The Impact of RF, and Anti-CCP on RA Patients in Response to Etanercept
Conditions: Arthritis, Rheumatoid
Sponsor: Pfizer

Etanercept
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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
The impact of RF, and anti-CCP on RA 
patients in response to Etanercept
Protocol number
B1801417
Protocol version identifier
3.0
Date
27 July 2021
Active substance
etanercept
Medicinal product
etanercept
Research question and objectives
The RF and anti-CCP are found to be 
positive in 70% and 65% of RA patients 
respectively. Researchers have found that 
RF and anti-CCP have an impact on RA 
response. The objective is to evaluate the 
impact of RF and ACCP on RA patients in 
response to Enbrel from the local data.
Author
 – MD, M.Sc.
Pfizer Inc. - Iraq
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in 
writing, by accepting or reviewing this document, you agree to hold this information in confidence and not 
copy or disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In 
the event of any actual or suspected breach of this obligation, Pfizer must be promptly notified.
PPD
PPD

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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................4
3. RESPONSIBLE PARTIES....................................................................................................5
4. AMENDMENTS AND UPDATES.......................................................................................6
5. MILESTONES.......................................................................................................................7
6. RATIONALE AND BACKGROUND..................................................................................7
7. RESEARCH QUESTION AND OBJECTIVES ...................................................................7
8. RESEARCH METHODS ......................................................................................................7
8.1. Study Design .............................................................................................................7
8.2. Setting........................................................................................................................8
8.2.1. Inclusion Criteria ..........................................................................................8
8.2.2. Exclusion Criteria.........................................................................................8
8.3. Data Sources..............................................................................................................9
8.4. Study Size..................................................................................................................9
8.5. Data Management .....................................................................................................9
8.6. Data Analysis ............................................................................................................9
8.7. Quality Control..........................................................................................................9
8.8. Limitations of the Research Methods........................................................................9
8.9. Other Aspects ..........................................................................................................10
9. PROTECTION OF HUMAN SUBJECTS ..........................................................................10
9.1. Patient Information..................................................................................................10
9.2. Patient Consent........................................................................................................10
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ..............10
9.4. Ethical Conduct of the Study ..................................................................................10
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................10
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........10
12. REFERENCES ..................................................................................................................11
13. LIST OF TABLES.............................................................................................................12
14. LIST OF FIGURES ...........................................................................................................12

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ANNEX 1. LIST OF STANDALONE DOCUMENTS ..........................................................12

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACR
American College of Rheumatology 
AE
Adverse Event
anti-CCP
Anti-Cyclic Citrullinated Peptide
CDAI
Clinical Disease Activity Index
DAS28
Disease Activity Score 28
DMARD
Disease -Modifying Antirheumatic Drug
EULAR
The European League Against Rheumatism 
GEP
Good Epidemiological Practice
GGP
Guidelines for Good Pharmacoepidemiology 
Practices
IEA
International Epidemiological Association
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISPE
International Society for Pharmacoepidemiology
ISPOR
International Society for Pharmacoeconomics and 
Outcomes Research
MTX
Methotrexate
NA
Not Applicable 
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
RA
Rheumatoid Arthritis
RF
Rheumatoid Factor

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
Medical Advisor
NI Study Lead
Pfizer Inc – Iraq
PPD
PPD

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4. AMENDMENTS AND UPDATES
Amendment 
number
Date
Protocol 
section(s) 
changed
Summary of amendment(s)
Reason
1
22 June 
2021
Section 5. 
Milestones
Updated to align with Study Report
Administrative
2
27 July 
2021
Throughout the 
document
Spelling errors
Administrative

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5. MILESTONES
Milestone
Planned date
Actual Date
Start of data collection
01 July 2020
01 July 2020
End of data collection
01 August 2020
01 August 2020
Final study report
30 June 2021
29 June 2021
6. RATIONALE AND BACKGROUND
In the past 1–2 decades, treatment paradigms in rheumatoid arthritis (RA) have shifted 
dramatically from initial treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), 
followed by cautiously progressive addition of disease-modifying antirheumatic drugs 
(DMARDs), to the current treatment approach of aggressive initiation of DMARD therapy 
soon after the diagnosis of RA has been made. This change in RA management results from 
increasing data supporting improved prognosis and outcomes with the initiation of DMARD 
therapy early in the course of symptomatic disease.1,3
Rheumatoid factor (RF) has long been a component of the diagnostic criteria for rheumatoid 
arthritis and although it positive in 70% of RA patients. RF is well studied and its 
associations with a more severe disease course have been extensively described in Western 
countries. In more recent years, anti-CCP was positive in 65%-80% of RA patients. The 
anti-CCP status provides important prognostic information in RA. Also, Rönnelid et 
al showed that anti-CCP seropositive patients had more active disease during follow-up than 
seronegative patients.2
Given the optionality of biological treatment for RA patients, identifying a predictor for 
response will required more attention from rheumatologists for such patients.4
7. RESEARCH QUESTION AND OBJECTIVES
The objective of this study is to evaluate the impact of RF and anti-CCP positivity on RA 
patients.
8. RESEARCH METHODS 
8.1. Study Design

Retrospective analysis of patients with RA that received etanercept from Baghdad 
Teaching Hospital (Rheumatology center) from May 2012 until August 2019
(inclusion and exclusion criteria will apply for selecting patients).

Primary objective: Determine the clinical impact of RF and anti-CCP for 
management (etanercept) in patients with RA compared to negative RF and anti-CCP
in RA patients.

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8.2. Setting
Patients and Methods
Data will be collected from the Baghdad Teaching Hospital registry. The rheumatology 
patient registry is a prospective longitudinal multicenter cohort initiated in 2012. It captures 
all patients treated with biologic therapies managed in the rheumatology department.  The 
decision to initiate and maintain the treatment is guided by the American College of 
Rheumatology (ACR) recommendations. 
Study population
Patients will be included in the study if they meet the American College of 
Rheumatology/The European League Against Rheumatism (EULAR) 2010 criteria for 
Rheumatoid Arthritis,5 with at least 1 year of follow-up after starting their first biologic 
therapy.  This includes patients who were in monotherapy or in combo-therapy with
concomitant conventional DMARDs.
Hypothesis
Our hypothesis is that there is no difference in response between seropositive and 
seronegative RA patients to Enbrel.
8.2.1. Inclusion Criteria
Patients must meet all the following inclusion criteria to be eligible for inclusion in the study:
1. Diagnosed RA patients. 
2. ≥18 years of age. 
3. Did not receive previous another biological treatment.
8.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Had previous biological treatment.
2. Use of etanercept for less than 1 year.

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8.3. Data Sources
Patients will be identified from the rheumatology patient registry with rheumatoid arthritis 
and obtained information on patient demographics (age, gender), education level (years), 
present smoking status, disease duration (years), current MTX and steroid therapy (yes/no), 
baseline Disease Activity Score 28(DAS28) and Clinical Disease Activity Index (CDAI ), RF
status, anti-CCP status. Primary Outcomes: DAS28 and CDAI in last follow-up visit. 
8.4. Study Size
There is no pre-identified study size sample. All patients that meet the criteria will be
entered into the study.
8.5. Data Management 
The structured data is exported into an Excel spreadsheet and then transferred to the SPSS 
(version 23) database for statistical analysis.
8.6. Data Analysis 
Categorical covariates will be described by frequency distribution while continuous 
covariates will be expressed in terms of their mean and standard deviation or median and 
interquartile range as appropriate. Patients will be divided for seropositive RA and 
seronegative RA (according to anti-CCP status). The unadjusted comparisons between 
groups of the covariates and the outcomes will be evaluated using chi2 tests for categorical
data, while for continuous data, the Student’s t-test will be used for normally distributed 
variables and the Kruskall-Wallis test for non-parametric data.
The effect of biologic treatment response in patients with sero-positive RA will be 
determined with a multivariate analysis by using a stepwise linear regression model. The 
response variable is defined as DAS28 and CDAI at last visit. The baseline variables 
considered demographic data, disease duration (years), methotrexate (yes/no), current steroid 
therapy (yes/no), baseline DAS28 and CDAI, RF positive (yes/no), anti-CCP (yes/no), and 
present smoking (yes/no).
The effect of response will be determined by using change from baseline in DAS28 and 
CDAI at the last visit.  A p-value of <0.05 is considered statistically significant, without 
multiplicity adjustment, for this post-hoc analysis.
8.7. Quality Control
NA.
8.8. Limitations of the Research Methods
Missing data that could lead to bias is an identified limitation of this study.

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8.9. Other Aspects
NA.
9. PROTECTION OF HUMAN SUBJECTS
9.1. Patient Information 
This study involves data that exist in anonymized structured format and contain no patient 
personal information. 
9.2. Patient Consent
As this retrospective study involves anonymized structured data, which according to
applicable legal requirements do not contain data subject to privacy laws, obtaining informed 
consent from patients by Pfizer is not required.  
9.3. Institutional Review Board (IRB)/Independent Ethics Committee (IEC)
Not required.
9.4. 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 (GPP) issued by the 
International Society for Pharmacoepidemiology (ISPE), Good Epidemiological Practice 
(GEP) guidelines issued by the International Epidemiological Association (IEA), and Good
Practices for Outcomes Research issued by the International Society for Pharmacoeconomics 
and Outcomes Research (ISPOR).
10. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS 
This study involves data that exist as structured data by the time of study start.  
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (ie, identify a potential association between) a particular product and 
medical event for any individual.  Thus, the minimum criteria for reporting an adverse event 
(AE) (ie, identifiable patient, identifiable reporter, a suspect product, and event) cannot be 
met.
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
In the event of any prohibition or restriction imposed (eg, 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.  

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12. REFERENCES
1.
Van der Helm-van Mil AH, le Cessie S, van Dongen H, Breedveld FC, Toes RE,
Huizinga TW. A prediction rule for disease outcome in patients with recent-onset 
undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 
2007 Feb; 56(2):433-40.
2.
Rönnelid J, et al. Longitudinal analysis of citrullinated protein/peptide antibodies 
(anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts 
worse disease activity and greater radiological progression. Ann Rheum Dis 
2005;64:1744–9.
3.
2012 update of the 2008 American College of Rheumatology recommendations for the
use of disease-modifying antirheumatic drugs and biologic agents in the treatment of 
rheumatoid arthritis. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF, Kremer 
JM, Moreland LW, O'Dell J, Winthrop KL, Beukelman T, Bridges SL Jr, Chatham 
WW, Paulus HE, Suarez-Almazor M, Bombardier C, Dougados M, Khanna D, King
CM, Leong AL, Matteson EL, Schousboe JT, Moynihan E, Kolba KS, Jain A, 
Volkmann ER, Agrawal H, Bae S, Mudano AS, Patkar NM, Saag KG. Arthritis Care 
Res (Hoboken). 2012 May; 64(5):625-39.
4.
Factors predicting response to treatment in rheumatoid arthritis: the importance of 
disease duration. Anderson JJ, Wells G, Verhoeven AC, Felson DT. Arthritis Rheum. 
2000 Jan; 43(1):22-9.
5.
Neogi T, Aletaha D, Silman AJ, et al.  The 2010 American College of 
Rheumatology/European League Against Rheumatism classification criteria for 
rheumatoid arthritis: phase 2 methodological report, Arthritis Rheum, 2010, vol. 62 (pg.
2582 - 91).

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13. LIST OF TABLES 
NA.
14. LIST OF FIGURES
NA.
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.

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