Defining Which Remission Criterion At Month 6 Predicts Remission At Month 12 In A Real Life Clinical Practice, In A Cohort Of Rheumatoid Arthritis Patients Treated With Etanercept (Enbrel (Registered))
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
 
Study information 
Title 
Defining which remission criterion at Month 
6 predicts remission at Month 12 in a real 
life clinical practice, in a cohort of 
rheumatoid arthritis patients treated with 
etanercept (Enbrel®) 
Protocol number 
B1801378 
Protocol version identifier 
Amendment 2 
Date of last version of protocol 
26 January 2015 
Active substance 
Tumor necrosis factor alpha (TNF-Į
inhibitors (L04AB01): Etanercept 
Medicinal product 
Enbrel® 
Research question and objectives 
This study aims both to evaluate rheumatoid 
arthritis remission according to different 
criteria and to look at which remission 
criterion at Month 6 is the most predictive 
for remission at Month 12. 
Author 
, PhD 
 
 
Belgium 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 1 of 29 
PPD
PPD

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................................................................2 
1. LIST OF ABBREVIATIONS ......................................................................................................4 
2. RESPONSIBLE PARTIES ..........................................................................................................5 
3. AMENDMENTS AND UPDATES .............................................................................................6 
4. MILESTONES .............................................................................................................................7 
5. RATIONALE AND BACKGROUND ........................................................................................7 
6. RESEARCH QUESTION AND OBJECTIVES .......................................................................12 
6.1. Primary Objective .........................................................................................................12 
6.2. Secondary Objectives ....................................................................................................12 
7. RESEARCH METHODS ..........................................................................................................13 
7.1. Study design ..................................................................................................................13 
7.2. Setting ............................................................................................................................15 
7.2.1. Inclusion criteria ...............................................................................................15 
7.2.2. Exclusion criteria ..............................................................................................15 
7.3. Variables ........................................................................................................................15 
7.4. Data sources ..................................................................................................................16 
7.5. Study size ......................................................................................................................16 
7.6. Data management ..........................................................................................................16 
7.7. Data analysis .................................................................................................................17 
7.8. Quality control ...............................................................................................................17 
7.9. Limitations of the research methods .............................................................................17 
7.10. Other aspects ...............................................................................................................18 
8. PROTECTION OF HUMAN SUBJECTS ................................................................................18 
8.1. Patient Information and Consent ...................................................................................18 
8.2. Patient withdrawal .........................................................................................................18 
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ....................18 
8.4. Ethical Conduct of the Study ........................................................................................19 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS .......................................................................................................................19 
9.1. Requirements .................................................................................................................19 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 2 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
9.1.1. Reporting period ...............................................................................................21 
9.1.2. Causality assessment ........................................................................................21 
9.2. Definitions of safety events ...........................................................................................22 
9.2.1. Adverse events ..................................................................................................22 
9.2.2. Serious adverse events ......................................................................................23 
9.2.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours .................24 
9.3. Single reference safety document..................................................................................27 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS..............27 
11. REFERENCES ........................................................................................................................27 
12. LIST OF TABLES ...................................................................................................................29 
13. LIST OF FIGURES .................................................................................................................29 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS ...............................................................29 
ANNEX 2. ADDITIONAL INFORMATION ...............................................................................29 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 3 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
1. LIST OF ABBREVIATIONS  
Abbreviation 
Definition 
ACR 
American College of Rheumatology 
AE 
Adverse Event 
AEM 
Adverse Event Monitoring 
CDAI 
Clinical Disease Activity Index 
CRP 
C-Reactive Protein 
DAS28 
Disease Activity Score-28 
DCP 
Data Collection Point 
eCRF 
electronic Case Report Form 
EDP 
Exposure During Pregnancy 
EULAR 
European League  Against Rheumatism 
GSUS 
Grey-scale Ultrasonography 
HAQ 
Health Assessment Questionnaire 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MKUS 
Musculoskeletal Ultrasonography 
NIS 
Non-Interventional Study 
PDUS 
Power Doppler Ultrasonography 
PtGA 
Patient Global Assessment of disease 
RA 
Rheumatoid Arthritis 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SDAI 
Simplified Disease Activity Index 
SJC 
Swollen Joint Count 
SmPC 
Summary of Product Characteristics 
TJC 
Tender Joint count 
TNF-alpha 
Tumor Necrosis Factor Alpha 
US 
Ultrasound 
US7 
Seven-joint ultrasound 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 4 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
2. RESPONSIBLE PARTIES 
Principal Investigator(s) of the Protocol 
Name, degree(s) 
Title 
Affiliation 
Address 
, MD 
Principal Investigator 
Rheumatologist 
 
Belgium 
, MD 
Principal Investigator 
Rheumatologist 
 
Belgium 
 
Responsible for input in protocol 
Name, degree(s) 
Title 
Affiliation 
Address 
, 
PharmD 
Medical 
Advisor/Clinical Lead 
Pfizer sa/nv 
 
 
Belgium 
 
eCRF/ePlatform vendor 
General Manager 
Lambda Plus sa/nv 
 
 
Belgium 
, 
PhD 
 of Medical 
Writing, Data 
Management and 
Biostatistics 
ECSOR sa/nv 
 
 
Belgium 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 5 of 29 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
3.  AMENDMENTS AND UPDATES 
On January 26, 2015, the recruitment status was as follows: 34 patients included in the 
cohort 1st biological versus 4 in the cohort 2nd biological.   
 
For our predictive model, we need 100 evaluable patients but the cohort in which the 
patients are recruited will not impact the results.  
 
In order to have 100 evaluable patients for the predictive model and given the above 
mentioned recruitment status, we decided to amend the protocol to allow the needed 
number of patients to be recruited in whichever cohort: 1st or 2nd. This will limit the 
potential extension of the recruitment period. . 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 6 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
  
4. MILESTONES 
Milestone 
Planned date 
Completion of feasibility assessment 
30 June 2014 
Start of data collection 
15 July 2014 
End of data collection 
30 June 2016 
Interim report 1 
30 January 2017 
Final study report 
31 May 2017 
 
5. RATIONALE AND BACKGROUND 
Today, both in clinical studies and clinical practice the Disease Activity Score-28 (DAS28) is the 
golden standard for measuring disease activity in rheumatoid arthritis (RA). 
 
In the 2013 guidelines from the European League Against Rheumatism (EULAR) for the 
management of RA, recommendation 2 clearly states: “Treatment should be aimed at reaching a 
target of remission or low disease activity in every patient.”  
 
This same article mentions that remission as defined by the DAS28 <2.6 is not regarded as 
sufficiently stringent to define remission, referring to the 2011 EULAR/American College of 
Rheumatology (ACR) remission criteria (Figure 1): 
• Clinical Practice: the Boolean definition (SJC<1, TJC<1 and  PtGA<1) and CDAI ≤ 2.8  
(SJC= Swollen Joint Count, TJC= Tender Joint Count, PtGA= Patient Global Assessment of 
disease, CDAI= Clinical Disease Activity Index) 
• Clinical Studies: the Boolean definition (SJC<1, TJC<1 and  PtGA<1, CRP <1) and 
SDAI ≤ 3.3 (CRP= C-Reactive Protein, SDAI= Simplified Disease Activity Index) 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 7 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Figure 1. Percentage of subjects maintaining remission as a function of time and criteria 
(Prince et al., 2012) 
 
Only one study has evaluated these new criteria in a real life clinical practice. The article by 
Prince et al. (year and reference at the end of the protocol) concludes that in an RA population, 
only a minority of patients is in sustained remission. Further evaluation of these criteria in 
observational studies is needed. 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 8 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Musculoskeletal ultrasonography (MKUS) has emerged as a tool with the potential to enhance 
disease assessment and management in this area. This includes applications in patients with 
undifferentiated arthropathy attending an early inflammatory arthritis clinic, in which the 
diagnosis of inflammatory disease may be confirmed or refuted at an early stage, and those with 
treated RA where accurate measurement of outcomes, such as response to therapy, structural 
damage and disease remission, are extremely important. This imaging modality is safe and 
portable, making it ideal for outpatient and inpatient settings, and can be used to assess many 
joints in multiple planes and to demonstrate changes in disease activity and structural damage 
over time. US is gaining popularity among rheumatologists, as increasing evidence supports the 
added value of a physician-performed ultrasonography assessment above traditional clinical, 
laboratory and radiographic measures, enabling greater confidence in diagnostic and 
management decisions (Brown, 2009, Dougados et al., 2010; Iagnocco et al., 2008). Remission 
when defined by clinical remission criteria (DAS, simplified disease activity index, etc…) does 
not always equate to the complete absence of inflammation as measured by US (Wakefield et al., 
2012). 
 
The new seven-joint ultrasound (US7) score was proposed by Backhaus et al. (2009). This is the 
first MKUS composite scoring system, combining soft tissue lesions (synovitis and 
tenosynovitis/paratenonitis) and destructive processes (erosions) in a single scoring system. The 
US7 score includes MKUS examination of the following joints of the clinically more affected 
side: wrist, MCP II and III, PIP II and III, MTP II and V. The joints are examined by Grey-Scale 
Ultrasonography (GSUS) and Power Doppler Ultrasonography (PDUS) for synovitis and 
tenosynovitis/paratenonitis from a dorsal and palmar/plantar aspect, and for erosions from a 
dorsal, palmar/plantar and radial/lateral (only MCP II and MTP V) aspect. Synovitis in GSUS is 
analysed semiquantitatively (0–3) according to Scheel et al. (2005): 0: absence; 1: small 
hypoechoic/anechoic line beneath the joint capsule (mild synovitis); 2: elevation of the joint 
capsule parallel to the joint area (moderate synovitis); 3: strong distension of the joint capsule 
(severe synovitis) (see Figure 2and Figure 3).  
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 9 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Figure 2. Semi-quantitative (grade 0-3) grey-scale ultrasound synovitis score at the wrist 
joint in the dorsomedian longitudinal axis 
 
Figure 3. Semiquantative (grade 0-3) grey-scale ultrasound synovitis score at the 
metacarpophalangeal II/III joints in the palmar longitudinal axis 
 
 
The PDUS evaluation for synovitis (see Figure 4 and Figure 5) and tenosynovitis/paratenonitis is 
scored according to the scoring system of Szkudlarek et al. (2003). 
Tenosynovitis/paratenonitis and erosions in GSUS are registered on a binary basis (0/1). 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 10 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
 
Figure 4. Semiquantitative (grade 0-3) power Doppler ultrasonography synovitis score at 
the wrist joint in the dorsomedian longitudinal axis 
 
Figure 5. Semiquantitative (grade 0-3) power Doppler ultrasonography synovitis score at 
the metacarpophalangeal II/III joints in the dorsal longitudinal axis 
 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 11 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
A recently published US7 reliability study investigated the inter-observer and intra-observer 
reliability of sonographers, determining the US7 score under conditions similar to those of daily 
rheumatological practice. The median overall κ value for detecting synovitis was κ=0.51, for 
tenosynovitis/paratenonitis κ=0.57 and for erosions κ=0.45. This study also showed that the US7 
score has the potential also in multicentre analysis to assess structural changes with moderate to 
good reliability (Ohrndorf et al. 2012).  
 
In today’s clinical practice, there is  still an existing need to define which remission criterion can 
best be used to predict remission in the long run. 
 
There is a tendency to link (sustained) remission with a dose down strategy. However, dose 
down often results in flaring of the disease and flare rates go as high as 70% in this dose down 
population, expressing an urgent need for better defining the pool of patients in which dose down 
could be an  option to consider. 
 
 
6. RESEARCH QUESTION AND OBJECTIVES 
This study aims both to evaluate remission according to different criteria and to look at which 
remission criterion at Month 6 is the most predictive for remission at Month 12. 
6.1. Primary Objective 
To determine which remission criterion at Month 6 predicts remission at Month 12 the best. 
6.2. Secondary Objectives 
• Describe the percentage of patients in remission at the different DCPs (Data Collection 
Points) according to different remission criteria: CDAI, SDAI, DAS28, DAS28 in 
combination with Ultrasound, EULAR Boolean definition for clinical practice and clinical 
studies. 
• Describe percentage of the same patients in remission at the different DCPs, according to 
different remission criteria: CDAI, SDAI, DAS28, DAS28 in combination with Ultrasound, 
EULAR Boolean definition for clinical practice and clinical studies. 
• Determine if the quantitative change in between baseline and Month 6 is predictive for the 
change at Month 12. 
• Determine which single component is the most predictive for the composite index of 
remission. 
• Determine predictors for remission, according to all the different criteria at each timepoint.  
• Comparison between DAS28 remission and US remission 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 12 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
• Prediction of remission based on US data 
7. RESEARCH METHODS  
7.1. Study design  
This will be an observational, multicenter study, in which patients with RA will be recruited in 2 
cohorts. The study design can be found in Figure 6.  
The first cohort is a cohort in which the decision by the treating rheumatologist has been taken to 
start treatment with Enbrel as first biological product, according to prevailing reimbursement 
criteria in Belgium and dosing in line with the Summary of Product Characteristics (SmPC). 
The second cohort is a cohort in which the decision of the treating rheumatologist has been taken 
to start treatment with Enbrel according to prevailing reimbursement criteria in Belgium as 
second biological product (either after use of another anti-TNF or another mechanism of action) 
and dosing in line with SmPC. 
The study flow chart can be found in Table 1. 
At baseline, demographics, disease duration (defined as the time between diagnosis and 
etanercept treatment initiation), Health Assessment Questionnaire (HAQ) and different remission 
criteria (DAS28, SDAI, CDAI, Boolean definition of both CDAI and SDAI, DAS28 in 
combination with US) will be recorded.  
The evaluation will take place at Data Collection Points (DCPs) which will coincide with regular 
visits, not scheduled for the purpose of the study, but at Q3 months with a time window of ± one 
month, recording the same data, as well as current medication and related adverse events (AEs).  
The ultrasound will only take place in selected centers with a proven record of US training and 
day-to-day clinical experience. Bruyn et al. (2013) concluded that the scoring of US intra-reader 
variability was excellent (κ=0.91) and inter-reader variability was good (κ=0.75). 
A recently published US7 reliability study investigated the inter-observer and intra-observer 
reliability of sonographers, determining the US7 score under conditions similar to those of daily 
rheumatological practice. The median overall κ value for detecting synovitis was κ=0.51, for 
tenosynovitis/paratenonitis κ=0.57 and for erosions κ=0.45. This study also showed that the US7 
score has the potential also in multicentre analysis to assess structural changes with moderate to 
good reliability (Ohrndorf et al. 2012).  
 
Ultrasound images will be collected and saved. When needed for analysis, they can afterwards be 
read by central readers. 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 13 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Figure 6. Study design 
 
Table 1. Study flow chart 
 
 
 
Baseline 
DCP1 
DCP 2 
DCP 3 
DCP 4 
Time 
0 m 
Month 3 
(2-4) 
Month 6 
(5-7) 
Month 9 
(8-10) 
Month 12 
(11-13) 
 
 
 
 
Demographics 
X 
 
 
 
 
Disease duration 
X 
 
 
 
 
DAS28 
X 
X 
X 
X 
X 
SDAI 
X 
X 
X 
X 
X 
CDAI 
X 
X 
X 
X 
X 
BOOLEAN CDAI 
SJC≤1, TJC≤1, 
PtGA≤1 
X 
X 
X 
X 
X 
BOOLEAN SDAI 
SJC≤1, TJC≤1, 
PtGA≤1and CRP≤1 
X 
X 
X 
X 
X 
Ultrasound 
(Selected Centers) 
X 
 
X 
 
X 
HAQ 
X 
X 
X 
X 
X 
Current medication 
X 
X 
X 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 14 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
7.2. Setting 
7.2.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the study: 
1. Patients with active RA who start treatment with Enbrel according to the prevailing 
reimbursement criteria in Belgium and dosing in line with the SmPC. 
a) First cohort: Enbrel is the first biological product prescribed. 
b) Second cohort: Enbrel is the second biological product prescribed. 
2. Capable of understanding and willing to provide signed and dated written, voluntary 
informed consent before any protocol-specific procedures are performed. 
3. Eighteen (18) years of age or older at time of consent. 
4. Evidence of a personally signed and dated informed consent document indicating that the 
patient (or a legally acceptable representative) has been informed of all pertinent aspects of 
the study. 
7.2.2. Exclusion criteria 
Patients meeting any of the following criteria will not be included in the study: 
1. History of or current psychiatric illness that would interfere with the subject’s ability to 
comply with protocol requirements or to give informed consent. 
7.3. Variables 
Table 2. Variables, roles, data sources and operational definitions 
Variable 
Role 
Data source(s) 
Operational definition 
Demographics 
Baseline variables 
Medical records 
Please refer to the SAP* 
Disease duration 
Baseline variables 
Medical records 
Please refer to the SAP* 
Cohort 1 or 2 
Sub-group identifier 
Medical records 
Please refer to the SAP* 
DAS28 
Outcome variable 
Medical records 
Please refer to the SAP* 
SDAI 
Outcome variable 
Medical records 
Please refer to the SAP* 
CDAI 
Outcome variable 
Medical records 
Please refer to the SAP* 
BOOLEAN CDAI 
SJC≤1, TJC≤1, PtGA≤1 
Outcome variable 
Medical records 
Please refer to the SAP* 
BOOLEAN SDAI 
SJC≤1, TJC≤1, 
PtGA≤1and CRP≤1 
Outcome variable 
Medical records 
Please refer to the SAP* 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 15 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Variable 
Role 
Data source(s) 
Operational definition 
Ultrasound 
(Selected Centers) 
Outcome variable 
Medical records 
Please refer to the SAP* 
HAQ 
Outcome variable 
Medical records 
Please refer to the SAP* 
Current medication 
Exposure 
Medical records 
Please refer to the SAP* 
Adverse events 
Safety 
Medical records 
Please refer to the SAP* 
* SAP = Statistical Analysis Plan 
 
 
7.4. Data sources  
This study will be a primary data collection study. The data source will be the medical records 
for all variables. For all details please refer to the Statistical Analysis Plan (SAP). 
 
7.5. Study size 
It will not be possible to justify the sample size of the study on the basis of inferential statistical 
assumptions. Indeed, there are currently insufficient data available concerning the prediction of 
remission on the basis of CDAI, SDAI, DAS28, DAS28 and Ultrasound, and EULAR Boolean 
definition for clinical practice and clinical studies. 
The analysis of the primary endpoint will be based on a logistic regression defining the 
dependent variable as the remission at Month 12 and the 5 independent variables as CDAI, 
SDAI, DAS28, DAS28 and Ultrasound, and EULAR Boolean definition for clinical practice and 
clinical studies. 
This analysis will be conducted in each armof the study if possible as well as after  pooling of 
both patient groups. 
In this context it seems reasonable to ensure the completion of the study by a total approximate 
number of 100 patients (approximately 50 patients per arm). In order to ensure 50 completers in 
each arm, 70 patients will be recruited at baseline, taking into account a drop out rate of 30% 
over 1 year period. In order to have 100 evaluable patients for the predictive model and given the 
current recruitment status (January 26th 2015 RA 1st: 34 vs RA 2nd : 4) we will allow the needed 
number of patients to be recruited in whichever cohort: 1st or 2nd. This will limit the potential 
extension of the recruitment period. 
7.6. Data management  
All the data will be recorded by the Investigators and their study nurses in an electronic Case 
Report Form (eCRF). 
The Data Management of the study will be done directly in the eCRF by the automatic 
generation of inconsistencies and by the manual generation of queries. 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 16 of 29 
PPD

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
The statistical software which will be used for the analyses is the IBM-SPSS Statistics program 
(Version 21.0 and eventual upgrades/updates). 
7.7. Data analysis  
Detailed methodology for summary and statistical analyses of data collected in this study will be 
documented in a SAP, which will be dated, filed and maintained by the sponsor. The SAP may 
modify the plans outlined in the protocol; any major modifications of primary endpoint 
definitions or their analyses would be reflected in a protocol amendment. 
 
The analysis of the primary endpoint will be based on a logistic regression defining the 
dependent variable as the remission at month 12 and the 5 independent variables as CDAI, 
SDAI, DAS28, DAS28 and Ultrasound, and EULAR Boolean definition for clinical practice and 
clinical studies. This analysis will be conducted in each arm of the study as well as after a 
pooling of both patient groups. 
 
The other statistical methods used for the analysis of the data will be mainly descriptive.  
 
Appropriate inferential analyses will be used to compare the over-time modifications of study 
parameters and potentially to compare the two arms of the study.  
 
Time to event variables will be analyzed using the Kaplan-Meier’s method with comparison 
between groups being ensured by the log rank test. 
 
An interim analysis of baseline data will be performed at Month 6. 
 
7.8. Quality control 
The sponsor will perform quality control and assurance checks of the study. Before enrolling any 
subjects in this study, sponsor personnel and the investigator will review the protocol, the SmPC, 
the eCRF and the instructions for their completion, the procedure for obtaining informed 
consent, and the procedure for reporting AEs and serious adverse events (SAEs).  
A qualified representative of the sponsor will monitor the conduct of the study by visiting the site 
and by contacting the site by telephone. During the visits, information recorded on the eCRFs 
will be verified against source documents. Automatic inconsistencies will be generated by the 
ePlatform directly in the eCRF and Clinical Research Associates will have the opportunity to add 
manual queries directly in the eCRF. 
All statistical programs used to manage and analyze the data will be validated and archived with 
the clinical database. 
7.9. Limitations of the research methods 
The limitations of the study are intrinsic to its observational, non-controlled, non-randomized 
design. 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 17 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
7.10. Other aspects 
Not applicable. 
8. PROTECTION OF HUMAN SUBJECTS 
8.1. Patient Information and Consent 
All parties will ensure protection of patient personal data and will not include patient names on 
any sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws. In case of data transfer, Pfizer will maintain high standards of confidentiality and 
protection of patient personal data. 
The informed consent form must be in compliance with local regulatory requirements and legal 
requirements. 
The informed consent form used in this study, and any changes made during the course of the 
study, must be prospectively approved by both the Institutional Review Board (IRB), the 
Independent Ethics Committee (IEC) and Pfizer before use. 
The investigator must ensure that each study patient, or his/her legally acceptable representative, 
is fully informed about the nature and objectives of the study and possible risks associated with 
participation. The investigator, or a person designated by the investigator, will obtain written 
informed consent from each patient or the patient’s legally acceptable representative before any 
study-specific activity is performed. The investigator will retain the original of each patient's 
signed consent form. 
8.2. Patient withdrawal 
Patients may withdraw from the study at any time at their own request, or they may be 
withdrawn at any time at the discretion of the investigator or sponsor for safety, behavioral, or 
administrative reasons. In any circumstance, every effort should be made to document subject 
outcome, if possible. The investigator should inquire about the reason for withdrawal and follow-
up with the subject regarding any unresolved adverse events.  
If the patient withdraws from the study, and also withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The sponsor may retain and continue to use any data collected before such withdrawal 
of consent. 
8.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, and informed consent forms, and other relevant documents, 
(e.g., recruitment advertisements), if applicable, from the IRB/IEC. All correspondence with the 
IRB/IEC should be retained in the Investigator File. Copies of IRB/IEC approvals should be 
forwarded to Pfizer.  
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 18 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
8.4. Ethical Conduct of the Study 
The study will be conducted in accordance with legal and regulatory requirements, as well as 
with scientific purpose, value and rigor and follow generally accepted research practices 
described in Guidelines for Good Pharmacoepidemiology Practices issued by the International 
Society for Pharmacoepidemiology, Good Epidemiological Practice guidelines issued by the 
International Epidemiological Association, Good Practices for Outcomes Research issued by the 
International Society for Pharmacoeconomics and Outcomes Research, International Ethical 
Guidelines for Epidemiological Research issued by the Council for International Organizations 
of Medical Sciences, European Medicines Agency, European Network of Centres for 
Pharmacoepidemiology and Pharmacovigilance, Guide on Methodological Standards in 
Pharmacoepidemiology. 
9. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
9.1. Requirements 
Table 3 below summarizes the requirements for recording safety events on the eCRF and for 
reporting safety events on the non-interventional study (NIS) adverse event monitoring (AEM) 
Report Form to Pfizer Safety. These requirements are delineated for three types of events: (1) 
SAEs; (2) non-serious AEs (as applicable); and (3) scenarios involving drug exposure, including 
exposure during pregnancy (EDP), exposure during breast feeding, medication error, overdose, 
misuse, extravasation, and occupational exposure. These events are defined in the section 
“Definitions of safety events”. 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 19 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Table 3. Requirements for recording and reporting safety events 
Safety event 
Recorded on the eCRF 
Reported on the NIS AEM 
Report Form to Pfizer 
Safety within 24 hours of 
awareness 
SAE 
All 
All 
Non-serious AE 
All 
None: Even if the study 
involves a site of the 
European Economic Area 
(EEA), the study team 
decided that the non-serious 
adverse events should not 
be reported to Pfizer Safety 
because none of the 
objectives of the study 
involves the active 
collection of safety 
information and the clinical 
team doesn’t want to 
actively seek any specific 
non-serious adverse events. 
Scenarios involving exposure 
to a drug under study, 
including EDP, exposure 
during breast feeding, 
medication error, overdose, 
misuse, extravasation; lack of 
efficacy; and occupational 
exposure 
All (regardless of whether 
associated with an AE), 
except occupational 
exposure  
All (regardless of whether 
associated with an AE) 
 
For each AE, the investigator must pursue and obtain information adequate both to determine the 
outcome of the adverse event and to assess whether it meets the criteria for classification as a 
SAE (see section "Serious Adverse Events” below).  
Safety events listed in the table above must be reported to Pfizer within 24 hours of awareness of 
the event by the investigator regardless of whether the event is determined by the 
investigator to be related to a drug under study. In particular, if the SAE is fatal or life-
threatening, notification to Pfizer must be made immediately, irrespective of the extent of 
available event information. This timeframe also applies to additional new (follow-up) 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 20 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
information on previously forwarded safety event reports. In the rare situation that the 
investigator does not become immediately aware of the occurrence of a safety event, the 
investigator must report the event within 24 hours after learning of it and document the time of 
his/her first awareness of the events. 
For safety events that are considered serious or that are identified in the far right column of the 
table above that are reportable to Pfizer within 24 hours of awareness, the investigator is 
obligated to pursue and to provide any additional information to Pfizer in accordance with this 
24-hour timeframe. In addition, an investigator may be requested by Pfizer to obtain specific 
follow-up information in an expedited fashion. This information is more detailed than that 
recorded on the eCRF. In general, this will include a description of the adverse event in sufficient 
detail to allow for a complete medical assessment of the case and independent determination of 
possible causality. Any information relevant to the event, such as concomitant medications and 
illnesses must be provided. In the case of a patient death, a summary of available autopsy 
findings must be submitted as soon as possible to Pfizer or its designated representative.  
 
9.1.1. Reporting period  
For each patient, the safety event reporting period begins at the time of the patient’s first dose of 
Enbrel®, and lasts through the end of the observation period of the study, which must include at 
least 28 calendar days following the last administration of a drug under study; a report must be 
submitted to Pfizer Safety (or its designated representative) for any of the types of safety events 
listed in the table above occurring during this period. If a patient was administered a drug under 
study on the last day of the observation period, then the reporting period should be extended for 
28 calendar days following the end of observation. 
If the investigator becomes aware of a SAE occurring at any time after completion of the study 
and s/he considers the SAE to be related to Enbrel®, the SAE also must be reported to Pfizer 
Safety. 
 
9.1.2. Causality assessment 
The investigator is required to assess and record the causal relationship. For all AEs, sufficient 
information should be obtained by the investigator to determine the causality of each adverse 
event. For AEs with a causal relationship to Enbrel®, follow-up by the investigator is required 
until the event and/or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.  
An investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that Enbrel® caused or contributed to an adverse event. If the investigator’s final 
determination of causality is “unknown” and s/he cannot determine whether Enbrel® caused the 
event, the safety event must be reported within 24 hours.  
If the investigator cannot determine the etiology of the event but s/he determines that Enbrel® did 
not cause the event, this should be clearly documented on the eCRF and the NIS AEM Report 
Form.  
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 21 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
9.2. Definitions of safety events 
9.2.1. Adverse events 
An AE is any untoward medical occurrence in a patient administered a medicinal product. The 
event need not necessarily have a causal relationship with the product treatment or usage. 
Examples of AE include but are not limited to:   
• Abnormal test findings (see below for circumstances in which an abnormal test finding 
constitutes an adverse event); 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings; 
• Hypersensitivity; 
• Progression/worsening of underlying disease; 
• Lack of efficacy;  
• Drug abuse;  
• Drug dependency. 
Additionally, for medicinal products, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug withdrawal; 
• Drug misuse;  
• Off-label use;  
• Drug interactions; 
• Extravasation; 
• Exposure during pregnancy; 
• Exposure during breast feeding; 
• Medication error; 
• Occupational exposure. 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 22 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Abnormal test findings 
The criteria for determining whether an abnormal objective test finding should be reported as an 
adverse event are as follows:  
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical intervention, and/or 
• Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment, or other therapy, and/or 
• Test result is considered to be an adverse event by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event. Any abnormal test result that is determined to be an error does not 
require reporting as an adverse event. 
9.2.2. Serious adverse events 
A SAE is any untoward medical occurrence in a patient administered a medicinal or nutritional 
product (including pediatric formulas) at any dose that: 
• Results in death; 
• Is life-threatening; 
• Requires inpatient hospitalization or prolongation of hospitalization (see below for 
circumstances that do not constitute adverse events); 
• Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions); 
• Results in congenital anomaly/birth defect. 
Medical and scientific judgment is exercised in determining whether an event is an important 
medical event. An important medical event may not be immediately life-threatening and/or result 
in death or hospitalization. However, if it is determined that the event may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the definition above, 
the important medical event should be reported as serious. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
Additionally, any suspected transmission via a Pfizer product of an infectious agent, pathogenic 
or non-pathogenic, is considered serious. The event may be suspected from clinical symptoms or 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 23 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
laboratory findings indicating an infection in a patient exposed to a Pfizer product. The terms 
“suspected transmission” and “transmission” are considered synonymous. These cases are 
considered unexpected and handled as serious expedited cases by PV personnel. Such cases are 
also considered for reporting as product defects, if appropriate. 
 
Hospitalization 
Hospitalization is defined as any initial admission (even if less than 24 hours) to a hospital or 
equivalent healthcare facility or any prolongation to an existing admission. Admission also 
includes transfer within the hospital to an acute/intensive care unit (e.g., from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, neurological floor to a tuberculosis 
unit). An emergency room visit does not necessarily constitute a hospitalization; however, an 
event leading to an emergency room visit should be assessed for medical importance.  
Hospitalization in the absence of a medical AE is not in itself an AE and is not reportable. For 
example, the following reports of hospitalization without a medical AE are not to be reported.  
• Social admission (e.g., patient has no place to sleep) 
• Administrative admission (e.g., for yearly exam) 
• Optional admission not associated with a precipitating medical AE (e.g., for elective 
cosmetic surgery) 
• Hospitalization for observation without a medical AE 
• Admission for treatment of a pre-existing condition not associated with the development of a 
new AE or with a worsening of the pre-existing condition (e.g., for work-up of persistent pre-
treatment lab abnormality) 
• Protocol-specified admission during clinical study (e.g., for a procedure required by the study 
protocol) 
9.2.3. Scenarios necessitating reporting to Pfizer Safety within 24 hours  
Scenarios involving EDP, exposure during breastfeeding, medication error, overdose, misuse, 
extravasation, lack of efficacy, and occupational exposure are described below. 
Exposure during pregnancy 
An EDP occurs if: 
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed to (e.g., environmental) Enbrel®, or the female becomes, or is found to be, 
pregnant after discontinuing and/or being exposed to Enbrel® (maternal exposure). 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 24 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
An example of environmental exposure would be a case involving direct contact with a 
Pfizer product in a pregnant woman (e.g., a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products). 
2. A male has been exposed, either due to treatment or environmental exposure to Enbrel® 
prior to or around the time of conception and/or is exposed during the partner pregnancy 
(paternal exposure). 
As a general rule, prospective and retrospective EDP reports from any source are reportable 
irrespective of the presence of an associated AE and the procedures for SAE reporting should be 
followed. 
If a study participant or study participant’s partner becomes, or is found to be, pregnant during 
the study participant’s treatment with Enbrel®, this information must be submitted to Pfizer, 
irrespective of whether an adverse event has occurred using the NIS AEM Report Form and the 
EDP Supplemental Form. 
In addition, the information regarding environmental exposure to Enbrel® in a pregnant woman 
(e.g., a subject reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) must be submitted using the NIS AEM Report Form and the EDP 
supplemental form. This must be done irrespective of whether an AE has occurred.  
Information submitted should include the anticipated date of delivery (see below for information 
related to termination of pregnancy). 
Follow-up is conducted to obtain general information on the pregnancy; in addition, follow-up is 
conducted to obtain information on EDP outcome for all EDP reports with pregnancy outcome 
unknown. A pregnancy is followed until completion or until pregnancy termination (e.g., 
induced abortion) and Pfizer is notified of the outcome. This information is provided as a follow 
up to the initial EDP report. In the case of a live birth, the structural integrity of the neonate can 
be assessed at the time of birth. In the event of a termination, the reason(s) for termination should 
be specified and, if clinically possible, the structural integrity of the terminated fetus should be 
assessed by gross visual inspection (unless pre-procedure test findings are conclusive for a 
congenital anomaly and the findings are reported). 
If the outcome of the pregnancy meets the criteria for an SAE (e.g., ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a live 
born, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the procedures for 
reporting SAEs should be followed. 
Additional information about pregnancy outcomes that are reported as SAEs follows:  
x Spontaneous abortion includes miscarriage and missed abortion; 
x Neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 25 of 29 
PPD

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
when the investigator assesses the infant death as related or possibly related to exposure 
to investigational product 
Additional information regarding the EDP may be requested. Further follow-up of birth 
outcomes will be handled on a case-by-case basis (e.g., follow-up on preterm infants to identify 
developmental delays).  
In the case of paternal exposure, the study participant will be provided with the Pregnant Partner 
Release of Information Form to deliver to his partner. It must be documented that the study 
participant was given this letter to provide to his partner. 
Exposure during breastfeeding 
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of an 
associated AE. An exposure during breastfeeding report is not created when a Pfizer drug 
specifically approved for use in breastfeeding women (e.g., vitamins) is administered in accord 
with authorized use. However, if the infant experiences an AE associated with such a drug’s 
administration, the AE is reported together with the exposure during breastfeeding. 
Medication error 
A medication error is any unintentional error in the prescribing, dispensing or administration of a 
medicinal product that may cause or lead to inappropriate medication use or patient harm while 
in the control of the health care professional, patient, or consumer. Such events may be related to 
professional practice, health care products, procedures, and systems including: prescribing; order 
communication; product labeling, packaging, and nomenclature; compounding; dispensing; 
distribution; administration; education; monitoring; and use.  
Medication errors include: 
• Near misses, involving or not involving a patient directly (e.g., inadvertent/erroneous 
administration, which is the accidental use of a product outside of labeling or prescription 
on the part of the healthcare provider or the patient/consumer); 
• Confusion with regard to invented name (e.g., trade name, brand name). 
The investigator must submit the following medication errors to Pfizer, irrespective of the 
presence of an associated AE/SAE: 
• Medication errors involving patient exposure to the product, whether or not the 
medication error is accompanied by an AE. 
• Medication errors that do not involve a patient directly (e.g., potential medication errors 
or near misses). When a medication error does not involve patient exposure to the 
product the following minimum criteria constitute a medication error report: 
• An identifiable reporter; 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 26 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
• A suspect product; 
• The event medication error. 
Overdose, Misuse, Extravasation 
Reports of overdose, misuse, and extravasation associated with the use of a Pfizer product are 
reported to Pfizer by the investigator, irrespective of the presence of an associated AE/SAE.  
Lack of Efficacy 
Reports of lack of efficacy to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE or the indication for use of the Pfizer 
product. 
Occupational Exposure 
Reports of occupational exposure to a Pfizer product are reported to Pfizer by the investigator, 
irrespective of the presence of an associated AE/SAE. 
9.3. Single reference safety document 
The Enbrel® SmPC will serve as the single reference safety document during the course of the 
study, which will be used by Pfizer safety to assess any safety events reported to Pfizer Safety by 
the investigator during the course of this study.  
 
The single reference safety document should be used by the investigator for prescribing purposes 
and guidance. 
10. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
Competent Authority in any area of the world, or if the investigator is aware of any new 
information which might influence the evaluation of the benefits and risks of a Pfizer product, 
Pfizer should be informed immediately.  
In addition, the investigator will inform Pfizer immediately of any urgent safety measures taken 
by the investigator to protect the study patients against any immediate hazard, and of any serious 
breaches of this NI study protocol that the investigator becomes aware of. 
11. REFERENCES 
Backhaus M, Ohrndorf S, Kellner H, et al. Evaluation of a novel 7 joint ultrasound score in daily 
rheumatologic practice: a pilot project. Arthritis Rheum 2009; 61: 1194-201 
Brown AK, Using ultrasonography to facilitate best practice in diagnosis and management of 
RA. Nat. Rev. Rheumatol. 2009: 5: 698–706. 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 27 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
Bruyn GAW, Hanova P, Iagnocco A, D’Agostine M-A, et al. on behalf of the OMERACT 
Ultrasound Task Force. Ultrasound definition of tendon damage in patients with rheumatoid 
arthritis. Results of a OMERACT consensus-based ultrasound score focussing on the diagnostic 
reliability. Ann Rheum Dis doi:10.1136/annrheumdis-2013-203596. 
Dougados M, Jousse-Joulin S, Mistretta F, et al. Evaluation of several ultrasonography scoring 
systems for synovitis and comparison to clinical examination: results from a prospective 
multicentre study of rheumatoid arthritis. Ann Rheum Dis. 2010: 69:828-33. 
Iagnocco A, Perella C, Naredo E, Meenagh G, Ceccarelli F, Tripodo E, Basili S, Valesini G. 
Etanercept in the treatment of rheumatoid arthritis: clinical follow-up over one year by 
ultrasonography. Clin Rheumatol. 2008: 27:491-6. 
Ohrndorf S, Fischer IU, Kellner H, et al. Reliability of the novel 7 joint ultrasound score (US7): 
results from an inter-and intra-observer study performed by rheumatologists. Arthritis Care Res 
(Hoboken) 2012; 64:1238-43. 
Prince FHM, Bykerk VP, Shadick NA, Lu B, Cui J, Frits M, Iannaccone CK, Weinblatt ME, 
Solomon DH. Sustained rheumatoid arthritis remission is uncommon in clinical practice. 
Arthritis Research & Therapy. 2012: 14: R68. 
Scheel AK, Hermann KG, Kahler E et al. A novel ultrasonographic synovitis scoring system 
suitable for analyzing finger joint inflammation in rheumatoid arthritis. Arthritis Rheum 2005; 
52: 733-43 
Szuklarek M, Court-Payen M, Jacobsen S et al. Interobserver agreement in ultrasonography of 
the finger and toe joints in rheumatoid arthritis. Arthritis Rheum 2003; 48: 955-62 
Wakefield RJ, D'Agostino MA, Naredo E, Buch MH, Iagnocco A, Terslev L, Ostergaard M, 
Backhaus M, Grassi W, Dougados M, Burmester GR, Saleem B, de Miguel E, Estrach C, Ikeda 
K, Gutierrez M, Thompson R, Balint P, Emery P. After treat-to-target: can a targeted ultrasound 
initiative improve RA outcomes? Postgrad Med J. 2012: 88: 482-6. 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 28 of 29 

Etanercept 
B1801378, NON-INTERVENTIONAL STUDY PROTOCOL 
Amendment 2, 26 January 2015  
 
12. LIST OF TABLES  
Table 1. Study flow chart ...............................................................................................................14 
Table 2. Variables, roles, data sources and operational definitions ...............................................15 
Table 3. Requirements for recording and reporting safety events .................................................20 
 
13. LIST OF FIGURES 
Figure 1. Percentage of subjects maintaining remission as a function of time and criteria 
(Prince et al., 2012) .......................................................................................................8 
Figure 2. Semi-quantitative (grade 0-3) grey-scale ultrasound synovitis score at the wrist 
joint in the dorsomedian longitudinal axis ..................................................................10 
Figure 3. Semiquantative (grade 0-3) grey-scale ultrasound synovitis score at the 
metacarpophalangeal II/III joints in the palmar longitudinal axis ..............................10 
Figure 4. Semiquantitative (grade 0-3) power Doppler ultrasonography synovitis score at 
the wrist joint in the dorsomedian longitudinal axis ...................................................11 
Figure 5. Semiquantitative (grade 0-3) power Doppler ultrasonography synovitis score at 
the metacarpophalangeal II/III joints in the dorsal longitudinal axis .........................11 
Figure 6. Study design ...................................................................................................................14 
 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
None. 
ANNEX 2. ADDITIONAL INFORMATION 
Not applicable. 
 
 
CT24-GSOP-RF03 NI Study Protocol Template; Version 1.0, Effective Date 31-Dec-2013 
 
 
 
Page 29 of 29