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

The concepts and information contained in this document or generated during the study are considered proprietary and may 
not be disclosed in whole or in part without the expressed, written consent of CELLTRION, Inc. and CELLTRION, Pharm. 
The study will be conducted according to the International Conference on Harmonisation Tripartite Guideline E6(R1): Good 
Clinical Practice. 
 
 
 
 
STUDY PROTOCOL 
 
An Observational, Prospective Cohort Study to Evaluate 
Safety and Efficacy of RemsimaTM in Patients with 
Ankylosing Spondylitis 
 
 
PROTOCOL NUMBER CT-P13 4.4 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL  

CELLTRION, Inc. 
  
Protocol Number CT-P13 4.4  
Protocol Version 2.1 (EU specific) – 01 June 2015 
 
 
CONFIDENTIAL 
2 
 
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 ................................................................................................. 9 
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 
Secondary safety objective...................................................................... 15 
3.2.2 
Secondary efficacy objective .................................................................. 15 
3.2.3 
Health-economics objective .................................................................... 16 
4 
Methods ........................................................................................................................... 17 
4.1 
Study Design ...................................................................................................... 17 
4.2 
Study Population ................................................................................................ 18 
4.2.1 
Inclusion criteria ..................................................................................... 18 
4.2.2 
Exclusion Criteria ................................................................................... 19 
4.3 
Patient Withdrawal ............................................................................................ 20 
4.4 
Sample Size ....................................................................................................... 21 
4.5 
Assessments ....................................................................................................... 21 
4.5.1 
Collection of core baseline data .............................................................. 22 
4.5.2 
Safety assessments .................................................................................. 22 
4.5.2.1 
Events of special interest ................................................................ 22 
4.5.2.2 
Other adverse events ...................................................................... 24 
4.5.2.2.1 Assessment of causality ................................................................. 24 
4.5.2.2.2 Reporting of Adverse Events and Pregnancy................................. 25 
4.5.2.3 
Hypersensitivity monitoring........................................................... 27 
4.5.2.4 
Tuberculosis assessment ................................................................ 27 
4.5.2.5 
Immunogenicity testing (optional) ................................................. 29 
4.5.2.6 
Clinical laboratory parameters ....................................................... 29 
4.5.2.7 
Pregnancy test ................................................................................ 29 
4.5.2.8 
Physical examination ..................................................................... 30 
4.5.2.9 
Vital signs and weight .................................................................... 30 
4.5.2.10 Hepatitis B and C, and human immunodeficiency virus testing .... 30 
4.5.2.11 Prior and concomitant medication ................................................. 30 
4.5.3 
Efficacy assessments ............................................................................... 31 
4.5.3.1 
BASDAI ......................................................................................... 31 
4.5.3.2 
BASFI ............................................................................................ 31 
4.5.3.3 
Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) 
Physician and Patient global assessment of disease status ............................. 31 

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4.5.3.4 
Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) 
Patient Assessment of Spinal Pain .................................................................. 31 
4.5.4 
Health-economic data eveluation ............................................................ 32 
4.6 
Sample Storage and Shipment ........................................................................... 32 
4.7 
Data Collection .................................................................................................. 32 
4.8 
Data Handling .................................................................................................... 33 
4.9 
Data Analysis ..................................................................................................... 33 
4.10 
Data archiving .................................................................................................... 35 
4.11 
Limitations of the Research Methods ................................................................ 35 
5 
Ethical Considerations .................................................................................................... 35 
5.1 
Good Clinical Practice ....................................................................................... 35 
5.2 
Informed Consent .............................................................................................. 36 
5.3 
Other Ethical and Regulatory Issues.................................................................. 37 
6 
Project Management ....................................................................................................... 38 
6.1 
Final Report and Publication Policy .................................................................. 38 
7 
References ....................................................................................................................... 39 
8 
Appendices ...................................................................................................................... 40 
8.1 
Schedule of Events ............................................................................................ 40 
8.2 
Informed consent form ...................................................................................... 43 
8.3 
BASDAI ............................................................................................................ 43 
8.3.1 
BASDAI Questionnaire .......................................................................... 44 
8.4 
BASFI ................................................................................................................ 45 
8.4.1 
BASFI Questionnaire .............................................................................. 46 
8.5 
Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Physician and 
Patient Global Assessment of Disease Status ................................................................. 48 
8.6 
Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Patient 
Assessment of Spinal Pain .............................................................................................. 48 
 

CELLTRION, Inc. 
  
Protocol Number CT-P13 4.4  
Protocol Version 2.1 (EU specific) – 01 June 2015 
 
 
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Protocol Approval 
 
Study Title 
An Observational, Prospective Cohort Study to Evaluate 
Safety and Efficacy of RemsimaTM in Patients with 
Ankylosing Spondylitis 
Protocol Number 
CT-P13 4.4 
Protocol Version and Date 
Protocol Version 2.1 (EU specific) – 01 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 4.4 
Title of Study: An Observational, Prospective Cohort Study to Evaluate Safety and Efficacy of 
RemsimaTM in Patients with Ankylosing Spondylitis 
Marketing Authorization Holder: Celltrion Healthcare Hungary Kft, 1023 Budapest, Regus Ó buda Gate, 
Á rpád fejedelem útja 26-28 Hungary 
Study Center(s): Approximately 50 centers in Europe and South Korea 
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 safety of RemsimaTM in ankylosing 
spondylitis (AS) patients, in comparison with patients receiving other anti-TNF drugs, by evaluation of 
events of special interest (ESI) for up to 5 years from the first visit of each patient. 
The secondary objectives of this study are to evaluate efficacy and additional safety of RemsimaTM in AS 
patients, in comparison with patients receiving other TNF blockers. 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 AS in comparison with patients receiving other TNF blockers. 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. Patients who have been treated with Remicade® 
prior to enrolment, their dosing schedule will be continued appropriately. A dose visit window of ±3 days is 
recommended up to and including Dose 3; a dose visit window of ±14 days is recommended thereafter, 
including the End-of-Study (EOS) Visit. 
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: Approximately 1000 male or female patients with confirmed diagnosis of AS (approximately 
500 patients treated with RemsimaTM, 500 patients treated with other anti-TNF drugs). At least 50 
percentage of target number of patients will be enrolled in European regions; recruitment in selected 
Eastern European and Western European countries will continue for 5 years after respective launches. 
Study Drug, Dose and Regimen: RemsimaTM (5 mg/kg) will be administered intravenously during this 
study. Dose and treatment schedule are recommended to comply with the approved posology in each 
regulatory authority or investigator’s clinical decision and time intervals between doses are controlled 
flexibly upon the investigator’s clinical decision according to the product label of RemsimaTM. 
Comparator, Dose and Regimen: The first comparator cohort will be patients recruited with AS who are 
being treated with other anti-TNFs such as (infliximab (Remicade®), etanercept, adalimumab and etc.). 
Dose and regimen are recommended to comply with the approved posology in each regulatory authority. 
The second comparator cohort will be the historical AS cohort of patients who have been exposed to anti-
TNF drug (infliximab(Remicade®), etanercept, adalimumab and etc.) from published reports and articles 
presenting studies conducted with anti-TNF drug (infliximab(Remicade®), etanercept, adalimumab and 
etc.). The historical AS cohort will be compared with RemsimaTM and other TNF blockers cohorts in this 
study. 
Main selection criteria: Male or female patients with active AS will be considered for enrolment in the 

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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 AS diagnosed according to the 1984 modified New York classification criteria 
[van der Linden et al 1984].  
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 conditions at the 
time of enrolment:  
 
Patients who have started to be treated with an established anti –TNF such as Infliximab 
(Remicade®), Etanercept, Adalimumab and etc. within 6 months 
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 (other anti-TNF drug), 
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 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, one 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 of TB following treatment based on local 
guidelines can be treated before confirming the IGRA results. 
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. 

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Safety Assessment: Safety will be assessed by collection of data in the patient medical records as part of 
routine clinical practice. Data collection will include ESIs and adverse events (AEs) including serious AEs 
other than those classified as ESI. Safety analysis will also include immunogenicity test (optional), 
interferon-γ release assay test, pregnancy test, Hepatitis B and C and HIV tests, physical examination, vital 
sign measurement, chest X-ray, clinical laboratory analyses, hypersensitivity monitoring, concomitant 
medications (name, dose and duration) and signs and symptoms of TB. 
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 explorative comparison of Bath 
Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index 
(BASFI), Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Physician and Patient Global 
Assessment of Disease Status, Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Patient 
Assessment of Spinal Pain. 
Data analysis: Statistical analysis: The statistical analysis will be performed using SAS software Version 
9.1.3 or later (SAS Institute, Inc, Cary, North Carolina).  
Interim analysis and an annual regulatory report will be generated if it is required from a regulatory 
perspective. 
Descriptive analysis will be performed for safety data including drug exposure (e.g. number of patients 
exposed, number of infusion, duration of exposure and etc.) and data will be presented for RemsimaTM 
cohort, and other anti-TNF drug 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, 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. 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 items will be specified on statistical analysis plan. For missing data, appropriate imputation 
methods will be used, if required.   
The statistical considerations summarized in this section outline the plan for data analysis of this study. A 
final and complete statistical analysis plan will be prepared prior to data analysis. 
Milestones: 
Milestones  
Planned Date 
Start of data collection  
 Korea: 3Q 2014 
 European region: 2Q 2014  
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 
Final report of study results 
 2026 
 

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1 Presentation 
1.1 Title 
An observational, prospective cohort study to evaluate the safety and efficacy of RemsimaTM 
in patients with ankylosing spondylitis (AS)  
 
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, Republic of Korea 
 
1.4 Lead Investigator  
 
 
 
 
1.5 Research Centers  
This study will be conducted at approximately 50 research centers in European region and 
South Korea.  

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1.6 Milestones 
Milestones  
Planned Date 
Start of data collection  
 Korea: 3Q 2014 
 European region: 2Q 2014 
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 
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 AS, rheumatoid arthritis (RA), 
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; Yoo 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 to demonstrate 

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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. [Park et al. 2013; 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 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 AS, there is a need to establish the 

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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 AS who are recipients of 
RemsimaTM and patients receiving other TNF blockers. 

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3 Study Objectives 
3.1 Primary Objective 
The primary objective of this longitudinal, observational, prospective cohort study is to 
assess the safety of RemsimaTM in AS patients receiving infusions of RemsimaTM over a 5-
year period (2 years initially, followed by an additional 3 years for patients who consent to 
participate in an extension study), in comparison with patients receiving other TNF blockers, 
by evaluation of events of special interest (ESI). 
 
The risk associated with the following endpoints (ESI) will be evaluated: 
 
Identified risks: 
 Hepatitis B virus reactivation 
 Congestive heart failure 
 Opportunistic infections (excluding tuberculosis) 
 Serious infections including sepsis (excluding opportunistic infection and 
tuberculosis) 
 Tuberculosis 
 Serum sickness (delayed hypersensitivity reactions) 
 Haematologic reactions 
 Systemic lupus erythematosus/lupus-like syndrome 
 Demyelinating disorders 
 Lymphoma (not HSTCL) 
 Hepatobiliary events 
 Hepatisplenic T-cell Lymphoma (HSTCL) 
 Serious infusion reaction during a re-induction following disease flare 
 Sarcoidosis/sarcoid-like reactions 
 Leukaemia 
 
Potential risks: 

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 Malignancy (excluding lymphoma) 
 Skin cancer 
 Pregnancy exposure† 
 
†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 in the statistical analysis plan. 
 
3.2 Secondary Objectives 
3.2.1 Secondary 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) 
 Other safety assessments (hypersensitivity monitoring, pregnancy test, Hepatitis B/C, 
human immunodeficiency virus [HIV] test, physical examination, vital sign, clinical 
laboratory tests, chest X-ray and concomitant medication) 
 
3.2.2 Secondary efficacy objective 
The secondary efficacy objective of this study is to evaluate the efficacy of RemsimaTM in 
AS patients, in comparison with patients receiving other TNF blockers, in relation to the 
following endpoints (Specific schedule of measurement is provided in section 8. Appendix.): 

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a. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)  
b. Bath Ankylosing Spondylitis Functional Index (BASFI)  
c. Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Physician and 
Patient Global Assessment of Disease Status  
d. Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Patient Assessment 
of Spinal Pain 
 
3.2.3 Health-economics objective  
Cost-effectiveness will be evaluated in AS 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 Study Design 
This is a longitudinal, observational, prospective cohort study to assess the safety and 
efficacy of RemsimaTM in patients with AS in comparison with patients receiving other TNF 
blockers. 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 and/or legal guardian according to the regulatory and legal requirements 
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 enrol the patient in this registry. 
 
The study will be carried out at approximately 50 centers in European region and South 
Korea with a sample size of approximately 1000 male and female patients with confirmed 
diagnosis of AS (approximately 500 patients treated with RemsimaTM and 500 patients 
treated with other anti-TNF drugs). 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 patients who have started to be treated with other anti-TNFs within the 
last 6 months prior to enrolment, medical records will also be collected from the date of first 
exposure prior to enrolment and the date of first exposure is considered as a baseline. For the 
historical AS cohort, data will be collected for patients who treated with anti-TNF from 
published studies conducted with Remicade® or other anti-TNF products. The historical AS 
cohort will be compared with RemsimaTM and other TNF blockers cohorts in this study. 
 

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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. Dose and 
treatment schedule are recommended to comply with the approved posology in each 
regulatory authority or investigator’s clinical decision and the time intervals between doses 
are controlled flexibly upon the investigator’s clinical decision according to the product label 
of RemsimaTM. If a patient has been treated with Remicade® prior to enrolment, their dosing 
schedule will be continued appropriately. 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 other anti-TNFs prior to enrolment, 
their dosing schedule will be continued appropriately. 
 
Patients may be pre-treated with antihistamines, hydrocortisone and/or paracetamol, and 
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.  
 
4.2 Study Population  
The study group will consist of adult patients (≥18 years old) diagnosed with AS to be 
treated with RemsimaTM or other TNF blockers.  
 
4.2.1 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 AS diagnosed according to the 1984 modified New York 
classification criteria [van der Linden et al 1984]. 
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 
conditions at the time of enrolment: 
 Patients who have started to be treated with an established anti-TNF such as 
infliximab (Remicade®), etanercept, adalimumab and etc. within 6 months 
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 (other anti-
TNF drug), 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. 
 
4.2.2 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. 
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. 

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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, one 
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 of TB following 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. 
 
4.3 Patient Withdrawal 
Patients will be recruited at participating study centers and allocated to the RemsimaTM or 
other TNF blockers cohorts. 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 
 no efficacy from study drug 
 withdrawal of consent or refusal to continue treatment or procedures/observations 
 development of any malignancy 

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 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. 
 
4.4 Sample Size 
This study aims to recruit approximately 1,000 male and female patients with confirmed 
diagnosis of AS (approximately 500 patients treated with RemsimaTM and approximately 500 
patients treated with other anti-TNFs drugs) from participating test centers. At least 50 
percentage of target number of patients will be enrolled in European regions; recruitment in 
selected Eastern European and Western European countries will continue for 5 years after 
respective launches. A sample size is determined not on the basis of formal statistical 
hypotheses but using an exploratory descriptive approach. The proposed number of subjects 
is considered to be sufficient to achieve the objectives of the study. The number of patients is 
sufficient enough to detect adverse events which occur at 1 % of frequency.  
 
4.5 Assessments 
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 

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practice. Data will be collected for the time points specified in the schedule of events in 
section 8 Appendix, where available. 
 
4.5.1 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  
 
Date of birth, ethnicity, 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 
 
BASDAI 
 
BASFI 
 
Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Physician and Patient 
Global Assessment of Disease Activity 
 
Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Patient Assessment of 
Spinal Pain 
 
In addition, personal and medical information will be obtained directly from each patient 
recruited (e.g. smoking history). Smoking status will also be collected at the EOS visit. 
 
4.5.2 Safety assessments 
4.5.2.1 Events of special interest 
In order to assess the primary study outcomes, the following ESI will be evaluated: 

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Identified risks: 
 Hepatitis B virus reactivation 
 Congestive heart failure 
 Opportunistic infections (excluding tuberculosis) 
 Serious infections including sepsis (excluding opportunistic infection and 
tuberculosis) 
 Tuberculosis 
 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 reaction during a re-induction following disease flare 
 Sarcoidosis/sarcoid-like reactions 
 Leukaemia 
 
Potential risks: 
 Malignancy (excluding lymphoma) 
 Skin cancer 
 Pregnancy exposure† 
 
†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. 

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Alternatively, the treatment should be discontinued. All pregnancy cases will be followed-up 
for the outcome. 
 
Other items may be added or specified in the statistical analysis plan. 
 
4.5.2.2 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; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living. 
Grade 3: 
Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care activities of daily 
living. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated. 
Grade 5: 
Death related to AE 
 
4.5.2.2.1 Assessment of causality 
The relationship or association of the test article in causing or contributing to the AE will be 
characterised using the following classification and criteria: 
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, i.e., 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. 

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4.5.2.2.2 Reporting of Adverse Events and Pregnancy 
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. 
 
An adverse drug reaction defined as any untoward medical occurrence in patient and its 
causal relationship to study drug cannot be ruled out. 
 
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 
fax or email 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 of being 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.  
 
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. 

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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.  
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgement, 
they may jeopardize the patient and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development 
of drug dependency or drug abuse. If a patient is hospitalized purely for convenience (eg, for 
easier performance of study assessments), the hospitalization does not qualify as an 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. 
 
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.  
 
All pregnancy cases from female patients and partner of male patients 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. 
 
[Contact Information] 
CELLTRION, Inc. Pharmacovigilance Team 
Address: 19, Academy-ro 51beon-gil, Yeonsu-gu, Incheon, Korea 

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4.5.2.3 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. 
 
4.5.2.4 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 

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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. 
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 four 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 will also be taken at every year and EOS visit. 
IGRA will be performed at Screening, every year and EOS visit to identify positive 
conversion of previously negative results according to the schedule of events in section 8 
Appendix. 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. IGRA will be carried out at the 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]. 
 

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4.5.2.5 Immunogenicity testing (optional) 
Blood samples for immunogenicity testing (anti-infliximab antibodies) will be collected from 
patients who will be treated with infliximab (RemsimaTM and Remicade®), given patient’s 
written informed consent. Immunogenicity testing will be performed at the central laboratory. 
To see a detailed test schedule, please refer section 8 Appendix. 
 
4.5.2.6 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: 
 
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 and Protein 
 
4.5.2.7 Pregnancy test 
Pregnancy tests will be performed in accordance with the investigator’s medical judgement. 
If available, a serum pregnancy test results will be documented at Screening and EOS. All 
urine pregnancy test results, for women of childbearing potential who have not been 
surgically sterilized, will be documented during the observation period to confirm the 

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absence of pregnancy. Tests will be conducted at the local laboratory. To see a test schedule, 
please refer section 8 Appendix. 
 
4.5.2.8 Physical examination 
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. 
Physical examination results will be documented at the time points specified in section 8 
Appendix, where available. 
 
4.5.2.9 Vital signs and weight 
Vital signs (including blood pressure, heart and respiratory rates, and body temperature) and 
weight will be measured after 5 minute rest (sitting). 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. 
 
4.5.2.10 
Hepatitis B and C, and human immunodeficiency virus testing 
Hepatitis B and C and HIV tests will be performed referring to a test schedule in section 8 
Appendix. 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. 
Tests will be conducted at the local laboratory. 
 
4.5.2.11 
Prior and concomitant medication 
Use of all concomitant medications from within six months prior to Screening and during the 
study will be recorded in the patient’s eCRF. Any biologic therapy for treatment of AS will 
be recorded, regardless of the time when these were administered, including duration of 
therapy and reason for stopping. Any changes in concomitant medications will also be 
recorded in the patient’s eCRF. Any concomitant medication deemed necessary for the 

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welfare of the patient during the study may be given at the discretion of the investigator. 
However, it is the responsibility of the principal investigator to ensure that details regarding 
the medication are recorded in full in the eCRF. 
 
4.5.3 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. 
4.5.3.1 BASDAI 
Patient disease activity will be assessed using the BASDAI at baseline and every six months 
thereafter during maintenance therapy (Section 8.3). 
 
4.5.3.2 BASFI 
Functional ability will be assessed using the BASFI at baseline and every six months 
thereafter during maintenance therapy (Section 8.4). 
 
4.5.3.3 Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Physician and 
Patient global assessment of disease status 
Physician and Patient global assessment of disease status will be assessed at baseline and 
every six months thereafter during maintenance therapy (Section 8.5). 
 
4.5.3.4 Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Patient 
Assessment of Spinal Pain 
Patient assessment of pain is measured will be assessed at baseline and every six months 
thereafter during maintenance therapy (Section 8.6). 
 

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4.5.4 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)  
 
4.6 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 either freezing or refrigerating. Additionally, blood samples 
for immunogenicity should be retained at the central laboratory (PPD Global Central Labs) 
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. The samples for 
immunogenicity testing will be shipped from the study center to the central laboratory for 
testing in weekly or monthly batches.  
 Details in storage and shipment will be followed according to the lab manual. 
 
4.7 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 

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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.   
 
4.8 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. 
 
4.9 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 and an annual regulatory report will be generated if it is required from a 
regulatory perspective. 
For analyses, patients who switch to a second biologic (either RemsimaTM or Remicade® 
only) will have their follow-up censored at the time of switching treatments and the data 
before switching will be analyzed under the prior drug cohort and data after switching will 
be analyzed under the new drug cohort. 
Descriptive analysis will be performed for safety data including drug exposure and data will 
be presented for RemsimaTM cohort, and other anti-TNF drug cohort. Additionally, meta-
analysis will be performed with historical data for anti-TNF drug. 

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The data documented in this study and the clinical parameters measured will be described 
using descriptive statistics (n, mean, median, 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. 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 items will be specified on statistical analysis plan.  
For missing data, appropriate imputation methods will be used, if required.   
For an assessment out of window, methods of analysis will be provided in the statistical 
analysis plan. 
The statistical considerations summarized in this section outline the plan for data analysis of 
this study. A final and complete statistical analysis plan will be prepared prior to data 
analysis.  
 

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4.10 
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. 
 
4.11 
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. 
 
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. 

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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 investigator 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 investigator 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. 
 
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. 
 

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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 
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): 2158–2163. 
Park W et al. A randomised, double-blind, multicenter, 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. Published Online First 16 May 2013. doi:10.1136/annrheumdis-2012-203091 
Sieper J et al. The Assessment of SponyloArthritis International Society (ASAS) handbook: a 
guide to assess spondyloarthritis. Ann Rheum Dis 2009; 68(Suppl 2): ii1-ii44. 
Yoo D-H, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to 
demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator 
infliximab when co-administered with methotrexate in patients with active rheumatoid 
arthritis: the PLANETRA study. Ann Rheum Dis 2013. Published Online First 21 May 
2013. doi:10.1136/annrheumdis-2012-203090 
Zink A et al. European biologicals registers: methodology, selected results and perspectives. 
Ann Rheum Dis 2009; 68: 1240–1246. 
 

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Adverse events (ESI)19 
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Efficacy 
BASDAI11 
 
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BASFI11 
 
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Global Assessment Score 
(VAS or NRS)11 
 
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Spinal Pain Score (VAS or 
NRS)11 
 
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Health-economics 
 
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eCRF, electronic case report form; HIV, human immunodeficiency virus; M, Month; NRS, Numerical Rating Scale; TB, tuberculosis; VAS, visual analogue scale 
Assessment of which names in brackets is subject to the investigator’s decision on its test method or schedule. See details aforementioned details in the protocol.  
1. For RemsimaTM and Remicade® treatments, a dose visit window of ± 3 days is recommended up to and including Dose 3; a visit window of ± 14 days at maximum is 
recommended after Dose 3. Administration of other anti-TNFs should follow the drug’s own dosing schedule and regimen as approved. 
2. Time points will be calculated from the first dose of either RemsimaTM or other anti-TNFs. For Assessments at Month 3 and every 6 month and 1 year, a visit window of ± 6 
weeks at maximum is recommended. Investigator will choose an assessment time point among visits near Month 3 and every 6 months or 1 year.  
3. 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. 
4. 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. 
5. Patients who have been followed-up for 2 year are asked to sign a new informed consent before being observed in the extension period 
6. Demography: date of birth, age, gender, height, weight and race 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. 
9. Assessment is not required at Screening if a result from within 3 months prior to Screening is available. The results of that assessment should be entered in an eCRF at 
Screening. 
10. Pregnancy Test (local laboratory): using serum or urine chosen by the investigator. A serum pregnancy test will be documented at Screening and EOS, if available. All urine 
pregnancy test results will be documented on each dosing day. 
11. Assessment will be performed prior to dose infusion. 
12. Any clinically significant abnormal findings, upon judgement of the investigator, will be reported. 
13. Vital signs (including blood pressure, heart and respiratory rates, temperature) and weight will be measured after 5 minutes of rest (sitting). 
14. 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) 

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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 and Protein 
15. Test will be performed at the central laboratory (PPD Global Central labs). 
16. 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. 
17. Anti-infliximab antibody will be measured in patients who are treated with infliximab (RemsimaTM and Remicade®). 
18. Patients will be monitored from the start of infusion, and until 1-2 hours after the end of infusion. 
19. The risk associated with the following endpoints (events of special interest – ESI) will be evaluated. 

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8.2 Informed consent form 
The ICF will be provided as a separate document 
 
8.3 BASDAI 
The BASDAI is one of the measures used to assess the signs and symptoms of AS (pain, 
spinal stiffness), spinal mobility, and physical function [Sieper et al 2009]. The BASDAI 
score is generated from a set of 6 questions and calculated using the following formula: 
BASDAI = Q1 + Q2 +Q3 + Q4 + ([Q5 + Q6]/2) 
5 
An example of the questionnaire is included in 8.3.1. 

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8.3.1 BASDAI Questionnaire 
Please cross the box which represents your answer, ie, 
 
All questions refer to last week.  
1. How would you describe the overall level of fatigue/tiredness you have experienced? 
 
 
 
 
none 
 
 
 
 
 
 
 
 
 
very severe 
 
2. How would you describe the overall level of AS neck, back or hip pain you have had?  
 
 
 
none 
 
 
 
 
 
 
 
 
 
very severe 
 
3. How would you describe the overall level of pain/swelling in joints other than neck, back or hips you 
have had?   
 
 
 
 
none 
 
 
 
 
 
 
 
 
 
very severe 
 
4. How would you describe the overall level of discomfort you have had from any areas tender to touch 
or pressure? 
 
 
 
 
none 
 
 
 
 
 
 
 
 
 
very severe 
 
5. How would you describe the overall level of morning stiffness you have had from the time you wake 
up? 
 
 
 
 
none 
 
 
 
 
 
 
 
 
 
very severe 
 
6. How long does your morning stiffness last from the time you wake up? 
 
 
 
 
0 hour  
 
 
 
 1 hour  
 
 
2 or more hours 
 
10
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
10
5
0
1
2
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6
7
8
9
10
5
0
1
2
3
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7
8
9
10
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0
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
10
5
0

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8.4 BASFI 
The BASFI is one of the measures used to assess the signs and symptoms of AS (pain, spinal 
stiffness), spinal mobility, and physical function [Sieper et al 2009]. The BASFI is the mean 
of scores for the 10 items completed on a numerical rating scale. An example of the 10-item 
questionnaire is in 8.4.1. 

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8.4.1 BASFI Questionnaire 
Please indicate your level of ability with each of the following activities during the last week, 
ie, 
 
 
(An aid is a piece of equipment which helps you to perform an action or movement) 
1. Putting on your socks or tights without help or aids (eg sock aid). 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
2. Bending forward from the waist to pick up a pen from the floor without an aid. 
  
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
3. Reaching up to a high shelf without help or aids (eg helping hand). 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
4. Getting up out of an armless dining room chair without using your hands or any other help. 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
5. Getting up off the floor without help from lying on your back. 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
6. Standing unsupported for 10 minutes without discomfort. 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
7. Climbing 12-15 steps without using a handrail or walking aid. One foot at each step. 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
10
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
10
5
0
1
2
3
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6
7
8
9
10
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0
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
10
5
0
1
2
3
4
6
7
8
9
10
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0

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8. Looking over your shoulder without turning your body. 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
9. Doing physically demanding activities (eg physiotherapy exercises, gardening or sports). 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
10. Doing a full day’s activities, whether it be at home or at work. 
 
 
 
 
easy 
 
 
 
 
 
 
 
 
 
impossible 
 
1
2
3
4
6
7
8
9
10
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0
1
2
3
4
6
7
8
9
10
5
0
1
2
3
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6
7
8
9
10
5
0

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8.5 Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Physician and 
Patient Global Assessment of Disease Status 
Patient global assessment of disease status is measured by the patient indicating their current 
disease status by crossing the box, ie             (0 equals no activity and 10 equals extreme 
activity). The value is recorded in the patient’s case report form. 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Extreme 
 
8.6 Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) Patient Assessment 
of Spinal Pain 
Patient assessment of pain is measured by the patient indicating the extent of their pain by 
crossing the box, ie,         (0 equals no pain and 10 equals extreme pain). The value is 
recorded in the patient’s case report form. 
 
 
 
 
None 
 
 
 
 
 
 
 
 
 
Extreme 
 
 
1
2
3
4
6
7
8
9
10
5
0
10
1
2
3
4
6
7
8
9
10
5
0
10