An Observational, Prospective Cohort Study to Evaluate Safety and Efficacy of Remsima™ in Patients With Rheumatoid Arthritis
Conditions: Rheumatoid Arthritis
Sponsor: Celltrion

The concepts and information contained in this document are intended solely as guidance for the IRB of Head of 
institution, Lead investigator, Principal investigator, relevant government agencies and clinical research organization 
and are considered proprietary of CELLTRION, Inc. and CELLTRION, Pharm. This document may not be disclosed in 
whole or in part without the expressed, written consent of CELLTRION, Inc. CELLTRION, Pharm. 
 
 
 
STUDY PROTOCOL 
 
An Observational, Prospective Cohort Study to 
Evaluate Safety and Efficacy of RemsimaTM in Patients 
with Rheumatoid Arthritis 
 
PROTOCOL NUMBER CT-P13 4.2 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL  
 

CELLTRION, Inc. 
  
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Table of contents 
 
Protocol Approval ............................................................................................................... 4 
Declaration of Investigator ................................................................................................. 5 
Protocol Synopsis ................................................................................................................ 6 
1 
Presentation ................................................................................................................. 9 
1.1 
Title ................................................................................................................ 9 
1.2 
Marketing Authorization Holder ................................................................... 9 
1.3 
Sponsor .......................................................................................................... 9 
1.4 
Lead Investigator ........................................................................................... 9 
1.5 
Research Centers ......................................................................................... 10 
1.6 
Milestones .................................................................................................... 10 
2 
Background and Justifications .................................................................................. 11 
3 
Study Objectives ....................................................................................................... 14 
3.1 
Primary Objective ........................................................................................ 14 
3.2 
Secondary Objectives .................................................................................. 15 
3.2.1 
Safety objective ................................................................................. 15 
3.2.2 
Efficacy objective ............................................................................. 15 
3.2.3 
Health-economics objective .............................................................. 15 
4 
Methods ..................................................................................................................... 16 
4.1 
Subject Randomization ................................................................................ 16 
4.2 
Study Design ................................................................................................ 16 
4.3 
Study Population .......................................................................................... 17 
4.3.1 
Inclusion criteria ............................................................................... 17 
4.3.2 
Exclusion Criteria ............................................................................. 18 
4.4 
Withdrawal of Patients from the Study ....................................................... 19 
4.5 
Sample Size ................................................................................................. 20 
4.6 
Data Required .............................................................................................. 21 
4.6.1 
Collection of core baseline data ........................................................ 21 
4.6.2 
Safety assessments ............................................................................ 21 
4.6.2.1 
Events of special interest .......................................................... 21 
4.6.2.2 
Other adverse events ................................................................ 23 
4.6.2.3 
Assessment of causality ........................................................... 23 
4.6.2.4 
Immunogenicity testing (optional) ........................................... 24 
4.6.2.5 
Clinical laboratory parameters ................................................. 24 
4.6.2.6 
Pregnancy test .......................................................................... 25 
4.6.2.7 
Physical examination ............................................................... 25 
4.6.2.8 
Vital signs and weight measurement ........................................ 25 
4.6.2.9 
Hypersensitivity monitoring..................................................... 26 
4.6.2.10 Tuberculosis assessment .......................................................... 26 
4.6.2.11 Hepatitis B and C, and human immunodeficiency virus testing
 
27 
4.6.2.12 Prior and concomitant medication ........................................... 27 
4.6.3 
Efficacy assessments ......................................................................... 28 
4.6.3.1 
DAS28 ...................................................................................... 28 
4.6.3.2 
HAQ ......................................................................................... 29 

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4.6.4 
Health-economic data eveluation ...................................................... 29 
4.7 
Sample Storage and Shipment ..................................................................... 29 
4.8 
Data Collection ............................................................................................ 30 
4.9 
Data Handling .............................................................................................. 30 
4.10 
Data Analysis ............................................................................................... 30 
4.11 
Data archiving .............................................................................................. 32 
4.12 
Limitations of the Research Methods .......................................................... 32 
4.13 
Adverse Events and Pregnancy Reporting .................................................. 32 
4.13.1 
Adverse Event ................................................................................... 32 
4.13.2 
Adverse Drug Reaction ..................................................................... 33 
4.13.3 
Serious Adverse Event ...................................................................... 33 
4.13.4 
Collection and Reporting of Serious Adverse Events ....................... 34 
4.13.5 
Pregnancy .......................................................................................... 34 
5 
Ethical Considerations .............................................................................................. 35 
5.1 
Good Clinical Practice ................................................................................. 35 
5.2 
Informed Consent ........................................................................................ 36 
5.3 
Other Ethical and Regulatory Issues............................................................ 36 
6 
Project Management ................................................................................................. 37 
6.1 
Final Report and Publication Policy ............................................................ 37 
7 
References ................................................................................................................. 38 
8 
Appendices ................................................................................................................ 40 
8.1 
Schedule of Events ...................................................................................... 40 
8.2 
Informed consent form ................................................................................ 42 
8.3 
DAS28 and VAS.......................................................................................... 42 
8.4 
HAQ and Scoring of the HAQ..................................................................... 44 
  

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Protocol Approval 
 
Study Title 
An Observational, Prospective Cohort Study to Evaluate 
Safety and Efficacy of RemsimaTM in Patients with 
Rheumatoid Arthritis 
Protocol Number 
CT-P13 4.2 
Protocol Version and Date 
Protocol Version 2.1  (EU specific) – 03 June 2015 
 
Protocol accepted and approved by: 
Clinical Planning Department Leader 
CELLTRION, Inc.,  
23, Academy-ro, Yeonsu-gu, Incheon, 
406-840, Republic of Korea 
 
 
 
 
Signature 
 
Date 
 
Qualified Person Responsible for Pharmacovigilance 
 
 
 
 
Signature 
 
Date 

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Declaration of Investigator 
 
I have reviewed and understand the purpose of the study and all sections of the protocol 
with the sponsor and its representatives. I will not disclose information regarding this 
observational study or publish results of the investigation without authorization from 
CELLTRION, Inc. 
I agree to supervise all aspects of the protocol and to conduct this observational study in 
accordance with the protocol, the International Conference on Harmonisation harmonised 
tripartite guideline E6(R1): Good Clinical Practice, and all applicable government 
regulations. I will not make changes to the protocol before consulting with CELLTRION, 
Inc., or implement protocol changes without independent ethics committee approval 
except to eliminate an immediate risk to patients 
Confidentiality will be protected. Patient identity will not be disclosed to third parties or 
appear in any study reports or publications. 
 
 
 
 
Signature of Principal Investigator 
 
Date 
 
 
 
 
 
 
Printed Name of Principal Investigator 
 
 

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Protocol Synopsis 
Protocol Number: CT-P13 4.2 
Title of Study: An Observational, Prospective Cohort Study to Evaluate Safety and Efficacy of 
RemsimaTM in Patients with Rheumatoid Arthritis 
Sponsor: CELLTRION, Inc. 
Marketing Authorization Holder:  Celltrion Healthcare Hungary Kft, 1023 Budapest, Regus Ó buda Gate, 
Á rpád fejedelem útja 26-28 Hungary 
Study Center(s): Approximately 61 centers in South Korea and EU. 
Length of Study: A 5-year period (2 years initially, 
followed by an additional 3 years for patients who 
consent to participate in an extension study) 
Phase of Development: IV 
Objectives: The primary objective of this study is to assess the long-term safety of RemsimaTM in 
Rheumatoid Arthritis (RA) patients by evaluation of events of special interest (ESI) up to 5 years and to 
exploratory compare patients receiving RemsimaTM with patients receiving non-biologic treatments or other 
anti-TNF drugs.   
The secondary objectives of this study are to evaluate efficacy. Further, additional safety of RemsimaTM in 
RA patients, in comparison with patients receiving non-biologic treatments or other anti-TNF drugs.  
Health-economics parameters will also be assessed. 
Study Design: This is a longitudinal, observational, prospective cohort study to assess the safety and 
efficacy of RemsimaTM in patients with RA in comparison with patients receiving non-biologic treatments 
or other anti-TNF drugs. For the RemsimaTM cohort data will be collected for patients who commence 
treatment with RemsimaTM in accordance with the product label at the time of enrolment (3 mg/kg of 
RemsimaTM by IV infusion at weeks 0, 2, 6 (±3 days) and every 8 weeks (±14 days) thereafter). For patients 
who have been treated with Remicade® prior to enrolment, their dosing schedule will be continued 
appropriately.  
The End-of-Study (EOS) visit only needs to be completed if the patient withdraws prior to study 
completion. An EOS visit will be made 8 weeks after the last dose is received. If the patient has completed 
the full 5-year study period, a separate EOS visit is not required. In this case, last visit will be considered 
the EOS visit. This observational study allows drug switching between anti-TNF drugs. If switched to 
RemsimaTM, data will be collected until the end of study for each patient. If switched to other anti-TNF 
drugs (infliximab (Remicade®), etanercept, adalimumab and etc.), data will be collected until 1 year from 
the day of switch or until the end of study for each patient, whichever reaches earlier. For switched patients, 
their assessment schedule will be re-started from the day of switch. Patients will undergo safety and 
efficacy assessments in accordance with routine medical practice. The decision to treat with RemsimaTM 
will be independent of the decision to enroll the patient in this registry. 
Sample Size: Planned 950 male and female patients with confirmed diagnosis of RA (planned: 450 patients 
treated with RemsimaTM, 50 biologic naïve  patients [in Korea only] and 450 patients treated with other anti-
TNFs drugs); recruitment in selected European countries will continue for 5 years after respective launches. 
Fifty percent or more of the target number of patients will be enrolled from the EU or relevant European 
region for RemsimaTM and other anti-TNFs drugs. 
Study Drug, Dose and Regimen: RemsimaTM (3 mg/kg) will be administered intravenously at weeks 0, 2, 
6 (±3 days) and every 8 weeks (±14 days) thereafter and co-administered with methotrexate (MTX) in 
accordance to the approved posology in the respective country. Dose and treatment schedule are 
recommended to comply with the approved posology in each regulatory authority or investigator’s clinical 
decision. 
Comparator, Dose and Regimen: The first comparator cohort will be patients who have been treated with 
non-biologic treatments. Fifty patients will be enrolled for this control group. 
The second comparator cohort will include RA patients receiving other anti-TNF drug than RemsimaTM. 
Patients with RA who have been registered within 6 months of first exposure to an established anti-TNF 
drug such as infliximab (Remicade®), etanercept, adalimumab and etc. will be recruited to the cohort. 

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The third comparator cohort will be historical RA cohort of patients who have been exposed to anti-TNF 
drug (infliximab, etanercept, adalimumab and etc.) from published reports and articles presenting studies 
conducted with anti-TNF drug (infliximab (Remicade®), etanercept, adalimumab and etc.). 
For the comparators, dose and regimen are recommended to comply with the approved posology in each 
regulatory authority. 
Main Selection Criteria: Patients, with active RA diagnosed according to the revised 1987 ACR or 2010 
ACR/EULAR classification criteria, for the RemsimaTM and other anti-TNF drug cohort and patients who 
require treatment with DMARDs and have never been exposed to biologic therapeutics for treatment of 
RA, for the biologic-naïve  cohort will be considered for enrollment in the study if they meet all of the 
inclusion criteria and none of the exclusion criteria. 
Inclusion Criteria: 
Inclusion criteria will be applied to all cohorts, if not otherwise specified. 
1. Adult patients (aged ≥18 years old). 
2. Patients with active RA diagnosed according to the revised 1987 ACR [Arnett et al.1988] or 2010 
ACR/EULAR classification criteria [Aletaha et al. 2010].  
3. Patients who meet the following conditions can be enrolled. 
i) The RemsimaTM cohort will include all patients who will start RemsimaTM at the time of enrolment 
in accordance to the approved product label  
ii) The other anti-TNF drug cohort will include patients who meet the following condition at the time 
of enrolment:  
 
Patients who have started to treat with an established anti-TNF such as infliximab 
(Remicade®), etanercept, adalimumab and etc. within 6 months 
iii) Patients who require treatment with disease-modifying anti-rheumatic drugs (DMARDs), 
including MTX, and have never been exposed to biologic therapeutics for treatment of RA, may be 
allocated to the biologic-naïve cohort.  
4. Female patients of childbearing potential who agree to use of adequate contraception to prevent 
pregnancy and continuation of contraceptive use for at least 6 months after their final dose of 
RemsimaTM.  According to EU SmPC, the use of infliximab during pregnancy is not recommended. 
However should the severity of the condition and treatment benefits outweigh potential risk to the 
mother and the baby and provided that there is no other available treatment options and provided that 
pregnant patient is fully informed and aware of the risks and upon careful judgement of the 
investigator, the treatment may continue throughout the pregnancy. Alternatively, the treatment of 
RemsimaTM should not be done for pregnant patient. For the comparators, duration for contraceptive 
use is recommended to comply with the product labels.  
5. Patients (or legal guardian, if applicable) have been informed of the full nature and purpose of the 
study, including possible risks and side effects, and provide signed and dated written informed consent 
for long term follow-up including access to all medical records. 
Exclusion Criteria: 
Exclusion criteria will be applied to all cohorts, if not otherwise specified. 
1. Patients with a history of hypersensitivity to murine, chimeric, human, or humanized proteins. 
2. Patients with a current or past history of chronic infection with Hepatitis B, Hepatitis C or infection 
with human immunodeficiency virus (HIV), or testing positive to those infections at Screening. 
3. Current diagnosis of tuberculosis (TB) or severe or chronic infections (e.g. sepsis, abscess or 
opportunistic infections or invasive fungal infections), or a past diagnosis of TB or severe or chronic 
infection, without sufficient documentation of complete resolution following treatment. 
4. Recent exposure to persons with active TB, or a positive test result for latent TB (defined as a positive 
interferon-γ release assay [IGRA] with a negative examination of chest X-ray) at Screening. If the 
result of the IGRA is indeterminate at Screening, 1 retest will be possible during the Screening period. 
If the repeated IGRA result is again indeterminate, the patient will be excluded from the study. If the 
repeated IGRA result is negative, the patient may be included in the study. A patient who has received 

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at least the first 30 days or recommended period of country specific TB prophylaxis and intends to 
complete the entire course of prophylaxis may be enrolled. Patients with sufficient documentation of 
prophylaxis or complete resolution following TB treatment based on local guidelines can be treated 
before confirming the IGRA result. 
5. Patients with moderate or severe heart failure (NYHA class III/IV).  
6. Patients for whom there are investigator’s concerns about treatment with TNF-α blockers, such as a 
history of any malignancy within the previous five years prior to enrolment or a history of herpes 
zoster within one month prior to enrolment, may be excluded at the investigator’s discretion. 
Safety Assessment: Safety will be assessed by the collection of data in the patient medical records as part 
of routine clinical practice. Data collection will include ESIs, adverse events (AEs) including serious AEs, 
other than those classified as ESI. Safety analysis will also include hypersensitivity monitoring, signs and 
symptoms of TB, interferon-γ release assay test and chest X-ray, immunogenicity test (optional), pregnancy 
test, Hepatitis B and C and HIV tests, physical examination, vital sign measurement, clinical laboratory 
analyses, and concomitant medications.   
Efficacy Assessments: Efficacy will be assessed by collection of data recorded in the patient medical 
records as part of routine clinical practice. Data collected will be used for evaluation of Disease Activity 
Score 28 (DAS28) and Health Assessment Questionnaire (HAQ). 
Data Analysis: The statistical analysis will be performed using SAS software Version 9.1.3 or later (SAS 
Institute, Inc, Cary, North Carolina).  
Interim analysis will be performed after 2 years prior to 3 year- period follow up. Periodic interim analyses 
are planned for regulatory reporting purposes. An annual regulatory report will be generated and reported to 
the regulatory authority. This will contain safety and efficacy data observed since the start of the study until 
December of each year.  
Descriptive analysis will be performed for safety data including drug exposure and data will be presented 
for RemsimaTM cohort, other anti-TNF drug cohort and biologic-naïve cohort. Additionally, meta -analysis 
will be performed with historical data for anti-TNF drug. 
The data documented in this study and the clinical parameters measured will be described using descriptive 
statistics (n, mean, median, standard deviation(SD), minimum, and maximum) for quantitative variables 
and frequencies and proportions for qualitative variables. 
AEs will be coded using the most recent version of the MedDRA and summarized by the number and 
percentage of patients reporting an event. The grade, duration, and relationship to treatment of each AE will 
be recorded. Severity of adverse events will be graded according to the CTCAE v4.0. Previous and 
concomitant treatments will be coded using the World Health Organization Drug Dictionary and medical 
history will be coded using MedDRA.   
Subgroup analysis might be conducted for handling risk factors. Subgroup analysis for each risk factor 
level will be considered. Additionally, propensity score might be considered if it is necessary and relevant. 
The main risk factor to be considered is geographical region by the level of incidence rates or prevalence 
rates of events such as TB or pneumonia. Other risk factors such as demographics, co-morbid condition and 
prior or concomitant medication can be also considered in the analysis. An adjusted relative risk by relevant 
risk factors may be adapted if suitable.  
For descriptive purpose, incidence rates per 100 patient-years or 10,000 patient-years will be calculated and  
analysis will be specified on Statistical Analysis Plan (SAP). For missing data, appropriate imputation 
methods will be used, if required.   
The statistical considerations summarised in this section outline the plan for data analysis of this study.  A 
final and complete SAP will be prepared prior to data analysis. 
Milestones: 
Milestones  
Planned Date 
Start of data collection  
 Korea: December 2013 
 European region: 2Q 2015  
End of data collection  
 Korea: 2026 

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 European region: 2026 
Study progress report(s)  
 Included in Periodic Safety Update Report and/or;  
 Upon request from the national competent authorities 
Interim report(s) of study results 
 Annual report: every May from 2015  
 2 years result: 2023 
Final report of study results 
 2026 
 
1 Presentation 
1.1 Title 
An observational, prospective cohort study to evaluate the safety and efficacy of 
RemsimaTM in patients with rheumatoid arthritis (RA) 
 
1.2 Marketing Authorization Holder 
Celltrion Healthcare Hungary Kft, 1023 Budapest, Regus Ó buda Gate, Á rpád fejedelem 
útja 26-28 Hungary 
Contact person: 
 
 
1.3 Sponsor 
CELLTRION, Inc., 23, Academy-ro, Yeonsu-gu, Incheon, 406-840, Korea 
 
1.4 Lead Investigator  
 

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1.5 Research Centers  
This study will be conducted in research centers located in European region and South 
Korea.  
 
1.6 Milestones 
Milestones  
Planned Date 
Start of data collection  
 Korea: December 2013 
 European region: 2Q 2015 
End of data collection  
 Korea: 2026 
 European region: 2026 
Study progress report(s)  
 Included in Periodic Safety Update Report and/or;  
 Upon request from the national competent 
authorities 
Interim report(s) of study results 
 Annual report: every May from 2015  
 2 years result: 2023 
Final report of study results 
 2026 
 

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2 Background and Justifications  
RemsimaTM is an IgG1 chimeric human-murine mAb biosimilar to Remicade® (infliximab, 
Janssen Biologics B.V.) developed by CELLTRION, Inc. RemsimaTM is produced in the 
same type of cell-line and has an identical amino acid sequence to Remicade®.   
RemsimaTM has been approved by the European Medicines Agency (EMA) and Ministry 
of Food and Drug Safety (MFDS) in Korea for the treatment of RA, ankylosing 
spondylitis, psoriatic arthritis, psoriasis, ulcerative colitis and Crohn’s disease. The 
approval of RemsimaTM was based on the results of two large, randomized, double-blind, 
phase I and III studies, called the PLANETAS and PLANETRA studies, respectively. 
[Park et al. 2013; Yoo et al. 2013]  
The PLANETAS study was a phase I study conducted in patients with AS and aimed to 
compare the pharmacokinetics (PKs), safety and efficacy of RemsimaTM to Remicade®. A 
total of 250 patients (RemsimaTM=125; Remicade®=125) took part in the study. [Park et 
al. 2013] The primary endpoints were area under the concentration-time curve (AUCτ) at 
steady state and observed maximum steady state serum concentration (Cmax,ss) between 
weeks 22 and 30. [Park et al. 2013] Additional PK, efficacy endpoints, and safety 
outcomes were also assessed. Additional efficacy endpoints included 20% and 40% 
improvement response according to Assessment in Ankylosing Spondylitis International 
Working Group criteria (ASAS20 and ASAS40). [Park et al. 2013] The PK profiles of 
RemsimaTM and Remicade® were equivalent in patients with active AS (AUCτ: 
RemsimaTM, 32,765.8μgh/mL; Remicade®, 31,359.3μgh/mL; Cmax,ss: RemsimaTM, 
147.0μg/mL; Remicade®, 144.8μg/mL), and the efficacy of the two treatments was also 
comparable at week 30 (ASAS20; 70.5% vs. 72.4%; ASAS40; 51.8% vs. 47.4%, 
respectively). In the PLANETAS study RemsimaTM was well tolerated, with efficacy and 
safety profile comparable to that of Remicade® up to week 30. [Park et al. 2013] 
The PLANETRA study was a phase III study conducted in RA patients with inadequate 
response to methotrexate (MTX). [Yoo et al. 2013] A total of 606 patients 
(RemsimaTM=302; Remicade®=304) took part in the study and the primary endpoint was 

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to demonstrate equivalence in efficacy of RemsimaTM and Remicade® at week 30, as 
determined by ACR20 response criteria. [Yoo et al. 2013] Additional secondary efficacy, 
PK and safety endpoints were assessed up to week 30. At week 30, ACR20 responses 
were 60.9% for RemsimaTM and 58.6% for Remicade® (95% Confidence interval: −6%, 
10%), demonstrating equivalent efficacy. Comparable PKs and safety profile including 
immunogenicity were also observed at week 30. [Yoo et al. 2013] 
These two studies demonstrated that the clinical efficacy and PK of RemsimaTM are 
equivalent to that of Remicade®, and that the two treatments are both well tolerated with 
comparable immunogenicity and safety, in patients with AS and RA. The evidence from 
these two studies was deemed appropriate by the EMA and the MFDS in Korea to grant a 
license for RemsimaTM equivalent to the license for Remicade®.  
Although randomized controlled trials (RCTs) provide a powerful means of evaluating 
therapies, they are limited by relatively short study durations and highly selected patient 
groups that may not represent the wide range of patient characteristics found in a real-
world setting. Since the licensing of the first biologic treatment for RA, national 
rheumatology societies in a number of European countries have established independent 
registries with the aim of evaluating the long-term safety and real-life effectiveness of 
these drugs. [Zink et al. 2009]. Registry studies involve the monitoring of a larger cohort 
of patients than would be possible in a RCT and also provide an opportunity to observe 
patients with a much longer follow-up period. Patient registers recruit unselected patients 
treated in routine care, overcoming the drawbacks of either spontaneous reporting 
systems or open label extensions of clinical trials. [Zink et al. 2009]. Patient registries are 
highly valuable for monitoring the long-term efficacy and safety profiles of rheumatology 
therapies in real-world clinical practice. To date, the European biologicals registers have 
greatly contributed to our understanding of biologic therapies in rheumatology beyond 
the patient groups and study durations that are typical of RCTs. [Zink et al. 2009] 
As well as the demonstration of comparable immunogenicity and safety and equivalent 
clinical efficacy and PK with Remicade® in patients with RA, there is a need to establish 

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the safety and efficacy profile of RemsimaTM in long-term, real-world clinical practice. 
This may be effectively accomplished through a registry study.  
The proposed study is a prospective registry cohort study to compare safety and efficacy 
over 5 years (2 years initially, followed by an additional 3 years for patients who consent 
to participate in an extension study), between patients with RA who are recipients of 
RemsimaTM and reference cohorts of other anti-TNF drugs and biologic naïve patients.  

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3 Study Objectives 
3.1 Primary Objective 
The primary objective of this study is to assess the long-term safety of RemsimaTM in RA 
patients by evaluation of events of special interest (ESI) up to 5 years and to exploratory 
compare patients receiving RemsimaTM with patients receiving non-biologic treatments or 
other anti-TNF drugs.   
 
The risk associated with the following endpoints (events of special interest – ESI) will be 
evaluated: 
 Hepatitis B virus reactivation  
 Congestive heart failure 
 Opportunistic infection (excluding tuberculosis) 
 Serious infections including sepsis (excluding opportunistic infections and 
tuberculosis) 
 Tuberculosis (TB)  
 Serum sickness (delayed hypersensitivity reactions) 
 Haematologic reactions  
 Systemic lupus erythematosus/lupus like syndrome  
 Demyelinating disorders 
 Lymphoma (not HSTCL) 
 Hepatobiliary events 
 Hepatosplenic T cell lymphoma (HSTCL) 
 Serious infusion reactions during a re-induction regimen following disease flare 
 Sarcoidosis/sarcoid-like reactions 
 Leukaemia 
 Malignancy (excluding lymphoma) 
 Skin cancer 
 Pregnancy exposure 
 Infusion reaction associated with shortened infusion duration 

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 Others 
 
Other items may be added or specified on the statistical analysis plan. 
3.2 Secondary Objectives 
3.2.1 Safety objective 
 Adverse events (AEs) including serious AEs (SAEs), other than those classified 
as ESI. 
 TB monitoring 
 Interferon- γ release assay (IGRA) test 
 Immunogenicity (anti-infliximab antibody, optional test) 
 Other safety assessments (hypersensitivity monitoring, pregnancy test, Hepatitis 
B/C, human immunodeficiency virus [HIV] test, physical examination, vital sign, 
laboratory tests, chest X-ray and concomitant medication) 
 
3.2.2 Efficacy objective 
The secondary efficacy objective of this study is to evaluate efficacy in patients with RA. 
 Disease Activity Score using 28 joint count (DAS28) at every six months during 
study period 
 Health Assessment Questionnaire (HAQ) at every six months during study period 
 
3.2.3 Health-economics objective    
Cost-effectiveness will be evaluated in RA patients treated with anti-TNF drug.  
 Days of hospitalizations 
 Medication and surgery interventions related to disease 
 Days off work in employed patients  
 Early retirement and return to work (working days gained)  
 

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4 Methods 
4.1 Subject Randomization 
As this is a longitudinal, observational, prospective cohort study, randomization will not 
be carried out. 
 
4.2 Study Design 
This is a longitudinal, observational, prospective cohort study to assess the safety and 
efficacy of RemsimaTM in patients with RA in comparison with patients receiving non-
biologic treatments or other anti-TNF drugs. The study will be conducted in accordance 
with the Declaration of Helsinki and the International Conference on Harmonisation 
(ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use – 
Good Clinical Practice. Informed consent from all patients will be obtained prior to 
enrolment. This observational study allows drug switching between anti-TNF drugs. If 
switched to RemsimaTM, data will be collected until the end of study for each patient. If 
switched to other anti-TNF drugs (infliximab (Remicade®), etanercept, adalimumab and 
etc.), data will be collected until 1 year from the day of switch or until the end of study 
for each patient, whichever reaches earlier. For switched patients, their assessment 
schedule will be re-started from the day of switch. Patients will undergo safety and 
efficacy assessments in accordance with routine medical practice. The decision to treat 
with RemsimaTM will be independent of the decision to enroll the patient in this registry. 
 
The study will be carried out with a sample size of approximately 950 patients with 
confirmed diagnosis of RA (planned: 450 patients treated with RemsimaTM, 450 patients 
treated with other anti-TNFs within 6 months prior to enrolment and 50 biologic naïve  
patients). Study participants will be followed for a 5-year period (2 years initially, 
followed by an additional 3 years for patients who consent to participate in an extension 
study). For patient who have started to be treated with other anti-TNFs within the last 6 
months prior to enrollment, medical records will also be collected from the date of first 
exposure prior to enrollment, and the date of first exposure is considered as a baseline. 

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For the historical RA cohort, data will be collected for patients who treated with anti-TNF 
from published studies conducted with Remicade® or other anti-TNF products. 
 
For the RemsimaTM cohort data will be collected for patients who commence treatment 
with RemsimaTM in accordance with the product label at the time of enrolment (3 mg/kg 
intravenously at weeks 0, 2, 6 (±3 days) and every 8 weeks (±14 days) thereafter and co-
administered with methotrexate (MTX). Dose and treatment schedule are recommended 
to comply with the approved posology in each regulatory authority or investigator’s 
clinical decision. For the other anti-TNFs cohort data will be collected for patients who 
are receiving treatment with other anti-TNF drug (infliximab(Remicade®), etanercept, 
adalimumab and etc.) according to the approved dose and regimen of the drug. If a 
patient has been treated with Remicade® prior to enrolment, their dosing schedule will be 
continued appropriately. MTX will be co-administered for the duration of the study, 
unless it is contraindicated. Patients may be pre-treated with antihistamines, 
hydrocortisone and/or paracetamol, or infusion rate may be slowed in order to decrease 
the risk of infusion-related reactions, especially if infusion-related reactions have 
occurred previously. The End-of-Study (EOS) visit only needs to be completed if the 
patient withdraws prior to study completion. An EOS visit will be made 8 weeks after the 
last dose is received. If the patient has completed the full 5-year Study period, a separate 
EOS visit is not required. In this case, last visit will be considered the EOS visit.  
4.3 Study Population  
The study group will consist of adult patients (≥18 years old) diagnosed with RA.  
 
4.3.1 Inclusion criteria 
Inclusion criteria will be applied to all cohorts, if not otherwise specified. 
1. 
Adult patients (aged ≥18 years old). 
2. 
Patients with active RA diagnosed according to the revised 1987 ACR 
[Arnett et al.1988] or 2010 ACR/EULAR classification criteria [Aletaha et al. 2010].  
3. 
Patients who meet the following conditions can be enrolled. 

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i) 
The RemsimaTM cohort will include all patients who will start RemsimaTM at the 
time of enrolment in accordance to the approved product label 
ii) 
The other anti-TNF drug cohort will include patients who meet the following 
condition at the time of enrolment: 
 Patients who have started to treat with an established anti-TNF such as 
infliximab (Remicade®), etanercept, adalimumab and etc. within 6 months 
iii) 
Patients who require treatment with disease-modifying anti-rheumatic drugs 
(DMARDs), including MTX, and have never been exposed to biologic 
therapeutics for treatment of RA, may be allocated to the biologic-naïve  cohort. 
4. 
Female patients of childbearing potential who agree to use of adequate contraception 
to prevent pregnancy and continuation of contraceptive use for at least 6 months 
after their final dose of RemsimaTM. According to EU SmPC, the use of infliximab 
during pregnancy is not recommended. However should the severity of the condition 
and treatment benefits outweigh potential risk to the mother and the baby and 
provided that there is no other available treatment options and provided that 
pregnant patient is fully informed and aware of the risks and upon careful judgement 
of the investigator, the treatment may continue throughout the pregnancy. 
Alternatively, the treatment of RemsimaTM should not be done for pregnant patient. 
For the comparators, duration for contraceptive use is recommended to comply with 
the product labels. 
5. 
Patients (or legal guardian, if applicable) have been informed of the full nature and 
purpose of the study, including possible risks and side effects, and provide signed 
and dated written informed consent for long term follow-up including access to all 
medical records. 
 
4.3.2 Exclusion Criteria 
Exclusion criteria will be applied to all cohorts, if not otherwise specified. 
1. Patients with a history of hypersensitivity to murine, chimeric, human, or humanized 
proteins. 

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2. 
Patients with a current or past history of chronic infection with Hepatitis B, Hepatitis 
C or infection with human immunodeficiency virus (HIV), or testing positive to 
those infections at Screening.  
3. 
Current diagnosis of TB or severe or chronic infections (e.g. sepsis, abscess or 
opportunistic infections or invasive fungal infections), or a past diagnosis of TB or 
severe or chronic infection, without sufficient documentation of complete resolution 
following treatment. 
4. 
Recent exposure to persons with active TB, or a positive test result for latent TB 
(defined as a positive interferon-γ release assay [IGRA] with a negative examination 
of chest X-ray) at Screening. If the result of the IGRA is indeterminate at Screening, 
1 retest will be possible during the Screening period. If the repeated IGRA result is 
again indeterminate, the patient will be excluded from the study. If the repeated 
IGRA result is negative, the patient may be included in the study. A patient who has 
received at least the first 30 days or recommended period of country specific TB 
prophylaxis and intends to complete the entire course of prophylaxis may be 
enrolled. Patients with sufficient documentation of prophylaxis or complete 
resolution following TB treatment based on local guidelines can be treated before 
confirming the IGRA result. 
5. 
Patients with moderate or severe heart failure (NYHA class III/IV).  
6. 
Patients for whom there are investigator’s concerns about treatment with TNF-α 
blockers, such as a history of any malignancy within the previous five years prior to 
enrolment or a history of herpes zoster within one month prior to enrolment, may be 
excluded at the investigator’s discretion. 
 
4.4 Withdrawal of Patients from the Study 
Patients will be recruited at participating study centers and allocated to the RemsimaTM, 
biologic naïve cohorts , or other anti-TNF drug cohort. Patients may withdraw their 
consent at any time during the study. Patients may also withdraw from the study if any of 
the following occur:    
 development of a life-threatening infusion-related anaphylactic reaction 
 development of signs of disease progression 

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 no efficacy from study drug 
 refusal to continue treatment or procedures/observations 
 development of any malignancy 
 any AE that would compromise the safety of the patient if they continue their 
participation in the study 
 a significant or major protocol violation 
 patient is lost to follow-up 
 death of the patient. 
In case of early discontinuation from the observation, an investigator should record all the 
data collected until the time of discontinuation in the patient’s case report form including 
the date of discontinuation, reason for discontinuation, treatment and follow-up result. If 
the patient stopped treatment due to safety reason, it should be recorded in (S)AE page. 
Study result from the discontinued patient may be reviewed and evaluated by sponsor at 
the final assessment stage. If a patient in the RemsimaTM cohort is discontinued, collection 
of available safety data should be continued until 6 months from the day of withdrawal 
and the data will be included in the analyses. 
 
4.5 Sample Size 
This study aims to be planned to recruit 450 patients taking RemsimaTM from 
participating study centers. For comparison, 50 RA patients receiving treatment other 
than biologics and 450 patients treated with other anti-TNF drugs are planned to recruit. 
A sample size is determined not on the basis of formal statistical hypotheses but using an 
exploratory descriptive approach.  
The number of patients in the RemsimaTM cohort is sufficient enough to detect adverse 
events which occur at 1 % of frequency and the number of patient in the biologic naïve  
cohort is to determine 50 patients which is 10% of that of RemsimaTM cohort. Biologic 
naïve  cohort will be recruited in Korea only. Fifty percent or more of the target number of 
patients will be enrolled from the EU or relevant European region for RemsimaTM and 
other anti-TNFs drugs. 
 

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4.6 Data Required 
The following data will be collected in order to assess the primary and secondary study 
outcomes. Data will be obtained from assessments performed as part of routine clinical 
practice. Data will be collected for the time points specified in the schedule of events in 
section 8 Appendix, where available. 
 
4.6.1 Collection of core baseline data  
Patients will be informed of the full nature and purpose of the study, and provide signed 
and dated written informed consent before entering this study. The following information 
will be collected from the patient medical records by the recruiting clinician, using a 
standardized form: 
 
 
Diagnosis of rheumatoid arthritis 
 
Date of birth, gender 
 
Previous drug history of non-biologic DMARDs and biologics, including duration 
of therapy 
 
Any significant co-morbidity and medical history 
 
All current therapy/medications 
 
Height, weight, blood pressure 
 
DAS28 
 
HAQ scores 
In addition, personal and medical information will be obtained from each patient 
recruited (e.g. smoking status at Screening and at EOS visit). 
 
4.6.2 Safety assessments 
4.6.2.1 Events of special interest 
In order to assess the primary study outcomes, the following ESI will be evaluated: 
 Hepatitis B virus reactivation  

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 Congestive heart failure 
 Opportunistic infection (excluding tuberculosis) 
 Serious infections including sepsis (excluding opportunistic infections and 
tuberculosis) 
 Tuberculosis (TB)  
 Serum sickness (delayed hypersensitivity reactions) 
 Haematologic reactions  
 Systemic lupus erythematosus/lupus like syndrome  
 Demyelinating disorders 
 Lymphoma (not HSTCL) 
 Hepatobiliary events 
 Hepatosplenic T cell lymphoma (HSTCL) 
 Serious infusion reactions during a re-induction regimen following disease flare 
 Sarcoidosis/sarcoid-like reactions 
 Leukaemia 
 Malignancy (excluding lymphoma) 
 Skin cancer 
 Pregnancy exposure† 
 Infusion reaction associated with shortened infusion duration 
 Others 
† According to EU SmPC, the use of Infliximab during pregnancy is not recommended. 
However should the severity of the condition and treatment benefits outweigh potential 
risk to the mother and the baby and provided that there is no other available treatment 
options and provided that pregnant patient is fully informed and aware of the risks and 
upon careful judgement of the investigator, the treatment may continue throughout the 
pregnancy. Alternatively, the treatment should be discontinued. All pregnancy cases will 
be followed-up for the outcome.  
 
Other items may be added or specified on the statistical analysis plan. 
 

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4.6.2.2 Other adverse events  
Assessment of AEs including infections, and serious AEs, other than those classified as 
ESI will be assessed during the study. AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA) and severity will be graded according to the 
Common Terminology Criteria for Adverse Events (CTCAE) v4.0 as shown below. 
Grade 1: 
Mild AE (minor; no specific medical intervention; asymptomatic laboratory 
findings only; radiographic findings only; marginal clinical relevance) 
Grade 2: 
Moderate 
AE 
(minimal 
intervention; 
local 
intervention; 
non-invasive 
intervention [packing, cautery]) 
Grade 3: 
Severe and undesirable AE (significant symptoms requiring hospitalization or 
invasive intervention; transfusion; elective interventional radiological procedure; 
therapeutic endoscopy or operation) 
Grade 4: 
Life-threatening or disabling AE (complicated by acute, life-threatening 
metabolic or cardiovascular complications such as circulatory failure, 
hemorrhage, sepsis; life-threatening physiological consequences; need for 
intensive care or emergent invasive procedure; emergent interventional 
radiological procedure, therapeutic endoscopy, or operation) 
Grade 5: 
Death related to AE 
 
4.6.2.3 Assessment of causality 
The relationship or association of the test article in causing or contributing to the AE will 
be characterized using the following classification and criteria: 

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Unrelated: 
This relationship suggests that there is no association between the study drug and 
the reported event. 
Possible: 
This relationship suggests that treatment with the study drug caused or contributed 
to the AE, ie, the event follows a reasonable temporal sequence from the time of 
drug administration or follows a known response pattern to the study drug, but 
could also have been produced by other factors. 
Probable: 
This relationship suggests that a reasonable temporal sequence of the event with 
drug administration exists and, based upon the known pharmacological action of the 
drug, known or previously reported adverse reactions to the drug or class of drugs, 
or judgement based on the investigator’s clinical experience, the association of the 
event with the study drug seems likely. 
Definite: 
This relationship suggests that a definite causal relationship exists between drug 
administration 
and 
the 
AE, 
and 
other 
conditions 
(concurrent 
illness, 
progression/expression of disease state, or concurrent medication reaction) do not 
appear to explain the event. 
 
4.6.2.4 Immunogenicity testing (optional) 
Blood samples for immunogenicity testing (anti-infliximab antibodies) will be collected 
from patients who are treated with infliximab (RemsimaTM and Remicade®), given 
patient’s written informed consent at baseline, at 6 months (Week 30), at every year and 
EOS visit . Test will be performed at central laboratory. 
 
4.6.2.5 Clinical laboratory parameters 
Blood and urine samples for clinical laboratory assessments can be collected, schedules 
for each referring a test schedule in section 8 Appendix. The following laboratory 
analyses can be performed at local laboratory and any clinically significant abnormal 
findings, upon judgement of the investigator, will be reported: 
 

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Clinical 
Chemistry 
Total protein, serum bilirubin, alanine aminotransferase, aspartate 
aminotransferase, alkaline phosphatase, γ-glutamyltransferase, blood 
urea nitrogen, creatinine, albumin, sodium, potassium, calcium, 
chloride, inorganic phosphorus, glucose, creatine kinase, lactate 
dehydrogenase, and C-reactive protein (CRP) 
Hematology 
Red blood cell count, Erythrocyte sedimentation rate (ESR), total and 
differential white blood cell count, absolute neutrophil count, 
lymphocyte count, platelet count, hemoglobin, mean corpuscular 
volume, 
mean 
corpuscular 
hemoglobin, 
mean 
corpuscular 
hemoglobin concentration, and hematocrit 
Urinalysis 
White blood cell, Red blood cell, Protein 
 
4.6.2.6 Pregnancy test 
A serum or urine pregnancy test will be conducted at Screening for women of 
childbearing potential who have not been surgically sterilized, in order to confirm that 
these patients are not pregnant. Test will be performed at local laboratory. 
 
4.6.2.7 Physical examination 
Physical examinations results will be documented at each visit. Investigators will 
carefully evaluate patients for any indication of infection or infusion-related reaction and 
pursue further investigation and treatment, according to the investigator’s clinical 
judgement. Any clinically significant abnormal findings and illnesses reported after the 
start of the study that meets the definition of an AE will be recorded. 
 
4.6.2.8 Vital signs and weight measurement 
Vital signs (including blood pressure, heart and respiratory rates, and body temperature) 
and weight will be measured at every visit when patient is stable (sitting position). Any 
clinically significant abnormal findings, upon judgement of the investigator, will be 
reported. Results will be documented at the time points specified in section 8 Appendix, 
where available. 

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4.6.2.9  Hypersensitivity monitoring 
Vital signs collected as a result of hypersensitivity monitoring on each dosing day (from 
the start of infusion, and until 1-2 hours after the end of infusion) will be documented. If 
required, electrocardiography (ECG) will be performed as per local guidelines and 
documented. Any clinically significant abnormal findings, upon judgement of the 
investigator, will be reported. 
 
4.6.2.10 
Tuberculosis assessment 
At Screening, a current diagnosis of TB or a past diagnosis without sufficient 
documentation of complete resolution following treatment will result in patient exclusion 
from the study. Patients with latent TB, or who have had recent exposure to persons with 
active TB at Screening will not be enrolled. Latent TB is defined as the presence of a 
positive IGRA with a negative chest X-ray.  
Throughout the study, including Screening and the End-of-Study Visit, if the result of the 
IGRA is indeterminate, 1 retest will be performed at the visit. 
If the repeat IGRA result is again indeterminate at Screening, the patient will be excluded 
from the study. If the repeat IGRA result is negative, the patient may be included in the 
study.  
A patient who has received at least the first 30 days or recommended period of country 
specific TB prophylaxis and intends to complete the entire course of prophylaxis can be 
enrolled. Patients with sufficient documentation of prophylaxis or complete resolution 
following TB treatment based on local guidelines can be treated before confirming the 
IGRA result. 
At scheduled visits during the study, if a patient has a positive result at the initial test or at 
the repeated test for IGRA and a negative examination of chest x-ray at any other visits, 
the patient will be treated according to country specific TB prophylaxis and complete the 
entire course of the prophylaxis. 

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A chest X-ray (both posterior–anterior and/or lateral views) will be taken at Screening 
and read by a qualified radiologist or pulmonary physician to specifically look for 
evidence of active or prior TB. If a chest X-ray taken 4 weeks prior to Screening is 
available, the results of this will be recorded in the patient’s electronic CRF (eCRF) at 
Screening. A chest X-ray also will be taken at every year and EOS visit. 
IGRA will be performed at Screening, at every year (± 6 weeks) and EOS visit to identify 
positive conversion of previously negative results. Additional IGRA will be performed if 
symptoms raise a suspicion of TB upon judgement of the investigator during study period. 
As described in the literature, [Park et al. 2009] IGRA can be used as a method of 
identifying patients with a false negative response to latent TB infections or new TB 
infections in patients with RA. Assay will be performed at central laboratory. 
Throughout the study, patients will be monitored for clinical signs and symptoms of TB. 
Active TB is more likely to be developed during induction phase. Recurrent TB can occur 
at any time after the completion of TB treatment but mostly after 3-6 months [Korean 
Guideline for Tuberculosis 2nd Edition. 2014, Johnson J.L. et al. 2012, Jasmer R.M. et al. 
2004]. Patients with an abnormal chest radiograph consistent with past TB who have 
received previous adequate treatment, should be monitored clinically every three months 
with a chest radiograph and sputum cultures if respiratory symptoms develop [BTS 
Guideline. 2005]. 
 
4.6.2.11 
Hepatitis B and C, and human immunodeficiency virus testing 
At screening, hepatitis B and C and HIV tests will be performed at the investigator’s 
discretion based on results of previously performed test or patient’s status. Test will be 
performed at local laboratory. 
 
4.6.2.12 
Prior and concomitant medication 
Use of all concomitant medications from within 6 months prior to Screening and during 
the study will be recorded in the patient’s eCRF. Any biologic therapy for treatment of 
RA will be recorded, regardless of the time when these were administered, including 

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duration of therapy and reason for stopping. Any changes in concomitant medications or 
co-administration drug (MTX) treatment will also be recorded in the patient’s eCRF. Any 
concomitant medication deemed necessary for the welfare of the patient during the study 
may be given at the discretion of the investigator. However, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded in full in the 
eCRF. 
 
4.6.3 Efficacy assessments 
All efficacy assessments will be performed in accordance with routine clinical practice 
and results will be collected only from patients who will be treated with infliximab 
(RemsimaTM and Remicade®). Efficacy outcomes will be assessed by collection of 
available results from patient medical records. 
 
4.6.3.1 DAS28 
DAS28 will be collected at baseline at every 6 months thereafter (± 6 weeks) and EOS 
visit and calculated in two ways at the efficacy visits using the following equations: 
i)         
)
014
.0
(
))
ln(
70
.0
(
)
28
28
.0
(
)
28
56
.0
(
)
(
28
GH
ESR
SJC
TJC
ESR
DAS








 
ii) 








))
1
ln(
36
.0
(
)
28
28
.0
(
)
28
56
.0
(
)
(
28
CRP
SJC
TJC
CRP
DAS
                            
96
.0
)
014
.0
(

GH
 
 
Where: 
 
TJC28 = number of tender joints (0-28)  
SJC28 = number of swollen joints (0-28)  
ESR = ESR measurement (mm/h) 
CRP = CRP measurement (mg/L) 
GH = patient’s general assessment of disease activity measured on the Visual Analog 
Scale (VAS) (0-100 mm) (Section 8.3) 

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4.6.3.2 HAQ 
HAQ will be assessed at baseline, at every 6 months thereafter (± 6 weeks) and EOS visit 
to evaluate treatment effectiveness (Section 8.4). 
 
4.6.4 Health-economic data eveluation  
For cost-effectiveness evaluation, the following information will be collected throughout 
the study. 
 Days of hospitalizations 
 Medication and surgery interventions related to disease 
 Days off work in employed patients  
 Early retirement and return to work (working days gained)  
 
4.7 Sample Storage and Shipment 
During the study, blood samples will be collected for IGRA assessment and 
immunogenicity analysis (optional). Where appropriate, the serum should be transferred 
into a sufficient number of transfer vials prior to freezing. The samples will be shipped 
from the study center to the central laboratory (PPD Global Central Labs). Details in 
storage and shipment will be followed according to the lab manual. Additionally, blood 
samples for immunogenicity should be retained at the central laboratory up to the End of 
the Study, in case additional analysis is required. If additional analysis is not required 
during the study or after the End of the Study, blood samples will be stored in a 
CELLTRION, Inc. or designated biobank for a further 5 years (from the date the sample 
is transferred to the CELLTRION, Inc. or biobank) unless a specific authorization is 
given by CELLTRION, Inc. to destroy the sample. At CELLTRION, Inc. or biobank, 
additional tests can be conducted if it is required from a regulatory or medical perspective. 
 

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4.8 Data Collection  
The study monitor will check the recording of data during monitoring visits to the site. 
The investigator will ensure that the data collected are accurate, complete and legible. 
All data obtained during the study will be promptly recorded on eCRFs which allow for 
on-site data entry and data management. Site users can read from and write to the 
sponsor’s database where the clinical data are collected. This provides immediate, direct 
data transfer to the database, as well as immediate detection of discrepancies, enabling 
site coordinators to resolve and manage discrepancies in a timely manner. All source 
documents from which eCRF entries are derived will be placed in the subject’s personal 
records. The original eCRF entries for each subject will be checked against source 
documents by the monitor. 
Following the report of any serious morbidity, either by subject or physician, the referring 
physician will be contacted and asked to provide further details, where available. For ESI, 
specific details may be requested.   
 
4.9 Data Handling 
All clinical trial findings and documents will be regarded as confidential. The investigator 
and members of their research team must not disclose any such information. 
The anonymity of participating subjects will and must be maintained. Subjects will be 
specified on CRFs and other documents by their subject number, initial or birth date and 
not by name. Documents that identify the subject (e.g., the signed subject information 
sheet and informed consent document) will, and must, be maintained as confidential by 
the investigator. 
 
4.10 
Data Analysis 
The statistical analysis will be performed using SAS software Version 9.1.3 or later (SAS 
Institute, Inc, Cary, North Carolina). Interim analysis will be performed at 2 years prior to 
3 years period follow up. Periodic interim analyses are planned for regulatory reporting 

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purposes. An annual regulatory report will be generated and reported to the regulatory 
authority. This will contain safety and efficacy data observed since the start of the study 
until December of each year.  
Descriptive analysis will be performed for safety data including drug exposure and data 
will be presented for RemsimaTM cohort, other anti-TNF drug cohort and biologic-naïve  
cohort. Additionally, meta-analysis will be performed with historical data for anti-TNF 
drug. 
The data documented in this study and the clinical parameters measured will be described 
using descriptive statistics (n, mean, median, standard deviation (SD), minimum, and 
maximum) for quantitative variables and frequencies for qualitative variables. AEs will 
be coded using the most recent version of the MedDRA and summarized by the number 
and percentage of patients reporting an event. The grade, duration, and relationship to 
treatment of each AE will be recorded. Severity of adverse events will be graded 
according to the CTCAE v4.0. Previous and concomitant treatments will be coded using 
the World Health Organization Drug Dictionary and medical history will be coded using 
MedDRA.  
Subgroup analysis might be conducted for handling risk factors. Subgroup analysis for 
each risk factor level will be considered. Additionally, propensity score might be 
considered if it is necessary and relevant. The main risk factor to be considered is 
geographical region by the level of incidence rates or prevalence rates of events such as 
TB or pneumonia. Other risk factors such as demographics, co-morbid condition and 
prior or concomitant medication can be also considered in the analysis. Adjusted relative 
risk by relevant risk factors may be adapted if suitable.  
For descriptive purpose, incidence rate per 100 patient-years or 10,000 patient-years will 
be calculated and analysis items will be specified on Statistical Analysis Plan (SAP). For 
missing data, appropriate imputation methods will be used, it required. 
The statistical considerations summarised in this section outline the plan for data analysis 
of this study. A final and complete SAP will be prepared prior to data analysis. 

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4.11 
Data archiving 
Any and all documents and data created from this registry including protocol, CRF, other 
source documents, database, all computer programs and study report will be kept in 
proper storage at least for 5 years after final report or first publication of the study results, 
which comes later. However, these documents should be retained for a longer period if 
required by the applicable legal or regulatory requirements. 
 
4.12 
Limitations of the Research Methods 
Because subjects are not randomized to treatments, bias in the allocation of treatments to 
subjects and less monitoring compared to interventional trial may compromise study 
findings. In addition, the inclusion and exclusion criteria, potential of the inclusion of 
ineligible patients, accuracy and completeness of data, types of patients participating in 
the comparison groups  (potential for bias), use of historical data (type and quality) and 
type of data which are collected may influence the study results. 
 
4.13 
Adverse Events and Pregnancy Reporting 
4.13.1 Adverse Event 
All adverse events, including SAE, reported or observed during the study must be 
recorded on the relevant pages of the case report form, regardless of their causality with 
study drug treatment, with regard to the time of onset and resolution of adverse events, 
severity/intensity, and causality with study drug, and related action and outcomes. 
An AE is defined as any untoward medical occurrence, including a clinically significant 
laboratory finding, symptom, or disease in a patient enrolled into this study regardless of 
its causal relationship to study drug. A treatment-emergent AE (TEAE) is defined as any 
event not present before exposure to study drug or any event already present that worsens 
in either intensity or frequency after exposure to study drug. 

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4.13.2 Adverse Drug Reaction 
An adverse drug reaction defined as any untoward medical occurrence in patient and its 
causal relationship to study drug cannot be ruled out. 
 
4.13.3 Serious Adverse Event 
An SAE is defined as any event that  
 results in death,  
 is immediately life threatening (includes events which put patients at risk of 
death at the time of the event but not events which may have caused patient 
death if more severe), 
 requires inpatient hospitalization or prolongation of existing hospitalization,  
 results in persistent or significant disability/incapacity,  
 is a congenital anomaly/birth defect.  
 
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious such as important medical events that might not be 
immediately life-threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed in the 
definition above. Examples of such events are intensive treatment in an emergency room 
or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalization, or development of drug dependency or drug abuse. If a patient is 
hospitalized purely for convenience (eg, for easier performance of study assessments), the 
hospitalization does not qualify as a SAE. If a patient is hospitalized solely due to disease 
progression, the hospitalization does not qualify as a SAE but that event should be 
reported as an AE.. 
 

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4.13.4 Collection and Reporting of Serious Adverse Events 
If any serious adverse event (as defined herein) occurs, the investigator must inform this 
event to the study Sponsor or CRO within 24 hours by completing the eCRF or by phone 
or by fax or e-mail to ensure Sponsor or CRO can take necessary actions. In addition, 
SAE will be reported to Ethics Committee (EC) or Institutional Review Board (IRB) 
according to the site policy/local regulation. The Sponsor or CRO, within 15 days from 
the day it is informed of the SAE, must report the occurrence of such event in 
RemsimaTM cohort to regulatory authorities along with the results of actions taken and 
relevant basic data, through website, phone, fax, mail, or otherwise electronically.  
The reporting of serious expected AEs in an expedited manner varies among countries. 
Time frames for other types of serious reports vary among countries, depending on 
source, expectedness and outcome. 
 
CELLTRION, Inc. Pharmacovigilance team 
Address: 23, Academy-ro, Yeonsu-gu, Incheon, Korea 
 
 
4.13.5 Pregnancy 
All pregnancy cases from female patients and partner of male patient’s should be reported 
to the Sponsor or CRO within 24 hours after awareness and the outcome of all pregnancy 
will be followed-up for mother and new born baby. Specific guideline and form for 
reporting will be provided to the study centers. 
 

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5 Ethical Considerations 
5.1 Good Clinical Practice 
The procedures set out in this registry protocol are designed to ensure that the 
investigator abides by the principles of the International Conference on Harmonisation 
guideline E6 (R1): Good Clinical Practice, and the Declaration of Helsinki (WMA 2013). 
The clinical trial will also be carried out in keeping with national and local legal 
requirements. 
Before study onset, the protocol, informed consent, advertisements to be used for the 
recruitment of study subjects, and any other written information regarding this study to be 
provided to the subject or the subject’s legal guardian must be approved by the IRB/IEC. 
Documentation of all IRB/IEC approvals, including the IRB/IEC compliance with Good 
Clinical Practice, will be obtained prior to beginning the study. 
All IRB/IEC approvals should be signed by the IRB/IEC chairman or designee and must 
identify the IRB/IEC name and address, the clinical protocol by title and/or protocol 
number and the date of approval and/or a when favourable opinion was granted. 
The principal investigator or subinvestigator is responsible for obtaining continued 
review of the clinical research at intervals not exceeding 1 year or otherwise specified by 
the IRB/IEC. The principal investigator or subinvestigator must supply the sponsor or its 
designee with written documentation of continued review of the clinical research. 
To alter the protocol, amendments must be written and released by the responsible staff 
and receive IRB/IEC/competent authority approval prior to implementation (as 
appropriate). 
Administrative changes may be made without the need for a formal amendment, but will 
also be mentioned in the integrated clinical trial report. All amendments will be 
distributed to all study protocol recipients, with appropriate instructions. 
 

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5.2 Informed Consent 
Prior to enrolment, written informed consent will be obtained from each subject 
according to the regulatory and legal requirements. The subject information sheet and 
informed consent document must be signed and dated; one copy will be handed to the 
subject and the investigator will retain a copy as part of the clinical trial records. The 
investigator must ensure that the subject is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the study. Subjects 
must also be notified that they are free to withdraw from the study at any time without 
prejudice to future care. The subject should be given the opportunity to ask questions and 
allowed time to consider the information provided. 
If a protocol amendment is required, the subject information sheet and informed consent 
document may need to be revised to reflect the changes to the protocol. If the subject 
information sheet and informed consent document is revised, it must be reviewed and 
approved by the responsible IRB/IEC, and signed by all subjects subsequently enrolled in 
the clinical trial as well as those currently enrolled in the clinical trial. 
 
5.3 Other Ethical and Regulatory Issues 
A safety issue of clinical relevance is one that has a relevant impact on the course of the 
clinical trial or program (including the potential for suspension of the clinical trial 
program or amendments to protocols) or warrants immediate update of the subject 
information sheet and informed consent document. 
 

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6 Project Management 
6.1 Final Report and Publication Policy 
By signing the clinical trial protocol, the investigator agrees that the results of the clinical 
trial may be used for the purposes of national and international registration, publication 
and information for medical and pharmaceutical professionals. If necessary, the 
competent authorities will be notified of the investigator’s name, address, qualifications 
and extent of involvement. 
An investigator or Clinical Research Organization shall not publish, or present for 
publication, any articles or papers or make any presentations, nor assist any other person 
in publishing any articles or papers or making any presentations, or making any public 
declaration relating or referring to the clinical trial, the results of the clinical trial, in 
whole or in part, without the prior written consent of the Sponsor. 

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7 References 
Aletaha D, et al. 2010 Rheumatoid arthritis classification criteria: An American College 
of Rheumatology/European League Against Rheumatism collaborative initiative. 
Arthritis Rheum 2010; 62(9): 2569–81. 
Arnett FC, et al. The American Rheumatism Association 1987 revised criteria for the 
classification of rheumatoid arthritis. Arthritis Rheum, 1988; 31(3): 315-24. 
Jasmer R.M. et al. Recurrent Tuberculosis in the United States and Canada Relapse or 
Reinfection? Am J Respir Crit Care Med Vol 170. pp 1360–1366, 2004. 
Johnson J.L. et al. Time until Relapse in Tuberculosis Treatment Trials: Implication for 
Phase 3 Trial Design. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL 
CARE MEDICINE VOL 186, 2012. 
Korean Guidelines for Tuberculosis Second edition, 2014. Joint Committee for the 
Revision of Korean Guidelines for Tuberculosis Korea Centers for Disease Control and 
Prevention. 
Ormerod, L. P. et al. "BTS GUIDELINES: BTS recommendations for assessing risk and 
for managing Mycobacterium tuberculosis infection and disease in patients due to start 
anti-TNF-alpha treatment." Thorax 2005; 60 : 800-805. 
Park JH, et al. Positive conversion of tuberculin skin test and performance of interferon 
release assay to detect hidden tuberculosis infection during anti-tumor necrosis factor 
agent trial. J Rheumatol 2009; 36(10): 2158-63. 
Park W, et al. A randomised, double-blind, multicentre, parallel-group, prospective study 
comparing the pharmacokinetics, safety, and efficacy of CT-P13 and innovator 
infliximab in patients with Ankylosing spondylitis: the PLANETAS study. Ann Rheum 
Dis 2013;72:1605–1612. 
Yoo DH, et al. A randomised, double-blind, parallel-group study to demonstrate 
equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when 

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co-administered with methotrexate in patients with active rheumatoid arthritis: The 
PLANETRA study. Ann Rheum Dis 2013;72:1613–1620. 
Zink A et al. European biologicals registers: methodology, selected results and 
perspectives. Ann Rheum Dis 2009; 68: 1240-46. 

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8 Appendices 
8.1 Schedule of Events 
The RemsimaTM cohort/ Other TNFs drug cohort 
Visit 
Assessment 
Screening 
(-56D~ 
D0) 
Baseline 
(Dose 1, 
D0)2 
Study Period 
End of 
Study 
visit5 
2W 
6W3 
14W4 22W4 30W4 
Every 
8Weeks4 
Every 
6Months4 
Every 
year4 
Drug Infusion 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Informed Consent1 
● 
 
 
 
 
 
 
 
 
 
 
Demography6 
● 
 
 
 
 
 
 
 
 
 
 
Medical History7 
● 
 
 
 
 
 
 
 
 
 
 
Smoking status 
● 
 
 
 
 
 
 
 
 
 
● 
Prior Medication 
History 
● 
 
 
 
 
 
 
 
 
 
 
Hepatitis B&C, HIV8 
● 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
Exclusion Criteria 
● 
● 
 
 
 
 
 
 
 
 
 
Safety 
Pregnancy 
Test9 
● 
 
 
 
 
 
 
 
 
 
 
Physical 
Examination17 
● 
●10 
●16 
●16 
●16 
●16 
●16 
●16 
●16 
●16 
● 
Vital Sign and 
weight11,17 
● 
●16 
●16 
●16 
●16 
●16 
●16 
●16 
●16 
●16 
● 
Clinical 
Laboratory12,17 
● 
●10 
 
 
●16 
 
●16 
 
●16 
●16 
● 
Chest X-ray 
● 
 
 
 
 
 
 
 
 
●16 
● 
Interferon-γ 
release assay 
(IGRA)13 
● 
●2 
 
 
 
 
 
 
 
●16 
● 
TB symptoms 
and signs 
monitoring17 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Immunogenici
ty Test 
(Optional)13, 14 
 
●16 
 
 
 
 
●16 
 
 
●16 
● 
Hypersensitivi
ty 
monitoring17 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Adverse 
events (ESI)15 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Concomitant 
medication 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
Effica
cy 
DAS28 
 
●16 
 
 
 
 
●16 
 
●16 
●16 
● 
HAQ 
 
●16 
 
 
 
 
●16 
 
●16 
●16 
● 
Health-economics  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
HIV, human immunodeficiency virus; TB, tuberculosis; DAS28, Disease Activity Score 28; HAQ, Health Assessment 
Questionnaire; 

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*The schedule is presented with focus on dosing schedule for patients who started with infliximab at the time of 
enrollment for better understanding.  The schedule of events in the other TNFs cohort basically follows that of the 
RemsimaTM cohort. Administration of other TNFs drug should follow the drug’s own dosing schedule and regimen.  
1. Patients who have been followed-up for 2 years are asked to sign a new informed consent before being observed in 
the extension period. 
2. For all switched patients, their assessment schedule will be re-started from the day of switch. IGRA test will be 
required for those who switched to RemsimaTM with no positive IGRA result in previous testing. If IGRA test is 
performed within 8 weeks prior to switching, no additional test is required. 
3. A visit window of ±3 days is recommended. 
4. A visit window of ±14 days is recommended. 
5. The End-of-Study (EOS) visit only needs to be completed if the patient withdraws prior to study completion. An 
EOS visit will be made 8 weeks after the last dose is received. If the patient has completed the full 5-year study 
period, a separate EOS visit is not required. In this case, the last visit will be considered the EOS visit. 
6. Demography: date of birth, age, gender, race and height will be collected.  
7. Medical records should include whether patients have been BCG-vaccinated or not. 
8. At screening, hepatitis B and C and HIV test will be performed at the investigator’s discretion based on results of 
previously performed test or patient’s status. Test will be performed at local laboratory. 
9. Pregnancy Test (local laboratory): using serum or urine  
10. Test result between the start of screening (-56 days) and prior to 1st dose infusion could be used at the investigator’s 
discretion.  
11. Vital signs (including blood pressure, heart and respiratory rates, temperature) and weight will be measured after 5 
minutes of rest (sitting). 
12. Recommended parameters for clinical laboratory (local laboratory)  
Clinical Chemistry 
Total protein, serum bilirubin, alanine aminotransferase, aspartate aminotransferase, 
alkaline phosphatase, γ-glutamyltransferase, blood urea nitrogen, creatinine, albumin, 
sodium, potassium, calcium, chloride, inorganic phosphorus, glucose, creatine kinase, 
lactate dehydrogenase, and C-reactive protein (CRP) 
Hematology 
Red blood cell count, Erythrocyte sedimentation rate (ESR), total and differential white 
blood cell count, absolute neutrophil count, lymphocyte count, platelet count, hemoglobin, 
mean corpuscular volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin 
concentration, and hematocrit 
Urinalysis 
White blood cell, Red blood cell, Protein 
13. Test will be performed at the central laboratory (PPD Global Central Labs). Additional IGRA will be performed if 
symptoms raise a suspicion of TB upon judgement of the investigator during study period. Patients who test 
positive for IGRA during the Study period, including Screening, with sufficient documentation of prophylaxis or 
complete resolution of TB following treatment based on local guidelines, the IGRA tests are not required at every 
year at EOS visit. 
14. Anti-infliximab antibody will be measured in patients who are treated with infliximab (RemsimaTM and 
Remicade®).  
15. The risk associated with any adverse event (especially events of special interest – ESI) will be evaluated 
16. Assessment will be performed prior to dose infusion  
17. Any clinically significant abnormal findings, upon judgement of the investigator, will be reported. 
 
 

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8.2 Informed consent form 
The ICF will be provided as a separate document 
 
8.3 DAS28 and VAS 
DAS28 
The DAS28 score uses a calculation that requires the assessment of 28 joints for swelling 
and tenderness. The 28 joints are: shoulders, elbows, wrists, metacarpophalangeal joints, 
proximal interphalangeal joints, and the knees.  
More information on DAS28 can be found at http: www.das-score.nl 
 
Left 
Right 
 
Swollen 
tender 
Swollen 
Tender 
Shoulder 
 
 
 
 
Elbow 
 
 
 
 
Wrist 
 
 
 
 
MCP 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
PIP 
1 
 
 
 
 
 
2 
 
 
 
 
 
3 
 
 
 
 
 
4 
 
 
 
 
 
5 
 
 
 
 
Knee 
 
 
 
 
Subtotal 
 
 
 
 
Total 
Swollen 
 
Tender 
 
 
MCP: metacarpophalangeal joints; PIP: proximal interphalangeal joints 
Reference: http://www.reuma-nijmegen.nl/www.das-score.nl/DAS28frm.doc 
 

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VAS Patient Global Assessment of Disease Activity 
Patient global assessment of disease activity is determined by the patient indicating the 
patient’s current disease status by marking an X through a 100-mm line (0 mm equalling 
no activity and 100 mm equalling extreme activity). The length of the line is measured 
from the left (in mm) and the value (in mm) is recorded in the patient’s CRF. 
 
 
None  
 
 
 
 
 
 
 
Extreme 
 

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8.4 HAQ and Scoring of the HAQ 
 

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