
 
once 
twice 
3 times 
 
Serum TRACP-5b concentration 
 
(once)a 
(twice)a 
(twice)a 
 
β-D glucan 
3 mL 
once 
 
twice 
twice 
 
Vasculitis marker tests 
5.8 mL 
 
once 
twice 
6 times 
 
Serum E6011 concentration 
2 or 5 mL 
 
onceb 
8 timesb 
20 timesb 
 
Serum anti-E6011 antibody 
 
onceb 
6 timesb 
20 timesb 
 
Serum total FKN 
 
(once)a 
 
 
 
Serum cytokine concentration, 
serum LRG1, and Ang2 
5 mL 
 
once 
3 times 
twice 
 
Vectra™ DA 
 
(once)a 
(twice)a 
(twice)a 
 
Immunocytes such as blood  
CX3CR1-positive cells 
5 mL 
 
once 
4 times 
once 
 
Total volume of blood samples 
Each Phase 
52.5 mL 
41.8 mL 
226.1 mL 
593.3 mL 
16 mL 
Screening to Week 24 
320.4 mL 
 
Screening to Week 104 
913.7 mL 
 
Screening to the Follow-up Phase 
929.7 mL 
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E6011-J081-201 
3 
(After) Table 2 Volume of Blood Samples 
Test item 
Volume per 
sampling 
Screening 
Phase 
Observation
Phase 
Treatment 
Phase 
Extension 
Phase 
Follow-up 
Phase 
Days –42 
to –1 
Predose of 
Day 1 
Weeks 1 
to 24 
Weeks 26 
to 104 
Viral test, syphilis test, TB test 
26 mL 
once 
twice 
Erythrocyte sedimentation rate 
2 mL 
once 
once 
7 times 
20 times 
Hematology 
2 mL 
once 
once 
7 times 
20 times 
once 
Blood chemistry 
10 mL 
once 
once 
7 times 
20 times 
once 
Pregnancy test 
(once)a 
(twice)a 
(3 times)a 
Serum KL-6 
(once)a 
(twice)a 
(twice)a 
Anti-JCV antibody test 
3 mL 
once 
once 
3 times 
Blood CD4-positive cells 
2 mL 
once 
twice 
3 times 
RF, anti-CCP antibody, MMP-3 
4 mL 
once 
once 
7 times 
20 times 
once 
Autoantibody 
3 mL 
once 
twice 
3 times 
Serum TRACP-5b concentration 
(once)a 
(twice)a 
(twice)a 
β-D glucan 
3 mL 
once 
twice 
twice 
Vasculitis marker tests 
5.8 mL 
once 
twice 
6 times 
Serum E6011 concentration 
2 or 5 mL 
onceb 
8 timesb 
20 timesb 
Serum anti-E6011 antibody 
onceb 
6 timesb 
20 timesb 
Serum total FKN 
(once)a 
Serum cytokine concentration, 
serum LRG1, and Ang2 
5 mL 
once 
3 times 
twice 
Vectra™ DA 
(once)a 
(twice)a 
(twice)a 
Immunocytes such as blood 
CX3CR1-positive cells 
5 mL 
once 
4 times 
once 
Total volume of blood samples 
Each Phase 
52.0 mL 
41.8 mL 
225.6 mL 
591.8 mL 
16 mL 
Screening to Week 24 
319.4 mL 
Screening to Week 104 
911.2 mL 
Screening to the Follow-up Phase 
927.2 mL 
Eisai
Confidential
Page 79 of 217


E6011-J081-201 
1 
Overview of Protocol Amendment between Ver. 2 and Ver. 3 
A Dose Response Study of E6011 in Subjects with Rheumatoid Arthritis Inadequately Responding to Methotrexate 
(The parts of change: underline) 
Protocol body 
Pertinent page 
Before Amendment (Ver.2, October 13, 2016) 
After Amendment (Ver. 3, February 23, 2017) 
Reason for Amendment 
P5, 2 
CLINICAL 
PROTOCOL 
SYNOPSIS 
Exclusion criteria 
P23, 
9.3.2 Exclusion criteria 
(23) Tested positive for any of the following
in the Screening Phase: HIV, hepatitis B virus
surface antigen (HBs antigen), hepatitis B
virus surface antibody (HBs antibody),
hepatitis B virus core antibody (HBc
antibody), hepatitis B virus DNA (HBV
DNA), hepatitis C virus antibody (HCV
antibody), human T-lymphotrophic virus type
I antibody (HTLV-1 antibody), or syphilis
(except if positive for the HBs antibody only,
and it is clear that this is due to hepatitis B
vaccination)
(23) Tested positive for any of the following in the
Screening Phase: HIV, hepatitis B virus surface antigen
(HBs antigen), hepatitis B virus surface antibody (HBs
antibody), hepatitis B virus core antibody (HBc
antibody), hepatitis B virus DNA (HBV DNA), hepatitis
C virus antibody (HCV antibody), human
T-lymphotrophic virus type I antibody (HTLV-1
antibody), or syphilis (except if positive for the HBs
antibody only, and it is clear that this is due to hepatitis
B vaccination. In case of positive RPR and negative TP
antibody results, the positive result is not considered
valid if a false positivity is confirmed by repeated TP 
antibody negative results of other syphilis tests 
performed 21 days or more later.) 
To allow enrollment of 
patients with a false 
positive syphilis test 
result. 
P7, 2 
CLINICAL 
PROTOCOL 
SYNOPSIS 
Concomitant 
Drug/Therapy 
P30, 
<Prohibited concomitant therapies and drugs> 
•Over-the-counter medications containing
folic acid as main component
<Prohibited concomitant therapies and drugs> 
•Folic acid preparation or over-the-counter medications
containing folic acid as main component
To clarify the 
description. 
Eisai
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Page 80 of 217


E6011-J081-201 
 
 
 
 
 
 
 
 
2 
Pertinent page 
Before Amendment (Ver.2, October 13, 2016) 
After Amendment (Ver. 3, February 23, 2017) 
Reason for Amendment 
9.4.7.1.1 PROHIBITED 
CONCOMITANT 
THERAPIES AND 
DRUGS 
P7, 2 
CLINICAL 
PROTOCOL 
SYNOPSIS 
Concomitant 
Drug/Therapy 
 
P30, 
9.4.7.1.2RESTRICTED 
CONCOMITANT 
DRUGS 
<Restricted medicine> 
-MTX and folic acid are to be continued at a 
stable dose regimen until completion of the 
Extension Phase (or until study 
discontinuation). If an adverse event 
associated with MTX is noted, dose reduction 
is permitted. If the event disappears after dose 
reduction, the dose can be increased to the 
previous level. 
<Restricted medicine> 
-MTX and folic acid are to be continued at a stable dose 
regimen until completion of the Extension Phase (or 
until study discontinuation). If an adverse event 
associated with MTX is noted during the Extension 
Phase, dose reduction or interruption is permitted. If the 
event disappears after dose reduction or interruption, the 
dose can be increased to the previous level. 
To clarify the 
description. 
P20, 
9.1.1 Screening Phase 
For subjects who require prophylactic 
treatments with isoniazid based on the results 
of the tuberculosis test at the Screening Phase, 
the prophylactic treatments are needed for at 
least 21 days before starting the study 
treatment, so the duration of the Screening 
Phase is allowed to be extended until 21 days 
from the start of isoniazid administrations. 
For subjects who require prophylactic treatments with 
isoniazid based on the results of the tuberculosis test at 
the Screening Phase, the prophylactic treatments are 
needed for at least 21 days before starting the study 
treatment, so the duration of the Screening Phase is 
allowed to be extended until 21 days from the start of 
isoniazid administrations. If a patient requires another 
syphilis test based on the result in the Screening Phase, 
reexamination has to be performed after an interval of 
21 days or longer during the Screening Phase. The 
Following 
reconsideration of 
Exclusion Criterion 
(23). 
Eisai
Confidential
Page 81 of 217


E6011-J081-201 
 
 
 
 
 
 
 
 
3 
Pertinent page 
Before Amendment (Ver.2, October 13, 2016) 
After Amendment (Ver. 3, February 23, 2017) 
Reason for Amendment 
Screening Phase can be extended until the 
reexamination result is obtained. 
P25, 
9.3.3 Removal of 
Subjects From Therapy 
or Assessment 
(8) Tested positive for any of the following: 
HIV, HBs antigen), HBV DNA, HCV 
antibody, HTLV-1 antibody, or syphilis. 
(8) Tested positive for any of the following: HIV, HBs 
antigen, HBV DNA, HCV antibody, HTLV-1 antibody, 
or syphilis (Confirmed false positive syphilis test result 
is excluded). 
Following 
reconsideration of 
Exclusion Criterion 
(23). 
P43, Table 4 Schedule 
of 
Procedures/Assessments 
in Study 
E6011-J081-201 
 
At discontinuation: 
Immunocytes such as 
blood CX3CR1-positive 
cells 
note 
(Not mentioned) 
j: Basically performed at study discontinuation, and a 
missing value is permissible only when collection of the 
sample is difficult due to abrupt discontinuation. 
Anticipating some 
cases of abrupt 
discontinuation, when 
collection of the 
specimen is difficult. 
 
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E6011-J081-201 
1 
Overview of Protocol Amendment between Ver. 3 and Ver. 4 
A Dose Response Study of E6011 in Subjects with Rheumatoid Arthritis Inadequately Responding to Methotrexate 
(The parts of change: underline) 
Protocol body 
Pertinent page 
Before Amendment (Ver.3, February 23, 2017) 
After Amendment (Ver. 4, April 24, 2017) 
Reason for Amendment 
P30, 9.4.9 Drug 
Supplies and 
Accountability 
The drug accountability logs must be 
made available, upon request, for 
inspection by a CRA or a representative 
of a health authority.  The study drug 
manager (or designee) must check the 
number of all unused study drugs, 
exchange the documentation of drug 
return and collection with the sponsor, 
and return unused study drugs 
(including empty boxes) to the sponsor. 
The CRA collects study drugs returned 
from the site and stores in the depot 
designated by the sponsor. 
The drug accountability logs must be made 
available, upon request, for inspection by a 
CRA or a representative of a health authority.  
The study drug manager (or designee) must 
check the number of all unused study drugs, 
exchange the documentation of drug return 
and collection with the sponsor, and return 
unused study drugs to the sponsor. The CRA 
collects study drugs returned from the site and 
stores in the depot designated by the sponsor. 
Instruction for handling 
of empty box was 
described in the 
instructions for handling 
of investigational 
products 
P39, 9.5.2.1 Schedule of 
Procedures/Assessments 
Each assessment will be performed within 3 
days before or after the scheduled date during 
Weeks 1 to 12 or within 7 days before or after 
the scheduled date after Week 14 using Week 0 
as a reference point. In the Follow-up Phase, 
each assessment will be performed within 7 
days before or after the scheduled date (“within 
after 7 days” for the interview at “70 days after 
Each assessment will be performed within 3 days 
before or after the scheduled date during Weeks 1 to 
12 or within 7 days before or after the scheduled date 
after Week 14 using Week 0 as a reference point. In 
the Follow-up Phase, each assessment will be 
performed within 7 days before or after the scheduled 
date (“within after 7 days” for the interview at 
“70 days after the last dosing”). However, the interval 
To clarify the description 
(omitted unnecessary 
words) 
Eisai
Confidential
Page 83 of 217


E6011-J081-201 
 
 
 
 
 
 
 
 
2 
Pertinent page 
Before Amendment (Ver.3, February 23, 2017) 
After Amendment (Ver. 4, April 24, 2017) 
Reason for Amendment 
the last dosing”). However, the interval 
between study treatments should be at least 3 
days until 2 weeks after the start of study 
treatment, and at least 6 days after 4 weeks 
have elapsed since the start of study treatment. 
If any scheduled assessment or administration 
of the study drug cannot perform within the 
above period, such event will be considered as 
a protocol deviation.  In such a case, each 
assessment will still be performed, but 
administration of the study drug will be 
skipped. 
 
between study treatments should be at least 3 days 
treatment until 2 weeks after the start of study 
treatment, and at least 6 days after 4 weeks have 
elapsed since the start of study treatment. If any 
scheduled assessment or administration of the study 
drug cannot perform within the above period, each 
assessment will still be performed, but administration 
of the study drug will be skipped. 
 
P59, 11.8 Handling of 
Study Drug 
All drug supplies are to be used only for this 
study and not for any other purpose. The 
investigator (or study drug manager/designee) 
must not peel off any drug labels or discard 
any partly used or unused drug supply before 
approval to do so by the sponsor.  At the 
conclusion of the study and as appropriate 
during the study, the investigator (or study drug 
manager/designee) will return all used drugs 
and unused drug containers, and submit a copy 
of the completed drug accountability ledger (if 
requested) to the sponsor. 
All drug supplies are to be used only for this study 
and not for any other purpose. The investigator (or 
study drug manager/designee) must not peel off any 
drug labels or discard any partly used or unused drug 
supply before approval to do so by the sponsor. At 
the conclusion of the study and as appropriate during 
the 
study, 
the 
investigator 
(or 
study 
drug 
manager/designee) will return all unused drugs and 
submit a copy of the completed drug accountability 
ledger (if requested) to the sponsor. 
 
Instruction for handling 
of used drugs and the 
box was described in the 
instructions for handling 
of investigational 
products 
Eisai
Confidential
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E6011-J081-201 
Creation 
2018/8/31 
1 
Overview of Protocol Amendment between Ver. 4 and Ver. 5 
A Dose Response Study of E6011 in Subjects with Rheumatoid Arthritis Inadequately Responding to Methotrexate 
(The parts of change: underline) 
Protocol body 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
P2， 
2. CLINICAL
PROTOCOL SYNOPSIS
Study Design
(text omitted) 
When subjects insufficiently respond to the treatment or 
when their disease relapses in the Extension Phase (show 
no improvement from the Observation Phase in both of 
tender joint counts and swollen joint counts at 2 
consecutive assessments with an interval of ≥1 week), dose 
escalation will be allowed only once (6 administrations of 
E6011 400 mg every 2 weeks). 
(text omitted) 
*:  When subjects insufficiently respond to the treatment 
or when their disease relapses in the Extension Phase 
(show no improvement from the Observation Phase in both 
of tender joint counts and swollen joint counts at 2 
consecutive assessments with an interval of ≥1 week), dose 
escalation will be allowed only once (6 administrations of 
E6011 400 mg every 2 weeks). 
(text omitted) 
If the investigator or subinvestigator judges that the 
response to treatment is insufficient in the Extension 
Phase, administration of E6011 400 mg every 2 weeks will 
also be allowed (reduction of the dose back to 200 mg after 
an increase to 400 mg will also be allowed). 
(text omitted) 
*:  If the investigator or subinvestigator judges that 
response to treatment is insufficient during the Extension 
Phase, administration of E6011 400 mg every 2 weeks will 
also be allowed. 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
Eisai
Confidential
Page 85 of 217


E6011-J081-201 
Creation 
2018/8/31 
2 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
P6， 
2. CLINICAL
PROTOCOL SYNOPSIS
Study Treatments
(text omitted) 
Extension Phase: E6011 200 mg will be subcutaneously 
administered every 2 weeks until Week 102.  When 
subjects insufficiently respond to the treatment or when 
their disease relapses, dose escalation will be allowed only 
once (6 repeated subcutaneous administrations of 400 mg 
E6011 every 2 weeks). 
(text omitted) 
However, 4 mL of the study drug may be given 
subcutaneously in 2 separate sites, 2 mL each, only if the 
investigator or subinvestigator judges that the study drug 
can be administered properly. 
(text omitted) 
Extension Phase: E6011 200 mg will be subcutaneously 
administered every 2 weeks until Week 102.  When 
subjects insufficiently respond to the treatment, repeated 
subcutaneous administration (400 mg of E6011 every 2 
weeks) will be allowed. 
(text omitted) 
However, 2 mL of the study drug may be given 
subcutaneously in 1 site only if the investigator or 
subinvestigator judges that the study drug can be 
administered properly. 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
Because the safety 
of administering 2 
mL at 1 site was 
confirmed 
P19， 
9.1  Overall Study 
Design and Plan 
(text omitted) 
When subjects insufficiently respond to the treatment or 
when their disease relapses in the Extension Phase (show 
no improvement from the Observation Phase in both of 
tender joint counts and swollen joint counts at 2 
consecutive assessments with an interval of ≥1 week), dose 
escalation will be allowed only once (6 administrations of 
E6011 400 mg every 2 weeks). 
 (text omitted) 
*:  When subjects insufficiently respond to the treatment 
or when their disease relapses in the Extension Phase 
(text omitted) 
If the investigator or subinvestigator judges that the 
response to treatment is insufficient in the Extension 
Phase, administration of E6011 400 mg every 2 weeks will 
also be allowed (reduction of the dose back to 200 mg after 
an increase to 400 mg will also be allowed). 
(text omitted) 
*:  If the investigator or subinvestigator judges that 
response to treatment is insufficient during the Extension 
Phase, administration of E6011 400 mg every 2 weeks will 
also be allowed. 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
Eisai
Confidential
Page 86 of 217


E6011-J081-201 
Creation 
2018/8/31 
3 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
(show no improvement from the Observation Phase in both 
of tender joint counts and swollen joint counts at 2 
consecutive assessments with an interval of ≥1 week), dose 
escalation will be allowed only once (6 administrations of 
E6011 400 mg every 2 weeks). 
P20， 
9.1.4  Extension Phase 
(text omitted) 
When subjects insufficiently respond to the treatment or 
when their disease relapses in the Extension Phase (show 
no improvement from the Observation Phase in both of 
tender joint counts and swollen joint counts at 2 
consecutive assessments with an interval of ≥1 week), dose 
escalation will be allowed only once (6 administrations of 
400 mg every 2 weeks). 
(text omitted) 
If the investigator or subinvestigator judges that the 
response to treatment is insufficient in the Extension 
Phase, administration of E6011 400 mg every 2 weeks will 
also be allowed (reduction of the dose back to 200 mg after 
an increase to 400 mg will also be allowed). 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
P21， 
9.2  Discussion of Study 
Design, Including Choice 
of Control Groups 
(text omitted) 
Furthermore, when subjects insufficiently respond to the 
treatment or when their disease relapses in the Extension 
Phase (show no improvement from the Observation Phase 
in both of tender joint counts and swollen joint counts at 2 
consecutive assessments with an interval of ≥1 week), dose 
escalation will be allowed only once (6 administrations of 
E6011 400 mg every 2 weeks). 
(text omitted) 
Furthermore, if the subjects insufficiently respond to the 
treatment in the Extension Phase, the design also allows 
for administration of E6011 400 mg every 2 weeks 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
Eisai
Confidential
Page 87 of 217


E6011-J081-201 
Creation 
2018/8/31 
4 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
P25， 
9.4.1  Treatments 
Administered 
(text omitted) 
Extension Phase: Subjects will receive E6011 200 mg 
every 2 weeks from Week 24 to Week 102 by repeated 
subcutaneous administration.  When subjects 
insufficiently respond to the treatment or when their 
disease relapses, dose escalation will be allowed only once 
(6 repeated subcutaneous administrations of E6011 400 mg 
every 2 weeks). 
(text omitted) 
However, 4 mL of the study drug may be given 
subcutaneously in 2 separate sites, 2 mL each, only if the 
investigator or subinvestigator judges that the study drug 
can be administered properly. 
(text omitted) 
Extension Phase: Subjects will receive E6011 200 mg 
every 2 weeks from Week 24 to Week 102 by repeated 
subcutaneous administration. When subjects insufficiently 
respond 
to 
the 
treatment, 
repeated 
subcutaneous 
administration (400 mg of E6011 every 2 weeks) will be 
allowed. 
(text omitted) 
However, 2 mL of the study drug may be given 
subcutaneously in 1 site only if the investigator or 
subinvestigator judges that the study drug can be 
administered properly. 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
Because the safety 
of administering 2 
mL at 1 site was 
confirmed 
P26， 
9.4.1  Treatments 
Administered 
Table 1  Dose and Administration of the Study Drug 
Extension 
Phase: 
Weeks 24 to 
102 
(Open label) 
200 mg 
2 mL 
(2 vialsd) 
Study drug will be given 
subcutaneously 
in 
2 
separate sites, 1.0 mL each, 
among the following sites: 
right or left upper arm, 
right or left abdomen, or 
right or left thigh. 
400 mga 
4 mL 
(4 vialse) 
Study drug will be given 
subcutaneously 
in 
4 
Table 1  Dose and Administration of the Study Drug 
Extension 
Phase: 
Weeks 24 to 
102 
(Open label) 
200 mg 
2 mL 
(2 vials d) 
Study drug will be given 
subcutaneously 
in 
2 
separate sites, 1.0 mL each, 
among the following sites: 
right or left upper arm, 
right or left abdomen, or 
right or left thigh.  
(2 mL of the study drug 
may 
be 
given 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
Because the safety 
of administering 2 
mL at 1 site was 
Eisai
Confidential
Page 88 of 217


E6011-J081-201 
 
 
 
 
 
 
 Creation 
2018/8/31 
5 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
separate sites, 1.0 mL each, 
among the following sites: 
right or left upper arm, 
right or left abdomen, or 
right or left thigh.   
(The study drug may be 
given subcutaneously in 2 
separate sites, 2 mL each, 
only if the investigator or 
subinvestigator judges that 
the study drug can be 
administered properly.) 
a:  When subjects insufficiently respond to the treatment or when their 
disease relapses, dose escalation from 200 mg to 400 mg will be allowed 
only once (6 repeated subcutaneous administrations of E6011 400 mg 
every 2 weeks). 
subcutaneously in 1 site 
only if the investigator or 
subinvestigator judges that 
the study drug can be 
administered properly.) 
400 mga 
4 mL 
(4 vialse) 
Study drug will be given 
subcutaneously 
in 
4 
separate sites, 1.0 mL each, 
among the following sites: 
right or left upper arm, 
right or left abdomen, or 
right or left thigh.   
(The study drug may be 
given subcutaneously in 2 
separate sites, 2 mL each, 
only if the investigator or 
subinvestigator judges that 
the study drug can be 
administered properly.) 
a:  When subjects insufficiently respond to the treatment, repeated 
subcutaneous administration (400 mg of E6011 every 2 weeks) will be 
allowed. 
confirmed 
Eisai
Confidential
Page 89 of 217


E6011-J081-201 
 
 
 
 
 
 
 Creation 
2018/8/31 
6 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
P28， 
9.4.4  Selection of 
Doses in the Study 
(text omitted) 
In the Extension Phase, subjects will receive 200 mg 
administrations of E6011 (central dose) every 2 weeks.  
When subjects insufficiently respond to the treatment or 
when their disease relapses in the Extension Phase (show 
no improvement from the Observation Phase in both of 
tender joint counts and swollen joint counts at 2 
consecutive assessments), dose escalation will be allowed 
only once (6 administrations of E6011 400 mg every 2 
weeks).  As the guidelines indicate that drug therapies for 
RA should be reviewed every 3 or 6 months, it is 
appropriate to set the period for administration of E6011 
400 mg every 2 weeks to be 3 months (6 administrations). 
(text omitted) 
In the Extension Phase, subjects will receive 200 mg 
administrations of E6011 (central dose) every 2 weeks. 
However, when subjects insufficiently respond to the 
treatment (E6011 200 mg every 2 weeks), dose escalation 
will be allowed (E6011 400 mg every 2 weeks). 
To revise the dose 
escalation criteria 
and abolish the 
restrictions on the 
number of dose 
escalations 
P43， 
Table 4  Schedule of 
Procedures/Assessments 
in Study E6011-J081-201 
70 days after the last 
dosing: 
Immunocytes such as 
blood CX3CR1-positive 
cells 
(no text) 
Xk (Blood collection for immunocytes such as blood 
CX3CR1-positive cells 70 days after administration was 
added) 
k.  Will only be conducted if blood sample is judged to be 
feasible at the visit. 
To evaluate changes 
in parameters such 
as CX3CR1-positive 
cells 
after 
administration as an 
exploratory 
investigation 
 
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Page 90 of 217


E6011-J081-201 
 
 
 
 
 
 
 Creation 
2018/8/31 
7 
Pertinent page 
Before Amendment (Ver. 4, April 24, 2017) 
After Amendment (Ver. 5, August 31, 2018) 
Reason for 
Amendment 
P44， 
9.5.2.2  Volume of 
Blood Samples 
Table 5 
See following pages 
To evaluate changes 
in parameters such 
as CX3CR1-positive 
cells 
after 
administration as an 
exploratory 
investigation 
 
To revise the text 
Eisai
Confidential
Page 91 of 217


E6011-J081-201 
 
 
 
 
 
 
 
Creation 
2018/8/31 
8 
 
(Before Amendment) Table 5  Volume of Blood Samples 
 
Test item 
Volume 
per 
sampling 
Screening 
Phase 
Observation 
Phase 
Treatment 
Phase 
Extension 
Phase 
Follow-up 
Phase 
Days –42 
to –1 
Predose of 
Day 1 
Weeks 1  
to 24 
Weeks 26 
to 104 
Viral test, syphilis test, TB test 
26 mL 
once 
 
 
twice 
 
Erythrocyte sedimentation rate 
2 mL 
once 
once 
7 times 
20 times 
 
Hematology 
2 mL 
once 
once 
7 times 
20 times 
once 
Blood chemistry 
10 mL 
once 
once 
7 times 
20 times 
once 
Pregnancy test 
(once)a 
 
(twice)a 
(3 times)a 
 
Serum KL-6 
(once)a 
 
(twice)a 
(twice)a 
 
Anti-JCV antibody test 
3 mL 
once 
 
once 
3 times 
 
Blood CD4-positive cells 
2 mL 
once 
 
twice 
3 times 
 
RF, anti-CCP antibody, MMP-3 
4 mL 
once 
once 
7 times 
20 times 
once 
Autoantibody 
3 mL 
 
once 
twice 
3 times 
 
Serum TRACP-5b concentration 
 
(once)a 
(twice)a 
(twice)a 
 
β-D glucan 
3 mL 
once 
 
twice 
twice 
 
Vasculitis marker tests 
5.8 mL 
 
once 
twice 
6 times 
 
Serum E6011 concentration 
2 mL 
or 
5 mL 
 
onceb 
8 timesb 
20 timesb 
 
Serum anti-E6011 antibody 
 
onceb 
6 timesb 
20 timesb 
 
Serum total FKN 
 
(once)a 
 
 
 
Serum cytokine concentration, 
serum LRG1, and Ang2 
5 mL 
 
once 
3 times 
twice 
 
Vectra™ DA 
 
(once)a 
(twice)a 
(twice)a 
 
Immunocytes such as blood 
CX3CR1-positive cells 
5 mL 
 
once 
4 times 
once 
 
Each Phase 
52.0 mL 
41.8 mL 
225.6 mL 
591.8 mL 
16 mL 
Screening to Week 24 
319.4 mL 
 
Screening to Week 104 
911.2 mL 
 
Screening to the Follow-up Phase 
927.2 mL 
a:  Blood collections for these items (inside the brackets) are included in those for the items just above. 
b:  The volume of blood sample is 5 mL at the time point for assessing both serum E6011 concentration and serum anti-E6011 
antibody and 2 mL at the time point for assessing serum E6011 concentration only. 
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E6011-J081-201 
Creation 
2018/8/31 
9 
(After Amendment) Table 5 Volume of Blood Samples 
a:  Blood collections for these items (inside the brackets) are included in those for the items just above. 
b:  The volume of blood sample is 5 mL at the time point for assessing both serum E6011 concentration and serum anti-E6011 
antibody and 2 mL at the time point for assessing serum E6011 concentration only. 
c:  Twice for subjects who discontinue treatment later than Week 52 
d:  Will only be conducted if blood collection is judged to be feasible at the visit. 
Test item 
Volume per 
sampling 
Screening 
Phase 
Observation 
Phase 
Treatment 
Phase 
Extension 
Phase 
Follow-up 
Phase 
Days –42 
to –1 
Predose of 
Day 1 
Weeks 1 
to 24 
Weeks 26 
to 104 
Viral test, syphilis test, TB test 
26 mL 
once 
twice 
Erythrocyte sedimentation rate 
2 mL 
once 
once 
7 times 
20 times 
Hematology 
2 mL 
once 
once 
7 times 
20 times 
once 
Blood chemistry 
10 mL 
once 
once 
7 times 
20 times 
once 
Pregnancy test 
(once)a 
(twice)a 
(3 times)a 
Serum KL-6 
(once)a 
(twice)a 
(twice)a 
Anti-JCV antibody test 
3 mL 
once 
once 
3 times 
Blood CD4-positive cells 
2 mL 
once 
twice 
3 times 
RF, anti-CCP antibody, MMP-3 
4 mL 
once 
once 
7 times 
20 times 
once 
Autoantibody 
3 mL 
once 
twice 
3 times 
Serum TRACP-5b concentration 
(once)a 
(twice)a 
(twice)a 
β-D glucan 
3 mL 
once 
twice 
twice 
Vasculitis marker tests 
5.8 mL 
once 
twice 
6 times 
Serum E6011 concentration 
2 mL 
or 
5 mL 
onceb 
8 timesb 
20 timesb 
Serum anti-E6011 antibody 
onceb 
6 timesb 
20 timesb 
Serum total FKN 
(once)a 
Serum cytokine concentration, 
serum LRG1, and Ang2 
5 mL 
once 
3 times 
twice 
Vectra™ DA 
(once)a 
(twice)a 
(twice)a 
Immunocytes such as blood 
CX3CR1-positive cells 
5 mL 
once 
4 times 
oncec 
onced 
Each Phase 
52.0 mL 
41.8 mL 
225.6 mL 
591.8 mL 
21 mL 
Screening to Week 24 
319.4 mL 
Screening to Week 104 
911.2 mL 
Screening to the Follow-up Phase 
932.2 mL 
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E6011-J081-201 
 
 
 
 
 
 
Creation 
2019/3/25 
1 
Overview of Protocol Amendment between Ver. 5 and Ver. 6 
 
A Dose Response Study of E6011 in Subjects with Rheumatoid Arthritis Inadequately Responding to Methotrexate 
 
(The parts of change: underline) 
Protocol body 
Pertinent page 
Before Amendment (Ver. 5, August 31,2018) 
After Amendment (Ver. 6, March 25, 2019) 
Reason for Amendment 
P7， 
2. CLINICAL PROTOCOL 
SYNOPSIS 
Concomitant Drug/Therapy 
P31， 
9.4.7.1.2  Restricted 
Concomitant Drugs 
(no text) 
<Restricted Concomitant Drugs> 
·After the date Version 6 of the protocol is approved by IRB, 
dose reduction, dose interruption, dose increase following the 
dose reduction (up to the initial dose level), and restarting 
administration after interruption will be allowed for MTX, folic 
acid, corticosteroids, or herbal medicine indicated for RA). 
There will be no restrictions in using NSAIDs (oral, suppository, 
or topical). 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
P8， 
2. CLINICAL PROTOCOL 
SYNOPSIS 
Assessments 
(no text) 
After the date Version 6 of the protocol is approved by IRB, it is 
unnecessary to conduct assessments other than <safety>. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
P19， 
7. INTRODUCTION 
(no text) 
The last subject entered the Extension Phase (open-label) in 
March 2018, and all subjects had completed 52 weeks of 
treatment with E6011 by March 2019. Consequently, it was 
considered unnecessary to conduct any non-safety assessments 
after March 2019, and the protocol will be revised to Version 6. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
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E6011-J081-201 
 
 
 
 
 
 
Creation 
2019/3/25 
2 
Pertinent page 
Before Amendment (Ver. 5, August 31,2018) 
After Amendment (Ver. 6, March 25, 2019) 
Reason for Amendment 
P26， 
9.3.3  Removal of Subjects 
From Therapy or Assessment 
(no text) 
(9) When the investigator or subinvestigator judges that efficacy 
of E6011 is insufficient, after the date Version 6 of the protocol 
was approved by IRB 
(10) When the investigator or subinvestigator judges that there 
are other effective treatment options available besides 
continuing this study, after the date Version 6 of the protocol 
was approved by IRB 
To add provisions 
P30， 
9.4.7  Prior and Concomitant 
Therapy 
(no text) 
After the date Version 6 of the protocol is approved by IRB, it is 
unnecessary to record concomitant medications/therapies in the 
CRF. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
P33， 
9.5.1.3  Efficacy Assesments 
(no text) 
After the date Version 6 of the protocol is approved by IRB, it is 
unnecessary to conduct assessments for efficacy. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
P34， 
9.5.1.4  Pharmacokinetic, 
Pharmacogenomic, Biomarker, 
and Immunogenicity 
Assessments 
(no text) 
After the date Version 6 of the protocol is approved by IRB, it is 
unnecessary to conduct assessments for pharmacokinetic, 
pharmacogenomic, biomarker, and immunogenicity. However, 
pharmacokinetic and immunogenicity assessments will be 
conducted at discontinuation. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
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E6011-J081-201 
 
 
 
 
 
 
Creation 
2019/3/25 
3 
Pertinent page 
Before Amendment (Ver. 5, August 31,2018) 
After Amendment (Ver. 6, March 25, 2019) 
Reason for Amendment 
P40， 
9.5.2.1  Study Schedule 
(no text) 
After the date Version 6 of the protocol is approved by IRB, it is 
unnecessary to conduct "tender and swollen joint counts/ESR", 
"VAS/HAQ", "joint X-rays", "RF/anti-CCP antibody/MMP-3", 
"serum E6011 concentration", "serum anti-E6011 antibody", 
"serum total FKN concentration", "cytokines/LRG1/Ang2", 
"TRACP-5b", "CX3CR1-positive cell count", or "Vectra™ 
DA". However, assessments of "serum E6011 concentration" 
and "serum anti-E6011 antibody" will be conducted at 
discontinuation. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
P44， 
9.5.2.1  Study Schedule 
Table 4 Remarks 
(no text) 
l  After the date Version 6 of the protocol is approved by IRB, 
applicable assessments will not be conducte. However, 
assessments of serum E6011 concentration and serum 
anti-E6011 antibody will be conducted at discontinuation. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
P45， 
9.5.2.2  Volume of Blood 
Samples 
(no text) 
As it is unnecessary to conduct non-safety assessments after the 
date Version 6 of the protocol is approved by IRB, the volume 
of blood samples may be lower in applicable subjects. 
Because it was 
considered unnecessary 
to conduct any 
non-safety assessments 
 
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Page(s) removed - non-English text removed

SAP_001.pdf: 
16.1.9 
Documentation of Statistical Methods 
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Statistical Analysis Plan 
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Confidential 
Page 1 of 39 
 
 
STATISTICAL ANALYSIS PLAN 
Study Protocol 
Number: 
E6011-J081-201 
Study Protocol 
Title: 
A Dose Response Study of E6011 in Subjects With Rheumatoid 
Arthritis Inadequately Responding to Methotrexate 
Date: 
19 Mar 2018 
Version: 
Final Version 2.0 
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Statistical Analysis Plan 
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1 
TABLE OF CONTENTS 
1 
TABLE OF CONTENTS ...................................................................................................2 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ....................................5 
3 
INTRODUCTION .............................................................................................................8 
3.1 
Study Objectives ......................................................................................................8 
3.1.1 
Primary Objectives ......................................................................................8 
3.1.2 
Secondary Objectives...................................................................................8 
3.1.3 
Exploratory Objective .................................................................................8 
3.2 
Overall Study Design and Plan ................................................................................8 
4 
DETERMINATION OF SAMPLE SIZE ..........................................................................9 
5 
STATISTICAL METHODS ..............................................................................................9 
5.1 
Study Endpoints .....................................................................................................10 
5.1.1 
Primary Endpoint ......................................................................................10 
5.1.2 
Secondary Endpoints .................................................................................10 
5.2 
Study Subjects ........................................................................................................11 
5.2.1 
Definitions of Analysis Sets .......................................................................11 
5.2.2 
Subject Disposition.....................................................................................12 
5.2.3 
Protocol Deviations ....................................................................................12 
5.2.4 
Demographic and Other Baseline Characteristics ..................................12 
5.2.5 
Prior and Concomitant Therapy ..............................................................15 
5.2.6 
Treatment Compliance ..............................................................................15 
5.3 
Data Analysis General Considerations ..................................................................15 
5.3.1 
Pooling of Centers ......................................................................................15 
5.3.2 
Adjustments for Covariates ......................................................................16 
5.3.3 
Multiple Comparisons/Multiplicity ..........................................................16 
5.3.4 
Examination of Subgroups ........................................................................16 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers ................................16 
5.3.6 
Other Considerations.................................................................................17 
5.3.6.1 
Total number of joints ........................................................................17 
5.3.6.2 
HAQ subcategory score .................................................................17 
5.4 
Efficacy Analyses ..................................................................................................18 
5.4.1 
Primary Efficacy Analyses ........................................................................18 
5.4.2 
Secondary Efficacy Analyses ....................................................................19 
5.4.3 
Other Efficacy Analyses ............................................................................20 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and Other 
Biomarker Analyses ...............................................................................................20 
5.5.1 
Pharmacokinetic Analyses ........................................................................20 
Serum E6011 Concentration ..................................................................................20 
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5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses ......................................................................................................21 
5.5.2.1 
Pharmacodynamic, Pharmacogenomic Analyses ..............................21 
5.5.2.2 
Other Biomarker Analyses..............................................................21 
5.5.2.3 
Immunogenicity Analyses ...............................................................21 
5.6 
Safety Analyses ......................................................................................................21 
5.6.1 
Extent of Exposure .....................................................................................22 
5.6.2 
Adverse Events ...........................................................................................22 
5.6.3 
Laboratory Values .....................................................................................23 
5.6.4 
Vital Signs ...................................................................................................24 
5.6.5 
Electrocardiograms....................................................................................24 
5.6.6 
Other Safety Analyses................................................................................24 
5.6.6.1 
Chest X-Ray ......................................................................................24 
5.6.6.2 
Neurological findings .......................................................................24 
5.6.6.3 
Blood CD4 positive cell counts ........................................................25 
5.7 
Other Analyses .......................................................................................................25 
5.7.1 
Anti-JCV Antibody Test............................................................................25 
5.8 
Exploratory Analyses .............................................................................................25 
5.9 
Extension Phase Analyses......................................................................................25 
6 
INTERIM ANALYSES ...................................................................................................25 
7 
CHANGES IN THE PLANNED ANALYSES ...............................................................26 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING...............................27 
8.1 
Baseline, Time Windows for statistical analyses ...................................................27 
8.1.1 
Definition of baseline value .......................................................................27 
8.1.2 
Definition of change from baseline and percent change from 
baseline ........................................................................................................28 
8.1.3 
Time windows .............................................................................................28 
8.2 
Pharmacokinetic data handling ..............................................................................30 
8.2.1 
Lower Limit of Quantification of E6011 Serum Concentration ............30 
8.2.2 
BLQ Handling for Developing Concentration–Time Profiles ...............31 
8.2.3 
BLQ Handling for Developing Tables .....................................................31 
8.2.4 
Handling of anomalous concentration values .........................................31 
8.2.5 
General Rules for Presentation of Drug Concentrations .......................31 
8.3 
Imputation rule for partial date ..............................................................................31 
8.3.1 
Date of Diagnosis ........................................................................................31 
8.3.2 
Medication ..................................................................................................31 
8.3.3 
Adverse Events ...........................................................................................32 
8.4 
Decimal places .......................................................................................................33 
8.5 
TNF Agent .............................................................................................................34 
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9 
PROGRAMMING SPECIFICATIONS ..........................................................................34 
10 STATISTICAL SOFTWARE ..........................................................................................34 
11 MOCK TABLES, LISTINGS, AND GRAPHS ..............................................................34 
12 REFERENCES ................................................................................................................34 
13 APPENDICES .................................................................................................................36 
13.1 
National Institute for Health: Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.0 ................................................................................36 
13.2 
Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results .....38 
 
 
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2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term 
ACR 
American College of Rheumatology 
AE 
adverse event 
ATC 
anatomical therapeutic class 
ANCOVA 
analysis of covariance 
Ang2 
angiopoietin 2 
ATC 
anatomical therapeutic class 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BP 
Blood pressure 
CCP 
cyclic citrullinated peptide 
CDAI 
clinical disease activity index 
CI 
confidence interval 
CRF 
case report form 
CRP 
C-reactive Protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAS28 
disease activity score in 28 joints, 
DP 
Decimal places 
EGF 
epidermal growth factor 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
European League Against Rheumatism 
FAS 
full analysis set 
γ-GTP 
γ-glutamine transpeptidase 
HAQ 
Health Assessment Questionnaire 
HAQ-DI 
Health Assessment Questionnare Disability Index 
IL 
Interleukin 
LLOQ 
lower limit of quantification 
LOCF 
last observation carried forward 
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Abbreviation 
Term 
LRG1 
leucine-rich alpha-2 glycoprotein 1 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMP 
matrix metalloproteinase 
mTSS 
modified total sharp score 
MTX 
Methotrexate 
NCI 
National Cancer Institute 
NRI 
non-responder imputation 
OC 
observed cases 
PD 
pharmacodynamics 
PK 
Pharmacokinetic 
PPS 
per protocol set 
PT 
preferred term 
RA 
rheumatoid arthritis 
RF 
rheumatoid factor 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SDAI 
simple disease activity index 
SI 
Système International 
SJC 
swollen joint counts 
SJC28 
swollen joint counts in 28 joints 
SJC66 
swollen joint counts in 66 joints 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TEMAV 
treatment-emergent markedly abnormal laboratory value 
TJC 
tender joint counts 
TJC28 
tender joint counts in 68 joints 
TJC68 
tender joint counts in 28 joints 
TLG 
tables, listings, and graphs 
TNF-RI 
tumor necrosis factor receptor-I 
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Abbreviation 
Term 
TRACP-5b 
tartrate resistant acid phosphatase 5b 
VAS 
visual analog scale 
VCAM-1 
vascular cell adhesion molecule-1 
VEGF 
vascular endothelial growth factor 
WHO DD 
World Health Organization Drug Dictionary 
 
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3 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the 
statistical methods that will be used to analyze and report results for Eisai Protocol E6011-
J081-201. 
Statistical methods of Treatment Phase are provided in this document. 
 
3.1 
Study Objectives 
3.1.1 
Primary Objectives 
• 
To evaluate the efficacy of E6011 compared with placebo by ACR20 response rate at 
Week 12 as a primary endpoint 
• 
To evaluate the safety and tolerability of E6011 
 
3.1.2 
Secondary Objectives 
• 
To evaluate the effect of E6011 on suppressing radiographic progression of joint 
destruction at Week 24 
• 
To evaluate the pharmacokinetics (PK) and immunogenicity of E6011 
 
3.1.3 
Exploratory Objective 
• 
To explore the PK/pharmacodynamics (PD) and biomarkers of E6011 
 
3.2 
Overall Study Design and Plan 
This study is a multicenter, randomized, double-blind, placebo-controlled, parallel-group 
comparison study.  The following 4 treatment groups are selected for the study: E6011 
100 mg, 200 mg, 400 mg, and placebo.  In the E6011 100 mg, 200 mg, and placebo groups, 
subjects will receive 100 mg, 200 mg, or placebo at Weeks 0, 1, 2, and every 2 weeks 
subsequently.  In the E6011 400 mg group, subjects will receive 400 mg at Weeks 0, 1, 2, 4, 
6, 8, 10 and then 200 mg every 2 weeks subsequently. 
The study consists of Screening, Observation, Treatment, Extension, and Follow-up Phases. 
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Undergoing screening assessments within 42 days prior to the study treatment, subjects with 
the certain eligibility confirmed in the Observation Phase will be allocated into any of the 
100 mg, 200 mg, 400 mg, or placebo groups at a 1:2:2:2 ratio through dynamic allocation 
using the following factors: C- reactive protein (CRP) level at Screening,  Rheumatoid 
Arthritis (RA) Duration, and Prior Use of Biologics Treatment. 
In the Treatment Phase (24 weeks), subjects will receive either E6011 or placebo at Weeks 0, 
1, 2, and every 2 weeks until Week 22 in a double-blind manner. 
Subjects who complete evaluations at Week 24 of the Treatment Phase will enter the 
Extension Phase.  The Extension Phase is up to Week 104 from the starting of the study 
treatment, and subjects will receive an open-label E6011 200 mg every 2 weeks until 
Week 102.  When subjects insufficiently respond to the treatment or when their disease 
relapses in the Extension Phase (show no improvement from Observation Phase in both of 
tender joint counts (TJC) and swollen joint counts (SJC) at 2 consecutive assessments with 
an interval of ≥1 week), a dose escalation will be allowed only once (6 administrations of 
E6011 400 mg every 2 weeks). 
Follow-up investigations will be conducted on-site 28 days after the completion of the study 
or the discontinuation of the treatment, and either an on-site or telephone-interview 
investigation will be conducted 70 days after the last dosing. 
 
4 
DETERMINATION OF SAMPLE SIZE 
The sample size was based on an expected ACR20 response rate of 30% at Week 12 in the 
placebo group and at least 60% in both of the E6011 200 mg and 400 mg groups, as per 
previous Study 103 and the results from other drugs for treatment of RA.  Although multiplicity 
adjustment using Hochberg method will be carried out in the primary analysis, sample size was 
calculated at a 1-sided significance level of α=0.0125 (α=0.025/2) conservatively.  The sample 
sizes of 50 for E6011 200 mg, 400 mg, and placebo will have 91% power to detect a difference 
in response rate of 35% between placebo and each E6011 group and will have 79% power to 
detect a difference in response rate of 30% based on a chi-square test.   
 
5 
STATISTICAL METHODS 
All descriptive statistics for continuous variables will be reported using mean, standard 
deviation (SD), median, minimum and maximum.  Categorical variables will be summarized 
as number (percentage) of subjects. 
 
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5.1 
Study Endpoints 
5.1.1 
Primary Endpoint 
• 
ACR20 response rate at Week 12 
The ACR20 response is defined as if the following 3 criteria (ACR components) are met: 
1. Greater than or equal to 20% reduction from baseline in the TJC in 68 joints (TJC68)  
2. Greater than or equal to 20% reduction from baseline in the SJC in 66 joints (SJC66)  
3. Greater than or equal to 20% reduction from baseline in at least 3 of the following 
5 assessments: 
- 
Physician's Global Assessment of Disease Activity (VAS)  
- 
Patient's Global Assessment of Disease Activity (VAS) 
- 
Patient's Assessment of Pain (VAS) 
- 
HAQ-DI 
- 
CRP 
 
5.1.2 
Secondary Endpoints 
• ACR20, ACR50, and ACR70 response rate at each visit (excluding ACR20 at Week 12) 
• Values and change from baseline in ACR components (TJC, SJC, VAS [patient's 
assessment of pain, patient's global assessment of disease activity and physician's global 
assessment of disease activity], functional assessment by subjects [HAQ-DI], and 
CRP∙ESR), DAS28-ESR, DAS28-CRP, SDAI, and CDAI at each visit 
• EULAR response criteria at each visit; subjects will be classified based on DAS28-ESR 
or DAS28-CRP 
• DAS28-ESR, DAS28-CRP, SDAI, CDAI, and Boolean remission rates at each visit 
• Values and change from baseline in modified total sharp score (mTSS) at each visit 
The ACR50 response is defined similar to the ACR20 with a 50% reduction. 
The ACR70 response is defined similar to the ACR20 with a 70% reduction. 
The DAS28-CRP calculates on the following formula, and disease activity is categorized as 
High at > 4.1, Moderate at > 2.7 and ≤4.1, Low at <= 2.7, and Remission at <= 2.3. 
0.56 × sqrt{TJC in 28 joints (TJC28)} + 0.28×sqrt{SJC in 28 joints (SJC28)} + 0.36 
× ln{CRP (mg/dL) × 10 + 1} + 0.014 × Patient's Global Assessment of Disease 
Activity (VAS) (mm) + 0.96 
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The DAS28-ESR will be calculated on the following formula, and disease activity is 
categorized as High at > 5.1, Moderate at > 3.2 and <= 5.1, Low at <= 3.2, and Remission at 
< 2.6. 
0.56 × sqrt{TJC28}+ 0.28 × sqrt{SJC28}+0.70×ln{ESR (mm/h)}+0.014 × Patient's 
Global Assessment of Disease Activity (VAS) (mm) 
EULAR Response Criteria: 
Present DAS28 
DAS28 change from baseline 
<–1.2 
>= –1.2 and <–0.6 
>= –0.6 
(missing included) 
Low 
Good response 
Moderate response 
No response 
Moderate 
Moderate response 
Moderate response 
No response 
High 
Moderate response 
No response 
No response 
 
The CDAI will be calculated on the following formula, and disease activity is categorized as  
High at > 22, Moderate at >10 and <= 22, Low at <= 10, and Remission at <= 2.8. 
SJC28+ TJC28 
+ Patient's Global Assessment of Disease Activity (VAS) (mm)/10 
+ Physician's Global Assessment of Disease Activity (VAS) (mm)/10 
The SDAI will be calculated on the following formula, and disease activity is categorized as  
High at > 26, Moderate at > 11 and <= 26, Low at <= 11, and Remission at <= 3.3. 
SJC28+ TJC28 
+ Patient's Global Assessment of Disease Activity (VAS) (mm)/10 
+ Physician's Global Assessment of Disease Activity (VAS) (mm)/10 + CRP (mg/dL) 
The Boolean remission is defined as satisfied all of the following conditions: 
1. TJC68 <= 1 
2. SJC66 <= 1 
3. CRP (mg/dL) <= 1 
4. Disease activity assessments VAS (mm) by subjects <= 10 
 
5.2 
Study Subjects 
5.2.1 
Definitions of Analysis Sets 
Definition of analysis sets are as follows: 
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• 
The Full Analysis Set (FAS) is the group of randomized subjects who received at least 1 
dose of study drug and had at least 1 postdose primary efficacy measurement 
• 
The Per Protocol Analysis Set(PPS) is the subset of subjects in the corresponding FAS 
who do not meet any of following criteria: 
 Subjects who have any major protocol violations (major inclusion/exclusion 
violations or other major protocol deviation that affect the evaluation of efficacy  
 Subjects who are <80% compliant with study drug during treatment phase 
A comprehensive list of excluded subjects from the PPS will be verified by the sponsor’s 
medical officer before database lock. 
• 
The Safety Analysis Set is the group of subjects who received at least 1 dose of study 
drug and had at least 1 postdose safety assessment 
The number of subjects randomized, the number and the percentage of subjects included in 
each analysis set, and the number and the percentage of subjects excluded from each analysis 
set will be presented by treatment group and overall. 
 
5.2.2 
Subject Disposition 
The numbers of subjects who have provided informed consent, and who are screen failures 
together with reasons for screening failure will be summarized.  The numbers of randomized 
subjects and the numbers of treated subjects will be summarized for each treatment group and 
overall.  The number and percentage of subjects who completed treatment phase and 
discontinued the study, and reasons for discontinuation will be summarized for each treatment 
group and overall. 
 
5.2.3 
Protocol Deviations 
Major protocol deviation criteria will be established and subjects with major protocol 
deviations will be identified and documented before the database lock.  The protocol 
deviations identified according to the criteria at study entry and during treatment will not be 
included in tables, listings, and graphs (TLGs) covered by SAP, but presented in the clinical 
study report (CSR). 
 
5.2.4 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics for the Safety Analysis Set and FAS will be 
summarized for each treatment group and overall using descriptive statistics.   
Continuous demographic and baseline variables include: 
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 Age (year) 
 Height (cm) 
 Weight (kg) 
 BMI (kg/m2) at Screening 
 Rheumatoid Arthritis (RA) Duration (years) 
 Dose of MTX (mg/week) 
 Serum Rheumatoid Factor (RF) Concentration (IU/mL) 
 Serum Anti-Cyclic Citrullinated Peptide (CCP) Antibody Concentration (U/mL) 
 Oral Steroid*1 (mg/day) 
 ACR Components 
- 
TJC68 at Baseline 
- 
SJC66 at Baseline 
- 
TJC28 at Baseline 
- 
SJC28 at Baseline 
- 
CRP (mg/dL) at Screening 
- 
CRP (mg/dL) at Baseline 
- 
ESR (mm/h) at Baseline 
- 
Physician's Global Assessment of Disease Activity (VAS) (mm) at Baseline  
- 
Patient's Global Assessment of Disease Activity (VAS) (mm) at Baseline  
- 
Patient's Assessment of Pain (VAS) (mm) at Baseline  
- 
HAQ-DI at Baseline 
 DAS28-CRP at Baseline 
 DAS28-ESR at Baseline 
 CDAI at Baseline 
 SDAI at Baseline 
 Joint Space Narrowing at Baseline 
 Number of Bone Erosions at Baseline 
 mTSS at Baseline 
 mTSS divided by RA Duration (/year) 
 
Categorical variables include: 
 Age group (18<= <35, 35<= <50, 50<= <75) 
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 Sex (Male, Female) 
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Race (White, Black or African American, Japanese, Chinese, Other Asian, American 
Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, Other) 
 RA Duration (< 5 years, 5 years <=) 
 RA Duration (< 1 year, 1 year <= < 5 years, 5 years  <= < 10 years, 10 years <= < 15 
years, >= 15 years) 
 Smoking History (Current, Former, Never) 
 Current Medical Conditions (Yes, No) 
 Prior Use of Biologics Treatment (Yes - TNF*2/Non-TNF, No) 
 Drug experience of MTX (Yes, No) 
 Dose of MTX (< 6 mg/week, 6 mg/week <= < 12 mg/week, >= 12 mg/week) 
 Drug experience of DMARDs within 12 weeks before informed consent except MTX 
(Yes - 1/2/…, No) 
 Continuation of Steroid 
 Serum RF Concentration (Seropositive - High Positive/Low Positive, Seronegative)*3 
 Anti-CCP Antibody (Seropositive - High Positive/Low Positive, Seronegative)*4 
 Classification of Global Functional Status in RA 
 DAS28-CRP Category (High: >4.1, Moderate: 2.7 < <= 4.1, Low: <= 2.7) 
 DAS28-ESR Category (High: >5.1, Moderate: 3.2 < <= 5.1, Low: <= 3.2) 
 CDAI (High: > 22, Moderate: 10 < <= 22, Low: <= 10) 
 SDAI (High: > 26, Moderate: 11 < <= 26, Low: <= 11) 
 CRP level at Screening (< 0.6mg/dL, >= 0.6mg/dL) 
 CRP level at Baseline (< 0.6mg/dL, >= 0.6mg/dL) 
 ESR level at Baseline (< 28mm/h, >= 28mm/h) 
*1 Prednisone-equivalent dose 
*2 Refer section 8.5 “TNF agent” 
*3 Categories of Serum RF Concentration are derives as follows: 
 
Seropositive:  > 15 (IU/mL) 
 
 
High Positive:  < 45 (IU/mL) 
 
 
Low Positive:  15 <=  <= 45 (IU/mL) 
 
Seronegative:  <= 15 (IU/mL) 
*4 Categories of Anti-CCP Antibody are derives as follows: 
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Seropositive:  >= 4.5 (U/mL) 
 
 
High Positive:  < 13.5 (U/mL) 
 
 
Low Positive:  4.5 < <= 13.5 (U/mL) 
 
Seronegative:  < 4.5 (U/mL) 
 
Subject data listings will be provided. 
 
MEDICAL HISTORY 
A subject data listing will be provided. 
 
5.2.5 
Prior and Concomitant Therapy 
All investigator terms for medications recorded in the case report form (CRF) will be coded 
to an 11-digit code using the World Health Organization Drug Dictionary (WHO DD) 
version (Mar2016 or later).  The number (percentage) of subjects who took prior and 
concomitant medications will be summarized on the FAS by treatment group, Anatomical 
Therapeutic Chemical (ATC) class, and WHO DD preferred term.  Prior medications will be 
defined as medications that stopped before the first dose of study drug.  Concomitant 
medications will be defined as medications that (1) started before the first dose of study drug 
and were continuing at the time of the first dose of study drug, or (2) started on or after the 
date of the first dose of study drug.  A subject data listing of all medications will be provided. 
 
5.2.6 
Treatment Compliance 
Treatment compliance will be described in section 5.6.1. 
 
5.3 
Data Analysis General Considerations 
5.3.1 
Pooling of Centers 
Subjects from all centers will be pooled for all analyses. 
 
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5.3.2 
Adjustments for Covariates 
Determination of covariates are as follows: 
• 
Prior Use of Biologics Treatment (Yes/No) 
• 
RA Duration (< 5 years, >= 5 years) 
• 
CRP Level at Baseline (< 0.6mg/dL, >= 0.6mg/dL ) 
In case that the number of subjects in each category of covariates for logistic regression models 
and ANCOVA is very small, to integrate the categories will be planned. 
 
5.3.3 
Multiple Comparisons/Multiplicity 
Hochberg method will be used to control the overall type I error rate for the comparison 
between placebo and either E6011 200 mg or 400 mg in primary efficacy analysis.  The 
Pvalues from the comparisons will be calculated using SAS PROC MULTTEST. 
 
5.3.4 
Examination of Subgroups 
The primary efficacy endpoint, ACR50, ACR70 and mTSS will be summarized and analyzed 
by subgroups defined by section 5.2.1 for categorical variables.  Also, forest plot will be 
created by subgroups for comparison of response rate at primary efficacy endpoint and the 
changes from baseline at mTSS. 
Additional subgroup analyses may also be conducted, if deemed appropriate. 
 
5.3.5 
Handling of Missing Data, Dropouts, and Outliers 
For the efficacy analyses, approaches to handling missing data for continuous variables, except 
mTSS, will be the observed cases (OC) method and the last observation carried forward 
(LOCF) method; binary variables and EULAR response criteria will be the observed cases 
(OC) method, the last observation carried forward (LOCF) method and the non-responder 
imputation (NRI) method as each visit. 
mTSS value at Week 52 will be extrapolated from values of baseline and values of postbaseline, 
which will be used in summary statistics and ANCOVA. 
The linear extrapolation method will be used for analysis of the structural progression endpoint 
(van der Heijde mTSS) to impute missing data at time points when analyses are conducted 
(including the analyses at Week 24 and Week 52).  For patients who discontinue the study or 
the study treatment or for patients who miss a radiograph for any reason, baseline data and the 
most recent radiographic data prior to discontinuation or the missed radiograph, adjusted for 
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time, will be used for linear extrapolation to impute missing data at subsequent time points.  
All patients originally randomized to placebo will be switched to active treatment at Week 24; 
thus, there will be no observed data for the placebo arm for the structural comparison at 
subsequent time points. Therefore, baseline data and the most recent radiographic data prior to 
initiation of the new therapy, adjusted for time, will be used for linear extrapolation at Week 
52. The linear extrapolation method has been established as an appropriate missing data 
imputation method in other Phase 3 RA trials (Keystone et al. 2004, 2008, 2009; Cohen et al. 
2006; Smolen et al. 2008, 2009). Missing postbaseline values will be imputed only if both a 
baseline value and a postbaseline value from another time point are available, as long as the 
patient was on the same treatment at each applicable time point. 
Calculation for value of mTSS extrapolation will be derived by follow formula: 
• 
Week 52 = (Postbaseline ) + ( Postbaseline – Baseline ) * ( ( 52 – ( Study Day of 
Postbaseline / 7 ) / Study Day of Postbaseline / 7 ) 
The two individual components of mTSS (Erosion and joint space narrowing [JSN] score) will 
be analyzed in the same way as the mTSS. 
For the safety analyses for continuous value, descriptive statistics are used OC method and 
LOCF method, this is applied only the last observation of each phase, in tables and figures. 
In the cases of laboratory result contains less (or more) than quantitation limit value is treated 
as:  
a. zero, when less than quantitation limit value, 
b. quantitation limit value, when more than quantitation limit value. 
In the cases of pharmacokinetic data, refer “8.2 Convention for Pharmacokinetic data 
handling”. 
 
5.3.6 
Other Considerations 
5.3.6.1 
Total number of joints 
For the calculation of the total number of joints that are tender/swollen, if any joints are not 
evaluable, the score is prorated by taking the number of joints that are tender/swollen divided 
by the number of evaluable joints and multiplied by the target number of joints, rounded to 
nearest integer. If assessment of joints are “Not Done”, the joints will be handled as tender and 
swollen.  
5.3.6.2 
HAQ subcategory score 
The HAQ-DI is composed of 20 items in 8 categories (Dressing and Grooming, Arising, 
Eating, Walking, Hygiene, Reach, Grip, Activities).  To calculate the HAQ-DI, the highest 
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sub-category score determines the value for each category, there must be responses in at least 
6 of the 8 categories or else a HAQ-DI cannot be computed. The category scores are then 
averaged into an overall HAQ-DI. 
HAQ-DI = (Amount of score with all categories) / (Number of categories scored) 
 
5.4 
Efficacy Analyses 
The FAS will be used as the primary population for the efficacy analyses, while the PPS will 
be used as a supportive analysis. 
 
5.4.1 
Primary Efficacy Analyses 
ACR20 response rate at Week 12 will be analyzed using a logistic regression model, baseline 
CRP, RA Duration and Prior Use of Biologics Treatment as covariates, for the comparison 
between placebo and either E6011 200 mg or 400 mg.  Overall significance level is α=0.025 
(one-sided). Hochberg method will be used to control the overall type I error rate. 
Hypothesis for logistic regression model is: 
• 
Primary hypothesis 
⎩⎪⎨
⎪⎧𝐻𝐻0:
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂400 𝑚𝑚𝑚𝑚 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
= 1 𝑎𝑎𝑎𝑎𝑎𝑎 𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂200 𝑚𝑚𝑚𝑚 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
= 1
𝐻𝐻1:
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂400 𝑚𝑚𝑚𝑚 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
> 1 𝑜𝑜𝑜𝑜 𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂200 𝑚𝑚𝑚𝑚 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
> 1
 
Subjects with missing primary efficacy endpoint due to early discontinuation or other reasons 
will be considered non-responders.  In case that the number of subjects in each category of 
covariates is very small, to integrate the categories will be planned.  ACR20 response rate 
and its 2-sided 95% confidence interval for each treatment group will be calculated.  The 
difference in ACR20 response rate between each of E6011 dose and placebo and its 2-sided 
95% confidence interval will also be calculated.  Subgroup analyses or sensitivity analyses 
will be conducted. 
In addition, following analyses will be conducted for ACR20 response rate at Week 12. 
• 
To compare ACR20 response between E6011 100 mg and placebo using logistic 
regression model same as above. The difference in ACR20 response rate between E6011 
100 mg and placebo and its 2-sided 95% confidence interval will also be calculated. 
Additional hypothesis: 
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⎩⎪⎨
⎪⎧𝐻𝐻0:
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂100 𝑚𝑚𝑚𝑚 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
= 1
𝐻𝐻1:
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂100 𝑚𝑚𝑚𝑚 
𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑂𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃
> 1
 
• 
To evaluate the overall dose response relationship using a logistic regression model with 
treatment as continuous variable(placebo=0, 100mg=100, 200mg=200 and 400mg=400), 
and baseline CRP, RA Duration and Prior Use of Biologics Treatment as covariates. 
 
5.4.2 
Secondary Efficacy Analyses 
The multiplicity adjustment will not be considered for secondary efficacy analyses. For 
ACR20 (excluding Week 12), ACR50, and ACR70, similar analyses as primary analyses will 
be conducted. For each component of ACR (TJC, SJC, VAS [patient's assessment of pain, 
patient's global assessment of disease activity and physician's global assessment of disease 
activity], functional assessment by subjects (HAQ) and CRP∙ESR), DAS28-ESR, DAS28- 
CRP, SDAI, and CDAI in each visit, the values and the changes from baseline will be 
summarized by treatment group. The changes from baseline will also be analyzed using 
ANCOVA with baseline value, CRP Level at Baseline, RA Duration, and Prior Use of 
Biologics Treatment as covariates. The significance level for comparisons between placebo 
and each treatment group of E6011 (100 mg, 200 mg, and 400 mg) is α=0.05 (2-sided).  
For mTSS, values and changes from baseline will be summarized by treatment group. The 
changes from baseline will be analyzed using rank ANCOVA same as above. In this analysis, 
all mTSS score will first be rank transformed for both baseline and changes from baseline 
separately. The Hodges-Lehman method will be used in this analysis concerning the median 
changes from baseline in mTSS score to show treatment differences and associated 95% 
confidence intervals (CI) for each active treatment group. Also, frequency and percentage of 
proportion for changes from baseline (criteria: <= 0.5/year) will be summarized by treatment 
group.  For DAS28-ESR and DAS28-CRP, frequency and percentage of each classification 
(no response, moderate response, good response) by EULAR response criteria will be 
summarized by treatment group and visit in a shift table.  For DAS28-ESR, DAS28-CRP, 
SDAI and CDAI, frequency and percentage of each category (Remission, Low, Moderate, 
High) will be summarized by treatment group and visit in a shift table.  For remission rates in 
DAS28-ESR, DAS28-CRP, SDAI, CDAI, and Boolean, similar analyses as primary analyses 
will be conducted. 
The mean of variables (ACR components, DAS28-CRP, DAS28-ESR, CDAI and SDAI) and 
change from baseline - visit will be displayed by treatment group. ACR response rate - visit, 
including week 12, will be displayed by treatment group. Bar chart of each variables (ACR 
response rate, remission rate in DAS28-CRP, DAS28-ESR, CDAI, SDAI and Boolean) will 
be displayed at week 12 and week 24. Stacked bar chart of DAS28-CRP and DAS28-ESR by 
EULAR response criteria will be displayed at week 12 and week 24. Stacked bar chart of 
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category of DAS28-CRP and DAS28-ESR will be displayed at baseline and week 12 and 
week 24.  Cumulative probability of the change from baseline in mTSS will be displayed at 
week 24. 
All efficacy endpoints for the treated subjects will be listed. 
 
5.4.3 
Other Efficacy Analyses 
No other efficacy analyses are planned for this study. 
 
5.5 
Pharmacokinetic, Pharmacodynamic, Pharmacogenomic, and 
Other Biomarker Analyses 
5.5.1 
Pharmacokinetic Analyses 
Serum E6011 Concentration 
Serum PK samples for PK analyses will be collected on Week 0 (predose), Week 1 (predose), 
Week 2 (predose), Week 4 (predose), Week 8 (predose), Week 12 (predose) , Week 16 
(predose), Week 20 (predose), Week 24 (predose). 
The Safety Analysis Set will be used for PK analyses. 
<Table> 
Individual serum concentration values of E6011 will be listed and summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum and maximum) by dose 
and nominal time point.  The data of time points in subject with interruption will not be 
included on calculation of summary statistics. 
<Listing> 
Actual sampling time and serum concentrations of E6011 for each subject will be listed. 
<Figure> 
The individual serum E6011 concentration–time profile will be displayed in linear and semi–
log scales using actual sampling times in the same graph by dose. 
The mean serum concentrations of E6011 will be displayed using nominal blood sampling 
times with standard deviation in linear and semi–log scales by dose in the same graph. 
 
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5.5.2 
Pharmacodynamic, Pharmacogenomic, and Other Biomarker 
Analyses 
5.5.2.1 
Pharmacodynamic, Pharmacogenomic Analyses 
No Pharmacodynamic and Pharmacogenomic analyses are planned for this study. 
 
5.5.2.2 
Other Biomarker Analyses 
All biomarker analyses will be performed using the Full Analysis Set.   
For the Treatment Phase, summary statistics for serum RF concentration, serum anti-CCP 
antibody concentration, and serum matrix metalloproteinase-3 concentration, serum tartrate 
resistant acid phosphatase 5b (TRACP-5b) concentration, serum cytokine concentration, 
serum leucine-rich alpha-2 glycoprotein 1 (LRG1) concentration, serum angiopoietin 2 (Ang2) 
concentration, Vectra™ DA and it’s component (vascular cell adhesion molecule-1 (VCAM-
1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF)-A, interleukin 
(IL)-6, tumor necrosis factor receptor-I (TNF-RI), serum matrix metalloproteinase-1, serum 
matrix metalloproteinase-3, YKL-40, leptin, resistin, SA and CRP) value, change from 
baseline and percent change from baseline, by treatment group and time point, will be 
calculated.  Exploratory investigations of the relationship between efficacy and biomarkers 
will be conducted. The analysis plan for CX3CR1 is out of scope of this document. All other 
biomarkers will be collected on baseline and postbaseline, referring section 8.1.3 “Time 
window”. 
Subject data listings will be provided. 
 
5.5.2.3 
Immunogenicity Analyses 
All immunogenicity analyses will be performed using the Safety Analysis Set.   
The percentage and frequency of occurrences will be calculated for serum anti-E6011 
antibodies and E6011-induced anti-E6011 antibodies by treatment group and time point.  If 
anti-E6011 antibody develops, the frequency and percentage of any anti-E6011 antibody 
neutralization activity and isotypes will be calculated. 
Subject data listings will be provided. 
 
5.6 
Safety Analyses 
All safety analyses will be performed on the Safety Analysis Set. Safety data, presented by 
treatment group, will be summarized on an “as treated” basis using descriptive statistics (eg, n, 
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mean, SD, median, minimum, maximum for continuous variables; n [%] for categorical 
variables). Safety variables include treatment-emergent adverse events (TEAEs), clinical 
laboratory parameters, vital signs, 12-lead ECG results, chest x-ray, neurological findings, and 
blood CD4 positive cell count. Day 1 for all safety analyses will be defined as the date of the 
first dose of study drug. 
 
5.6.1 
Extent of Exposure 
The extent of exposure to study drug will be characterized by duration of exposure, number of 
injection dose and study medication compliance for each treatment group.  Definition of 
analysis items are as follows: 
 Duration of exposure (weeks) = (Date of Last Dose - Date of First Dose + 14 ) / 7 
 Number of Injection = Count of records with non-zero treatment 
 Study Medication Compliance (%) = Number of Injection / Number of Expected 
Injection * 100 
Subject data listings will be provided. 
 
5.6.2 
Adverse Events 
The AE verbatim descriptions (investigator terms from the CRF) will be classified into 
standardized medical terminology using the Medical Dictionary for Regulatory Activities 
(MedDRA). Adverse events will be coded to the MedDRA (Version 19.1 or higher) lower level 
term (LLT) closest to the verbatim term. The linked MedDRA preferred term (PT) and primary 
system organ class (SOC) are also captured in the database. A treatment-emergent adverse 
event (TEAE) is defined as an AE that emerges during treatment, having been absent at 
pretreatment (Baseline) or 
• 
Reemerges during treatment, having been present at pretreatment (Baseline) but stopped 
before treatment, or 
• 
Worsens in severity during treatment relative to the pretreatment state, when the AE is 
continuous. 
Only those AEs that are treatment-emergent will be included in summary tables. 
A subject will be counted only once within an SOC and PT, even if the subject experienced 
more than 1 TEAE within a specific SOC and PT.   
The TEAEs will be summarized by treatment group and E6011 overall.  The incidence of 
follow TEAEs will be reported as the number (percentage) of subjects with TEAEs by SOC 
and PT: 
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• 
TEAEs 
• 
TEAEs by maximum intensity 
• 
Serious TEAEs 
• 
TEAEs leading to study drug withdrawn 
• 
TEAEs leading to interruption of study drug 
• 
TEAEs leading to reduction from study drug 
• 
Treatment Related, TEAEs 
• 
Treatment Related, TEAEs by maximum grade 
• 
Treatment Related, Serious TEAEs 
• 
Treatment Related, TEAEs leading to study drug withdrawn 
• 
Treatment Related, TEAEs leading to interruption of study drug 
• 
Treatment Related, TEAEs leading to reduction from study drug 
In the 12/24 weeks analysis, the AEs emerged until disposition on Week 12/24 are intended, 
but for patients who discontinued in Treatment Phase, the AEs emerged until 70 days after the 
last dose are intended 
Subject data listings of All AEs, SAEs, AEs leading to death, leading to study drug withdrawn 
or leading to interruption from study drug will be provided.  
 
5.6.3 
Laboratory Values 
Laboratory results will be summarized using Système International (SI) units. For quantitative 
parameters listed in protocol Section 9.5.1.5.3, the actual value and the change from baseline 
to each postbaseline visit will be summarized by visit and treatment group using descriptive 
statistics.  Qualitative parameters listed in protocol Section 9.5.1.5.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables.  Percentages will 
be based on the number of subjects with both nonmissing baseline and relevant postbaseline 
results. 
Laboratory test results will be assigned a low/normal/high (LNH) classification according to 
whether the value was below (L), within (N), or above (H) the laboratory parameter’s reference 
range.  Within-treatment comparisons for each laboratory parameter will be based on 3-by-3 
tables (shift tables) that compare the baseline LNH classification to the LNH classification at 
each postbaseline visit and at the end of treatment.  Similar shift tables will be used to compare 
the baseline LNH classification to the LNH classification for the highest and lowest value 
during the study. 
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The Sponsor’s Grading for Laboratory Values using CTCAE v4.0 presents the criteria that will 
be used to identify subjects with treatment-emergent markedly abnormal laboratory values 
(TEMAVs).  Except for phosphate, a TEMAV is defined as a postbaseline value with an 
increase from baseline to a grade of 2 or higher.  For phosphate, a TEMAV is defined as a 
postbaseline value with an increase from baseline to a grade of 3 or higher.  When displaying 
the incidence of TEMAVs, each subject will be counted once in the laboratory parameter high 
and in the laboratory parameter low categories, as applicable. 
Laboratory results versus visit by treatment group will be displayed using box-plot. 
Subject data listings of Laboratory test results and TEMAV will be provided. 
 
5.6.4 
Vital Signs 
Descriptive statistics for vital signs parameters (systolic and diastolic BP, pulse, temperature, 
and weight) and changes from baseline will be presented by visit and treatment group. 
Subject data listings will be provided. 
 
5.6.5 
Electrocardiograms 
Shift tables will be presented changes from baseline in 12-lead ECG interpretation 
(normal/abnormal, not clinically significant/abnormal, not clinically significant) by visit and 
treatment group. 
Subject data listings will be provided. 
 
5.6.6 
Other Safety Analyses 
5.6.6.1 
Chest X-Ray 
Shift tables will be presented changes from baseline in chest x-ray (normal/abnormal, not 
clinically significant/abnormal, not clinically significant) by visit and treatment group. 
Subject data listings will be provided. 
 
5.6.6.2 
Neurological findings 
Descriptive statistics for neurological findings will be presented by visit and treatment group. 
Subject data listings will be provided. 
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5.6.6.3 
Blood CD4 positive cell counts 
For Blood CD4 positive cell counts, the actual value and the change from baseline to each 
postbaseline visit will be summarized by visit and treatment group using descriptive statistics. 
Blood CD4 positive cell counts will be assigned a low/normal/high (LNH) classification 
according to whether the value was below (L), within (N), or above (H) the it’s reference range. 
Within-treatment comparisons will be based shift tables that compare the baseline LNH 
classification to the LNH classification at each postbaseline visit. 
Subject data listings will be provided. 
 
5.7 
Other Analyses 
5.7.1 
Anti-JCV Antibody Test 
Anti-JCV antibody test result (positive or negative) is judged according to the results of 
screen assay and inhibition assay. 
Subject data listings will be provided. 
 
5.8 
Exploratory Analyses 
Exploratory analyses may be conducted as appropriate.  Any exploratory analyses that are 
performed will be appropriate titled and labeled as exploratory and will be clearly distinguished 
from planned analyses when results are reported in the Clinical Study Report. 
 
5.9 
Extension Phase Analyses 
SAP for extension phase will be separately prepared and finalized before each database lock. 
 
6 
INTERIM ANALYSES 
No interim analyses are planned for this study. 
 
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7 
CHANGES IN THE PLANNED ANALYSES 
Changes in the planned analyses for protocol are as follows: 
• 
Regarding primary efficacy analysis, baseline CRP will be used as covariate instead of 
CRP at screening. 
 
Additions in the planned analyses for protocol are as follows: 
• 
Efficacy Analysis 
 frequency and percentage of proportion for the changes from baseline (criteria: <= 
0.5/year) in mTSS will be summarized by treatment group. 
 frequency and percentage of each category (Remission, Low, Moderate, High) of 
DAS28-ESR, DAS28-CRP, CDAI and SDAI will be summarized by treatment group 
and visit in a shift table. 
 The mean of variables (ACR components, DAS28-CRP, DAS28-ESR, CDAI and 
SDAI) and change from baseline - visit will be displayed by treatment group.  
 ACR response rate - visit, including week 12, will be displayed by treatment group.  
 Bar chart of each variables (ACR response rate, remission rate in DAS28-CRP, 
DAS28-ESR, CDAI, SDAI and Boolean) will be displayed at week 12 and week 24. 
 Stacked bar chart of DAS28-CRP and DAS28-ESR by EULAR response criteria will 
be displayed at week 12 and week 24. 
 Stacked bar chart of category of DAS28-CRP and DAS28-ESR will be displayed at 
baseline and week 12 and week 24. 
 Cumulative probability of the change from baseline in mTSS will be displayed at 
week 24. 
 ACR50, ACR70 and mTSS will be summarized and analyzed by subgroups defined 
by section 5.2.1 for categorical variables. 
 Forest plot will be created by subgroups for comparison of response rate at primary 
efficacy endpoint and the changes from baseline at mTSS. 
 logistic regression model with treatment as continuous variable(placebo=0, 
100mg=100, 200mg=200 and 400mg=400), and baseline CRP, RA Duration and Prior 
Use of Biologics Treatment as covariates to evaluate the dose response relationship. 
 rank ANCOVA for the change from baselin in mTSS score with both baseline mTSS 
score and changes from baseline in mTSS score will be rank transformed.  
 The Hodges-Lehman estimates for the median difference and associated 95% 
confidence intervals (CI)  in change from baseline in mTSS score. 
 
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• 
Extent of Exposure 
 The extent of exposure to study drug will be characterized by number of injection and 
study medication compliance for each treatment group. 
 
• 
Adverse Events 
 The incidence of follow TEAEs will be reported as the number (percentage) of 
subjects with TEAEs by SOC and PT: 
 Serious TEAEs 
 TEAEs leading to study drug withdrawn 
 TEAEs leading to interruption of study drug 
 TEAEs leading to reduction from study drug 
 Treatment Related, Serious TEAEs 
 Treatment Related, TEAEs leading to study drug withdrawn 
 Treatment Related, TEAEs leading to interruption of study drug 
 Treatment Related, TEAEs leading to reduction from study drug 
 
• 
Laboratory Values 
 Qualitative parameters listed in protocol Section 9.5.1.5.3 will be summarized using 
frequencies (number and percentage of subjects), and changes from baseline to each 
postbaseline visit and to end of treatment will be reported using shift tables. 
 Percentages will be based on the number of subjects with both nonmissing baseline 
and relevant postbaseline results. 
 Each subject will be counted once in the laboratory parameter high and in the 
laboratory parameter low categories. 
 Laboratory results versus visit by treatment group will be displayed using box-plot. 
 
• 
Other Analyses 
 Anti-JCV antibody test result listings will be provided. 
 
8 
DEFINITIONS AND CONVENTIONS FOR DATA HANDLING 
8.1 
Baseline, Time Windows for statistical analyses 
8.1.1 
Definition of baseline value 
The baseline value was defined as the most recent value reported just before first dosing. 
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8.1.2 
Definition of change from baseline and percent change from baseline 
Change from baseline is defined as postbaseline value minus baseline value.  Percent change 
from baseline is defined as follows: 
% Change from baseline = (Change from baseline/Baseline) * 100 
For any Baseline value of 0, the subject’s corresponding percent change from baseline will 
not be included in the summary statistics table. 
 
8.1.3 
Time windows 
Time windows are defined as Table 8.1 to Table 8.8 for each assessment.  Observation that has 
the most recent date-time on base date-time is adopted if plural observations exist in the time 
window.  Observation recorded later is adopted if they recorded in that same period. 
Table 8.1  Definition of time windows and calculated visits for vital signs and Serum E6011 
concentration 
Visit 
Base date 
Time windows 
Week 1 (Day 8) 
Date of first drug 
administration + 7 days 
Base date - 3 days <=   < Base date + 3 
days 
Week 2 (Day 15) 
Date of first drug 
administration + 14 days 
Base date - 4 days <=   < Base date + 7 
days 
Week 4 (Day 29) 
Date of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 24 
by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 
14 days 
 
Table 8.2  Definition of time windows and calculated visits for Physical findings, 
administration site finding 
Visit 
Base date 
Time windows 
Week 1 (Day 8) 
Date of first drug 
administration + 7 days 
Base date - 3 days <=   < Base date + 3 
days 
Week 2 (Day 15) 
Date of first drug 
administration + 14 days 
Base date - 4 days <=   < Base date + 7 
days 
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Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 12 
by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
Week 24 
Date-time of first drug 
administration + 168 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.3  Definition of time windows and calculated visits for Joint assessment, ESR, VAS, 
HAQ, Laboratory tests (include Hematology, blood chemistry, urinalysis, RF, anti-CCP 
antibody and matrix metalloproteinase -3) 
Visit 
Base date 
Time windows 
Week 2 (Day 15) 
Date of first drug 
administration + 14 days 
Base date - 4 days <=   < Base date + 7 
days 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 24 
by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.4  Definition of time windows and calculated visits for body weight, 12-lead ECG, 
Chest x-ray, Pregnancy test, Neurological findings, Blood CD4 positive cells, Autoantibody, 
Serum KL-6, β D glucan, Vasculitis marker tests, Serum TRACP-5b concentration, Vectra™ 
DA 
Visit 
Base date 
Time windows 
Week 12 - Week 
24 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.5  Definition of time windows and calculated visits for Serum anti-E6011 antibody 
Visit 
Base date 
Time windows 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 8 - Week 24 
by 4 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
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Table 8.6  Definition of time windows and calculated visits for Serum cytokine concentration, 
LRG1, Ang2 
Visit 
Base date 
Time windows 
Week 4 (Day 29) 
Date-time of first drug 
administration + 28 days 
Base date - 7 days <=   < Base date + 14 
days 
Week 12 - Week 
24 by 12 weeks 
Date-time of first drug 
administration + X * 7 
days (Week X) 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.7  Definition of time windows and calculated visits for Anti-JCV antibody test 
Visit 
Base date 
Time windows 
Week 24 
Date-time of first drug 
administration + 168 
days 
Base date - 14 days <=   < Base date + 14 
days 
 
Table 8.8  Definition of time windows and calculated visits for Joint x-ray 
Visit 
Base date 
Time windows 
Week 0 
Date-time of first drug 
administration 
Base date <= 28 days 
Week 24* 
Date-time of first drug 
administration + 168 
days 
28 days < <= Base date + 28 days 
* Assessment date for mTSS is prior to Base date -7 <= <= Base date + 28, value of Week 24 
is extrapolated as follow formula: 
• 
Week 24 = ( Postbaseline ) + ( Postbaseline – Baseline ) * ( ( 24 – ( Study Day of 
Postbaseline / 7 ) / Study Day of Postbaseline / 7 ) 
 
8.2 
 Pharmacokinetic data handling 
8.2.1 
Lower Limit of Quantification of E6011 Serum Concentration 
The LLOQ of E6011 serum concentration is 0.1 µg/mL.  
 
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8.2.2 
BLQ Handling for Developing Concentration–Time Profiles 
When developing individual concentration-time profiles, BLQ values will be handled 
according to 302-104.00-MNL for non-compartmental pharmacokinetic analysis.  
 
8.2.3 
BLQ Handling for Developing Tables 
When developing tables, BLQ values will be handled according to 302-104.00-MNL for non-
compartmental pharmacokinetic analysis.  
 
8.2.4 
Handling of anomalous concentration values 
Handling anomalous concentration values will follow the 302-104.00-MNL for non-
compartmental pharmacokinetic analysis. 
8.2.5 
General Rules for Presentation of Drug Concentrations 
When presenting individual/raw (raw, hereafter) values and summary statistics,  the following 
rule will be applied:  for drug concentrations, all summary statistics (mean, median, geometric 
mean, standard deviation (SD)  and coefficient variation (CV) ) will have 3 significant digits.   
 
8.3 
Imputation rule for partial date 
8.3.1 
Date of Diagnosis 
Imputation rule for date of diagnosis is as follows:  
• 
Complete date:  Date as reported on CRF. 
• 
Year and Month are not missing but Day is missing:  Year and Month as reported on 
CRF, Date as 15th 
• 
Year is not missing but Month and Day are missing:  Year as reported on CRF, Month 
and Day as July 1st. 
• 
Year is missing or Date is completely missing:  Missing 
 
8.3.2 
Medication 
Imputation rule for medication start date is as follows: 
• 
Complete date:  Date as reported on CRF 
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• 
Year and Month are not missing but Day is missing:  Year and Month as reported on 
CRF, Day as 1st 
• 
Year is not missing but Month and Day are missing:  Year as reported on CRF, Month 
and Day as January 1st 
• 
Year is missing or Start Date is completely missing:  Missing 
Imputation rule for medication end date is as follows: 
• 
Complete date:  Date as reported on CRF 
• 
Year and Month are not missing but Day is missing:  Date of death or Year and Month 
as reported on CRF, last day of the reported month, which is earlier 
• 
Year is not missing but Month and Day are missing:  Year as reported on CRF, Month 
and Day as December 31st 
• 
Year is missing or Start Date is completely missing:  Missing 
 
8.3.3 
Adverse Events 
Imputation rule for adverse event start date is as follows: 
• 
Year and Month are not missing but Day is missing 
 Year and Month are the same as year and month of the earliest among non-missing 
values of first dosing date of study Treatment and imputed AE end date:  The 
earliest among non-missing values of first dosing date of study Treatment and 
imputed AE end date 
 Year and Month are not the same as year and month of the earliest among non-
missing values of first dosing date of study Treatment and imputed AE end date:  
Year and Month as reported on CRF, Day as 1st 
• 
Year is not missing but Month and Day are missing 
 Year is the same as year of the earliest among non-missing values of first dosing 
date of study Treatment and imputed AE end date:  The earliest among non-missing 
values of first dosing date of study Treatment and imputed AE end date 
 Year is not the same as year of the earliest among non-missing values of first dosing 
date of study Treatment and imputed AE end date:  Year as reported on CRF, Month 
and Day as January 1st 
• 
Completely missing:  First dosing date or imputed AE end date, which is earlier 
Imputation rule for adverse event end date is as follows: 
• 
Outcome is ‘fatal’ and End Date is not complete date:  Date of death 
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• 
Outcome is ‘fatal’ and End Date is complete date 
 different from the date of death:  Confirm to CDM 
 same as the date of death:  Date of death 
• 
Outcome is not ‘fatal’ and date of death is not missing 
 Year and Month are the same as the year and month of date of death:  Date of death 
 Year and Month are not the same as the year and month of date of death:  Year and 
Month as reported on CRF, Day as the last day of the month 
 Year is the same as the year of date of death:  Date of death 
 Year is not the same as the year of date of death:  Year as reported on CRF, Month 
and Day as December 31st 
 Completely missing:  Date of death 
• 
Outcome is not ‘fatal’ and date of death is missing  
 Year and Month are not missing but Day is missing:  Year and Month as reported on 
CRF, Day as the last day of the month 
 Year is not missing but Month and Day are missing, and Year is before the Year of 
date of discontinuation from study:  Year as reported on CRF, Month and Day as 
December 31st 
 Year is not missing but Month and Day are missing, and Year is same as the Year of 
date of discontinuation from study:  Date of discontinuation from study 
• 
Outcome is marked ‘Recovered’ or ‘Recovered with sequelae’:  Date of discontinuation 
from study 
• 
Outcome is missing or is ‘Not recovered’, ‘Recovering’ or ‘Unknown’, or Year is 
missing or Start Date is completely missing:  Missing 
• 
Year, Month and Day are all missing and date of death is not missing:  Date of death 
 
8.4 
Decimal places 
Decimal places (DP) for descriptive statistics, except PK analysis, is defined as follows: 
• 
Mean:  Significant digits + 1 
• 
SD:  Significant digits + 2 
• 
Median:  Significant digits + 1 
• 
Min, Max:  Significant digits 
• 
Percentage of frequency:  fixed one decimal place 
Significant digits for the derived parameter is defined as follows: 
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• 
TJC68, SJC66, TJC28, SJC28:  Integer 
• 
DAS28-CRP, DAS28-ESR, CDAI, SDAI, Calcium Corrected:  2 DP 
• 
HAQ-DI:  1 DP 
DP for the other calculated result is defined as follows: 
• 
Confidence Interval:  fixed  2 DP 
• 
Pvalue:  fixed 3 DP(truncated below 4 DP) , except < 0.001.  When < 0.001, as is. 
Summary of change from baseline is based on significant digits of each parameter, and percent 
change from baseline is defined as 1 DP. 
8.5 
TNF Agent 
Medications as TNF agent are extracted at ATC4 Code = L04AB. 
9 
PROGRAMMING SPECIFICATIONS 
The rules for programming derivations and dataset specifications are provided in separate 
documents. 
 
10 STATISTICAL SOFTWARE 
All statistical analyses will be performed using SAS version 9.3 or later. 
 
11 MOCK TABLES, LISTINGS, AND GRAPHS 
The study TLG shells will be provided in a separate document, which will show the content 
and format of all tables, listings, and graphs in detail. 
 
12 REFERENCES 
Keystone, E., et al., Radiographic, Clinical, and Functional Outcomes of Treatment With 
Adalimumab (a Human Anti-Tumor Necrosis Factor Monoclonal Antibody) in Patients With 
Active Rheumatoid Arthritis Receiving Concomitant Methotrexate erapy Keystone EC, 
Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischko SA, and Chartash EK 
Arthritis Rheum.2004 May; 50(5): p. 1400-11 
Keystone, E., et al., Certolizumab pegol plus methotrexate is significantly more effective 
than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, 
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phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. 
Arthritis Rheum, 2008. 58(11): p. 3319-29. 
Keystone, E.C., et al., Golimumab, a human antibody to tumour necrosis factor {alpha} 
given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate 
therapy: the GO-FORWARD Study. Ann Rheum Dis, 2009. 68(6): p. 789-96. 
Cohen, S.B., et al., Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor 
therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III 
trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum, 2006. 
54(9): p. 2793- 806. 
Smolen, J.S., et al., Effect of interleukin-6 receptor inhibition with tocilizumab in patients 
with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised 
trial. Lancet, 2008. 371(9617): p. 987-97. 
Smolen, J.S., et al., Golimumab in patients with active rheumatoid arthritis after treatment 
with tumour necrosis factor alpha inhibitors (GO-AFTER study): a multicentre, randomised, 
double-blind, placebo-controlled, phase III trial. Lancet, 2009. 374(9685): p. 210-21. 
 
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13 APPENDICES 
13.1 National Institute for Health: Common Terminology Criteria for Adverse Events (CTCAE) Version 
4.0 
National Cancer Institute (NCI) CTCAE version 4.0 May 2009 is available online at: 
https://evs.nci.nih.gov/ftp1/CTCAE/Archive/CTCAE_4.0_2009-05-29_QuickReference_5x7.pdf 
CTCAE grades for selected laboratory parameters are listed in the table below, where ULN is the upper limit of normal and LLN is 
the lower limit of normal. 
Lab Parameter 
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hematology 
Hemoglobin (low) 
< LLN - 100 (g/L) 
< 100 - 80 (g/L) 
< 80 - 65 (g/L) 
 
Death 
Hemoglobin (high)  
Increase in > 0 - 20 (g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in >20 - 40 (g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
Increase in > 40 (g/L) 
above ULN or above 
baseline if baseline is 
above ULN 
 
 
Platelet Count (PLT) (low) 
< LLN - 75.0 (10^9/L) 
< 75.0 - 50.0 (10^9/L) 
< 50.0 - 25.0 (10^9/L) 
< 25.0 (10^9/L) 
 
White Blood Cell Count  
(WBC) (low) 
< LLN - 3.0 (10^9/L) 
< 3.0 - 2.0 (10^9/L) 
< 2.0 - 1.0 (10^9/L) 
< 1.0 (10^9/L) 
 
White Blood Cell Count  
(WBC) (high) 
 
 
> 100 (10^9/L) 
 
Death 
Lymphocytes (low) 
< LLN - 0.8 (10^9/L) 
< 0.8 - 0.5 (10^9/L) 
< 0.5 - 0.2 (10^9/L) 
< 0.2 (10^9/L) 
 
Lymphocytes (high) 
 
> 4 - 20 (10^9/L) 
> 20 (10^9/L) 
 
 
Neutrophils (low) 
< LLN - 1.5 (10^9/L) 
< 1.5 - 1 (10^9/L) 
< 1 - 0.5 (10^9/L) 
< 0.5 (10^9/L) 
 
Blood Chemistry 
Albumin (low) 
< LLN - 3 (g/dL) ; 
< LLN - 30 (g/L) 
< 3 - 2 (g/dL) ; 
< 30 - 20 (g/L) 
< LLN - 2 (g/dL) ; 
< 20 (g/L) 
 
Death 
Alkaline Phosphatase (high) 
> ULN - 3.0 x ULN  
> 3.0 - 5.0 x ULN  
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
 
Alanine Aminotransferase  
(high) 
> ULN - 3.0 x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
 
Amylase (high) 
> ULN - 1.5 x ULN 
> 1.5 - 2.0 x ULN 
> 2.0 - 5.0 x ULN 
> 5.0 x ULN 
 
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Lab Parameter 
NCI Common Terminology Criteria for Adverse Events (CTCAE) - SI Units 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Aspartate Aminotransferase  
(high) 
> ULN - 3.0 x ULN  
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN  
> 20.0 x ULN 
 
Total Bilirubin (high) 
> ULN – 1.5 x ULN  
> 1.5 – 3.0 x ULN 
> 3.0 – 10.0 x ULN 
> 10.0 x ULN 
 
Corrected Calcium*, serum-
low (hypocalcemia) 
< LLN - 2.0 (mmol/L) ; 
< LLN - 8.0 (mg/dL) 
< 2 - 1.75 (mmol/L) ; 
< 8.0  - 7.0 (mg/dL) 
< 1.75 - 1.5 (mmol/L) ; 
< 7.0 - 6.0 (mg/dL) 
< 1.5 (mmol/L) ; 
< 6.0 (mg/dL) 
Death 
Corrected Calcium*, serum-
high (hypercalcemia) 
> ULN – 2.9 (mmol/L) ; 
> ULN – 11.5 (mg/dL) 
> 2.9 – 3.1 (mmol/L) ; 
> 11.5 – 12.5 (mg/dL) 
> 3.1 – 3.4 (mmol/L) ; 
> 12.5 – 13.5 (mg/dL) 
> 3.4 (mmol/L) ; 
> 13.5 (mg/dL) 
Death 
Cholesterol (high) 
> ULN - 300 (mg/dL) ; 
> ULN - 7.75 (mmol/L) 
> 300 - 400 (mg/dL) ; 
> 7.75 - 10.34 (mmol/L) 
> 400 - 500 (mg/dL) ; 
> 10.34 - 12.92 (mmol/L) 
> 500 (mg/dL) ; 
> 12.92 (mmol/L) 
 
Creatinine (high) 
> 1 - 1.5 x baseline ; 
> ULN - 1.5 x ULN 
> 1.5 - 3.0 x baseline ; 
> 1.5 - 3.0 x ULN 
> 3.0 x baseline ; 
> 3.0 - 6.0 x ULN 
> 6.0 x ULN 
 
Gammaglutamyltransferase 
(high) 
> ULN - 3.0 x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 x ULN 
> 20.0 x ULN 
 
Glucose, serum-low  
(hypoglycemia) 
< LLN - 55 (mg/dL) ;  
< LLN - 3.0 (mmol/L) 
< 55 - 40 (mg/dL) ;  
< 3.0 - 2.2 (mmol/L) 
< 40 - 30 mg/dL ;  
< 2.2 - 1.7 mmol/L 
< 30 mg/dL ; 
< 1.7 mmol/L 
Death 
Glucose, serum-high  
(hyperglycemia) 
> ULN - 160 (mg/dL) ; 
> ULN - 8.9 (mmol/L) 
> 160 - 250 (mg/dL) ; 
> 8.9 - 13.9 (mmol/L) 
> 250 - 500 (mg/dL) ; 
> 13.9 - 27.8 (mmol/L) 
> 500 (mg/dL) ;  
> 27.8 (mmol/L) 
Death 
Phosphate, serum-low  
(hypophosphatemia) 
< LLN - 2.5 mg/dL;  
< LLN - 0.8 mmol/L 
< 2.5 - 2.0 mg/dL;  
< 0.8 - 0.6 mmol/L 
< 2.0 - 1.0 mg/dL;  
< 0.6 - 0.3 mmol/L 
< 1.0 mg/dL;  
< 0.3 mmol/L; 
Death 
Potassium, serum-low  
(hypokalemia) 
< LLN - 3.0 mmol/L 
 
< 3.0 - 2.5 mmol/L 
< 2.5 mmol/L 
Death 
Potassium, serum-high  
(hyperkalemia) 
> ULN - 5.5 mmol/L 
> 5.5 - 6.0 mmol/L 
> 6.0 - 7.0 mmol/L 
> 7.0 mmol/L 
Death 
Sodium (Hyponatremia) (low) 
< LLN - 130 mmol/L 
 
< 130 - 120 mmol/L 
< 120 mmol/L; 
Death 
Sodium (Hypernatremia) 
(high) 
> ULN - 150 mmol/L 
> 150 - 155 mmol/L 
> 155 - 160 mmol/L 
> 160 mmol/L; 
Death 
Triglyceride 
(hypertriglyceridemia) (high) 
150 - 300 (mg/dL) ;  
1.71 - 3.42 (mmol/L) 
> 300 - 500 (mg/dL) ;  
> 3.42 - 5.7 (mmol/L) 
> 500 - 1000 (mg/dL) ; 
> 5.7 - 11.4 (mmol/L) 
> 1000 (mg/dL) ; 
> 11.4 (mmol/L) 
Death 
Uric 
Acid 
(hyperuricemia) 
(high) 
> ULN - 10 (mg/dL) ; 
> ULN - 0.59 (mmol/L) 
 
 
> 10 (mg/dL) ; 
> 0.59 (mmol/L) 
Death 
Urinalysis 
Protein 
1+ 
2+ or higher 
 
 
 
Other 
Blood CD4 Positive Cell  
Counts 
< LLN - 0.5 (10^9/L) 
< 0.5 - 0.2 (10^9/L) 
< 0.2 - 0.05 (10^9/L) 
< 0.05 (10^9/L) 
 
* Corrected serum calcium by albumin should be referred. If serum albumin is <4.0 g/dL, the corrected calcium will be calculated using the following formula: 
Corrected calcium (mg/dL) = Total calcium (mg/dL) – 0.8 x [Albumin (g/dL) – 4] 
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Statistical Analysis Plan 
E6011-J081-201 
 
 
Eisai 
FINAL Version 2.0:  19 Mar 2018 
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Page 38 of 39 
 
As to Alkaline Phosphatase and γ-GTP, criteria for Grade 2 is changed from ULN x 2.5 (in the CTCAE) to ULN x 3.0. 
 
13.2 Sponsor’s Grading for Determining Markedly Abnormal Laboratory Results 
Except for phosphate, a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 2 or higher.  For 
phosphate, a TEMAV is defined as a postbaseline value with an increase from baseline to a grade of 3 or higher. 
 
 
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PPD
PPD
PPD