Real-World Outcome of Rheumatoid Arthritis Patients in Korea on Adalimumab (ROCKA Study)
Conditions: Rheumatoid Arthritis
Sponsor: AbbVie

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Title Page 
Title
Real-World Outcome of Rheumatoid Arthritis Patients in Korea on 
Adalimumab (ROCKA Study)
Protocol Version Identifier
Amendment 01, 26 Dec 2017
Date of Last Version of
Protocol
26 Dec 2017
EU PAS Register Number
Not registered (Non-PASS PMOS)
Active Substance
Not applicable (Non-PASS PMOS)
Medicinal Product
Not applicable (Non-PASS PMOS)
Product Reference
Not applicable (Non-PASS PMOS)
Procedure Number
Not applicable (Non-PASS PMOS)
Marketing Authorization 
Holder(s)
AbbVie Limited
Joint PASS
Not applicable (Non-PASS PMOS)
Research Question and 
Objectives
The overall strategic objective of this non-interventional, observational 
study is to assess the effect of Adalimumab on health-related quality of 
life and work productivity in patients with Rheumatoid Arthritis (RA) 
in Korea.
Country(ies) of Study
Korea
Author
This study will be conducted in compliance with this protocol. 
Confidential Information 
No use or disclosure outside AbbVie is permitted without prior written authorization from 
AbbVie. 
/$5

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Marketing Authorization Holder(s) 
Marketing Authorization Holder(s)
AbbVie Ltd
MAH Contact Person
Not applicable (Non-PASS PMOS)

 
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1.0 
Table of Contents 
1.0 
Table of Contents .................................................................. 3 
2.0 
Abbreviations ........................................................................ 6 
3.0 
Responsible Parties ............................................................... 7 
4.0 
Abstract ................................................................................. 9 
5.0 
Amendments and Updates .................................................. 14 
6.0 
Milestones ............................................................................ 14 
7.0 
Rationale and Background ................................................. 14 
8.0 
Research Question and Objectives ..................................... 15 
9.0 
Research Methods ............................................................... 16 
 
Study Design ........................................................................................ 16 
9.1
 
Schedule of Events ............................................................................... 18 
9.1.1
 
Setting .................................................................................................. 18 
9.2
 
Inclusion Criteria: ................................................................................. 19 
9.2.1
 
Exclusion Criteria: ................................................................................ 19 
9.2.2
 
Investigator Selection Criteria .............................................................. 20 
9.2.3
 
Study Procedures .................................................................................. 20 
9.2.4
9.2.4.1 
Informed Consent ................................................................................. 20 
9.2.4.2 
Patient Assignment ............................................................................... 20 
9.2.4.3 
Investigator Recruitment ...................................................................... 21 
9.2.4.4 
Study site monitoring ........................................................................... 21 
9.2.4.5 
Patient Selection ................................................................................... 21 
9.2.4.6 
Data Collection..................................................................................... 22 
9.2.4.7 
Study Documents ................................................................................. 22 
 
Adverse Events..................................................................................... 25 
9.2.5
 
Variables .............................................................................................. 25 
9.3
 
Data Sources ........................................................................................ 25 
9.4
 
Study Size ............................................................................................ 26 
9.5
 
Data Management and Storage Process................................................. 26 
9.6
 
Data Management ................................................................................ 26 
9.6.1
 
Storage Process .................................................................................... 27 
9.6.2
 
Data Analysis ....................................................................................... 27 
9.7

 
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Statistical and Analytic plans ................................................................ 27 
9.7.1
 
Analyzable population .......................................................................... 27 
9.7.2
 
Planned Methods of Statistical Analysis ............................................... 28 
9.7.3
 
Primary Endpoint Analysis ................................................................... 28 
9.7.4
 
Secondary Endpoint Analysis ............................................................... 28 
9.7.5
 
Additional Secondary Endpoint Analysis .............................................. 29 
9.7.6
 
Safety Analysis..................................................................................... 29 
9.7.7
 
Additional Analysis .............................................................................. 30 
9.7.8
 
Missing Data ........................................................................................ 30 
9.7.9
 
Interim Analysis ................................................................................... 30 
9.7.10
 
Quality Control..................................................................................... 30 
9.8
 
Ethics and Quality ................................................................................ 30 
9.8.1
 
Quality Assurance ................................................................................ 30 
9.8.2
 
Limitations of the Research Methods .................................................... 31 
9.9
 
Other Aspects ....................................................................................... 31 
9.10
 
Note To File ......................................................................................... 31 
9.10.1
 
Training Log ........................................................................................ 32 
9.10.2
 
Visitor Log ........................................................................................... 32 
9.10.3
 
Responsibilities of the Principal Investigator ........................................ 32 
9.10.4
 
End of Trial .......................................................................................... 32 
9.10.5
10.0 
Protection of Human Subjects ............................................ 32 
11.0 
Management and Reporting of Complaints ....................... 33 
 
Medical Complaints ............................................................................. 33 
11.1
 
Adverse Event Definition and Serious Adverse Event Categories ......... 33 
11.1.1
 
Severity ................................................................................................ 35 
11.1.2
 
Relationship to Pharmaceutical Product ................................................ 35 
11.1.3
 
Serious Adverse Event Collection Period.............................................. 36 
11.1.4
 
Serious Adverse Event Reporting ......................................................... 36 
11.1.5
 
Pregnancy Reporting ............................................................................ 36 
11.1.6
 
Malignancy Reporting .......................................................................... 36 
11.1.7
 
Product Complaint ................................................................................ 37 
11.2
 
Definition ............................................................................................. 37 
11.2.1
 
Reporting ............................................................................................. 37 
11.2.2

 
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12.0 
Ethical and Legal Consideration ........................................ 38 
13.0 
Confidentiality ..................................................................... 39 
 
Patient confidentiality ........................................................................... 39 
13.1
 
Data confidentiality .............................................................................. 39 
13.2
14.0 
Study administration ........................................................... 39 
15.0 
Investigators compliance ..................................................... 40 
16.0 
Risks ..................................................................................... 40 
17.0 
Discontinuation or Drop-out ............................................... 40 
18.0 
Quality control and audit .................................................... 41 
19.0 
Communication of findings................................................. 41 
20.0 
References ............................................................................ 41 
21.0 
Appedndices......................................................................... 44 

 
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2.0 
Abbreviations 
 
ACR 
American College of Rheumatology 
AE 
Adverse Events 
AESI 
Adverse Event of Special Interest 
ANOVA 
Analysis of Variance 
CRF 
Case Report Form 
CRP 
C-Reactive Protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAS28 
Disease Activity Score in 28 Joints 
EQ-5D-3L 
EuroQol 5 dimension, 3 level quality of life questionnaire 
ESR 
Erythrocyte Sedimentation Rate 
EULAR 
The European League Against Rheumatism 
GP 
General Practitioner 
HAQ DI 
Health Assessment Questionnaire Disability Index 
HCRU 
Healthcare Resource Utilization 
ICF 
Informed Consent Form 
ICH-GCP 
International Conference on Harmonization of Good Clinical 
Practice 
NRS 
Numeric Rating Scale 
PGIC 
Patient Global Impression of Change  
PHI 
Protected Health Information 
PRO 
Patient-Reported Outcome 
QC 
Quality Check 
QoL 
Quality of Life  
RA 
Rheumatoid Arthritis 
SAP 
Statistical Analysis Plan 
SF-36 
Short Form 36-Item Health Survey 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TNF 
Tumor Necrosis Factor 
VAS 
Visual Analogue Scale 
WPAI 
Work Productivity and Activity Impairment 
 
 
 
 
 

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3.0
Responsible Parties
Study-Designated 
Physician/
Sponsor: 
Statistics Manager/ 
CRO(S):
Principal Investigator:
Investigator information is on file at AbbVie 
Sponsor:
Clinical Project 
Manager:
Emergency Contacts
Safety Review Team

 
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PROTOCOL SIGNATURES 
 
 
 
Investigator Signature: 
I have read and agree to the Protocol Number 11006, “Real-World Outcome of 
Rheumatoid Arthritis Patients in Korea on Adalimumab (ROCKA Study)”. I am aware of 
my responsibilities as an investigator under the guidelines of Good Clinical Practices, 
local laws and regulations (as applicable) and the study protocol. I agree to conduct the 
study according to these laws and guidelines and to appropriately direct and assist the 
staff under my control, who will be involved in the study. 
 
Principal (Site) Investigator: 
 
Name (typed or printed): 
 
Institution and Address: 
 
 
 
 
 
 
 
Telephone Number: 
 
Signature: 
 
Date: 
 
 
 
 
(Day/ Month /Year) 
 
Full investigational site contact details, including telephone numbers, will be documented 
in the Study Master File. 
 
 
 

 
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4.0 
Abstract 
Title:  Real-World Outcome of Rheumatoid Arthritis Patients in Korea on 
adalimumab (ROCKA Study). 
Rationale and Background: Given the requirement to keep a balance between 
effectiveness and cost containment to ensure that the available health resources are 
used in a cost-effective manner, there is an increasing demand for real-world evidence 
(RWE) from policy makers, regulators, providers and payers in the region to optimize 
spending and patient outcomes. 
 
So far, there are no data available regarding adalimumab’s impact on patients’ quality 
of life (QoL) and healthcare resource utilization (HCRU) in a realistic study design in 
Korea. 
 
The goal of this study is to determine the QoL, HCRU and costs of the patients care in 
subjects with RA who are treated with adalimumab in Korea. 
 
Results from study on the effect of adalimumab on Work Productivity and Activity 
Impairment (WPAI) scores and other Patient-Reported Outcomes (PROs) will be of 
interest to a variety of stakeholders in the healthcare system including patients, 
healthcare practitioners and payers in Korea. 
Research Question and Objectives: The objective of this non-interventional, 
observational study is to assess the effect of adalimumab on health-related QoL and 
work productivity in patients with Rheumatoid Arthritis (RA) in Korea. Specifically, to 
achieve the above objective the following concrete steps will be taken: 
1. Recruit investigators who are willing and able to recruit and follow new 
adalimumab users for 6 months follow-up 
2. Collect the patients’ clinical profile, patient-reported QoL, functioning, work 
productivity, treatment satisfaction and HCRU of RA patients at adalimumab 
initiation 
3. Follow the patients initiating adalimumab for 24 weeks and identify the 
changes in clinical, economic, and PROs associated with adalimumab 
Study Design: The study is designed as a prospective, observational study to assess the 
effect of adalimumab on health-related QoL and work productivity in patients with RA 
in Korea. 
 
Note: This study is non-interventional and the subjects/investigators will follow the 
current clinical practice in each site and also the routine clinical follow up as determine 
by the treating physician.  
 

 
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RA patients, for whom adalimumab treatment has already been decided, will be 
recruited from within the clinical settings of each rheumatologist participating in the 
study. Approximately 89 patients diagnosed with RA that meet the inclusion and 
exclusion criteria will be enrolled at approximately 9 sites in Korea. 
 
To assess health and disability outcomes, the Health Assessment Questionnaire 
Disability Index (HAQ DI) will be assessed at baseline, Week 12 and Week 24 after 
treatment initiation with adalimumab. In addition, other PROs of work activity and 
well-being, including the WPAI, EuroQol 5 dimension (EQ-5D), and Short Form 36-
Item Health Survey (SF-36), will also be assessed. 
 
In addition, the health care resource utilization will be collected. This includes surgical 
procedures, hospitalizations, bed days in hospital, physician consultations etc. Costs 
will be assigned based on the health care resource utilization using standardized costs 
for participating country. 
Population:  Subjects will be males and/or females who are attending a routine clinical 
visit and meet all of the inclusion criteria and none of the exclusion criteria. 
Approximately 89 patients diagnosed with RA will be recruited. 
 
Inclusion Criteria:  
Patients meeting all of the following inclusion criteria at baseline will be included: 
1. Subject has a diagnosis of RA as defined by the 1987 revised American College 
of Rheumatology (ACR) classification criteria and/or the ACR/the European 
League against Rheumatism (EULAR) 2010 classification criteria (any duration 
since diagnosis). 
2. Male or female subject ≥18 years of age (local definition according to 
adalimumab label) who is in compliance with eligibility for adalimumab based 
on the local label. 
3. Patients with moderate to severe RA defined as Disease Activity Score in 28 
Joints (DAS28) (ESR) or DAS28 (CRP) >3.2 
4. Biologically treatment naïve and initiated adalimumab at baseline visit 
5. Availability of clinical data of the previous 12 weeks prior to baseline 
6. Ability to self-complete patient questionnaires 
7. Subject must be able and willing to provide written informed consent and 
comply with the requirements of this study protocol. 
 
Exclusion Criteria:  
Patients meeting any of the following exclusion criteria at baseline will be excluded: 
1. Patients who are pregnant or breast feeding at enrolment or wish to become 
pregnant in the next 24 weeks.  

 
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2. Participation in any RA-related clinical trial at the time of enrolment, at 
baseline or at any point during the past 24 weeks prior to baseline 
3. Patients, who in the clinician’s view, may not be able to accurately report their 
QoL or prior resource utilization 
4. Patients, who in the clinician’s view, may not be able to adhere to adalimumab 
therapy over 24 weeks. 
Variables: 
Primary Variable 
x Change in HAQ DI score at weeks 12 and weeks 24 weeks from the baseline  
Secondary Variable 
x Change in other PROs (SF-36 domain scales, EQ-5D Index, Work Productivity 
and Activity Impairment Questionnaire [WPAI]) from baseline to weeks 12 and 
24  
x Number and percent of patients achieving a clinically meaningful improvement 
on the HAQ DI, from baseline to weeks 12 and 24  
x Healthcare Resource Utilization (HCRU) at baseline, 12 and 24 weeks 
Additional Secondary Variable  
x Change in HAQ DI score from baseline to 24 weeks  
x Changes in the disease severity and PROs from baseline to 24 weeks 
Exploratory Variable  
x Change in patient satisfaction questions from baseline to weeks 12 and 24  
Data Sources:  Case Report Forms (CRFs) and patient questionnaires. Collection of 
data includes but not limited to subject demographics, clinical history, comorbidities, 
spontaneous 
adverse 
events, 
and 
concomitant 
medications. 
The 
following 
questionnaires will be utilized to collect data directly from participating subjects: 
x EQ-5D 
x SF-36 
x HAQ DI 
x WPAI 
x HCRU 
x Patient Global Impression of Change (PGIC) 
x Patient Treatment Satisfaction Questions 
Study Size: Approximately 89 patients diagnosed with RA that meet the inclusion and 
exclusion criteria will be enrolled at approximately 9 sites in Korea. The sample size 
was calculated by assuming an alpha of 0.05 and a power of 0.80 in a one-sided test, 

 
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resulting in 36 subjects required to recognize a statistically significant improvement in 
HAQ DI (-0.21). Then, given the importance of other secondary endpoints, an 
improvement of 9.9±25 hours of work time lost requires 40 subjects. However, since it 
is expected that approximately half the study population may no longer be working due 
to their age, we assume a 50% employment rate in the study population and a drop-out 
rate of 10%, eventually approximately 89 patients will be required to achieve the 
required number of respondents. 
Data Analysis:   
Primary Endpoint Analysis 
Change in HAQ DI score at 24 weeks after the initiation of adalimumab (observed 
population). This change will be summarized as the mean and 95% confidence interval 
and will be tested with a paired t-test.  
Secondary Endpoint Analysis 
x Change in other PROs (SF-36 domain scales, EQ-5D Index, WPAI total lost 
productivity) at weeks 12 and 24 after the initiation of adalimumab (observed 
population). These changes will be summarized as the means and 95% 
confidence intervals and will be tested with paired t-tests. 
x Number and percent of patients achieving a clinically meaningful improvement 
on the HAQ DI, as defined by a -0.22 point improvement or greater, at weeks 
12 and 24 after the initiation of adalimumab (observed population).
Additional Secondary Endpoint Analysis 
x Change in HAQ DI score at 24 weeks after the initiation of adalimumab 
(observed population), compared with those patients not continuing on 
adalimumab (non-observeds). The mean changes in these two groups will be 
compared using an independent t-test. 
x HCRU will be described using number and percentage within each category 
(number of consultations, number of procedures received, number of surgeries, 
number of hospitalizations and length of stay, number of concomitant 
medications) 
x Associations between disease severity and PROs 
x Associations between change in disease severity and change in PROs 
Exploratory endpoint 
x Change in patient satisfaction questions at weeks 12 and 24 after the initiation 
of adalimumab (observed population). These changes will be summarized as 
number and percentage of each response and compared with Kruskal–Wallis 
test. Satisfaction will also be dichotomized and analyzed over time with 

 
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Cochrane-Armitage test for trends.  
Milestones: 
Start of Data Collection : 19 Oct, 2015 
End of Data Collection : 28 Feb, 2018 
Study Progress Report : Not applicable 
Interim Report : Not applicable 
Registration in the EU PASS Register : Not Applicable 
Final Report of Study Results : 31 Aug, 2018 

 
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5.0 
Amendments and Updates 
Number Date 
Section of Study 
Protocol 
Amendment or 
Update 
Reason 
1 
26 Dec 2017 
- Sample size 
- Milestones 
Amendment 
Change of 
sample size and 
milestones 
(See Appendix 
L for details) 
 
6.0 
Milestones 
Major study milestones and their planned dates are as follows: 
Start of Data Collection (FPFV): 
19 October 2015 
End of Data Collection: 
28 February 2018 
Study Progress Report: 
Not Applicable  
Interim Report: 
Not Applicable 
Registration in the EU PAS register: 
Not Applicable  
Final Report of Study Results: 
31 August 2018 
 
7.0 
Rationale and Background 
Disability has been defined as impairments, activity limitations and participation 
restrictions due to personal and environmental factors (1). The concept of disability is one 
where a physical health condition or disease is evaluated in terms of its impact, difficulties, 
or limitations on a range of tasks, activities, or roles that are considered typical of 
everyday life. Examples of affected activities include basic aspects of daily living such as 
eating, bathing, dressing, household chores and meal preparation, or participation in 
society, or participation in work.  
 
For public health purposes disability is becoming increasingly important as an outcome 
measure. Despite this, no data, within our knowledge, on the effectiveness of adalimumab 
on health-related QoL and work productivity in patients with Rheumatoid Arthritis (RA) 
in Korea.  
 

 
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Results from study of effect of adalimumab on Work Productivity and Activity 
Impairment (WPAI) scores and other Patient-Reported Outcomes (PROs) of work activity 
and well-being will be of interest to a variety of stakeholders in the healthcare system 
including patients, healthcare practitioners and payers in Korea. 
 
Reimbursement in Korea is strongly influenced by local “real -world” evidence of the 
intervention’s effects on outcomes and economic endpoints.  Therefore, having the 
economic and health outcomes “real world evidence” (RWE) for the use of Humira in 
moderate RA patients from Korea will be valuable to support the reimbursement / pricing 
maintenance and expansion in Korea.  
 
In Korea, Humira is reimbursed for both moderate and severe RA patients. However, the 
recent policy change in Korea indicated that the paradigm of using the ICER as the only 
value metric has been recently shifting toward considering other criteria such as patient 
reported outcomes, equity, innovation, and affordability. For example, the Korean 
government is in discussion with industry and academics to incorporate multi-criteria 
decision analysis (MCDA) such as including patient reported outcome into HTA for new 
medical technologies and post launch product price management. In this regard, 
generating the RWE is critical for the price re-negotiation and protection with the national 
payer, under current reimbursement and pricing policies in South Korea. 
 
The objective of this non-interventional, observational study is to assess the effect of 
adalimumab on health-related QoL, work productivity, and healthcare resource utilization 
(HCRU) in patients with RA in Korea. 
The Humira’s efficacy and patient’s outcomes data from this study could be used to 
mitigate the tapering issues of biologics. The patients’ work-productivity data aligned 
with global comparison could be used to keep the current co-payment ratio, 10% of 
patients. And aligned with T2T and fit for work data, we can pursue to expand the 
importance of early treatment of RA. 
 
8.0 
Research Question and Objectives 
 The objective of this study is to assess the effect of adalimumab on health and disability 
outcomes in patients with the immune-mediated inflammatory diseases of rheumatoid 
arthritis. The effect of adalimumab on health and disability outcomes in these patients will 
be assessed by the primary outcome measure which is the change in Health Assessment 
Questionnaire Disability Index (HAQ DI) score at 24 weeks after the initiation of 
adalimumab. The HAQ DI is selected as the primary point as it is commonly used to 
assess improvements in physical function in RA clinical trials and recommended by the 
US Food and Drug Administration (FDA) guidance on RA treatment development (3, 4). 

 
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In addition, the HAQ-DI has been utilized as a predictor variable in investigations of 
productivity (5). The HAQ-DI has been demonstrated to be significantly correlated with 
work-related measures such as work capacity, household work performance, work task 
performance, and work disability (6-9). In addition, the effect of adalimumab will also be 
assessed by the secondary outcome measures which are changes to the WPAI, EuroQol 5 
dimension (EQ-5D) score, and Short Form 36-Item Health Survey (SF-36) domain scores 
at 12 and 24 weeks after the initiation of adalimumab in RA. 
 
9.0 
Research Methods 
 
Study Design 
9.1
This study is designed as a prospective, observational study to assess the effect of 
adalimumab on health-related QoL and work productivity in patients with RA in Korea in 
clinical practice. 
 
Note: This study is non-interventional and the subjects/investigators will follow the 
current clinical practice in each site and also the routine clinical follow up as determine by 
the treating physician.  
 
RA patients will be recruited from within the clinical settings of each rheumatologist 
participating in the study. Approximately 89 patients diagnosed with RA that meet the 
inclusion and exclusion criteria will be enrolled at approximately 9 sites in Korea. 
 
To assess health and disability outcomes, the HAQ DI will be assessed at baseline, Week 
12 and Week 24 after treatment initiation with adalimumab. In addition, other PROs of 
work activity and well-being, including the WPAI, EQ-5D, and SF-36, will also be 
assessed. 
 
The patients identified by the recruiting investigators (specialty dependent on 
country/region; e.g. rheumatologist, internists, general practitioners, etc.) based on the 
study selection criteria will complete a set of patient questionnaires on QoL, functioning, 
work productivity, treatment satisfaction, impression of change and HCRU. Data will be 
captured at baseline (D0), Week 12 and Week 24.  
 
The HCRU will also be collected. This includes surgical procedures, hospitalizations, bed 
days in hospital, physician consultations etc. Costs will be assigned based on the HCRU 
using standardized costs for each participating countries. 
 

 
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Subjects may discontinue adalimumab treatment at any time during study participation. 
Subjects that end study participation early will have a Termination Visit. All subjects will 
have a follow-up phone call approximately 70 days after the last administration of 
adalimumab to obtain information on any new or ongoing AEs.  
This protocol requires all SAEs and AESIs as outlined in protocol section 11.0 to be 
actively solicited.  The safety profile of adalimumab which has over 3.5 million patient 
years of post-marketing exposure is stable and well established; non-serious events will 
not be actively solicited as these events are not likely to contribute to the further 
understanding of the safety profile of the product.   Any non-serious AEs will be collected 
as spontaneous reports if AbbVie is notified.
 
As this is a postmarketing observational study, Abbvie is NOT involved in the product 
supply since the drug is being used according to the approved market label and is to be 
prescribed by the physician under usual and customary practice of physician prescription. 
This study is non-interventional and the subjects/investigator will follow the current 
clinical practice in each site. Not additional task will be required other than current 
practice to keep the data as “real world data collect. 
 
Primary Endpoint
Change in HAQ DI score at 24 weeks after the initiation of adalimumab(observed 
population). This change will be summarized as the mean and 95% confidence interval 
and will be tested with a paired t-test.  
 
Secondary Endpoint Analysis 
x Number and percent of patients achieving a clinically meaningful improvement on 
the HAQ DI, as defined by a -0.22 point improvement or greater, at weeks 12 and 
24 after the initiation of adalimumab (observed population). 
Additional Secondary Endpoint Analysis 
x Change in HAQ DI score at 24 weeks after the initiation of adalimumab (observed 
population), compared with those patients not continuing on adalimumab (non-
observeds). The mean changes in these two groups will be compared using an 
independent t-test. 
x Healthcare resource utilization will be described using number and percentage 
within each category (number of consultations, number of procedures received, 
number of surgeries, number of hospitalizations and length of stay, number of 
concomitant medications) 
x Associations between disease severity and PROs 
x Associations between change in disease severity and change in PROs 

 
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x Change in other patient reported outcomes (SF-36 domain scales, EQ-5D Index, 
WPAI total lost productivity) at weeks 12 and 24 after the initiation of 
adalimumab (observed population). These changes will be summarized as the 
means and 95% confidence intervals and will be tested with paired t-tests. 
x Change in patient satisfaction questions at weeks 12 and 24 after the initiation of 
adalimumab (observed population). These changes will be summarized as number 
and percentage of each response and compared with Kruskal–Wallis test. 
Satisfaction will also be dichotomized and analysed over time with Cochrane-
Armitage test for trends.  
 
All instruments used in the study are translationally validated for the country language. 
 
 
Schedule of Events 
9.1.1
Table 1 
Study Activities (Day 1/Baseline Through 6 months) 
 
 
Study Activity 
Baselinea Week 12 
(V2) 
± 7 days 
Week 24 
(V3) 
± 7 days 
Early 
Termination / 
Drop out 
Clinician 
Packet 
Inclusion/exclusion form 
X 
 
 
 
Clinical history/patient demographics 
X 
 
 
 
Comorbidities 
X 
 
 
 
DAS28 (ESR) or DAS28 (CRP) 
X 
X 
X 
X 
Patient Packet 
EuroQoL 5-Dimension (EQ-5D) 
X 
X 
X 
X 
Short Form 36-Item Health Survey (SF-36) 
X 
X 
X 
X 
Health Assessment Questionnaire (HAQ) 
X 
X 
X 
X 
Work Productivity and Activity Impairment 
Questionnaire (WPAI) 
X 
X 
X 
X 
Healthcare Resource Utilization (HCRU) 
X 
X 
X 
X 
Patient Global Impression of Change (PGIC) 
 
X 
X 
X 
Patient Treatment Satisfaction Questions 
X 
X 
X 
X 
Adverse events (including malignancy) 
X 
X 
X 
X 
a. 
The Baseline visit date will serve as the reference for all subsequent visits. A ± 7 day window is 
permitted around scheduled study visits.  
 
Setting 
9.2
 The study will take place in single country (Korea) with multiple centers. The study sites 
will be identified and selected by AbbVie. The study population shall comprise of male 

 
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and/or female patients who are attending a routine clinical visit and meet all of the 
inclusion criteria and none of the exclusion criteria. Overall, approximately 89 subjects 
with clinically diagnosed RA are planned to be enrolled in the study at up to 9 sites. 
 
 The recruiting investigators will select potentially eligible patients from consecutive 
visits within their clinic based on the inclusion and exclusion criteria (Section 9.2.1 and 
Section 9.2.2). It is the responsibility of each physician to ask every consecutive patient 
who meets the inclusion criteria of the study to participate to avoid selection bias, and if 
investigators hold different types of clinics (e.g. routine visit clinics versus emergency 
clinics), only patients visiting their routine clinics will be used for patient selection. Site 
personnel should thoroughly assess the eligibility criteria and evidence of this should be 
stored with the source documentation at site.
 
 Where there is any deviation from the inclusion/exclusion criteria, the patient should be 
excluded from the study. 
 
Inclusion Criteria:  
9.2.1
Patients meeting all of the following inclusion criteria at baseline will be included: 
1. Subject has a diagnosis of RA as defined by the 1987 revised ACR classification 
criteria and/or the ACR/ the European League against Rheumatism (EULAR) 
2010 classification criteria (any duration since diagnosis) 
2. Male or female subjects ˻ 18 years of age (local definition according to 
adalimumab label) who is in compliance with eligibility for adalimumab based on 
the local label 
3. Patients with moderate to severe RA defined as DAS28 (ESR) or DAS28 
(CRP)>3.2 
4. Biologically treatment naïve and initiated adalimumab at baseline visit 
5. Availability of clinical data of the previous 12 weeks prior to baseline 
6. Ability to self-complete patient questionnaires 
7. Subject must be able and willing to provide written informed consent and comply 
with the requirements of this study protocol 
 
 
 
Exclusion Criteria:  
9.2.2
Patients meeting any of the following exclusion criteria at baseline will be excluded: 
1. Patients who are pregnant or breast feeding at enrolment or wish to become 
pregnant in the next 24 weeks 
2. Participation in any RA-related clinical trial at the time of enrolment, at baseline 
or at any point during the past 24 weeks prior to baseline 

 
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3. Patients, who in the clinician’s view, may not be able to accurately report their 
QoL or prior resource utilization 
4. Patients, who in the clinician’s view, may not be able to adhere to adalimumab 
therapy over 24 weeks 
 
 
Investigator Selection Criteria 
9.2.3
 Selection of investigators will be made based on qualification by training and experience. 
AbbVie will provide IMS with a list of clinicians that would be able to assist in recruiting 
in a timely manner. IMS will contact each clinician to obtain their participation in the 
study and provide an expected number of patients to be enrolled from that clinic. The 
ethical review boards recognized by the respective participating sites are required to 
review and approve the study and patient informed consent. 
 
 
Study Procedures 
9.2.4
 The study procedures outlined in Table 1 will be discussed in detail in this section with 
the exception of adverse events procedures (discussed in Section11.0). 
 
9.2.4.1 
Informed Consent 
 In local languages will be given to every patient participating in the study before data 
collection commences. The recruiting clinicians or their representative(s) will provide 
each patient with the ICF to sign which includes consent to use the data for publication 
and information including their right to withdraw from the study without penalty or 
change in medical care the patient is otherwise entitled to. 
  
9.2.4.2 
Patient Assignment 
 Once the recruiting clinician has obtained the subject’s authorization to release medical 
information and written consent to participate in the study, the clinician will be asked to 
complete an inclusion and exclusion form (Appendix B) for patients, thus confirming the 
patient’s eligibility to participate in this study.   
Each participating patient will be assigned a 3-digit patient identification number. The 
numbers should be assigned in sequential, ascending order per site as shown below: 
 
• 
Site ID; and 
 

 
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• 
Patient ID: First eligible patient number will be 001, and then the second patient 
number would be 002 
 
X X  X X X 
Site ID        Patient ID 
 
9.2.4.3 
Investigator Recruitment 
 AbbVie will provide IMS with a list of clinicians that would be able to assist in recruiting 
in a timely manner. IMS will contact each clinician to obtain their participation in the 
study and provide an expected number of patients to be enrolled from that clinic. The 
ethical review boards recognized by the respective participating sites are required to 
review and approve the study and patient informed consent. 
 
9.2.4.4 
Study site monitoring 
 As the study entails patients completing PRO questionnaires and clinicians completing 
case report forms (CRFs), there is not a need for on-site monitoring visits. IMS will 
closely track enrolment progress for bi-monthly reporting. IMS will work closely with the 
study coordinator at each site to ensure they check the forms when returned from the 
patients and physicians (e.g., all questions were answered). IMS will also be available to 
answer questions and follow up with the sites if the recruitment process is slow or if there 
are any errors on the forms. Periodic phone follow-up will be conducted to ensure data 
collection completeness and quality. 
 
9.2.4.5 
Patient Selection 
 The recruiting investigators will select potentially eligible patients from consecutive 
visits within their clinic based on the inclusion and exclusion criteria (Section 9.2.1 and 
Section 9.2.2). It is the responsibility of each physician to ask every consecutive patient 
who meets the inclusion criteria of the study to participate to avoid selection bias, and if 
investigators hold different types of clinics (e.g. routine visit clinics versus emergency 
clinics), only patients visiting their routine clinics will be used for patient selection. The 
intent is to enroll patients who have been prescribed adalimumab upon the physicians’ 
own discretion. This study is non-interventional and the subjects/investigator will follow 
the current clinical practice in each site. Not additional task will be required other than 
current practice to keep the data as “real world data collect. 
  

 
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9.2.4.6 
Data Collection 
 IMS will coordinate data collection with each site. At study initiation (Baseline, D0), 
patients will be asked to provide their written informed consent. The patient then will 
complete the study questionnaires in paper form. At all follow up visits (week 12 and 24), 
the patient will complete the study questionnaires while waiting for their appointment at 
their clinic, approximately 30 minutes before they visit their physicians. It is important 
that they complete the questionnaires prior to speaking with their clinician during the visit, 
as the clinician feedback might impact patient perceptions measured by the PRO 
instruments.  
 
Patients must complete the survey by themselves without help from anyone. However, for 
patients who physically have difficulty filling out the questionnaires, help is allowed as 
long as there are no suggestions or discussion from the helpers 
In addition, physicians will also be asked to complete a clinical CRF in paper form based 
on the patient’s medical records at baseline, 12 weeks, and 24 weeks. The CRF completed 
by physicians will be returned to the study coordinator/nurse at each site as well.   
 
All data filled in by the patient and physician will be collected at each site and returned 
directly to IMS. The data collection time is expected to be 10-13 months. 
 
All patient and clinician data will be handled preserving confidentiality. 
 
9.2.4.7 
Study Documents 
Clinical case report form (CRF) 
The clinical CRF will document the patient’s current status (moderate, severe RA), 
Disease Activity Score in 28 joints (DAS28), prior and current treatments and other 
relevant clinical and demographic data to be used in segmenting the population during 
analysis.  
 
To calculate the DAS28 the physician or specialist nurse will:  
1. Count the number of swollen joints (out of the 28) 
2. Count the number of tender joints (out of the 28) 
3. Take blood to measure the erythrocyte sedimentation rate (ESR) or C reactive 
protein (CRP); the latest measurement in the medical records may also be used if a 
blood draw is not standard for that visit 
4. Ask the patient to make a ‘global assessment of health’ which will be indicated by 
marking a 10 cm line between very good and very bad 

 
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The physician or specialist nurse will then mark each component score on the CRF and 
the DAS28 score if calculated (an online scoring calculator for the DAS28 can be found at 
http://www.das-score.nl/das28/DAScalculators/dasculators.html).  
 
 
The DAS28 will be scored using the following formula: 
DAS28 ESR = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 
0.014 * (Global assessment of Health in cm) 
DAS28 CRP = 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.36 * ln(CRP) + 
0.014 * (Global assessment of Health in cm)+0.96 
 
DAS28 scores will be interpreted using the following categorization: 
• 
Remission: DAS28 ӊ 2.6  
• 
Low Disease activity: 2.6 < DAS28 ӊ 3.2  
• 
Moderate Disease Activity: 3.2 < DAS28 ӊ 5.1  
• 
High Disease Activity: DAS28 >5.1  
 
The full CRF is presented in Appendix C.  
PRO questionnaires 
The following PRO questionnaires will be included in the patient questionnaire packet.  
 
Health Assessment Questionnaire Disability Index (HAQ DI) 
The HAQ DI is a patient-reported questionnaire to assess functioning impacted by RA. It 
includes the categories of dressing and grooming, arising, eating, walking, hygiene, reach, 
grip and common daily activities. It asks patients about the amount of difficulty they 
experience in these activities as well as the use of aids and/or devices. The HAQ also has 
a numeric rating scale (NRS) (13) to assess pain on a scale from 0 to 10. Self-
administered by the patient, the completion time is approximately 3-4 minutes. The full 
version of HAQ DI is presented in Appendix D. 
  
Short Form (36) Health Survey (SF-36) 
The SF-36 is a patient-reported questionnaire of patient health-related QoL. It measures 
generic health concepts relevant across age, disease, and treatment groups. There are 36 
items in total and the recall period is the last 4 weeks. The SF-36 consists of eight scaled 
scores, which are the weighted sums of the questions in their section. Each scale is 
directly transformed into a 0-100 scale. Completion time for the SF-36 is approximately 
10 minutes. The full version of SF-36 is presented in Appendix E.  

 
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EuroQol 5 dimension, 3 level quality of life questionnaire (EQ-5D-3L) 
The EQ-5D-3L measures the patient’s overall health state in a descriptive system of 
health-related QoL states consisting of five dimensions (mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression) each of which can take one of three 
responses. The responses record three levels of severity (‘no problems’, ‘some problems’, 
and ‘extreme problems) within a particular EQ-5D-3L dimension (14,15). In addition, a 
VAS rates current health state between 0-100. The EQ-5D-3L results can be converted to 
health utility scores. Completion time for the EQ-5D-3L is approximately 2-3 minutes. 
The full version of EQ-5D-3L is presented in Appendix F.  
 
Work Productivity and Activity Impairment (WPAI) 
The WPAI is a patient-reported questionnaire to measure work and activity impairment 
during the past seven days. It determines employment status, hours missed from work due 
to the disease (i.e. RA), hours missed from work for other reasons, hours actually worked, 
the degree to which the disease affected work productivity while at work and the degree to 
which the disease affected activities outside of work. Additional questions around 
employment status will be incorporated into the survey. The completion time for the 
WPAI is approximately 2-5 minutes. The full version of WPAI is presented in Appendix 
G.  
 
Patient Global Impression of Change (PGIC) 
The PGIC measures the patient’s perceptions of changes in their disease. It consists of one 
question asking about the change in their condition; for this study, the base will be “since 
you initiated your adalimumab treatment”. The completion time for the PGIC is less than 
1 minute. The full version of PGIC is presented in Appendix H.  
 
Patient Treatment Satisfaction Questions 
The patient treatment satisfaction questions were developed de novo for this study and are 
not considered “validated” questions. Self-administered by the patient, the completion 
time for the patient treatment satisfaction questions is approximately 1-2 minutes. The full 
version of patient treatment satisfaction questions are presented in Appendix I.  
 
Healthcare Resource Utilization (HCRU) Questionnaire 
The HCRU questionnaire will collect data on the healthcare resources consumed in the 
prior 3 months, as recall beyond 3 months may be problematic in an older population(16). 
HCRU collection will include data such as the number of physician visits and to which 
physician (GP, specialist), Emergency Department visits, hospitalizations, and other drugs 

 
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as well as devices and aids purchased to assist in their mobility due to RA. The HCRU 
questionnaire will be part of the patient questionnaire and will be distributed to patients 
together with the PRO questionnaires (Appendix D to Appendix I). The full HCRU 
questionnaire is presented in Appendix J. 
 
All of the questionnaires will use the validated Korean version. 
 
 
Adverse Events 
9.2.5
Adverse events, whether in response to a query, observed by site personnel, or reported 
spontaneously by the subject will be recorded. Adverse events definition and serious 
adverse event categories are described in detail in Section 11.0. 
 
 
Variables 
9.3
Variables: 
Primary Variable 
x Change in HAQ DI score at weeks 12 and weeks 24 weeks from the baseline  
 
Secondary Variable 
x Change in other PROs (SF-36 domain scales, EQ-5D Index, Work Productivity 
and Activity Impairment Questionnaire [WPAI])  from baseline to weeks 12 and 
24  
x Change in patient satisfaction questions from baseline to weeks 12 and 24  
x Number and percent of patients achieving a clinically meaningful improvement on 
the HAQ DI, from baseline to weeks 12 and 24  
x Healthcare Resource Utilization (HCRU) at baseline, 12 and 24 weeks 
Additional Secondary Variable  
x Change in HAQ DI score from baseline to 24 weeks  
x Changes in the disease severity and PROs from baseline to 24 weeks 
 
 
Data Sources 
9.4
 
Case Report Forms (CRFs) and patient questionnaires. 

 
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Collection of data includes but not limited to subject demographics, clinical history, 
comorbidities, spontaneous adverse events, and concomitant medications. The following 
questionnaires will be utilized to collect data directly from participating subjects: 
x EQ-5D 
x SF-36 
x HAQ DI 
x WPAI 
x HCRU 
x Patient Global Impression of Change (PGIC) 
x Patient Treatment Satisfaction Questions
 
 
Study Size 
9.5
Approximately 89 patients diagnosed with RA will be recruited. The sample size was 
calculated by assuming an alpha of 0.05 and a power of 0.80 in a one-sided test, Z (1-
alpha) = 1.645 and Z (1-β) = 0.842. As to the primary variable, assuming a mean ΔHAQ-
DI of -0.21 and a standard deviation (SD) of 0.5, according to the formula, 36 subjects are 
required. Then, given the importance of the secondary endpoint (WPAI), an improvement 
of 9.9±25 hours of work time lost (mean=9.9, SD=25) requires 40 subjects. However, we 
assume a 50% employment rate in the study population and a drop-out rate of 10%, 
eventually approximately 89 patients will be required (40/0.5/(1-0.1) = 89).  
 
 
Data Management and Storage Process 
9.6
 
Data Management 
9.6.1
Data management and data quality check will be performed to remove errors and 
inconsistencies in order to assure the appropriateness of the study data set to assess the 
study objectives. Data entry screens will be developed and tested prior to initiating data 
collection to reduce data entry errors.  If required, IMS will provide AbbVie with data for 
analysis.  
 
Each principle investigator or his/her designees will be instructed to answer patients’ 
queries which may arise in relation to the questionnaires and check the patients’ input to 
make sure all questions are answered. 
 

 
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Storage Process 
9.6.2
Following data quality checks, each dataset will be converted to SAS and merged for 
analysis. All information included in the CRF and the patients’ questionnaires will be 
checked in order to detect possible queries to solve and will be extracted to a specifically 
designed database, where it will be validated by IMS personnel to ensure its quality. 
Finally, data analysis will be conducted and final results reported. 
 
The databases will be stored in IMS data servers. Data servers are submitted to daily 
backups in order to increase the security on all data managed in the collection process. 
 
All paper based questionnaires will be stored in a secured, locked area for a period of 
seven (7) years, after which all data will be shared using an agency specialized in disposal 
of confidential documents.   
 
 
Data Analysis 
9.7
 
Statistical and Analytic plans 
9.7.1
A statistical analysis plan (SAP) will be developed describing the specific analysis that 
will be performed including, and in addition to, the analysis described here. All analysis
will be performed in accordance with the approved analysis plan. The following provides 
an overview of some of the analysis.  
 
The scoring of the PRO questionnaires will be done in accordance to the developers’ 
recommendations.   
 
A separate statistical analysis plan will be developed describing the specific analysis that 
will be performed including and in addition to the analysis described here. 
 
 
Analyzable population 
9.7.2
All subjects who received at least one dose of adalimumab during the study will be 
included. The main analysis will be conducted on the pooled population, where 
appropriate, with each individual country analyzed separately as supportive data.  
 

 
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Planned Methods of Statistical Analysis 
9.7.3
 All statistical tests will be two-tailed with a significance level of 0.05. Descriptive 
statistics will be provided. Descriptive analysis will be conducted on all key parameters 
and presented as mean, standard deviation, minimum, maximum, and median when 
continuous and as “n” and percent when categorical. Change from adalimumab initiation 
to 24 weeks will be calculated and evaluated for significant improvements using paired t-
tests / ANOVA for parametric and Wilcoxon signed-rank for non-parametric data. 
Analysis will be also be conducted by severity level (moderate vs severe), disease 
duration quartile (to compare to prior work) and up to two (2) other subgroups. Cochran-
Armitage test of trends or other similar methods may be used to compare categories of 
subjects. 
 
 
Primary Endpoint Analysis 
9.7.4
 The primary endpoint variable will be the change in HAQ DI score at 24 weeks after the 
initiation of adalimumab (observed population). 
 
The objective of the primary endpoint analysis will be to demonstrate that treatment with 
adalimumab improves functioning as measured by the HAQ DI in subjects with RA 
following treatment initiation. This change will be summarized as the mean and 95% 
confidence interval and will be tested with a paired t-test.  
 
The primary analysis will be summarized as the mean and 95% confidence interval and 
will be tested with a paired t-test without adjusting for baseline disease severity. For 
sensitivity analysis, the mean change in HAQ DI at Week 24 will be analyzed using 
ANOVA adjusting for baseline disease severity. 
 
 
Secondary Endpoint Analysis 
9.7.5
 The main secondary endpoint variable will be the change in HAQ DI at 12 weeks after 
the initiation of adalimumab. 
 
The objective of endpoint analysis will be to demonstrate that treatment with adalimumab 
improves functioning as measured by HAQ DI in subjects with RA compared to baseline. 
 
The main secondary analysis will be summarized as the mean and 95% confidence 
interval and will be tested with a paired t-test without adjusting for baseline disease 
severity. For sensitivity analysis, the mean change in HAQ DI at Week 12 will be 
analyzed using ANOVA adjusting for baseline disease severity. 

 
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Other secondary analysis include: 
 
x Change in other patient reported outcomes (SF-36 domain scales, EQ-5D Index, 
WPAI total lost productivity) at weeks 12 and 24 after the initiation of 
adalimumab, in those patients continuing on adalimumab (observed population). 
These changes will be summarized as the means and 95% confidence intervals and 
will be tested with paired t-tests. 
x Number and percent of patients achieving a clinically meaningful improvement on 
the HAQ DI, as defined by a -0.22 point improvement or greater, at weeks 12 and 
24 after the initiation of adalimumab (observed population). 
 
 
Additional Secondary Endpoint Analysis 
9.7.6
Additional efficacy analysis includes:  
x Change in HAQ DI score at 24 weeks after the initiation of adalimumab, in those 
patients continuing on adalimumab, compared with those patients not continuing 
on adalimumab. The mean changes in these two groups will be compared using an 
independent t-test. 
x Healthcare resource utilization will be described using number and percentage 
within each category (number of consultations, number of procedures received, 
number of surgeries, number of hospitalizations and length of stay, number of 
concomitant medications) 
x Associations between disease severity and PROs 
x Associations between change in disease severity and change in PROs 
 
Exploratory endpoint 
Change in patient satisfaction questions at weeks 12 and 24 after the initiation of 
adalimumab (observed population). These changes will be summarized as number and 
percentage of each response and compared with Kruskal–Wallis test. Satisfaction will also 
be dichotomized and analyzed over time with Cochrane-Armitage test for trends. 
 
 
Safety Analysis 
9.7.7
 Adverse events occurring while participants are on adalimumab will be coded using 
Common Terminology Criteria for Adverse Events (CTCAE) classification individually 
listed by indication groups. The incidences and percentages of individuals experiencing 
AEs and SAEs within each indication will be summarized by System Organ Class (SOC) 
with further summaries by severity and relatedness (causality) categories. Adverse events 

 
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leading to discontinuation and concomitant medications will also be listed and 
summarized. 
 
 
Additional Analysis 
9.7.8
 Additional analysis will explore the potential modifying effects of baseline measures on 
the changes in primary and secondary efficacy outcomes. These measures will include age, 
gender, baseline severity, and other diagnoses/co-morbidities. The analysis will 
specifically test for differential changes across the subgroups defined by the potential 
modifiers using general linear models.  
 
 
Missing Data 
9.7.9
 Efficacy measures are not assessed after a participant discontinues adalimumab. The 
exception to this will be the analysis of proportion of patients at 24 weeks who remain on 
adalimumab. Item level data on the PROs will be imputed according to the developers’ 
recommendations. There will be no other imputation for missing data.  
 
 
Interim Analysis 
9.7.10
 There is no interim analysis planned for this study. 
 
 
Quality Control 
9.8
 
Ethics and Quality 
9.8.1
 Prior to any study-related data being collected, informed consent form will be reviewed, 
signed and dated by the patient and the person who administered the informed consent. A 
copy of the signed informed consent will be given to the patient and the original will be 
placed in the patient's medical record. 
 
 
Quality Assurance 
9.8.2
 Prior to the initiation of the study, physician and site personnel will be trained on the 
study. Training will include a detailed discussion of the protocol, performance of study 
procedures, and completion of the CRFs and paper questionnaires. 
 

 
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All sites will be monitored during the course of study participation. One hundred percent 
(100%) source document review for safety will be performed. 
 
All clinical data will be documented via the CRF. Study coordinators at each site will 
check the paper CRFs completed by the physicians and questionnaires completed by 
patients (e.g., all questions were answered). Data entry will be conducted by IMS. After 
entry of the data, computer logic checks will be run to check for inconsistent data. Any 
necessary corrections will be made to the database and documented via addenda, queries, 
and source data clarification forms.  
 
Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study centers, review of protocol procedures with 
the investigator and associated personnel before the study and periodic monitoring visits 
by the sponsor. Written instructions will be provided for administration and collection of 
study questionnaires.   
 
Guidelines for CRF completion will be provided and reviewed with study personnel 
before the start of the study. The sponsor will review CRFs and patient questionnaires for 
accuracy and completeness after transmission to the sponsor; any discrepancies will be 
resolved with the investigator or designee, as appropriate. After upload of the data into the 
clinical study database they will be verified for accuracy and consistency with the data 
sources. 
 
 
Limitations of the Research Methods 
9.9
 The study is to be performed as a non-interventional study. Unlike clinical studies, 
obtainable data are limited and there is a possibility of missing data. 
 
Other Aspects 
9.10
 
Note to File 
9.10.1
 The Principal Investigator or designee will be responsible for documenting study relevant 
information and occurrences that affects the course of the study. The information and 
occurrences are not protocol deviations but will be documented in a note to file and will 
be communicated to the sponsor.  
 

 
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Training Log 
9.10.2
 All designated study personnel must be trained on the study protocol and procedures.  
Training and retraining are documented on the Training Log. 
 
 
Visitor Log  
9.10.3
 All Sponsor or other related individuals who visit the study site must sign the Visitor Log.   
 
 
Responsibilities of the Principal Investigator  
9.10.4
 The Principal Investigator is responsible for oversight of enrolment, the patient consent 
process, study related procedures, compliance with the protocol, all institutional, state and 
local guidelines.  
 
It is the responsibility of the Principal Investigator to select, supervise, and delegate 
responsibility for study conduct to staff members. The Principal Investigator is 
responsible for determining the appropriate staff qualifications required for specific study-
related tasks to be delegated. Study-related tasks delegated to staff members will be 
documented on the Site Signature and Delegation Log. 
 
End of Trial 
9.10.5
 End of Trial is defined as last subject’s last visit (LSLV).  
 
10.0 
Protection of Human Subjects 
 This study must be conducted in compliance with the recommendations of the 
Declaration of Helsinki, 2008 (World Medical Association). In addition, this study will 
adhere to all general and local legal and regulatory requirements applicable to non-
interventional studies. 
 
Informed consent will be obtained from each subject before the subject can participate in 
the study. The contents and process of obtaining informed consent will be in accordance 
with all applicable regulatory requirements. 
 

 
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As required by applicable local regulations, the sponsor’s Regulatory Affairs group will 
ensure all legal regulatory aspects are covered, and obtain approval of the appropriate 
regulatory bodies, prior to study initiation in regions where an approval is required. 
 
This study is non-interventional and falls outside the scope of the EU Directive 
2001/20/EC, the EU Directive 2005/28/EC and International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines.  
 
This study complies with the EU Directive 95/46/EC of the European Parliament and of 
the Council of 24 October 1995 on the protection of individuals with regard to the 
processing of personal data and on the free movement of such data. 
 
11.0 
Management and Reporting of Complaints 
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution. 
The investigational product in this trial contains both:  
● Biologic compound(s) and 
● Device component(s) (pre-filled syringe, pen). 
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 11.2.2). For adverse events, please refer to Sections 
11.1.1 through11.1.6.  For product complaints, please refer to Section 11.2 
 
Medical Complaints 
11.1
 
Adverse Event Definition and Serious Adverse Event Categories 
11.1.1
 An adverse event (AE) is defined as any untoward medical occurrence in a patient, which 
does not necessarily have a causal relationship with their treatment.  An adverse event can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not the event is considered causally related to the use of the product. 
 

 
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Such an event can result from use of the drug as stipulated in the labeling, as well as from 
accidental or intentional overdose, drug abuse, or drug withdrawal. Any worsening of a 
pre-existing condition or illness is considered an adverse event. 
 
If an adverse event meets any of the following criteria, it is considered a serious adverse 
event (SAE): 
 
Death of Patient: 
An event that results in the death of a patient. 
Life-Threatening: 
An event that, in the opinion of the investigator, 
would have resulted in immediate fatality if medical 
intervention had not been taken. This does not include 
an event that would have been fatal if it had occurred 
in a more severe form. 
Hospitalization: 
An event that results in an admission to the hospital 
for any length of time. This does not include an 
emergency room visit or admission to an outpatient 
facility.
Prolongation of 
Hospitalization: 
An event that occurs while the study patient is 
hospitalized and prolongs the patient's hospital stay. 
Congenital Anomaly: 
An anomaly detected at or after birth, or any anomaly 
that results in fetal loss. 
Persistent or Significant 
Disability/Incapacity: 
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
patient. Disability is not intended to include 
experiences of relatively minor medical significance 
such as headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (e.g., sprained 
ankle). 
Important Medical Event 
Requiring Medical or 
Surgical Intervention to 
Prevent Serious Outcome: 
An important medical event that may not be 
immediately life-threatening or result in death or 
hospitalization, but based on medical judgment may 
jeopardize the patient and may require medical or 
surgical intervention to prevent any of the outcomes 
listed above (i.e., death of patient, life threatening, 
hospitalization, 
prolongation 
of 
hospitalization, 
congenital anomaly, or persistent or significant 

 
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disability/incapacity). Additionally, any elective or 
spontaneous abortion or stillbirth is considered an 
important medical event. Examples of such events 
include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
 
 
Severity 
11.1.2
 The following definitions will be used to rate the severity for any adverse event being 
collected as an endpoint/data point in the study and for all serious adverse events. 
 
Mild: 
The adverse event is transient and easily tolerated by the patient. 
Moderate: 
The adverse event causes the patient discomfort and interrupts the 
patient's usual activities. 
Severe: 
The adverse event causes considerable interference with the 
patient's usual activities and may be incapacitating or life 
threatening. 
 
 
Relationship to Pharmaceutical Product 
11.1.3
 The following definitions will be used to assess the relationship of the adverse event to 
the use of product: 
 
Reasonable Possibility 
An adverse event where there is evidence to suggest a 
causal relationship between the product and the adverse 
event. 
No Reasonable Possibility 
An adverse event where there is no evidence to suggest a 
causal relationship between the product and the adverse 
event. 
 
If no reasonable possibility of being related to product is given, an alternate etiology must 
be provided for the adverse event. 
 

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36
 
Serious Adverse Event Collection Period 
11.1.4
 Serious adverse events will be reported to AbbVie from the time the physician obtains the 
patient's authorization to use and disclose information (or the patient's informed consent) 
until 30 days or 5 half-lives following the intake of the last dose of physician-prescribed 
treatment. 
 
Serious Adverse Event Reporting 
11.1.5
 In the event of a serious adverse event, the physician will: 
x
For events from patients using and AbbVie product - notify the AbbVie 
contact person identified below within 24 hours of the physician becoming aware 
of the event. 
 
Pregnancy Reporting 
11.1.6
 In the event of a pregnancy occurrence in the patient, the physician will notify AbbVie 
contact person identified in Section 11.1.5 within 24 hours of the physician becoming 
aware of the pregnancy.
 
Malignancy Reporting 
11.1.7
In the event of any non-serious event of malignancy in subjects 30 years of age and 
younger, whether related to adalimumab or not, the investigator will notify AbbVie 
Emergency contact person identified at the beginning of the protocol within 24 hours of 
the site being made aware of the event.  
Adalimumab therapy has a well-established and well described safety profile based on 
extensive postmarketing experience and continued clinical trial patient exposure since the 
first approved indication in 2002 for rheumatoid arthritis. A detailed discussion of the pre-
clinical toxicology, metabolism, pharmacology and safety experience with adalimumab 
can be found in the current Investigator's Brochure. AbbVie is committed to continue to 
collect safety information including those events that may occur in this trial in order to 

 
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confirm this established safety profile and to identify any unknown potential adverse 
reactions, rare events and those events with a long latency. AbbVie is participating in an 
FDA-requested, TNF inhibitor class wide exploration of the rare appearance of 
malignancy in subjects/patients who are 30 years of age or younger at the time of 
diagnosis. The risk of malignancy in this age group has not been established and is 
difficult to study due to its rarity. AbbVie appreciates your attention to the additional 
reporting requirements needed in this unlikely event, outlined in Section 11.7 under 
Malignancy Reporting. 
 
 
Product Complaint 
11.2
 
Definition 
11.2.1
A Product Complaint is any Complaint (see Section 11.0 for the definition) related to the 
biologic or drug component of the product or to the medical device component(s). 
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, device not working properly, or packaging issues. 
For medical devices, a product complaint also includes all deaths of a patient using the 
device, any illness, injury, or adverse event in the proximity of the device, an adverse 
event that could be a result of using the device, any event needing medical or surgical 
intervention including hospitalization while using the device and use errors. 
Any information available to help in the determination of causality by the device to the 
events outlined directly above should be captured. 
 
Reporting 
11.2.2
Product Complaints concerning the investigational product and/or device must be reported 
to the Sponsor within 24 hours of the study site's knowledge of the event via local Product 
Complaint reporting practices.  Product Complaints occurring during the study will be 
followed-up to a satisfactory conclusion.  All follow-up information is to be reported to 
the Sponsor (or an authorized representative) and documented in source as required by the 

 
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Sponsor.  Product Complaints associated with adverse events will be reported in the study 
summary.  All other complaints will be monitored on an ongoing basis. 
Product complaints involving a non-Sponsor investigational product and/or device should 
be reported to the identified contact or manufacturer, as necessary per local regulations. 
Product Complaints may require return of the product with the alleged complaint 
condition (syringe, pen, etc.).  In instances where a return is requested, every effort should 
be made by the investigator to return the product within 30 days.  If returns cannot be 
accommodated within 30 days, the site will need to provide justification and an estimated 
date of return. 
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required. 
 
12.0 
Ethical and Legal Consideration 
 All participant data will be handled in a manner compliant with all local regulatory and 
privacy laws. All parties will ensure protection of subject personal data and will not 
include subject names on any sponsor forms, reports, publications, or in any other 
disclosures, except where required by law. Appropriate role-based access to minimum 
necessary information will be maintained so that only authorized individuals have access 
to protected health information (PHI).  
 
Abbvie shall comply with all applicable laws regarding the reporting of spontaneous 
adverse events (AEs) to the relevant local authorities in Korea. Abbvie will follow the 
International Conference on Harmonization of Good Clinical Practice (ICH-GCP) 
guidelines for AE reporting and report all spontaneously reported AEs within the required 
timeframe (usually within 24 hours of discovery).  
 
All IMS staff working directly with patient data and/or having direct contact with 
healthcare practitioners will have received formal training to ensure they have a clear 
understanding of how to recognize an AE and inform Affiliate Safety Specialist so that 
they are in full compliance with local laws regarding AE reporting. 
 

 
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The study will be reviewed and approved by the appropriate Ethics Committee(s) at each 
site prior to the start of patient recruitment, according to the specific legal requirements in 
each country.  
 
13.0 
Confidentiality 
 
Patient confidentiality 
13.1
 Information on patients’ identity shall be considered as confidential for all effects and 
purposes. Each site and patient will have a code in the study. Sites will be automatically 
coded by IMS. Patients will be assigned a sequential number by the site coordinator upon 
meeting all inclusion and no exclusion criteria.  
 
The patients’ identity should not be revealed nor published under any circumstances. 
Patient data recorded in the CRF will be documented anonymously, coded with a patient 
number in such a way that only the investigator and site staff may associate particular data 
with an identified or identifiable individual or his/her medical record. All other parties 
involved in data management, analysis and storage will receive, and subsequently analyze, 
non-identifiable patient data. 
 
 
Data confidentiality 
13.2
 By signing the investigator’s confidentiality agreement, the investigator affirms to 
AbbVie/IMS that information furnished by AbbVie/IMS to the investigator will be kept in 
confidence and such information will be divulged to any expert committee, affiliated 
institution, and employees only under an appropriate understanding of confidentiality with 
such committee, affiliated institution and employees.  
 
14.0 
Study administration 
 The entire study will be managed by an international project coordinator at IMS Japan 
K.K. who will coordinate the project and maintain fluid communication with the study 
sponsor, the study team and the director at IMS Japan K.K. 
 
As part of the monitoring plan, regular phone calls (at least every two weeks) will be 
made between IMS and local site coordinator in order to check inclusion status, resolve 
any issues, check data plausibility, etc.  
 

 
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15.0 
Investigators compliance 
 By signing the investigator’s agreement, the investigator agrees to conduct the study in an 
efficient and diligent manner and in conformance with this protocol, generally accepted 
standards of good clinical practice and all applicable laws, rules and regulations relating to 
the conduct of the study. 
 
The investigator shall prepare and maintain complete and accurate study documentation in 
compliance with applicable national and local laws, rules and regulations and, for each 
patient participating in the study, promptly record all data in the CRF as required by this 
protocol. 
 
16.0 
Risks 
 This is a non-interventional observational study. It does not involve any direct patient 
intervention with respect to laboratory tests, examinations or drug treatment. Patients will 
be asked to complete questionnaires related to their RA, QoL, functioning, work 
productivity, treatment satisfaction, and healthcare resource utilization at their clinic 
during their visit three times over the course of 6 months, requiring approximately 30 
minutes of their time each time. 
 
17.0 
Discontinuation or Drop-out 
 Patients’ participation in the study is completely voluntary, and they are allowed to 
withdraw or discontinue from the study. The following three situations will be counted as 
study drop-out:  
1) Patient is switched off Adalimumab  
2) Patient is not willing to continue participation in the study  
3) Patient disappears and cannot be contacted anymore 
For the first two situations, the Early Termination Form (Appendix K) will be provided 
for the patients and their physicians to fill in.  
Patients not completing questionnaires will not be classified as drop-out. For example, if a 
patient missed Week 12 questionnaires for some reason, he/she can still fill in Week 24 
questionnaires.  
Once a subject is dropped out from the study, no further information for that subject will 
be collected. However, the reason for drop-out will be collected and, if the reason for 
treatment discontinuation is due to as adverse event, the event will be reported as follows : 
x SAE : reported to Abbvie within 24 hours of physician awareness 

 
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x Non-serious AE : reported to Abbvie within 24 hours of PMOS physician 
awareness. 
 
18.0 
Quality control and audit 
 Steps to be taken to ensure the accuracy and reliability of data include the selection of 
qualified investigators and appropriate study centers, review of protocol procedures with 
the investigator and associated personnel before the study and periodic monitoring visits 
by the sponsor. Written instructions will be provided for administration and collection of 
study questionnaires.   
 
Guidelines for CRF completion will be provided and reviewed with study personnel 
before the start of the study. The sponsor will review CRFs and patient questionnaires for 
accuracy and completeness during on-site monitoring visits and after transmission to the 
sponsor; any discrepancies will be resolved with the investigator or designee, as 
appropriate. After upload of the data into the clinical study database they will be verified 
for accuracy and consistency with the data sources. 
 
The study will be performed following the IMS and AbbVie Standard Operating 
Procedures (SOPs) for Observational Studies.  
19.0 
Communication of findings 
AbbVie / IMS shall retain ownership of all screeners, case report forms, data analysis, and 
reports which result from this study.  
 
All information obtained as a result of the study will be regarded as confidential, until 
appropriate analysis and review by AbbVie and the investigator(s) are completed. The 
results of the study may be published or presented by the investigator(s) after the review 
by, and in consultation and agreement with AbbVie, such that confidential or proprietary 
information is not disclosed. 
 
Prior to publication or presentation, a copy of the final text should be forwarded by the 
investigator(s) to AbbVie for comment.  Such comments shall aim to ensure the scientific 
content of the proposed publications and/or presentations and ensure that the data and 
material receive fair, accurate, and reasonable presentation.  
 
20.0 
References 
 

 
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1 World Healht Organisation. Disability Fact Sheet.   [cited May 7, 2015]; Available 
from: http://www.who.int/disabilities/world_report/2011/factsheet.pdf 
2 AbbVie Limited. Adalimumab Data Sheet. 27 November 2014(Version 32). 
3 U.S. Department of Health and Human Services, Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and 
Research (CBER), (CDRH) CfDaRH. Guidance for Industry Rheumatoid Arthritis: 
Developing Drug Products for Treatment. 2013. 
4 Bruce B, Fries J. The health assessment questionnaire (HAQ). Clinical and experimental 
rheumatology. 2005;23(5):S14. 
5 Bruce B, Fries JF. The Stanford Health Assessment Questionnaire: a review of its 
history, issues, progress, and documentation. The Journal of rheumatology. 
2003;30(1):167-78. 
6 Barrett EM, Scott DG, Wiles NJ, Symmons DP. The impact of rheumatoid arthritis on 
employment status in the early years of disease: a UK community-based study. 
Rheumatology (Oxford, England). 2000 Dec;39(12):1403-9. 
7 Wolfe F, Hawley DJ. The longterm outcomes of rheumatoid arthritis: Work disability: a 
prospective 18 year study of 823 patients. The Journal of rheumatology. 1998 
Nov;25(11):2108-17. 
8 Jantti J, Aho K, Kaarela K, Kautiainen H. Work disability in an inception cohort of 
patients with seropositive rheumatoid arthritis: a 20 year study. Rheumatology (Oxford, 
England). 1999 Nov;38(11):1138-41. 
9 Fex E, Larsson BM, Nived K, Eberhardt K. Effect of rheumatoid arthritis on work status 
and social and leisure time activities in patients followed 8 years from onset. The 
Journal of rheumatology. 1998 Jan;25(1):44-50. 
10 Dougados M, Schmidely N, Le Bars M, et al. Evaluation of different methods used to 
assess disease activity in rheumatoid arthritis: analysis of abatacept clinical trial data. 
Annals of the rheumatic diseases. 2009 Apr;68(4):484-9. 
11 van der Bijl AE, Breedveld FC, Antoni CE, et al. An open-label pilot study of the 
effectiveness of adalimumab in patients with rheumatoid arthritis and previous 
infliximab treatment: relationship to reasons for failure and anti-infliximab antibody 
status. Clinical rheumatology. 2008 Aug;27(8):1021-8. 
12 Bejarano V, Quinn M, Conaghan PG, et al. Effect of the early use of the anti-tumor 
necrosis factor adalimumab on the prevention of job loss in patients with early 
rheumatoid arthritis. Arthritis and rheumatism. 2008 Oct 15;59(10):1467-74. 
13 Hawker GA, Mian S, Kendzerska T, French M. Measures of adult pain: Visual Analog 
Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain 
Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain 
Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of 
Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis care & research. 2011 
Nov;63 Suppl 11:S240-52. 

 
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14 The EuroQol Group. EuroQol--a new facility for the measurement of health-related 
quality of life. Health policy (Amsterdam, Netherlands). 1990 Dec;16(3):199-208. 
15 Oemar M, Oppe M. EQ-5D-3L User Guide: Basic information on how to use the EQ-
5D-3L instrument. The EuroQol Group; 2013. 
16 Evans C, Crawford B. Patient self-reports in pharmacoeconomic studies. Their use and 
impact on study validity. PharmacoEconomics. 1999 Mar;15(3):241-56. 
 
 
 

 
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21.0 
Appedndices 
Appendix A. Patient Informed Consent Form (ICF) 
 

 
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47 

 
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Appendix B. Inclusion/Exclusion Form 
 
 
 
 

 
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Appendix C. Clinical Case Report Form (CRF) 
Baseline:  
 

 
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52 
 
 

 
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53 
 
 

 
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54 
 
 

 
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55 
 

 
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56 
 
 

 
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Follow-up: 
 
 

 
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58 
 
 
 

 
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59 
 

 
Adalimumab  
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60 
 

 
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61 
 
 
 

 
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62 
Appendix D. Health Assessment Questionnaire Disability Index (HAQ DI) 
 

 
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Appendix E. Short Form (36) Health Survey (SF-36) 
 

 
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66 
 

 
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67 
 
 

 
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68 
 

 
Adalimumab  
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69 
 

 
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70 
 
 
 

 
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Appendix F. EuroQol 5 dimension, 3 level quality of life questionnaire (EQ-5D-3L) 
 

 
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Appendix G. Work Productivity and Activity Impairment (WPAI) 
 

 
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Appendix H. Patient Global Impression of Change (PGIC) 
 
 
 
 

 
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Appendix I. Patient Treatment Satisfaction Questions 
 
 
 
 

 
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Appendix J. Healthcare resource utilization (HCRU) questionnaire 
Baseline: 
 
 

 
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79 
 
 

 
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80 
 

 
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81 
 

 
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82 
 
 

 
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83 
 

 
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84 
 
 

 
Adalimumab  
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85 
 
 
 
 
 

 
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86 
 
 

 
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87 
 
 
 

 
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88 
 

 
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89 
 

 
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90 
 

 
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91 
 
 

 
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92 
Follow-up: 
 
 

 
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93 
 
 
 

 
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94 
 
 

 
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95 
 
 
 

 
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96 
 

 
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97 
 

 
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98 
 

 
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99 
 
 

 
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Appendix K. Early Termination Form
For Physician: 
 
 

 
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101 
 
 

 
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102 
 
 

 
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103 
 

 
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104 
 
 

 
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105 
For Patient:  
 

 
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106 
 
 

 
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107 
 
 

 
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108 
 
 

 
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109 
 
 

 
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110 
 

 
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111 
 

 
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112 
 
 
 
 

 
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Appendix L. Amendment 01 Changes 
 
Summary of Amendment changes: 
 
• 
Change of sample size 
• 
Change of milestones  
 
Section 4.0 Abstract 
 
Previously read: 
Study Design 
RA patients, for whom adalimumab treatment has already been decided, will be recruited 
from within the clinical settings of each rheumatologist participating in the study. 
Approximately 100 patients diagnosed with RA that meet the inclusion and exclusion 
criteria will be enrolled at approximately 9 sites in Korea. 
Population 
Subjects will be males and/or females who are attending a routine clinical visit and meet 
all of the inclusion criteria and none of the exclusion criteria. Approximately 100 patients 
diagnosed with RA will be recruited. 
Study Size 
Approximately 100 patients diagnosed with RA that meet the inclusion and exclusion 
criteria will be enrolled at approximately 9 sites in Korea. The sample size was calculated 
by assuming an alpha of 0.05 and a power of 0.80 in a two-sided test, resulting in 52 
subjects required to recognize a statistically significant improvement in HAQ DI (-0.21). 
Given the importance of other secondary endpoints, an improvement of 9.9±25 hours of 
work time lost requires 58 subjects, assuming an alpha of 0.05 and a power of 0.80 in a 
two-sided test. However, since it is expected that approximately half the study population 
may no longer be working due to their age, approximately twice this number (100 patients) 
will be required to achieve the required number of respondents. We have also assumed a 
drop-out rate of 13% (assuming between 10%-15%). 
Milestones 
Start of Data Collection: 19 Oct, 2015 
End of Data Collection: 31 Jan, 2017 
Study Progress Report: Not applicable 
Interim Report: Not applicable 

 
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Registration in the EU PASS Register: Not Applicable 
Final Report of Study Results: 31 Jul, 2017 
 
Has been changed to read: 
Study Design 
RA patients, for whom adalimumab treatment has already been decided, will be recruited 
from within the clinical settings of each rheumatologist participating in the study. 
Approximately 89 patients diagnosed with RA that meet the inclusion and exclusion 
criteria will be enrolled at approximately 9 sites in Korea. 
Population 
Subjects will be males and/or females who are attending a routine clinical visit and meet 
all of the inclusion criteria and none of the exclusion criteria. Approximately 89 patients 
diagnosed with RA will be recruited. 
Study Size 
Approximately 89 patients diagnosed with RA that meet the inclusion and exclusion 
criteria will be enrolled at approximately 9 sites in Korea. The sample size was calculated 
by assuming an alpha of 0.05 and a power of 0.80 in a one-sided test, resulting in 36 
subjects required to recognize a statistically significant improvement in HAQ DI (-0.21). 
Then, given the importance of other secondary endpoints, an improvement of 9.9±25 
hours of work time lost requires 40 subjects. However, since it is expected that 
approximately half the study population may no longer be working due to their age, we 
assume a 50% employment rate in the study population and a drop-out rate of 10%, 
eventually approximately 89 patients will be required to achieve the required number of 
respondents. 
Milestones 
Start of Data Collection: 19 Oct, 2015 
End of Data Collection: 28 Feb, 2018 
Study Progress Report: Not applicable 
Interim Report: Not applicable 
Registration in the EU PASS Register: Not Applicable 
Final Report of Study Results: 31 Aug, 2018 
 
 
 

 
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Section 6.0 Milestones 
 
Previously read: 
Major study milestones and their planned dates are as follows: 
Start of Data Collection (FPFV): 19 October 2015 
End of Data Collection: 31 January 2017 
Study Progress Report: Not Applicable  
Interim Report: Not Applicable 
Registration in the EU PAS register: Not Applicable  
Final Report of Study Results: 31 July 2017 
 
Has been changed to read: 
Major study milestones and their planned dates are as follows: 
Start of Data Collection (FPFV): 19 October 2015 
End of Data Collection: 28 February 2018 
Study Progress Report: Not Applicable  
Interim Report: Not Applicable 
Registration in the EU PAS register: Not Applicable  
Final Report of Study Results: 31 August 2018 
 
 
Section 9.1 Study Design 
 
Previously read: 
Approximately 100 patients diagnosed with RA that meet the inclusion and exclusion 
criteria will be enrolled at approximately 9 sites in Korea. 
 
Has been changed to read: 
Approximately 89 patients diagnosed with RA that meet the inclusion and exclusion 
criteria will be enrolled at approximately 9 sites in Korea. 
 

 
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Section 9.2 Setting 
 
Previously read: 
Overall, approximately 100 subjects with clinically diagnosed RA are planned to be 
enrolled in the study at up to 9 sites. 
 
Has been changed to read: 
Overall, approximately 89 subjects with clinically diagnosed RA are planned to be 
enrolled in the study at up to 9 sites. 
 
 
Section 9.5 Study Size 
 
Previously read: 
Approximately 100 patients diagnosed with RA will be recruited. The planned sample 
size provides at least 95% power for detecting a statistically significant improvement in 
HAQ-DI (∆HAQ-DI < 0) assuming a mean ∆HAQ-DI of -0.21 and a standard deviation 
of 0.5 (reference 11), at two-sided significance level of 0.05 and accounting for a 10% 
dropout rate. The sample size also provides at least 95% power for detecting a statistically 
significant clinically meaningful improvement in HAQ-DI (∆HAQ-DI < -0.22) assuming 
a mean ∆HAQ-DI of -0.5 and a standard deviation of 0.7, at two-sided significance level 
of 0.05 and accounting for a 10% dropout rate. For the secondary endpoint WPAI, the 
sample size provides 63% power for detecting a statistically significant improvement in 
“hours of work lost” at two-sided significance level of 0.05 and accounting for a 10% 
dropout rate, assuming a mean change in “hours of work lost” of 10 and standard 
deviation of 30 and assuming a 55% employment rate in the study population. 
 
Has been changed to read: 
Approximately 89 patients diagnosed with RA will be recruited. The sample size was 
calculated by assuming an alpha of 0.05 and a power of 0.80 in a one-sided test, Z (1-
alpha) = 1.645 and Z (1-β) = 0.842. As to the primary variable, assuming a mean ΔHAQ-
DI of -0.21 and a standard deviation (SD) of 0.5, according to the formula, 36 subjects are 
required. Then, given the importance of the secondary endpoint (WPAI), an improvement 
of 9.9±25 hours of work time lost (mean=9.9, SD=25) requires 40 subjects. However, we 
assume a 50% employment rate in the study population and a drop-out rate of 10%, 
eventually approximately 89 patients will be required (40/0.5/(1-0.1) = 89).