Clinical Outcomes of Early Versus Delayed Management of Iraqi Patients With Ankylosing Spondylitis (AS) With Etanercept
Conditions: Ankylosing Spondylitis
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 
ankylosing spondylitis (AS) With Etanercept
Protocol number
B1801415
Protocol version identifier
3.0
Date
29 July 2021
Active substance
Etanercept
Medicinal product
Etanercept
Research question and objectives
Many publications found that the early 
initiation of biological treatment had positive
impact on patients’ response to the treatment
regimen, and with this Real World Data
(RWD), our objective is to evaluate 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.
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1. TABLE OF CONTENTS
1. TABLE OF CONTENTS.......................................................................................................2
2. LIST OF ABBREVIATIONS................................................................................................4
3. RESPONSIBLE PARTIES....................................................................................................6
4. AMENDMENTS AND UPDATES.......................................................................................7
5. MILESTONES.......................................................................................................................8
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........................................................................................................11
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 ......................................................................................................................12
11. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........12
12. REFERENCES ..................................................................................................................13
13. LIST OF TABLES.............................................................................................................14
14. LIST OF FIGURES ...........................................................................................................14

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ANNEX 1. LIST OF STAND-ALONE DOCUMENTS.........................................................14

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2. LIST OF ABBREVIATIONS
Abbreviation
Definition
ACR
American College of Rheumatology 
AE
Adverse Event
Anti-CCP
Anti-Cyclic Citrullinated Peptide
AS
Ankylosing Spondylitis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
DMARDs
Disease-Modifying Antirheumatic Drugs 
EULAR
European League Against Rheumatism 
GEP
Good Epidemiological Practice
GPP
Guidelines for Good Pharmacoepidemiology 
Practices
HLA-B27
Human Leukocyte Antigen B27
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
N/A
Not Applicable 
NI
Non-Interventional
NSAIDs
Nonsteroidal Anti-Inflammatory Drugs
RA
Rheumatoid Arthritis

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Abbreviation
Definition
RWD
Real World Data

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3. RESPONSIBLE PARTIES
Principal Investigator(s) of the Protocol
Name, degree(s)
Job Title
Affiliation
Address
, MD, 
M.Sc.
Medical Advisor
NI Study Lead
Pfizer Inc. – Iraq
 
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4. AMENDMENTS AND UPDATES
Amendment 
number
Date
Protocol 
section(s) 
changed
Summary of amendment(s)
Reason
1
08 July 
2021
Section 5. 
Milestones
Updated to align with Study Report
Administrative
2
29 July 
2021
Throughout 
document
Spelling errors
Administrative
Section 5 
Milestones
Updated to align with Study Report
Administrative

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5. MILESTONES
Milestone
Planned date
Start of data collection
01 August 2020
End of data collection
01 October 2020
Final study report
01 September 2021
6. RATIONALE AND BACKGROUND
In the past 1–2 decades, treatment paradigms in Ankylosing Spondylitis (AS) have shifted 
dramatically from initial treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), 
followed by the cautiously progressive addition of disease-modifying antirheumatic drugs 
(DMARDs), to the current treatment approach of the aggressive initiation of DMARD 
therapy soon after the diagnosis of AS has been made. This change in AS 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 AS
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 AS has on these outcomes is essential.
Accurate diagnosis of early AS begins with clear definitions of AS, as there is considerable 
variability in the literature regarding the time frame defining early AS.1 Previous intervention 
studies in early AS have included early AS as disease duration from 3 months to 3 years; 
however, with the knowledge of improved outcomes with earlier treatment in AS, it becomes
clear that a shorter time interval for classification of early rheumatoid arthritis (RA) is 
clinically significant. Due to the wide range of definitions of early AS presented in the 
literature, it is difficult to characterize the specific time frame that defines early AS. 
Multiple studies have evaluated the benefits of early treatment of AS, including several that 
have evaluated the impact of early DMARD treatment on successful response to therapy. In 
particular, a meta-analysis of ~1,400 AS 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.
7. RESEARCH QUESTION AND OBJECTIVES
The objective of this study is to evaluate 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 AS that received etanercept from Baghdad 
teaching hospital (Rheumatology center) from August 2012 until March 2020
(inclusion and exclusion criteria will apply for selecting patients).

Primary objective: determine the clinical impact of early referral for management in 
patients with AS compared to delayed management.

Secondary objective: determine the influence of early referral on the response to
biological treatment.
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 met the American College of Rheumatology/The 
European League Against Rheumatism (EULAR) 2019 criteria for AS, 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
There is no difference in response between early and delayed referral to biological treatment.
8.2.1. Inclusion Criteria
Patients must meet each of the following inclusion criteria to be eligible for inclusion in the 
study:
1. Diagnosed AS patients. 
2. ≥18 years old. 
3. Did not receive previous biological treatment for any reason.

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8.2.2. Exclusion Criteria
Patients meeting any of the following criteria will not be included in the study:
1. Patients previously or currently treated with other biological therapies.
2. Use of etanercept for less than 1-year duration.
8.3. Data Sources
Patients will be identified from the rheumatology patient registry with rheumatoid arthritis 
and will obtain information on patient demographics (age, gender), education level (years), 
present smoking status, disease duration (years), current steroid therapy (yes/no), baseline 
bath ankylosing spondylitis disease activity index (BASDAI), Bath Ankylosing spondylitis
functional index (BASFI), human leukocyte antigen B27 (HLA-B27), anticitrullinated 
protein antibody (anti-CCP) status.
Primary Outcomes: Disease activity Index BASFI and BASDAI from the last follow-up visit.
8.4. Study Size
There is no pre-identified study size. All patients that meet the inclusion/exclusion criteria 
will be entered into the study.
8.5. Data Management 
The study data is structured data and will be exported into an excel spreadsheet. The 
rheumatology center in Baghdad Teaching Hospital will analyze the data and provide it with 
results based on the defined primary and secondary endpoints.
8.6. Data Analysis 
All covariates will be summarized to get information about frequency distribution and mean, 
median or standard deviation. Numbers and percentages will be provided for categorical 
variables when performing descriptive analysis. Means, medians, standard deviations, or 
interquartile range as appropriate will be provided for continuous variables when performing 
descriptive analysis of continuous data. 
Patients will be divided according to the mean of disease duration groups (below and above
mean) and unadjusted comparisons between groups of the covariates and they will be 
evaluated using appropriate tests: chi-squared test will be used for categorical variables, t-test 
will be used for continuous variables, and the Kruskal-Wallis test for non-parametric 
variables; p-values willl be generated.

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We will determine the effect of early referral on the biologic treatment response patients with 
AS a multivariate analysis by using a stepwise linear regression model. The response variable 
is defined as BASFI and BASDAI at last visit. The baseline variables are considered 
demographic data, disease duration (years), methotrexate (yes/no), Current steroid therapy 
(yes/no), baseline BASFI, BASDAI, HLA-B27 positive (yes/no), anti-CCP (yes/no), present 
smoking (yes/no).
We will determine the effect of early response by using the difference in change between the 
baseline of BASDAI and BASFI and last follow-up. P-value <0.05 will be considered 
statistically significant.
8.7. Quality Control
Not Applicable (N/A).
8.8. Limitations of the Research Methods
Missing data that could lead to bias is a limitation in this study.
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 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 the 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).

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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.
Davide Simone, M Hussein Al Mossawi, Paul Bowness, Progress in our understanding 
of the pathogenesis of ankylosing spondylitis, Rheumatology, Volume 57, Issue 
suppl_6, November 2018, Pages vi4–vi9.

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13. LIST OF TABLES 
Not Applicable (N/A).
14. LIST OF FIGURES
Not Applicable (N/A).
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS
None.

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