Clinical Outcomes of Early Versus Delayed Management of Iraqi Patients With Rheumatoid Arthritis With Etanercept
Conditions: Arthritis Rheumatoid
Sponsor: Pfizer

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NON-INTERVENTIONAL (NI) STUDY PROTOCOL
Study Information
Title
Clinical Outcomes of Early Versus Delayed 
Management of Iraqi Patients With 
Rheumatoid Arthritis With Etanercept
Protocol number
B1801411
Protocol version identifier
1
Date
04 November 2019
Active substance
etanercept
Medicinal product
etanercept
Research question and objectives
Many publications found that the early 
initiation of biological treatment had good 
impact on patient response to treatment, and 
with this RWD (Real World Data) our 
objective is to see the impact of early 
initiation of etanercept on patient response 
compared to delayed introduction of 
biological treatment.
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

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

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ANNEX 2. ENCEPP (EUROPEAN NETWORK OF CNETERS FOR 
PHARMACOEPIDEMIOLOGY AND PHARMACOVIGILANCE) CHECKLIST 
FOR STUDY PROTOCOLS ..............................................................................................13
ANNEX 3. ADDITIONAL INFORMATION.........................................................................13

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACR
American College of Rheumatology 
CCP
Cyclic Citrullinated Peptide
CDAI
Clinical Disease Activity Index
DAS28
Disease Activity Score
DMARDs
Disease Modified Anti Rheumatic Drugs 
ENCePP
European Network of Cneters for 
pharmacoepidemiology and pharmacovigilance
EULAR
The European League Against Rheumatism 
N/A
Non Applicable 
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
RA
Rheumatoid Arthritis
RDW
Real World Data
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
Pfizer Inc. – Iraq
 
PPD
PPD

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4. AMENDMENTS AND UPDATES
None.

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5. MILESTONES
Milestone
Planned date
Start of data collection
01 November 2018 
End of data collection
01 December2018 
Final study report
01 February 2019
This protocol was written post the conduct and completion of analysis.

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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. Since the goals in RA management 
include not only disease remission, but also improved functional status, which is strongly 
associated with radiographic joint damage, an understanding of the impact that the initiation 
of appropriate treatment during early RA has on these outcomes is essential.
Accurate diagnosis of early RA begins with clear definitions of RA, as there is considerable 
variability in the literature regarding the time frame defining early RA.1 Previous 
intervention studies in early RA have included early RA as disease duration from 3 months to
3 years; however, with the knowledge of improved outcomes with earlier treatment in RA, it 
becomes clear that a shorter time interval for classification of early RA is clinically 
significant. Due to the wide range of definitions of early RA presented in the literature, it is 
difficult to characterize the specific time frame that defines early RA. However, it is now 
generally accepted that early RA is the onset of symptoms of joint (typically polyarticular) 
pain, stiffness, or swelling within the past 3 months,2,3 although in practical terms it may be 
difficult for rheumatologists to evaluate patients within that 3-month time frame, due to a 
variety of factors, including delay in referral of patients with early symptoms of 
inflammatory arthritis (IA) or delays in patients seeking medical attention for their 
symptoms.
Multiple studies have evaluated the benefits of early treatment of RA, including several that 
have evaluated the impact of early DMARD treatment on successful response to therapy. In 
particular, a meta-analysis of ~1,400 RA patients from 14 randomized controlled trials 
identified that one of the strongest predictors of response to therapy was a shorter disease 
duration at the time of treatment initiation.4
7. RESEARCH QUESTION AND OBJECTIVES
The objective of this study is to see the impact of early initiation of etanercept on patient
response compared to delayed introduction of biological treatment.

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8. RESEARCH METHODS 
8.1. Study Design

Retrospective analysis of patients with RA that received etanercept from Baghdad 
teaching hospital (Rheumatology center) from 2012 until 2018 (inclusion and 
exclusion criteria will apply for selecting patients).

Primary aim: determine the impact of early referral for management in patients with 
RA compared to delayed management.

Secondary aims: Determine the influence of early referral on the response to 
biological treatment.
8.2. Setting
Patients and Methods
Data 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 ACR (American College of 
Rheumatology) recommendations. 
Study population
Patients included in the study if they met the American College of Rheumatology/EULAR
(The European League Against Rheumatism) 2012 criteria for Rheumatoid Arthritis, with at 
least 1 year of follow up after starting their first biologic therapy.
Exclusion criteria: patients previously or currently treated with other biological therapies.
Hypothesis
Our initial hypothesis is that there is no difference in response between early and delayed 
referral to biological treatment.
8.2.1. Inclusion Criteria
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Diagnosed RA patients. 
2. 18 years old and above. 
3. Did not receive pervious biological treatment.

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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 etanercept for less than 1 year.
8.3. Data Sources
We identified patients in rheumatology registry with rheumatoid arthritis and obtained 
information on patient demographics (age, gender), education level (years), present smoking 
status, disease duration (years), current steroid therapy (yes/no), baseline DAS28 (Disease 
Activity Index 28) & CDAI (Clinical Disease Activity Index) RF (Rheumatoid factor) status, 
anticitrullinated protein antibody (anti-CCP) status. Primary Outcomes: Disease activity 
Index (DAS28) and CDAI in last follow up visit.
8.4. Study Size
There is no pre identified study size. All patients that met the criteria entered for study.
8.5. Data Management 
The data structured and exported in excel sheet.
8.6. Data Analysis 
Categorical covariates described by frequency distribution while continuous covariates 
expressed in terms of their mean and standard deviation or median and interquartile range as 
appropriate. Patients were divided according to the mean of disease duration groups (below 
and above mean) and unadjusted comparisons between groups of the covariates and the 
outcomes are evaluated using chi2 tests for categorical data, while for continuous data, we 
used the student’s t-test for normally distributed variables and the Kruskall-Wallis test for 
non-parametric data.
We determined the effect of early referral on the biologic treatment response patients with 
RA a multivariate analysis by using a stepwise linear regression models. 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), present 
smoking (yes/no).
We determined the effect of early response by using the difference between the base line 
DAS28 and CDAI. P value <0.05 considered statistically significant.
8.7. Quality Control
N/A.

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8.8. Limitations of the Research Methods
The limitation of this project could be the missing data that could lead to some bias.
8.9. Other Aspects
Not Applicable (N/A).
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 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 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.

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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.
A prediction rule for disease outcome in patients with recent-onset undifferentiated 
arthritis: how to guide individual treatment decisions. van der Helm-van Mil AH, le 
Cessie S, van Dongen H, Breedveld FC, Toes RE, Huizinga TW . Arthritis Rheum. 
2007 Feb; 56(2):433-40.
2.
Attitudes to early rheumatoid arthritis: changing patterns. Results of a survey. Aletaha 
D, Eberl G, Nell VP, Machold KP, Smolen JS. Ann Rheum Dis. 2004 Oct; 
63(10):1269-75.
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.
13. LIST OF TABLES 
N/A.
14. LIST OF FIGURES
N/A.
ANNEX 1. LIST OF STAND ALONE DOCUMENTS
None.
ANNEX 2. ENCEPP (EUROPEAN NETWORK OF CNETERS FOR 
PHARMACOEPIDEMIOLOGY AND PHARMACOVIGILANCE) CHECKLIST FOR 
STUDY PROTOCOLS
Not required.
ANNEX 3. ADDITIONAL INFORMATION
N/A.