A MULTICENTER OPEN-LABEL STUDY OF ETANERCEPT WITHDRAWAL AND RETREATMENT IN SUBJECTS WITH NON-RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS WHO ACHIEVED ADEQUATE 24 WEEK RESPONSE
Phase: PHASE4
Conditions: Spondylitis, Ankylosing
Sponsor: Pfizer

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A MULTICENTER OPEN-LABEL STUDY OF ETANERCEPT WITHDRAWAL 
AND RETREATMENT IN SUBJECTS WITH NON-RADIOGRAPHIC AXIAL 
SPONDYLOARTHRITIS WHO ACHIEVED ADEQUATE 24 WEEK RESPONSE
Compound:
PF-05208752
Compound Name:
Enbrel
United States (US) Investigational New
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2015-000541-24
Protocol Number:
B1801381
Phase:
4
CCI

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Final Protocol, 24 June 2015
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Document History
Document
Version Date
Summary of Changes
Original protocol
24 June 2015
Not Applicable (N/A)

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TABLE OF CONTENTS
LIST OF FIGURES ...................................................................................................................7
APPENDICES ...........................................................................................................................7
1. INTRODUCTION ...............................................................................................................15
1.1. Mechanism of Action/Indication.............................................................................15
1.2. Background and Rationale ......................................................................................15
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................17
2.1. Objectives................................................................................................................17
2.1.1. Primary Objective.......................................................................................17
2.1.2. Secondary Objectives .................................................................................17
2.2. Endpoints.................................................................................................................17
2.2.1. Primary Endpoint........................................................................................17
2.2.2. Secondary Endpoints and Outcome Measures ...........................................17
2.2.3. Safety Endpoints.........................................................................................18
3. STUDY DESIGN.................................................................................................................19
3.1. Period 1 ...................................................................................................................19
3.2. Period 2 ...................................................................................................................19
3.3. Period 3 ...................................................................................................................19
3.4. Follow-up ................................................................................................................19
4. SUBJECT SELECTION......................................................................................................20
4.1. Inclusion Criteria – Period 1 ...................................................................................20
4.2. Inclusion Criteria – Period 2 ...................................................................................23
4.3. Inclusion Criteria – Period 3 ...................................................................................23
4.4. Exclusion Criteria....................................................................................................23
4.5. Lifestyle Guidelines ................................................................................................27
4.6. Sponsor’s Qualified Medical Personnel..................................................................28
5. STUDY TREATMENTS.....................................................................................................29
5.1. Allocation to Treatment ..........................................................................................29
5.2. Subject Compliance.................................................................................................29
5.3. Investigational Product Supplies.............................................................................30
5.3.1. Dosage Form(s) and Packaging..................................................................30
5.3.2. Preparation and Dispensing........................................................................30

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5.4. Administration.........................................................................................................30
5.5. Investigational Product Storage ..............................................................................30
5.6. Investigational Product Accountability...................................................................31
5.7. Destruction of Investigational Product Supplies.....................................................31
5.8. Concomitant Treatment(s).......................................................................................32
5.8.1. Non Pharmacologic Interventions ..............................................................33
5.8.2. Prohibited Medications...............................................................................33
6. STUDY PROCEDURES .....................................................................................................33
6.1. Screening.................................................................................................................33
6.1.1. Screening Procedures..................................................................................34
6.2. Baseline (Day 1)......................................................................................................36
6.3. Induction Period (Period 1).....................................................................................37
6.4. Withdrawal Period (Period 2)..................................................................................38
6.5. Re-Treatment Period for Subjects in the Withdrawal Phase (Period 3)..................39
6.6. Follow-up Call.........................................................................................................40
6.7. Early Discontinuation Visit.....................................................................................41
6.8. Subject Withdrawal.................................................................................................42
7. ASSESSMENTS..................................................................................................................44
7.1. Pregnancy Testing...................................................................................................44
7.2. Banked Biospecimens .............................................................................................45
7.2.1. Markers of Drug Response.........................................................................45
7.2.2. Additional Research....................................................................................46
7.3. Efficacy Assessments..............................................................................................47
7.3.1. Physician’s Global Assessment (PGA) ......................................................47
7.3.2. Tender/Painful Joint Count (44).................................................................47
7.3.3. Swollen Joint Count (44)............................................................................47
7.3.4. Dactylitis.....................................................................................................47
7.3.5. Maastricht Anklyosing Spondylitis Enthesitis Score (MASES) ................48
7.4. Health Outcomes Assessments................................................................................48
7.4.1. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)..............48
7.4.2. Bath Ankylosing Functional Index (BASFI)..............................................48
7.4.3. Subject’s Assessment of Disease Activity (SADA)...................................48

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7.4.4. Subject Nocturnal and Total Back Pain......................................................48
7.4.5. Bath Ankylosing Spondylitis Patient Global Assessment Score 
(BAS-G)...........................................................................................................48
7.4.6. EuroQoL-5D Health Questionnaire (EQ-5D).............................................48
7.4.6.1. Short Form-36 (SF-36)..............................................................49
7.4.7. Work Productivity and Activity Impairment (WPAI)................................49
7.5. Safety Assessments .................................................................................................49
7.5.1. Physical Examinations................................................................................49
7.5.2. Vital Signs/Height/Weight..........................................................................50
7.5.3. Chest X-ray and TB Testing.......................................................................50
7.5.4. IBD, Psoriasis, Uveitis Assessment............................................................50
7.5.5. Adverse Events and Serious Adverse Events.............................................50
7.5.6. Clinical Laboratory Evaluations.................................................................50
7.6. Laboratory Evaluations ...........................................................................................50
7.7. Imaging....................................................................................................................51
8. ADVERSE EVENT REPORTING......................................................................................52
8.1. Adverse Events........................................................................................................52
8.2. Reporting Period .....................................................................................................52
8.3. Definition of an Adverse Event...............................................................................53
8.4. Medication Errors....................................................................................................54
8.5. Abnormal Test Findings..........................................................................................54
8.6. Serious Adverse Events...........................................................................................55
8.6.1. Protocol-Specified Serious Adverse Events...............................................55
8.6.2. Potential Cases of Drug-Induced Liver Injury............................................55
8.7. Hospitalization ........................................................................................................56
8.8. Severity Assessment................................................................................................58
8.9. Causality Assessment..............................................................................................58
8.10. Exposure During Pregnancy..................................................................................58
8.11. Occupational Exposure .........................................................................................60
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject 
Withdrawal)...............................................................................................................60
8.13. Eliciting Adverse Event Information ....................................................................60
8.14. Reporting Requirements........................................................................................60

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8.14.1. Serious Adverse Event Reporting Requirements .....................................60
8.14.2. Nonserious Adverse Event Reporting Requirements ...............................61
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................61
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................61
9.1. Sample Size Determination.....................................................................................61
9.2. Efficacy Analysis ....................................................................................................61
9.2.1. Analysis of the Primary Endpoint...............................................................61
9.2.2. Analysis of Secondary Endpoints...............................................................62
9.3. Safety Analysis........................................................................................................63
9.4. Interim Analysis ......................................................................................................63
9.5. Data Monitoring Committee ...................................................................................63
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................63
11. DATA HANDLING AND RECORD KEEPING .............................................................64
11.1. Case Report Forms/Electronic Data Record .........................................................64
11.2. Record Retention...................................................................................................64
12. ETHICS..............................................................................................................................65
12.1. Institutional Review Board/Ethics Committee......................................................65
12.2. Ethical Conduct of the Study ................................................................................65
12.3. Subject Information and Consent..........................................................................65
12.4. Subject Recruitment ..............................................................................................66
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................66
13. DEFINITION OF END OF TRIAL...................................................................................66
13.1. End of Trial in a Member State.............................................................................66
13.2. End of Trial in All Other Participating Countries.................................................66
14. SPONSOR DISCONTINUATION CRITERIA ................................................................66
15. PUBLICATION OF STUDY RESULTS..........................................................................67
15.1. Communication of Results by Pfizer ....................................................................67
15.2. Publications by Investigators ................................................................................67
16. REFERENCES ..................................................................................................................69

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LIST OF FIGURES
Figure 1.
Study Schematic ...................................................................................................20
APPENDICES
Appendix 1. Abbreviations......................................................................................................70
Appendix 2. ASAS Classification Criteria for Axial Spondyloarthritis (ax SpA) in 
Patients with 3 Months of Back Pain and Age at Onset <45..............................73
Appendix 3. Radiographic Criterion in the Modified New York Criteria for Ankylosing 
Spondylitis ............................................................................................................74
Appendix 4. Definition of Parameters Applied in the Classification Criteria for Ax SpA .....75
Appendix 5. Grades of Adverse Events...................................................................................76
Appendix 6. ASAS Eligibility Flowchart................................................................................77

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PROTOCOL SUMMARY
Background and Rationale
Axial Spondyloarthritis (ax SpA) is a chronic disease whose most devastating clinical 
manifestation is the loss of mobility.  The Assessment of SpondyloArthritis international 
Society (ASAS) recently created a classification system for ax SpA based on whether 
patients meet clinical criteria or imaging criteria.  Patients meeting the ASAS criteria for ax
SpA without evidence of sacroiliitis on x-ray are classified as having non-radiographic axial 
spondyloarthritis (nr-ax SpA).  In several recent studies, anti-tumor necrosis factor (TNF) 
agents, including etanercept (ETN), demonstrated efficacy in patients with nr-ax SpA.  
However, additional long-term data are needed, and little is known about the effects of 
etanercept withdrawal in subjects who have achieved a significant clinical response.
In a small trial (ESTHER)3 of etanercept-treated patients who had achieved an ASAS partial 
remission after 48 weeks of etanercept treatment, 13 with nr-ax SpAwere withdrawn from 
therapy.  The flare rate in year 2 was 69%, and the mean time to flare was 24.4 weeks.  
Retreatment with etanercept showed an improvement in all clinical (Bath Ankylosiong 
Spondylitis Disease Activity Index [BASDAI], Ankylosing spondylitis Disease Activity 
Score [ASDAS], C-reactive protein [CRP]) and imaging (magnetic resonance imaging [MRI]
sacroiliac joint [SIJ], MRI spine, MRI enthesitis) variables.  Only a portion of the subjects 
re-established remission status (56% ASAS remission; 44% MRI remission; 33% MRI plus 
ASAS remission).
The proposed study is a followup of this small pilot study that will further our understanding 
of the benefits and risks of ETN withdrawal in patients who have achieved a significant 
clinical response.  Much is known already from B1801031 about relapse rates of those 
achieving remission and continuing on ETN, therefore an open-label study estimating the 
relapse rates in such patients withdrawn from ETN is planned.
Objectives and Endpoints

The primary objective of this study is to estimate the proportion of subjects who flare
within 40 weeks following withdrawal of ETN in subjects who have achieved 
inactive disease (defined as ASDAS less than 1.3).  The key secondary objective is to 
measure time to flare after withdrawal of ETN.

The primary endpoint for this study is occurrence of flare within 40 weeks (defined as 
an ASDAS greater than or equal to 2.1) following withdrawal of ETN.  The key 
secondary endpoint is the time to flare after withdrawal of ETN.
Study Design
This multicenter, open-label, three period study will evaluate withdrawal and retreatment of 
ETN in subjects with nr-ax SpA who achieved an adequate response, as measured by 
Ankylosing Spondylitis Disease Activity Score C-Reactive Protein (ASDAS CRP) less than 
1.3 (inactive disease) following 24 weeks of treatment.  The study is expected to randomize 

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approximately 200 subjects in Period 1, in order to have approximately 96 subjects qualify 
for Period 2. 
Period 1 is an open-label, 24-week period in which all eligible subjects will be enrolled and 
treated with ETN 50 mg once weekly plus a stable background non-steroidal 
anti-inflammatory drug (NSAID) at the optimal tolerated anti-inflammatory dosage.  The 
target for this period is therapeutic response defined as achieving ASDAS CRP less than 
1.3 at Week 24.  Subjects who do not achieve ASDAS CRP less than 1.3 will not enter 
Period 2 and will complete the study at the Week 28 day follow-up phone call/visit.
Period 2 is a 40-week withdrawal period where subjects will discontinue ETN following the 
Week 24 dose, yet maintain the background NSAID.  If the subject has not flared by the 
Week 64 visit, their participation in the study is complete.  Subjects who flare (defined as an
Ankylosing Spondylitis Disease Activity Score Erythrocyte Sedimentation Rate [ASDAS 
ESR] greater than or equal to 2.1) during Period 2 will enter a retreatment period (Period 3) 
and receive approximately 12 weekly doses of open-label ETN. 
Study Schematic

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Study Treatments
For the purposes of this study, investigational product will be defined as ETN.  The sponsor 
will supply ETN.  Investigational product will be administered only to subjects who have 
provided informed consent.  Once a subject’s participation in the study has ended, ETN will 
no longer be supplied to the subject by the investigative site and/or sponsor.
Statistical Method
The primary endpoint, the proportion of subjects who flare (ASDAS ESR greater than or 
equal to 2.1) in Period 2 will be summarized descriptively as the percent with flare with 
95% confidence intervals.  This estimate will include all subjects who qualify for the 
retreatment interval and have at least one evaluation after treatment is withdrawn.
For the key secondary endpoint of time to flare, descriptive statistics will include median 
time to flare and 95% confidence intervals using the Kaplan-Meier approach. 

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SCHEDULE OF ACTIVITIES
The schedule of activities table provides an overview of the protocol visits and procedures.  Refer to the STUDY PROCEDURES and 
ASSESSMENTS sections of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed on the schedule of activities, in order to conduct 
evaluations or assessments required to protect the well-being of the subject.
Study Interval
Screen
Period 1
Induction
Period 2
Withdrawal
Period 3
Retreatment
(If subject flares 
during Period 2)
Follow-upd
Early 
DC
Study Week
Screenb BL
Day 
1
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
24
Wk 
28c
Wk 
32
Wk 
40
Wk 
48
Wk 
56
Wk 
64
Wk 
R0e
Wk 
R4
Wk 
R8
Wk 
R12
28 Days After 
Last Dose
Early 
DCf
Visit Windowa (Days)
-28 to
-5
4
4
4
4
7
4
7
7
7
7
7
4
4
4
4
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
R1
R2
R3
R4
14
Informed Consent
X
Review Eligibility Criteria
X
X
Xg
Demographics
X
Medical Historyh
X
Chest Radiograph /TB Testingi
X
Contraception Checkj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Safety Assessments
Vital Signs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height/Weight
X
X
X
X
X
Physical Exam
X
X
X
X
X
IBD, Psoriasis, Uveitis 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse Eventsk
X


















Laboratory
Hematology/Blood Chemistryl
X
X
X
X
X
X
X
X
Urinalysisl
X
X
Pregnancy Testm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Study Interval
Screen
Period 1
Induction
Period 2
Withdrawal
Period 3
Retreatment
(If subject flares 
during Period 2)
Follow-upd
Early 
DC
Study Week
Screenb BL
Day 
1
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
24
Wk 
28c
Wk 
32
Wk 
40
Wk 
48
Wk 
56
Wk 
64
Wk 
R0e
Wk 
R4
Wk 
R8
Wk 
R12
28 Days After 
Last Dose
Early 
DCf
Visit Windowa (Days)
-28 to
-5
4
4
4
4
7
4
7
7
7
7
7
4
4
4
4
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
R1
R2
R3
R4
14
HLA B27
X
hsCRPl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESRl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Banked Specimen Prep D1
X
Banked Specimen Prep B1 and 
Prep R1
X
X
X
Xn
Hepatitis B, Hepatitis C Testing
X
Imaging
SIJ X-rayo
X
MRI Spine & SIJp
X
X
X
X
Xq
X
X
Investigational Product
Open-Label Treatment Assignment 
(First dose administered by study 
personnel)
X
Dispense Investigational 
Product (IP)
X
X
X
X
X
X
X
X
Collect IP & Accountabilityr
X
X
X
X
X
X
X
X
X
Dispense IP Diary Card
X
X
X
X
X
X
X
X
Collect & Review IP Diary Card
X
X
X
X
X
X
X
X
X
Prior/Concomitant Treatments
X
X















s
s
Efficacy Assessments
Joint Assessmentt,u
X
X
X
X
X
X
X
X
X
Physician Global Assessmentu
(PGA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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Study Interval
Screen
Period 1
Induction
Period 2
Withdrawal
Period 3
Retreatment
(If subject flares 
during Period 2)
Follow-upd
Early 
DC
Study Week
Screenb BL
Day 
1
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
24
Wk 
28c
Wk 
32
Wk 
40
Wk 
48
Wk 
56
Wk 
64
Wk 
R0e
Wk 
R4
Wk 
R8
Wk 
R12
28 Days After 
Last Dose
Early 
DCf
Visit Windowa (Days)
-28 to
-5
4
4
4
4
7
4
7
7
7
7
7
4
4
4
4
Visit Identifier
1
2
3
4
5
6
7
8
9
10
11
12
13
R1
R2
R3
R4
14
Health Outcome Assessments
    BASDAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
    BASFI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Assessment of Disease 
Activity (SADA)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject Nocturnal and 
Total Back Pain VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
BAS-G
X
X
X
X
X
X
X
X
X
EQ-5D
X
X
X
X
X
X
X
X
X
SF-36
X
X
X
X
X
X
X
X
X
WPAI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Abbreviations: BL=baseline; IBD = inflammatory bowel disease, IP = investigational product; TB=tuberculosis; = ongoing/continuous event; 
HLA-B27 = human leucocyte antigen B27; hsCRP = high sensitivity c-reactive protein; SIJ = sacroiliac joint; MRI = magnetic resonance imaging; 
BASDAI = Bath Ankylosing Spondylitis Disease Activity Score; BASFI = Bath Ankylosing Spondylitis Functional Index; BAS-G = Bath Ankylosing 
Spondylitis Patient Global Assessment Score; EQ-5D = EuroQol EG-5D Health State Profile; SF-36 = 36-Item Short-Form Health Survey; WPAI = Work 
Productivity and Activity Impairment Questionnaire .
a.
Day relative to start of study treatment (Day 1).
b.
Screening visit should occur within 4 weeks (28 days) of BL visit but no less than 5 days before BL visit.  The screening period may be extended up to 
42 days if repeat imaging is required or when tuberculosis prophylactic therapy is started during the screening period. 
c.
ASDAS CRP will be calculated at the Week 24 visit, which will determine if subjects are eligible to enter Period 2.  If the ASDAS CRP is <1.3 at Week 24, 
subjects will return to the site at Week 28 to continue with the Period 2 procedures.  If the Week 24 ASDAS CRP is 1.3, the subject should be notified by 
phone that their participation in the study is complete.  A follow-up call will be conducted in place of the Week 28 visit to assess new and ongoing adverse 
events and medication taken to treat them since the last dose of investigational product. 
d.
Follow-up: For subjects who discontinue the study during Period 1, or enter Period 2 and discontinue from the study before the Week 28 visit, or subjects 
who enter Period 3, there will be a follow-up telephone call to assess new and ongoing adverse events and the medications taken to treat them.  This call will 
be approximately 28 days after the last dose of IP.  No follow-up is needed if subjects enter Period 2 and do not experience a flare.  If required by local 
regulations, the follow-up visit may be conducted at the study site.

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e.
The first visit of the Retreatment period (Period 3) may occur at the same time as a regularly scheduled visit during Period 2 or it may occur as an 
unscheduled visit. 
f.
Early discontinuation: If a subject discontinues from the study prior to the last visit of any period every effort should be made during the early 
discontinuation visit to perform all procedures, laboratory assessments (including biomarker samples), questionnaires and obtain the MRI.
g.
Subjects must complete Period 1 and achieve ASDAS CRP <1.3 at the Week 24 visit in order to be eligible to enter Period 2.
h.
Medical history evaluation includes: general medical history, disease specific medical history, evaluation of background medication and family medical 
history.
i.
Chest x-ray and TB testing: local country guidelines should be followed for appropriate screening and prophylaxis in the setting of anti-TNF therapy, 
including a chest radiograph and objective TB testing, such as purified protein derivative (PPD) or Quantiferon.  If the subject is known to be PPD positive, 
the test need not be repeated if documentation is available to show the subject meets local criteria for anti-TNF therapy and has not had active TB in the last 
2 years.  If the subject has a documented negative PPD or Quantiferon test within 3 months prior to the screening visit, the test need not be repeated.
j.
Ensure that the subject is using the appropriate contraception as detailed in Section 4.5 of the protocol and document in the source notes. 
k.
Adverse Events both serious and non-serious should be recorded on the case report form (CRF) from the first dose of IP through the subject’s last visit.  In 
addition, serious adverse events (SAE) must be reported to Pfizer from the time that the subject provides informed consent.
l.
Hematology/Blood chemistry/Urinalysis/hsCRP/ESR: These laboratory tests do not need to be repeated at the baseline visit (Visit 2) if they were completed 
at the screening visit 14 days before baseline.  Should the laboratory results subsequently show that the subject does not meet the inclusion/exclusion
criteria and this is confirmed upon retest, the subject must be withdrawn from the study at that time.
m.
Pregnancy Testing: Women of child-bearing potential must have a negative serum pregnancy test at the screening and baseline visit.  Additionally they must 
have a confirmed negative urine pregnancy test prior to the first dose of investigational product at the baseline visit.  The pregnancy test(s) may be repeated 
at the discretion of the investigator if the subject misses a menses, or if the potential of pregnancy is otherwise suspected.  Women of this group must be 
willing to use a highly effective contraceptive method.  Pregnancy test may also be repeated as per request of institutional review board (IRB)/ethics 
committees (ECs) or if required by local regulations.
n.
Collection of the Prep B1 and Prep R1 banked specimens are only completed at this time point if the subject discontinues early during Period 1.
o.
Screening SIJ x-ray is the first imaging procedure that is performed.  The reading to assess eligibility is performed by a central imaging vendor.  If the SIJ
x-ray must be repeated, the screening period may be extended to 6 weeks.  Results of historical x-rays of the SIJ that have been obtained within 4 months 
prior (12 months in Germany only) to the screening visit could be used in lieu of performing screening x-rays.  If historical x-rays are used, the original 
films, or a copy, must be on site and a copy should be sent to the central reader.  If the results are considered unevaluable by the central reader, the x-ray 
must be performed during screening.  The central reader must be able to determine the presence of and/or the degree of sacroiliitis.  If the results are 
considered unevaluable by the central reader and the subject is unable to have a repeat x-ray due to the regulations issued by the German Federation of 
Radiation Council, the subject will be considered a screen failure.
p.
MRI should only be done after eligibility is determined by SIJ x-ray.  The MRI is performed during the screening period.  If the MRI must be repeated, the 
screening period may be extended to 6 weeks.
q.
If a subject experiences a flare in <8 weeks since their previous MRI, there is no need to conduct the MRI at the first retreatment visit. 
r.
Drug accountability is done at each clinical visit during Period 1 and Period 3 to assess compliance with the protocol dosing regimen.
s.
Record medications taken to treat any new or ongoing adverse events/serious adverse events that occurred since the last study visit.
t.
Joint Assessment includes: Tender and swollen joint count, dactylitis and enthesitis (Maastricht Anklyosing Spondylitis Enthesitis Score [MASES]) 
evaluation. 
u.
It is recommended that the same qualified personnel complete these assessments at each visit. 

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1. INTRODUCTION
Spondyloarthritis (SpA) is a chronic, inflammatory disease characterized by joint 
inflammation, enthesitis and certain extra-articular manifestations in organs such as the eyes, 
skin, and cardiovascular system.  It involves preferentially either the axial skeleton (axial 
SpA) or peripheral joints (peripheral SpA).  The etiology of SpA is unknown but may 
involve the interaction of genetic and environmental factors.  It is currently believed that 
axial SpA begins in the absence of the classic radiographic features which define ankylosing 
spondylitis (AS).  This beginning disease state is referred to as non-radiographic axSpA. 
Ankylosing Spondylitis can cause permanent structural changes leading to progressive 
disability impacting the quality of life.  It is unknown if treatment of nr-ax SpA will prevent 
progression to AS, but SpA at all stages represents significant health and socioeconomic 
burdens for the individual patient and society.1
The use of MRI and improved radiographic technology has generated new interest in 
initiating early intervention and treatment of axial SpA before significant, irreversible 
damage has occurred.  Early diagnosis could potentially lead to earlier intervention with the 
goal of disease activity control, maintenance of physical function, and optimization of quality 
of life.
The name, title, address and telephone number(s) of the sponsor’s medical expert for the trial 
document are provided in the study reference manual.
1.1. Mechanism of Action/Indication
Etanercept (ETN) is a recombinant human necrosis factor alpha (TNF) soluble receptor that 
blocks TNFbinding to cell surface receptors and initiation of intracellular signaling.  ETN 
is approved for the treatment of AS and nr-ax SpA. 
1.2. Background and Rationale
Axial Spondyloarthritis (ax SpA) is a chronic disease whose most devastating clinical 
manifestation is the loss of mobility.  Commonly ax SpA progresses from sacral 
inflammation to progressive spine ankylosis over time.  Since patients with early disease may 
not show x-ray abnormalities related to SpA, new technologies such as MRI are increasingly 
being utilized.  The Assessment of SpondyloArthritis international Society (ASAS) recently 
created a classification system for ax SpA based on whether patients meet clinical criteria or 
imaging criteria.  Patients meeting the ASAS criteria for ax SpA without evidence of 
sacroiliitis on x-ray are classified as having nr-ax SpA.  With the advent of new consensus 
based criteria that allow earlier identification of patients with ax SpA, before significant 
x-ray abnormalities develop,3 earlier therapeutic intervention may potentially impact the 
natural history of the disease by shutting down early inflammation, as this may be the 
forerunner of irreversible bony ankylosis.4 In several recent studies, anti-tumor necrosis 
factor (TNF) agents, including ETN, demonstrated efficacy in patients with nr-ax SpA.  
However, additional long-term data are needed, and little is known about the effects of ETN
withdrawal in subjects who have achieved a significant clinical response.

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In a small trial (ESTHER)3 of etanercept-treated patients who had achieved an ASAS partial 
remission after 48 weeks of etanercept treatment, 13 with nr-ax SpAwere withdrawn from 
therapy.  The flare rate in year 2 was 69%, and the mean time to flare was 24.4 weeks .  
Retreatment with etanercept showed an improvement in all clinical (BASDAI, ASDAS, 
CRP) and imaging (MRI SIJ, MRI spine, MRI enthesitis) variables.  Only a portion of the 
subjects re-established remission status (56% ASAS remission; 44% MRI remission; 
33% MRI plus ASAS remission).
In study B1801031, patients with nr-ax SpA given a 12 week course of ETN had 
significantly reduced clinical signs and symptoms as well as SIJ and spinal inflammation on 
MRI as compared to patients receiving placebo.2 An open-label extension is currently 
underway to examine long-term efficacy and safety.
Little is known about the effects of ETN withdrawal in subjects who have achieved a 
significant clinical response.  A small study with a mixture of AS and nr-ax SpA patients 
having achieved a significant clinical response showed that approximately 75-80% of 
subjects had relapses after 2 years.  After retreatment, only about a third recovered the level 
of clinical response they had achieved at the time of withdrawal.3 However, firm conclusions 
regarding the effects of withdrawal and retreatment could not be drawn due to the low 
numbers of patients in the study. 
The proposed study is a followup of this small pilot study that will further our understanding 
of the benefits and risks of ETN withdrawal in patients who have achieved a significant 
clinical response.  Much is known already from B1801031 about relapse rates of those 
achieving remission and continuing on ETN, therefore an open-label study estimating the 
relapse rates in such patients withdrawn from ETN is planned.
Overall, the benefits of ETN administration in patients with nr-ax SpA are expected to 
include reduced disease activity, including less pain, reduced inflammation of the SIJ, and 
improved physical function.  Based on the safety experience from the B1801031 study 
combined with the long-term safety data and post-marketing safety experience in AS, an 
acceptable safety profile is expected in nr-ax SpA patients treated with ETN.  Consequently, 
the risk-benefit balance of ETN for the treatment of nr-ax SpA is considered to be positive in 
patients who have high disease activity despite treatment with NSAIDs.  Furthermore, the 
risk benefit may be more favorable in patients with objective evidence of inflammation, 
ie, those who have high CRP and/or MRI inflammation.  The proposed study will further our 
understanding of the benefits and risks of ETN withdrawal in patients who have achieved a 
significant clinical response.
The dosing regimen chosen for this study is in agreement with the recommended dosage for 
AS in adults ages 18 or older. 
Complete information for this compound may be found in the single reference safety 
document (SRSD), which for this study is the Investigator Brochure (IB). 

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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
2.1.1. Primary Objective

To estimate the proportion of subjects who flare within 40 weeks following 
withdrawal of ETN in subjects who have achieved ASDAS CRP less than
1.3 (inactive disease).
2.1.2. Secondary Objectives

To estimate time to flare after withdrawal of ETN, and to compare it to that in 
subjects from B1801031 who continued ETN therapy.

To estimate the efficacy of 12 weeks of retreatment in subjects who experience a flare 
after withdrawal of ETN.

To estimate the efficacy of ETN over 24 weeks of initial treatment.

To estimate the safety and tolerability of ETN in this population.
2.2. Endpoints
This study will not use an Endpoint Adjudication Committee. 
2.2.1. Primary Endpoint

The primary endpoint is the occurrence of flare (defined as an ASDAS ESR greater 
than or equal to 2.1) within 40 weeks following withdrawal of ETN.
2.2.2. Secondary Endpoints and Outcome Measures
The following key secondary endpoint will be estimated:

The time to flare following withdrawal of ETN (as measured from treatment 
withdrawal until ASDAS ESR greater than or equal to 2.1).
The following secondary endpoints and outcome measures will be estimated within 40 weeks 
following withdrawal of ETN and during the 12 week re-treatment period (if applicable):

Occurrence of ASDAS CRP less than 1.3 (inactive disease);

Occurrence of ASAS 20 and ASAS 40;

Occurrence of ASAS partial remission;

ASDAS;

Occurrence of ASDAS major improvement and clinically important improvement;

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
Nocturnal and total back pain;

Bath Ankylosing Spondylitis Functional Index (BASFI) and its components;

Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and its components;

Occurrence of BASDAI 50;

High sensitivity C Reactive Protein (hsCRP);

Health Outcomes Assessments using the following instruments: EuroQoL-5D Health 
Questionnaire (EQ-5D), SF-36 and Work Productivity and Activity Impairment 
(WPAI);

MRI SIJ/spine as measured by Spondyloarthritis Research Consortium of Canada 
(SPARCC).
The following secondary endpoint will be estimated over 12 weeks following re-treatment of 
subjects who flare:

Time to ASDAS inactive disease after re-treatment.
Other endpoints:

Subject Assessment of Disease Activity (SADA);

Physician Global Assessment (PGA);

Bath Ankylosing Spondylitis Patient Global Assessment Score (BAS-G);

Tender and swollen joint counts (44 count);

Dactylitis and enthesitis score (Maastricht Anklyosing Spondylitis Enthesitis Score 
[MASES]).
2.2.3. Safety Endpoints
Safety will be assessed throughout the study.  The following variables will be assessed: 
physical examination, vital signs, hematology, chemistry, urinalysis, premature withdrawal, 
inflammatory bowel disease (IBD), psoriasis, and uveitis evaluations, adverse events and 
serious adverse events during the study.

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3. STUDY DESIGN
This multicenter, open-label, three period study will evaluate withdrawal and retreatment of 
ETN in subjects with nr-ax SpA who achieved an adequate response, as measured by
ASDAS CRP less than 1.3 (inactive disease) following 24 weeks of treatment.  The study is 
expected to randomize approximately 200 subjects in Period 1, in order to have 
approximately 96 subjects qualify for Period 2. 
3.1. Period 1
This is an open-label, 24-week period in which all eligible subjects with nr-ax SpA will be 
enrolled and treated with ETN 50 mg once weekly plus a stable background NSAID at the 
optimal tolerated anti-inflammatory dosage as determined by the investigator.  The target for 
this period is therapeutic response defined as achieving Ankylosing Spondylitis Disease 
Activity Scale C-reactive protein (ASDAS CRP) less than 1.3 at Week 24.  Subjects who 
qualify at Week 24 will enter Period 2 after all Period 1 procedures are completed.  Subjects 
who do not achieve ASDAS CRP less than 1.3 will not enter Period 2 and will complete the 
study following the Week 28 day follow-up phone call/visit.
3.2. Period 2
The Week 24 visit ends Period 1 and marks the beginning of Period 2.  This is a 40-week 
withdrawal period where subjects will discontinue ETN following the Week 24 dose, yet 
maintain the background NSAID.  If the subject has not flared by the Week 64 visit, their 
participation in the study is complete.
3.3. Period 3
Subjects who flare (defined as an ASDAS ESR greater than or equal to 2.1) during Period 2 
will enter a retreatment period and receive approximately 12 weekly doses of open-label 
ETN.  Subjects experiencing increased disease activity can come into the office any time for 
an evaluation; if flare criteria are met, open-label ETN is started at this unscheduled visit.  If 
the subject has experienced increased disease activity during Period 2, but does not meet the 
protocol defined criteria for flare, it is the investigator’s judgment to determine if the subject 
should remain in the study or discontinue the study to pursue alternative treatment.
3.4. Follow-up
A safety follow-up phone call/visit will only be completed for subjects who:

Receive investigational product (IP) in Period 1, but who do not enter Period 2, or, 

Enter Period 2 and discontinue from the study before the Week 28 visit or, 

Enter Period 3 (Retreatment period). 
The purpose of this visit is to assess any new and/or ongoing adverse events and will be 
performed approximately 28 days after the last dose of IP.  This follow-up visit will be done 
by telephone, unless local regulations require a visit to the study site.

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A safety follow-up visit does not need to be completed for subjects who discontinue from the 
study after the Week 28 visit and who do not enter Period 3 for retreatment.
Figure 1.
Study Schematic
4. SUBJECT SELECTION
This study can fulfill its objectives only if appropriate subjects are enrolled.  The following 
eligibility criteria are designed to select subjects for whom participation in the study is 
considered appropriate.  All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a particular subject is suitable for this protocol.
4.1. Inclusion Criteria – Period 1
Subject eligibility should be reviewed and documented by an appropriate member of the 
investigator’s study team before subjects are included in the study.  An eligibility worksheet 
will be provided to document the review of the inclusion and exclusion criteria.
Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the 
study:

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1. Evidence of a personally signed and dated informed consent document indicating that 
the subject has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, 
laboratory tests, and other study procedures.
3. Male subjects able to father children and female subjects of childbearing potential and 
at risk for pregnancy must agree to use a highly effective method of contraception 
throughout the entire study and for 28 days after the last study visit. 

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 
Achieved postmenopausal status, defined as follows: cessation of regular menses for 
at least 12 consecutive months with no alternative pathological or physiological 
cause; and have a serum follicle-stimulating hormone (FSH) level confirming the 
post-menopausal state
4. Duration of symptoms of >3 months and <5 years at the time of consent.
5. Diagnosis of ax SpA as defined by the ASAS criteria (Appendix 2). 
The ASAS criteria state that subjects have to have >3 months of back pain and 
age of onset <45 years, and:

Sacroiliitis on imaging plus 1 SpA feature 
OR 

Positive Human Leucocyte Antigen B27 (HLA-B27) plus 2 SpA features.
Sacroiliitis on imaging is defined as either:

Active inflammation on MRI highly suggestive of sacroiliitis associated with 
SpA 
OR

Defined radiographic sacroiliitis according to the Modified NY criteria**
**Subjects in this study cannot meet the criteria based on the second bullet (since 
defined radiographic sacroiliitis is an exclusion criterion). In order to meet the 
imaging criteria for ASAS, subjects must have positive sacroiliitis on MRI based 
on readings performed by the central imaging vendor.  This criterion cannot be 
based on local MRI evaluation or historical MRIs.

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If a subject has negative sacroiliitis on MRI, then they must have positive 
HLA-B27 plus 2 SpA features.  Conversely, if a subject is HLA-B27 negative, 
then they must have positive sacroiliitis on MRI and at least 1 SpA feature.  (See 
flowchart in Appendix 6).
The SpA features are listed below and defined in Appendix 4.

Inflammatory back pain;

Arthritis;

Enthesitis (heel);

Uveitis;

Dactylitis;

Psoriasis;

Crohn’s/ Colitis;

Good response to NSAIDs;

Family history of SpA;

HLA-B27;

Elevated hsCRP.
6. Subjects must have positive MRI findings (active inflammation on MRI highly 
suggestive of sacroiliitis associated with SpA) and/or positive hsCRP (defined as
hsCRP >3 mg/l).
7. Active symptoms defined by an ASDAS CRP greater than or equal to 2.1 at the 
screening visit.
8. Back pain with a less than favorable response to current intake of an NSAID at the 
optimal tolerated dose as determined by the investigator.  Subjects must have 
experienced less than favorable response to at least 2 NSAIDs (including the current 
one) taken separately at the optimal tolerated dose with a total combined duration of 
>4 weeks.
9. Subject must be taking a stable dose of an NSAID for at least 14 days before the first 
dose.
10. Female or male 18 years or older (20 or older if required by local regulations) but less 
than 50 at the time of consent.

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11. In the opinion of the investigator, subject is reasonable candidate for treatment with 
ETN.
12. No contraindication to MRI examination (metal implants or inability to lie flat for 
30-60 minutes for example).
13. Negative serum pregnancy test performed at screening, negative urine pregnancy test 
performed prior to the first dose and negative serum pregnancy test collected for 
analysis prior to the first dose.
14. Ability to self-inject investigational product or have a designee who can do so.
15. Ability to store injectable investigational product under refrigerated conditions.
16. Demonstrated an adequate screening for tuberculosis (TB) in accordance with local 
country guidelines.
17. Subject is able to complete health outcomes assessments and investigational product
diary.
18. In Germany only: Subjects who are not eligible to get new spine and/or pelvic x-rays, 
due to local regulations must have had these x-rays taken within 12 months prior to 
the screening visit.  The central reader must consider the x-rays to be acceptable for 
evaluation of sacroiliitis.
4.2. Inclusion Criteria – Period 2
1. Completion of Period 1.
2. Subjects must achieve ASDAS CRP (inactive disease) less than 1.3 at the Week 24 
visit in order to be eligible to enter Period 2.
4.3. Inclusion Criteria – Period 3
Subjects must meet the criteria for flare in order to be eligible to enter Period 3.  Flare is 
defined as ASDAS ESR greater than or equal to 2.1.
4.4. Exclusion Criteria
Subjects with any of the following characteristics/conditions will not be included in the 
study:
1. Subjects who are investigational site staff members directly involved in the conduct 
of the study and their family members, site staff members otherwise supervised by the 
investigator, or subjects who are Pfizer employees directly involved in the conduct of 
the study.

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2. Participation in other studies involving investigational drug(s) (Phases 1-4) within 
4 weeks before the current study begins and/or during study participation.  
Participation in studies involving investigational drug greater than 4 weeks to one 
year before the current study begins will be permitted on a case-by-case basis.
3. Radiological sacroiliitis Grades 3-4 unilaterally or Grade 2 bilaterally as defined by 
the NY criteria (Appendix 3).  Only results from the central imaging reader will 
determine eligibility.  In all countries except Germany: Historical x-rays (obtained 
within 4 months of screening) may be utilized, however these subjects must exhibit 
radiological sacroiliitis Grade 0-1 unilaterally or Grade 0 bilaterally.
4. Any previous treatment with a tumor necrosis factor-alpha (TNF-) inhibitor, B/T 
cell inhibitor or other biologic or immunosuppressive agent for a condition other than
IBD.
5. Subject is currently being treated or had previous treatment within 6 months for IBD 
with any tumor necrosis factor-alpha (TNF-) inhibitor or any other 
immunosuppressant.
6. Evidence of IBD flare within 6 months of first dose.
7. Evidence of active uveitis within 6 months of first dose.
8. Any current or past orthopedic or medical condition that in the opinion of the 
investigator could cause chronic back pain.
9. Subject has known or suspected allergy, hypersensitivity, or contraindication to ETN, 
its excipients, or other compounds, related to this class of medication.
10. Subject has concurrent treatment with more than 1 NSAID within 14 days at first 
dose.  Aspirin use, at daily doses up to 325 mg if indicated for cardiovascular 
protection is permissible and will not be counted as an additional NSAID.
11. Disease modifying anti-rheumatic drugs (DMARDs) other than methotrexate (MTX), 
sulfasalazine and hydroxychloroquine taken within 4 weeks of first dose.  Subjects 
may be taking only one allowable DMARD at a time.
12. Subject has had an oral dose of prednisone >10 mg/day (or equivalent) or has had a 
dose change within 4 weeks of first dose.
13. Subject has received an intra-articular, intravenous, intramuscular, or subcutaneous 
(SC) corticosteroid within 4 weeks of first dose. 
14. Subject has current or recent (within 2 years of screening) active TB infection.

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
Subjects with remote history (more than 2 years before screening) of active TB 
are allowed if clear documentation of completion of adequate treatment (as 
defined by local guidelines) exists.

Local country guidelines should be observed for appropriate TB screening in the 
setting of anti-TNF therapy, including a minimum of a chest radiograph and 
objective TB testing such as a purified protein derivative (PPD) or Quantiferon 
depending on what is acceptable per local guidelines.
15. Subject has untreated latent TB.  (Subjects with known latent TB may be allowed 
only if local guidelines are followed for therapy and if treatment for latent TB has 
been adequately completed or initiated at least 4 weeks prior to screening.)
16. Subject has received treatment for latent TB during screening and has had alanine 
aminotranferase (ALT) and/or aspartate aminotranferase (AST) 2 times the upper 
limit of normal (ULN) during this period.

For subjects that have been diagnosed with latent TB and started treatment during 
the screening period, additional blood samples for ALT and AST must be drawn 
between 3-4 weeks after initiating treatment.  The results need to be reviewed 
prior to first dose.
17. Subjects with a chronic infection, or a serious infection (infection associated with 
hospitalization and/or intravenous antibiotics) within 4 weeks prior to investigational 
product administration.
18. Subjects with active infection at the time of the screening visit and or the first dose
visit.  Certain minor active infections (ie, vaginitis, tinea, etc) could be allowed on a 
case-by-case basis only after approval from the Pfizer Physician Clinician.
19. Subject has planned elective surgery during the active dosing period (ie, Period 1).
20. Subject has received any live vaccines (attenuated vaccine) within 4 weeks prior to 
first dose.
21. Investigational drugs half-lives of greater than 5 weeks taken less than 6 months prior 
to first dose.
22. Pregnant female subjects; breastfeeding female subjects; male subjects with partners 
currently pregnant; male subjects able to father children and female subjects of 
childbearing potential who are unwilling or unable to use a highly effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
28 days after the last dose of investigational product or longer based upon the 
compound’s half-life characteristics.

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23. Subject has an abnormal hematology or blood chemistry profile during the screening 
period.  Refer to Section 6.8 for management of exclusionary lab values at baseline.

White blood cell (WBC) count <3.5 x 109/L;

Hemoglobin level <8.5 g/L or <5.3 mmol/L;

Hematocrit <27%;

Platelet count <125 x 109/L;

Serum creatinine level >175 mol/L (>1.98 mg/dL);

AST or ALT level >2 times the laboratory’s ULN.
24. Other severe acute or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or 
investigational product administration or may interfere with the interpretation of 
study results and, in the judgment of the investigator, would make the subject 
inappropriate for entry into this study.  Subject has any clinically relevant concurrent 
medical conditions, including;

Known history or presence of acute or chronic hepatitis B or hepatitis C or human 
immunodeficiency virus (HIV) infection; (If required by Health Authorities, an 
HIV test must be performed at a local lab during screening.  Results of this test 
will be used to determine eligibility).

Uncompensated congestive heart failure, or class III or IV heart failure defined by 
the New York Heart Association classification;

Uncontrolled hypertension (defined as screening systolic blood pressure 
>160 mm Hg or screening diastolic blood pressure >100 mm Hg;

Myocardial infarction within 12 months before the screening visit;

Coronary artery by-pass graft (CABG) or percutaneous transluminal coronary 
angioplasty (PTCA) within 12 months before the first dose visit;

Unstable angina pectoris within 6 months before the screening visit;

Severe pulmonary disease requiring recurrent hospitalization or supplemental 
oxygen;

Presence or history of confirmed blood dyscrasias;

Diagnosis of multiple sclerosis or other central or peripheral nervous system 
demyelinating diseases;

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
Presence or history of cancer (or carcinoma in situ) other than resected cutaneous 
basal cell or squamous cell carcinoma;

Uncontrolled diabetes mellitus;

Diagnosis of rheumatoid arthritis, systemic lupus erythematosus, scleroderma, or 
polymyositis;

Open cutaneous ulcers;

Liver cirrhosis or fibrosis.
4.5. Lifestyle Guidelines
All male subjects who are able to father children and female subjects who are of childbearing 
potential and are sexually active and at risk for pregnancy must agree to use a highly 
effective method of contraception consistently and correctly for the duration of the study and 
for 28 days after the last study visit.  According to investigator judgment, subjects may need 
to continue using a highly effective method of contraception beyond 28 days after the last 
study visit based on concomitant medications (eg, MTX) or local guidelines.  The 
investigator or his or her designee, in consultation with the subject, will confirm that the
subject has selected an appropriate method of contraception for the individual subject and his 
or her partner from the permitted list of contraception methods (see below) and instruct the 
subject in its consistent and correct use.  Subjects need to affirm that they meet the criteria 
for correct use of at least 1 of the selected methods of contraception.  The investigator or 
his/her designee will discuss with the subject the need to use highly effective contraception 
consistently and correctly according to the schedule of activities and document such 
conversation in the subject’s chart.  In addition, the investigator or his or her designee will 
instruct the subject to call immediately if the selected contraception method is discontinued 
or if pregnancy is known or suspected in the subject or the subject’s partner. 
Highly effective methods of contraception are those that, alone or in combination, result in a 
failure rate of less than 1% per year when used consistently and correctly (ie, perfect use) and 
include the following:
1. Established use of oral, inserted, injected, implanted or transdermal hormonal 
methods of contraception is allowed provided the subject plans to remain on the same 
treatment throughout the entire study and has been using that hormonal contraceptive 
for an adequate period of time to ensure effectiveness.
2. Correctly placed copper-containing intrauterine device (IUD).
3. Male condom or female condom used WITH a spermicide (ie, foam, gel, film, cream, 
or suppository). For countries where spermicide is not available or condom plus 
spermicide is not accepted as highly effective contraception, this option is not 
appropriate.

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4. Male sterilization with absence of sperm in the post vasectomy ejaculate.
5. Bilateral tubal ligation / bilateral salpingectomy or bilateral tubal occlusive procedure 
(provided that occlusion has been confirmed in accordance with the device’s label).
6. Female partner who meets the criteria for non-childbearing potential, as described 
below:
Female subjects of non-childbearing potential must meet at least one of the following 
criteria:

Have undergone a documented hysterectomy and/or bilateral oophorectomy;

Have medically confirmed ovarian failure; or 

Achieved postmenopausal status, defined as follows: cessation of regular menses 
for at least 12 consecutive months with no alternative pathological or 
physiological cause; and have a serum follicle stimulating hormone (FSH) level 
confirming the post-menopausal state.
All other female subjects (including females with tubal ligations) will be considered 
to be of childbearing potential.
4.6. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the study portal.
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, subjects are provided with a contact card.  The contact card contains, 
at a minimum, protocol and investigational compound identifiers, subject study numbers, 
contact information for the investigational site, and contact details for a contact center in the 
event that the investigational site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
subject’s participation in the study.  The contact number can also be used by investigational 
staff if they are seeking advice on medical questions or problems; however, it should be used 
only in the event that the established communication pathways between the investigational 
site and the study team are not available.  It is therefore intended to augment, but not replace, 
the established communication pathways between the investigational site and the study team 
for advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the subject directly, and if a subject calls that number, he 
or she will be directed back to the investigational site.

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5. STUDY TREATMENTS
For the purposes of this study, and per International Conference on Harmonization (ICH) 
guidelines investigational product is defined as a pharmaceutical form of an active ingredient 
or placebo being tested or used as a reference in a clinical trial, including a product with a 
marketing authorization when used or assembled (formulated or packaged) in a way different 
from the approved form, or when used for an unapproved indication, or when used to gain 
further information about an approved use (ICH E6 1.33).
For the purposes of this study, investigational product will be defined as ETN.  The sponsor 
will supply ETN.  Investigational product will be administered only to subjects who have 
provided informed consent.  Once a subject’s participation in the study has ended, ETN will 
no longer be supplied to the subject by the investigative site and/or sponsor.
5.1. Allocation to Treatment
This is an open-label study; however, subjects must also receive a treatment assignment 
number.  Enrollment will be accomplished using interactive response technology (IRT), an 
automated web/telephone system. At the screening visit, the investigative site will contact 
the IRT (online or by telephone call). The site will enroll the subject into the IRT by 
indicating minimal information sufficient to distinguish one subject from another and receive 
the unique Subject identification (ID) number. A subject who discontinues or is withdrawn 
from the study before receiving a treatment assignment code and who re-enrolls at a later 
time must be assigned a new unique Subject ID number. A Subject ID number must never be 
reassigned or reused for any reason.  At the baseline visit, enrollment will be accomplished 
by the IRT system, which will allocate a drug package to the subject. 
All subjects will have the option of discontinuing the study at any time (eg, for flare or if the 
subject and/or treating physician feels that it is in the best interest of the subject to do so).
Subjects who are screen failures or discontinue must have their statuses changed in the IRT 
system.
5.2. Subject Compliance
Reasonable efforts should be made to ensure that administration of investigational product 
occurs on the day that it is scheduled.  However, if unavoidable, the investigational product 
may be given 3 days from the scheduled day (ie, 4 to 10 days from the previous dose).  The 
next dose will then return to the normal schedule.  If more than 10 days have elapsed since 
the last dose then the next dose should be taken as soon as possible and the subsequent dose
will be given 7 days later, with a new dosing schedule established.
Compliance with IP administration will be reviewed at each study visit during Period 1 and 
Period 3.  At each visit, subjects will return any empty containers and provide information to 
the study personnel regarding their compliance with the IP.  Subjects will also be required to 
complete a subject diary card to capture weekly IP administration.  Compliance is monitored 
by study personnel at the site by using the subject diary card source documents and is 
recorded on the case report form (CRF).  If any subject misses more than 2 consecutive doses 
of investigational product, they must be discontinued from the study.  Temporary suspension 

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of the injectable IP for up to 2 consecutive injections is allowed following the occurrence of 
an adverse event (AE)/serious adverse event (SAE).  Reasons for missed doses will be 
recorded in the subject diary and CRF.
5.3. Investigational Product Supplies
5.3.1. Dosage Form(s) and Packaging
ETN will be supplied by the sponsor as 1 ml (50 mg/ml) pre-filled syringes for the duration 
of the trial.  This dose of IP is in alignment with the approved dose for this indication.  At 
each dispensing visit, subjects will receive sufficient quantity of IP to last until their next 
scheduled visit.  The pre-filled syringes are open-label and will be labeled to allow for 
identification of the contents.
5.3.2. Preparation and Dispensing
Refer to separate instructions for complete details regarding the preparation and 
administration of the investigational product.  Each subject will receive IP at scheduled 
visits; baseline (BL), Weeks 4, 8, 12 and 16 during Period 1, and if necessary, Weeks 0, 4 
and 8 during Period 3.  Investigational product should be prepared and dispensed by an 
appropriately qualified and experienced member of the study staff (eg, physician, nurse, 
physician’s assistant, practitioner, or pharmacist) as allowed by local, state, and institutional 
guidance.
5.4. Administration
Pfizer Pharmaceuticals will supply IP for the duration of the study.  Investigational product
will be administered only to subjects who have provided informed consent.  Once a subject’s 
participation in the study has ended, IP will no longer be supplied to the subject by the 
sponsor.  Subjects will record all IP dosing in a dosing diary which should be reviewed 
during each clinical visit.  Site personnel will instruct the subject or designated person on the 
proper sterile technique to administer a subcutaneous (SC) injection when using the pre-filled 
syringe at home.  During the baseline visit, the initial dose of investigational product must be 
administered in the office by study personnel, while the subject (or designee) observes.  The 
subject will be provided with an ethics committee (EC)/institutional review board 
(IRB)-approved administration guide to use at home.
5.5. Investigational Product Storage
ETN prefilled syringes must be stored under refrigerated conditions (2C to 8C) and must 
not be frozen.  The subject or designated person will be given instruction regarding the 
storage and transportation of ETN.
The investigator, or an approved representative (eg, pharmacist) will ensure that all 
investigational products, including any comparative agents and/or marketed products are 
stored in a secured area with controlled access under required storage conditions and in 
accordance with applicable regulatory requirements.

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Investigational product should be stored in its original container and in accordance with the 
label.  Storage conditions stated in the single reference safety document (SRSD)
(ie, investigator’s brochure [IB]) will be superseded by the storage conditions stated in the 
labeling.
Site systems must be capable of measuring and documenting (eg, via a log), at a minimum, 
daily minimum and maximum temperatures for all site storage locations (as applicable, 
including frozen, refrigerated and/or room temperature products).  This should be captured 
from the time of investigational product receipt throughout the study.  Even for continuous 
monitoring systems, a log or site procedure that ensures active daily evaluation for 
excursions should be available.  The operation of the temperature monitoring device and 
storage unit (eg, refrigerator), as applicable, should be regularly inspected to ensure it is 
maintained in working order.
Any excursions from the product label storage conditions should be reported upon discovery.  
The site should actively pursue options for returning the product to the storage conditions as 
described in the labeling, as soon as possible.  Deviations from the storage requirements, 
including any actions taken, must be documented and reported to the sponsor. 
Once an excursion is identified, the investigational product must be quarantined and not used 
until the sponsor provides documentation of permission to use the investigational product.  It 
will not be considered a protocol deviation if the sponsor approves the use of the 
investigational product after the temperature excursion.  Use of the investigational product, 
prior to sponsor approval will be considered a protocol deviation.
Specific details regarding information the site should report for each excursion will be 
provided to the site. 
Receipt of materials, door opening and closing, and other routine handling operations where 
the product(s) are briefly out of the temperature range described in the labeling are not 
considered excursions. More specific details will be provided to the sites separately.
Site staff will instruct subjects on the proper storage requirements for take home
investigational products. 
5.6. Investigational Product Accountability
The investigative site must maintain adequate records documenting the receipt, use, loss, or 
other disposition of the investigational product supplies.  All unused investigative product
must be returned to the investigator by the subject. 
5.7. Destruction of Investigational Product Supplies
The sponsor or designee will provide guidance on the destruction of unused investigational 
product (eg, at the site). If destruction is authorized to take place at the study site, the 
investigator must ensure that the materials are destroyed in compliance with applicable 
environmental regulations, institutional policy, and any special instructions provided by 
Pfizer and all destruction must be adequately documented.

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5.8. Concomitant Treatment(s)
1. Only one NSAID is allowed to be used chronically at a time (an additional NSAID 
may be given as needed for acute conditions [ie, not to exceed 4 days in duration], 
and provided it is not given within 24 hours before any visit).  During Period 1, the 
dose and type of NSAID should remain stable.  If there is an AE/SAE related to the 
NSAID the dose may be stopped or lowered temporarily up to two weeks.  If after 
reinstitution of the previous dose of NSAID the adverse event(s) recurs, a lower dose 
could be used for the remainder of Period 1.  If the subject cannot remain on an
NSAID during Period 1, they must be discontinued.
2. The intent during Period 2 and Period 3 is to maintain the NSAID at the optimal dose
as determined by the investigator.
a.
The NSAID dose may not be increased during these periods. 
b. If the subject develops an AE/SAE related to the NSAID, the dose may be 
lowered temporarily for up to two weeks.  If after reinstitution of the previous 
dose of NSAID the AE/SAE recurs, a lower dose could be used for the remainder 
of the study.  If the lower dose is not tolerated, the subject can remain in the study 
during these periods.
3. During all periods of the study, short acting analgesics with no anti-inflammatory 
action (such as paracetamol, or short acting narcotics) may be used at the discretion 
of the investigator.  However, on the day of the study visit, analgesics must not be 
taken until after all clinical evaluations have been performed and all blood samples 
collected.
4. Aspirin use, at daily doses up to 325 mg if indicated for cardiovascular protection is 
permissible and will not be counted as an additional NSAID.  Any regular 
administration of a dose higher than 325 mg will be considered as a second NSAID 
use, which is not permitted during this study.
5. If needed, oral corticosteroids are allowed during all periods of the study if they were 
used in stable doses for at least 4 weeks before first dose.  The dose of oral 
corticosteroids should be <10 mg/day of prednisone or equivalent.  The dose of 
corticosteroids must be kept constant.
6. Treatment with only one of the following 3 DMARDs: sulfasalazine, 
hydroxychloroquine, and methotrexate, are allowed during the study, but the dose
must be stable for at least 4 weeks before first dose and for the duration of the study.  
If the subject develops an AE/SAE related to the DMARD, the dose may be lowered 
temporarily for up to two weeks.  If after reinstitution of the previous dose of 
DMARD the AE recurs, a lower dose could be used for the remainder of the study.
Route of administration of DMARD must remain constant during the study.

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7. Medications for acute or chronic conditions that are not listed under exclusion criteria 
are permitted.
5.8.1. Non Pharmacologic Interventions
Subjects participating in this trial may continue all non-pharmacologic therapies such as 
physical therapy, herbal therapy or homeopathic therapy, if they were begun before 
screening.  These therapies should remain on a stable regimen for the duration of the study.
5.8.2. Prohibited Medications
The following list of medications is prohibited during the entire course of the study.
1. Any live (attenuated) vaccine.  Vaccinations with live components are prohibited 
within 4 weeks prior to the first dose of IP, during the study and for 6 weeks after the 
last study visit.
2. Treatment with other TNF antagonists, B cell depleters, T cell depleters, 
immunosuppressants (including biologic agents), and tofacitnib.
3. Multiple NSAIDs.
4. DMARDs other than sulfasalazine, hydroxychloroquine and methotrexate.
5. Dose of oral prednisone 10 mg/day (or equivalent) and used as described in 
exclusion criteria.
6. Intra-articular, intravenous, subcutaneous and intramuscular corticosteroid injections.
7. Long-acting analgesics and long-acting narcotics.
8. Investigational or experimental drugs.
6. STUDY PROCEDURES 
6.1. Screening
Screening tests and procedures should not commence until after the informed consent form 
has been signed for this study.  The results of the tests and procedures should be reviewed 
with the subject at the BL visit.  Subject screening should be conducted within 4 weeks and 
no less than 5 days prior to the BL visit.  The screening period may be extended up to 
42 days if repeat imaging is required or when tuberculosis prophylactic therapy is started 
during the screening period. No re-screening is permitted in this study.  However, if 
screening laboratory test results exclude the subject and the investigator is reasonably certain 
that the results(s) were due to laboratory error; or in the opinion of the investigator the 
result(s) were flawed by a transient condition, that laboratory test(s) may be repeated once 
during the screening period for confirmation.

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This change in process must be accurately recorded and documented in the subjects file and 
the test should be repeated in a very timely manner (within 4 days of obtaining the result).  
The re-test is done under the same subject number (this will not be considered a 
re-screening).
6.1.1. Screening Procedures

Informed consent must be read, signed and dated by subject and witnessed by the 
investigator or designee.

Record subject demography and medical history.  Medical history evaluation 
includes; general medical history, disease specific medical history, evaluation of 
background medication and family medical history.

Review all inclusion/exclusion criteria.

Record all prior medications including DMARDs, corticosteroids, and NSAID use.  
All medications taken within 30 days prior to screening should be recorded.

Physical examination (performed by a physician) evaluating any clinically significant 
abnormalities within the following body systems: general appearance, skin, 
head/eyes/ears/nose/throat, heart, lungs, abdomen, lower extremities, neurological, 
back/spinal, and lymph nodes.  Results must be recorded in the subject’s source 
documents and any significant findings must be recoded on the Medical History CRF 
and/or appropriate AE CRF.

Measure height in centimeters (cm) and weight in kilograms (kg).

Vital sign measurements, including pulse rate (after sitting 5 minutes) and blood 
pressure.  A sitting blood pressure (BP) will be obtained by qualified site personnel.  
If possible, a different arm should be used for the collection of blood samples.

BASDAI evaluation.

SADA.

Chest radiograph and TB testing:

Local country guidelines should be followed for appropriate TB screening in the 
setting of anti-TNF therapy, including a minimum of:

A chest radiograph, to be performed at the screening visit and read locally by 
a qualified reader unless a chest radiograph has been done within 12 weeks 
before the screening visit and the report is available and included in the 
subject’s source documents.  If required by local regulations, a chest x-ray 
taken within 6 months of the screening visit may be used as long as the report 
is available and included in the subject’s source documents;

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
Objective TB testing, such as Quantiferon or PPD depending on what is 
available and acceptable per local guidelines.

Quantiferon must be used unless not available or not accepted per local 
guidelines;

If the PPD tuberculin skin test is performed, the subject must return 
48-72 hours post-test for evaluation.  A PPD of >5 mm should be 
considered positive for TB unless local guidelines for testing of 
immunocompromised subjects are available and different;

TB testing with Quantiferon or PPD need not be done during screening if 
there is documentation of either test being negative within 12 weeks 
before the screening visit and if this approach is not prohibited by local 
guidelines;

If the subject is known to be Quantiferon positive or PPD positive, the 
Quantiferon or PPD tuberculin skin test need not be repeated at the 
screening visit.

Collect samples for the following laboratory evaluations:

Hematology, blood chemistry, HLA-B27, hsCRP and ESR;

Routine urinalysis;

Hepatitis B and Hepatitis C testing.

Serum pregnancy test for women of childbearing potential:
For female subjects and male subjects whose partners are of childbearing potential, 
evaluate childbearing potential and sexual activity.  This discussion should include 
highly effective methods of contraception (see Section 4.5 Life Style Guidelines).  
This evaluation and discussion must be documented in the subject’s source 
documents. 

Female subjects who, in the opinion of the investigator, are of childbearing 
potential will be required to have a serum pregnancy test; this includes subjects 
who are menstruating at the time of the visit and/or who are not sexually active;

Urine pregnancy test will also be done whenever one menstrual cycle is missed 
during the study period or when potential pregnancy is otherwise suspected.  
Pregnancy tests may also be repeated as per request of IRB/ECs or if required by 
local regulations.

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
X-ray of SIJ - Results of historical x-rays that have been obtained within 4 months 
(12 months in Germany only) prior to screening could be used in lieu of performing 
screening x-rays.  If historical x-rays are used, the original films, or a copy, must be 
on site and a copy should be sent to the central imaging vendor. Then central reader 
must be able to determine the presence of and/or degree of sacroiliitis.  If the results 
are considered unevaluable by the central reader, the x-ray must be repeated.  If the 
subject is unable to have a repeat x-ray due to the regulations issued by the German 
Federation of Radiation Council, the subject would be considered a screen failure.

MRI Spine and SIJ - MRI evaluation must occur after SIJ x-rays have been obtained
and the report from the central imaging vendor has been reviewed by the investigator.  
MRI should only occur after the subject is found to meet eligibility criteria by 
evaluation of the SIJ x-ray.

Adverse Event reporting - serious adverse events must be reported to Pfizer from the 
time that the subject provides informed consent.
6.2. Baseline (Day 1)
The baseline visit (Day 1) will occur no later than 4 weeks after the screening visit unless 
treatment for latent TB or repeat imaging is necessary; for which it may be extended to 
6 weeks only.  It is intended that all procedures for the baseline visit will occur on the same 
day.  All results from the screening visit (including any repeat laboratory tests) must be 
available and reviewed before the baseline visit.  Baseline tests and procedures must be 
performed before administration of the first dose of IP.  However, results of the baseline 
laboratory tests (with the exception of urine pregnancy test) are not required in advance of 
dispensing IP.  Should the laboratory results subsequently show that the subject does not 
meet the inclusion/exclusion criteria and this is confirmed upon retest, the subject must be 
withdrawn from the study at that time.
For women of childbearing potential, both a serum and urine pregnancy test should be 
performed at the baseline visit, prior to the first injection of the IP.  If the serum pregnancy 
test at baseline subsequently is resulted as positive, the subject MUST be withdrawn from the 
study.
The following tests and procedures will be performed at the Baseline visit.

Review all inclusion/exclusion criteria.

Record prior medications including DMARDs, corticosteroids, and NSAID use.

Urine and serum pregnancy test.

Vital signs including sitting BP and pulse.

Record any AEs that occur following the first dose of investigational product.

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
Blood chemistry, hematology, hsCRP and ESR (these parameters do not need to be 
repeated at the baseline visit if they were completed at the screening visit 14 days 
before baseline).

Collect blood samples for banked biospecimens Prep D1, Prep R1 and Prep B1.

Confirm and document that subject is using highly effective method of birth control.

Joint assessment 44 count, including MASES (enthesitis) and dactylitis evaluation.

Assessment of IBD, psoriasis and uveitis.

BASDAI, BASFI, BAS-G.

PGA.

SADA.

Subject Nocturnal and Total Back Pain Assessment.

Health Outcomes: EQ-5D, SF-36 and WPAI.

Open label treatment assignment (first dose).

Dispense IP and IP diary card if randomized.  The first dose of IP must be 
administered in the investigational site office by study personnel after all 
baseline evaluations are completed.
6.3. Induction Period (Period 1)
The following information/assessments will be collected at the study visits for Weeks 4, 8, 
12, and 16 (within 4 days of the projected visit date based on the actual baseline visit date); 
and Week 24 (7 days of the projected visit date based on the actual baseline visit date).  It is 
intended that all procedures for a visit will occur on the same day.  If the Week 24 ASDAS 
CRP is 1.3, the subject should be notified by phone that their participation in the study is 
complete.  A follow-up call will be conducted in place of the Week 28 visit to assess new and 
ongoing adverse events and medication taken to treat them since the last dose of 
investigational product. 

Review concomitant medications including NSAIDs, DMARDs, and corticosteroids
at every visit.

Vital signs including sitting BP and pulse at every visit.

Physical examination (performed by a physician) at Week 24.

Measure height (cm) and weight (kg) at Week 24.

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
Review of any AEs at every visit that occurred since the previous visit.

Collect samples for the following laboratory evaluations:

Hematology and blood chemistry at Week 12 and Week 24;

hsCRP and ESR at every visit;

Urine pregnancy test at every visit;

Banked biospecimens Prep B1 and R1 at Week 12 and Week 24.

Confirm and document at every visit the subject is using a highly effective method of 
birth control.

MRI of spine and SIJ at Week 24.

Joint assessment including MASES (enthesitis) and dactylitis evaluation at Week 12 
and Week 24.

Assessment of IBD, psoriasis and uveitis at every visit.

BASDAI, BASFI, PGA, SADA, Subject Nocturnal and Total Back Pain Assessment
and WPAI at every visit.

BAS-G, EQ-5D and SF-36 at Weeks 12 and 24.

Dispense IP and IP diary card at Weeks 4, 8, 12 and 16.

Collect and review IP diary card at every visit.

Collect IP and complete IP return and accountability document at every visit.
6.4. Withdrawal Period (Period 2)
Subjects who are eligible to enter the withdrawal period will have the following assessments 
performed at all visits during the withdrawal period unless otherwise indicated: 

Review Period 2 eligibility criteria at Week 28.

Review concomitant medications including NSAIDs, DMARDs, and corticosteroids
at every visit.

Vital signs including sitting BP and pulse at every visit.

Physical examination (performed by a physician) at Week 64.

Measure height (cm) and weight (kg) at Week 64.

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
Review of any AEs at every visit that occurred since the previous visit.

Collect samples for the following laboratory evaluations:

Hematology, blood chemistry and urinalysis at Week 64;

hsCRP and ESR at every visit;

Urine pregnancy test at every visit.

Confirm and document at every visit the subject is using a highly effective method of 
birth control.

MRI of spine and SIJ at Weeks 48 and 64.

Joint assessment including MASES (enthesitis) and dactylitis evaluation at Weeks 32, 
48 and 64.

Assessment of IBD, psoriasis and uveitis at every visit.

BASDAI, BASFI, PGA, SA DA, Subject Nocturnal and Total Back Pain Assessment 
and WPAI at every visit.

BAS-G, EQ-5D and SF-36 at Weeks 32, 48 and 64.
6.5. Re-Treatment Period for Subjects in the Withdrawal Phase (Period 3)
Subjects in the withdrawal period (Period 2) who experience disease flare will be seen for a 
re-treatment assessment visit at the study site, which should occur as soon as possible after 
disease flare.  The first visit of the Retreatment period (Period 3) may occur at the same time 
as a regularly scheduled visit during Period 2 or it may occur as an unscheduled visit.  
Subjects requiring re-treatment (based on a protocol-defined flare of ASDAS ESR greater 
than or equal to 2.1) will be offered the option to enter re-treatment (Period 3) and receive 
12 weekly doses of open-label ETN (50 mg).
Subjects who discontinue (eg, for an adverse event) at any time are ineligible to enter the 
re-treatment phase.
Subjects who are eligible to enter the re-treatment period will have the following assessments 
performed at all visits during the re-treatment period unless otherwise indicated: 

Review concomitant medications including NSAIDs, DMARDs, and corticosteroids
at every visit.

Vital signs including sitting BP and pulse at every visit.

Physical examination (performed by a physician) at Week R12.

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
Measure height (cm) and weight (kg) at Week R12.

Review of any AEs at every visit that occurred since the previous visit.

Collect samples for the following laboratory evaluations:

Hematology and blood chemistry at Weeks R0 and R12;

hsCRP and ESR at every visit;

Urine pregnancy test at every visit.

Confirm and document at every visit the subject is using a highly effective method of 
birth control.

MRI of spine and SIJ at Weeks R0 and R12.

Joint assessment including MASES (enthesitis) and dactylitis evaluation at 
Weeks R0 and R12.

Assessment of IBD, psoriasis and uveitis at every visit.

BASDAI, BASFI, PGA, SA DA, Subject Nocturnal and Total Back Pain Assessment 
and WPAI at every visit.

BAS-G, EQ-5D and SF-36 at Weeks R0 and R12.

Dispense IP and IP diary card at Weeks R0, R4, and R8.

Collect and review IP diary at Weeks R4, R8, R12.

Collect IP and complete IP return and accountability document at Weeks R4, R8
and R12.
6.6. Follow-up Call
A safety follow-up telephone call approximately 28 days after the last dose of investigational 
product will only be completed for subjects who: 

Receive IP in Period 1, but who do not enter Period 2, or, 

Enter Period 2 and discontinue from the study before the Week 28 visit or, 

Enter Period 3 (Retreatment period). 
No follow-up is needed if subjects enter Period 2 and do not experience a flare.  If required 
by local regulations, the follow-up visit may be conducted at the study site.  It is intended 

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that all procedures for the follow-up visit will occur on the same day.  The following 
information will be collected:

Record AEs that were ongoing at the time of the last visit as well as those starting 
between the last visit and the follow-up call.

Record medications taken to treat any new or ongoing AEs/SAEs that occurred since 
the last visit.
6.7. Early Discontinuation Visit
For all subjects who withdraw from the study prior to completing the last visit of any period,
the following information/assessments will be collected at the early discontinuation visit.  
The early withdrawal visit should be completed as soon as possible after the last dose of 
investigational product.  It is intended that all procedures for the early discontinuation visit 
will occur on the same day.

Review concomitant medications including NSAIDs, DMARDs, and corticosteroids.

Vital signs including sitting BP and pulse.

Physical examination (performed by a physician).

Measure height (cm) and weight (kg).

Review of any AEs that occurred since the previous visit.

Collect samples for the following laboratory evaluations:

Hematology and blood chemistry;

hsCRP and ESR;

Urine pregnancy test;

Banked biospecimens Prep B1 and R1 only if subject discontinues during 
Period 1.

Confirm and document the subject is using a highly effective method of birth control.

MRI of spine and SIJ.

Joint assessment including MASES (enthesitis) and dactylitis evaluation.

Assessment of IBD, psoriasis and uveitis.

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
BASDAI, BASFI, BAS-G, PGA, SADA, Subject Nocturnal and Total Back Pain 
Assessment, EQ-5D, SF-36 and WPAI.

Collect and review IP diary card.

Collect IP and complete IP return and accountability document.
6.8. Subject Withdrawal
The sponsor’s Clinical team must be consulted as soon as possible if any of the following 
occur during the active treatment period (Period 1 or Period 3) to determine whether the 
subject should continue taking the investigational product:

Any infection requiring parenteral (IV, IM) anti-infective agents but not meeting 
criteria for serious infection (see below).

The sponsor’s Clinical team must be notified as soon as possible if a subject is 
planning to undergo or has undergone any surgical procedure.  It is recommended that 
investigational product be withheld surrounding most surgical procedures.

For most planned surgeries, investigational product should be withheld for a 
period of time prior to the procedure; the specific duration should be determined 
by the clinical judgment of the investigator;

Investigational product should be withheld following most surgeries.  The 
investigational product can be reintroduced once the investigator judges the risk 
for post-operative infection to be low;

If it is clinically judged that more than two consecutive weekly does of 
investigational product should be withheld, then the subject must be withdrawn 
from the study.

Lack of compliance with the protocol, including protocol required schedule of study 
visits and/or lack of procedures.
Subjects MUST be withdrawn from investigational product if any of the following occurs:

If baseline lab value is confirmed to meet Exclusion criteria, the subject must be 
discontinued.  Confirmation of the value should be performed prior to the Week 4 
visit.

Pregnancy.

Grade 3 or 4 systemic toxicity or a SAE thought to be related to investigational 
product and not alleviated by symptomatic treatment after cessation of investigational 
product use of up to two doses or Grade 3 or 4 systemic toxicity that recurs after 
resumption of investigational product use (see Appendix 5).

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
Receipt of any live (attenuated) vaccines.

Subjects with clinical signs and symptoms suggestive of active tuberculosis should 
have investigational product withheld until a diagnosis can be confirmed.  If 
diagnosis or tuberculosis is confirmed, investigational product must be discontinued.

Suspected sepsis.

Any serious infection (defined as an infection meeting any SAE criteria).

Confirmed blood dyscrasia or a demyelinating disorder (such as multiple sclerosis or 
optic neuritis).

Confirmed malignancy other than squamous cell, basal cell carcinoma or cervical 
carcinoma in situ.

If more than 2 consecutive doses of investigational product are missed.

Joint surgical procedures (open or arthroscopic) and synoviorthesis in Period 1 or 
Period 3.

Withdrawal of consent: Subjects who request to discontinue study treatment will 
remain in the study and must continue to be followed for protocol specified follow-up 
procedures.  The only exception to this is when a subject specifically withdraws 
consent for any further contact with him or her or persons previously authorized by 
the subject to provide this information.  Subjects should notify the investigator in 
writing of the decision to withdraw consent from future follow-up, whenever 
possible.  The withdrawal of consent should be explained in detail in the medical 
records by the investigator, as to whether the withdrawal is only from further receipt 
of investigational product or also from study procedures and/or post treatment study 
follow-up, and entered on the appropriate CRF page.  In the event that vital status 
(whether the subject is alive or dead) is being measured, publicly available 
information should be used to determine vital status only as appropriately directed in 
accordance with local law.

Lost to follow-up: All reasonable efforts must be made to locate subjects to determine 
and report their ongoing status.  This includes follow-up with persons authorized by 
the subject as noted above.  Lost to follow-up is defined by the inability to reach the 
subject after a minimum of 2 documented phone calls, faxes, or e-mails as well as 
lack of response by the subject to 1 registered mail letter.  All attempts should be 
documented in the subject’s medical records.  If it is determined that the subject has 
died, the site will use permissible local methods to obtain the date and cause of death.  
If the investigator’s use of a third-party representative to assist in the follow-up 
portion of the study has been included in the subject’s informed consent, then the 
investigator may use a sponsor-retained third-party representative to assist site staff 
with obtaining the subject’s contact information or other public vital status data 

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necessary to complete the follow-up portion of the study.  The site staff and 
representative will consult publicly available sources, such as public health registries 
and databases, in order to obtain updated contact information.  If, after all attempts, 
the subject remains lost to follow-up, then the last-known-alive date as determined by 
the investigator should be reported and documented in the subject’s medical records.

Principal investigator decision [ie the investigator or the family doctor considers 
treatment indicated using a medication that is not permitted (within the scope of the 
trial).

Sponsor decision.

The study is stopped by the IRB or EC, or by a regulatory agency.
Subjects 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 or behavioral 
reasons, or the inability of the subject to comply with the protocol-required schedule of study 
visits or procedures at a given study site.
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  The number and types of attempts to reach the subject must be documented in the 
subject’s source documents.  In any circumstance, every effort should be made to document 
subject outcome, if possible.  The investigator should inquire about the reason for 
withdrawal, request that the subject return all used/unused investigational product(s) and 
packages, request that the subject return for a final visit, if applicable, and follow up with the 
subject regarding any unresolved AEs.
If the subject 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.
7. ASSESSMENTS
Every effort should be made to ensure that the protocol-required tests and procedures are 
completed as described. However, it is anticipated that from time to time there may be 
circumstances, outside of the control of the investigator that may make it unfeasible to 
perform the test. In these cases the investigator will take all steps necessary to ensure the 
safety and well-being of the subject. When a protocol-required test cannot be performed, the 
investigator will document the reason for this and any corrective and preventive actions that 
he or she has taken to ensure that normal processes are adhered to as soon as possible. The 
study team will be informed of these incidents in a timely fashion.
7.1. Pregnancy Testing
For female subjects of childbearing potential, a serum and/or urine pregnancy test, with 
sensitivity of at least 25 mIU/mL, will be performed at screening, before investigational 
product administration at the baseline visit, and at the end of treatment visit.  A negative 

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pregnancy result is required before the subject may receive the investigational product.  
Pregnancy tests will also be done whenever 1 menstrual cycle is missed during the active 
treatment period (or when potential pregnancy is otherwise suspected), repeated at every visit 
and at the end of the study to confirm the subject has not become pregnant during the study. 
Pregnancy tests may also be repeated as per request of IRBs/ECs or if required by local 
regulations. 
In the case of a positive confirmed pregnancy, the subject will be withdrawn from
administration of IP and from the study. 
7.2. Banked Biospecimens
7.2.1. Markers of Drug Response
Studying the variation in genetic markers and other biomarkers may help to explain some of 
the variability in response seen with some drugs among different individuals.  This is referred 
to as pharmacogenomic/biomarker research.  Comparing the DNA, RNA, protein, and 
metabolite variation patterns of subjects who respond well and those who respond poorly to 
treatment may help to better define the most appropriate group of patients in which to target a 
given treatment. Collecting biospecimens for exploratory pharmacogenomic/biomarker
analyses and retaining them in the Pfizer BioBank makes it possible to better understand the 
drug’s mechanism of action and to seek explanations for differences in, for example, 
exposure, efficacy, tolerability, or safety not anticipated prior to the beginning of the study.
Providing these biospecimens is a required study activity for study sites and subjects, unless 
prohibited as such by local regulations or ethics committee decision. 
To protect subjects’ confidentiality, the banked biospecimens and data generated from them 
will be coded with the subject’s study identification (ID) number. Samples will be kept in a 
facility accessible only by swiping a badge. Data will be stored on password-protected 
computer systems. The key between the code and the subject’s personal identifiers will be 
held at the study site; the researchers using the biospecimens and data generated from them 
will not have access to the key nor any personally identifying information. Biospecimens 
will be used only for the purposes described here and in the informed consent 
document/subject information sheet; any other uses require additional ethical approval. 
Unless a time limitation is required by local regulations or ethical requirements, 
biospecimens will be stored indefinitely to allow for future research on the topics described 
here, including research conducted during the lengthy drug development process and also 
postmarketing research. Subjects can withdraw their consent for the use of their 
biospecimens at any time by making a request to the investigator, in which event any 
remaining biospecimen will be destroyed; data already generated from the biospecimens will 
continue to be stored to protect the integrity of existing analyses. It is very unlikely that 
results generated from the biospecimens will have any clinical, diagnostic, or therapeutic 
implications for the individual study participants. Subjects are notified in the informed 
consent document/subject information sheet that their results will not be given to them, 
unless required by local laws or regulations, in which case results will be returned via the 
investigator. Results will not be provided to family members or other physicians, nor will 

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they be recorded in the subject’s medical record. There is no intention to contact subjects 
after completion of the clinical study.
A 4-mL blood biospecimen Prep D1 (K2 edetic acid [ethylenediaminetetraacetic acid]
[EDTA] whole blood collection optimized for DNA analysis) will be collected at the 
baseline visit to be retained for potential pharmacogenomic/biomarker analyses related to 
drug response, unless prohibited by local regulations or ethics committee decision.  For 
example, putative safety biomarkers, drug-metabolizing enzyme genes, drug-transport 
protein genes, or genes thought to be related to the mechanism of drug action may be 
examined.
Additional biospecimens to be retained for exploratory analyses in this study include the 
following:  

Prep B1 (K2 EDTA plasma collection optimized for 
biomarker/proteomic/metabonomic analysis): A 10-mL blood biospecimen will be 
collected at Baseline, Week 12, Week 24, and Early Discontinuation visit during 
Period 1.

Prep R1 (PAXGene whole blood collection optimized for RNA analysis): A 
2.5-mL blood biospecimen will be collected at Baseline, Week 12, Week 24, and 
Early Discontinuation visit during Period 1.
The banked biospecimens will be collected from all subjects unless prohibited by local 
regulations or ethics committee decision.  Detailed collection, processing, storage, and 
shipment instructions are provided in the central laboratory manual.
It is possible that the use of these biospecimens may result in commercially viable products.  
Subjects will be advised in the informed consent document/subject information sheet that 
they will not be compensated in this event.
7.2.2. Additional Research
Unless prohibited by local regulations or ethics committee decision, subjects will be asked to 
indicate on the consent form whether they will allow the banked biospecimens to also be 
used for the following research:

Investigations of the disease under study in the clinical study, and related conditions.

Biospecimens may be used as controls.  This includes use in case-control studies of 
diseases for which Pfizer is researching drug therapies; use in characterizing the 
natural variation among people in genes, RNA, proteins, and metabolites; and use in 
developing new technologies related to pharmacogenomics/biomarkers. 

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Subjects need not provide additional biospecimens for the uses described in this section; the 
biospecimen specified in the Markers of Drug Response section will be used.  Subjects may 
still participate in the clinical study if they elect not to allow their banked biospecimens to be 
used for the additional purposes described in this section.
7.3. Efficacy Assessments
It is recommended that the same qualified site personnel complete these assessments for a 
subject at every visit throughout the study.
Refer to the Schedule of Activities for specific time points at which the following efficacy 
assessments will be completed.
7.3.1. Physician’s Global Assessment (PGA)
The investigator will estimate the subject’s overall disease activity over the previous 48 
hours (this should be independent of the Subject’s Assessment of Disease Activity) using a 
scale between 0 millimeters (mm) [none] and 100 mm (severe).
7.3.2. Tender/Painful Joint Count (44)
Forty-four joints will be assessed by the qualified assessor to determine the number of joints 
that are considered tender or painful.  The response to pressure/motion on each joint will be 
assessed using the following scale: Present/Absent/Not Done/Not Applicable (to be used for 
artificial joints).  The 44 joints to be assessed are:

Upper Body: sternoclavicular, acromioclavicular.

Upper extremity: shoulder, elbow, wrist (includes radiocarpal, carpal and 
carpometacarpal considered as one unit),  metacarpophalangeals (MCP I, II, III, IV, 
V), thumb interphalangeal (IP), proximal interphalangeals (PIP II, III, IV, V).

Lower Extremity: knee, ankle, metatarsophalangeals (MTP I, II, III, IV, V).
7.3.3. Swollen Joint Count (44)
The qualified assessor will also assess joints for swelling using the following scale: 
Present/Absent/Not done/Not applicable (to be used for artificial joints).  Forty-four joints 
will be assessed for swelling, the same as those listed above for tenderness/pain.  Artificial 
joints will not be assessed.
7.3.4. Dactylitis
Each of the 10 fingers and 10 toes is evaluated by a qualified assessor for dactylitis.  A score 
of 0, 1, 2 or 3 (where 0 = none, 1= mild, 2 = moderate, 3 = severe) is assigned to each.

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7.3.5. Maastricht Anklyosing Spondylitis Enthesitis Score (MASES)
There are 13 sites evaluated by a qualified assessor for enthesitis: 1st costochondral joint 
(left/right), 7th costochondral joint (l/r), posterior superior iliac spine (l/r), posterior anterior 
iliac spine (l/r), iliac crest (l/r), proximal insertion of Achilles tendon (l/r) and 5th lumbar 
spinous process.  Each site is scored as 0 or 1 depending on whether enthesis is present or 
absent.
7.4. Health Outcomes Assessments
7.4.1. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
The BASDAI consists of a 0 through 100 mm scale (zero being no problem and 100 being 
very severe) which is used to answer 6 questions pertaining to the 5 major symptoms of AS: 
fatigue; spinal pain; joint swelling and pain; morning stiffness duration; morning stiffness 
severity.
7.4.2. Bath Ankylosing Functional Index (BASFI)
The BASFI is a set of 10 questions designed to determine the degree of functional limitation 
in those with AS.  The ten questions were chosen with a major input from patients with AS.  
The first 8 questions consider activities related to functional anatomy.  The final 2 questions 
asses the subjects’ ability to cope with everyday life.  A 100 mm visual analog scale ranging 
from 0 (Easy) to 100 (Impossible) is used to answer the questions. 
7.4.3. Subject’s Assessment of Disease Activity (SADA)
Subjects will assess the overall disease activity over the last 48 hours using a pain scale 
between 0 mm (none) and 100 mm (severe).
7.4.4. Subject Nocturnal and Total Back Pain
Two VAS items will be used to assess the level of nocturnal pain and total back pain during 
the past 48 hours.  For each of these assessments, subjects will mark their level of pain on a 
100 mm VAS anchored by 0 for “no pain” to 100 mm “most severe pain”.
7.4.5. Bath Ankylosing Spondylitis Patient Global Assessment Score (BAS-G)
The BAS-G is a two question assessment evaluating the effect of AS on the subject’s 
well-being over the last week and the last 6 months.  Responses are made on a 100 mm VAS
using an anchor of “very good” to “very bad” at the ends. 
7.4.6. EuroQoL-5D Health Questionnaire (EQ-5D)
The EQ-5D instrument is designed to assess impact on health-related quality of life in five 
domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  
Scores from the five domains calculate a single index value, known as a utility score. In 
addition, the EQ VAS records the respondent’s self-rated health on a vertical, visual 
analogue scale where the endpoints are labelled ‘Best imaginable health state’ and ‘Worst 
imaginable health state’.  This information can be used as a quantitative measure of health 
outcome as judged by the individual respondents. 

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7.4.6.1. Short Form-36 (SF-36)
The SF-36 is a widely used generic quality of life instrument that assesses the subject’s 
general health and functional status.  It consists of 36 questions that are grouped into 
8 domains (physical functioning, vitality, social functioning, mental health, role-physical, 
bodily pain, role-emotional and general health).  Domain scores range from 0-100, with 
greater scores reflecting better health status.  In addition, SF-36 has 2 summary scores, the 
Physical Component Summary (PCS) and the Mental Component Summary (MCS). 
7.4.7. Work Productivity and Activity Impairment (WPAI)
The WPAI assesses work productivity and impairment.  It is a 6-item questionnaire regarding 
current employment, hours missed and actually worked, and degree to which a specified 
health problem affected work productivity and regular activities over the past 7 days.  
Subscale scores include percent work time missed with to the health problem; percent 
impairment while working due to problem; percent overall work impairment due to problem; 
and percent activity impairment due to problem.  Each subscale score is expressed as an 
impairment percentage (0-100) where higher numbers indicate greater impairment and less 
productivity.
7.5. Safety Assessments
Safety will be assessed in all subjects who receive at least one dose of investigational product 
using the following measures.  Refer to the Schedule of Activities for specific time points at 
which the following safety assessments will be completed.  Safety assessments include the 
following:
7.5.1. Physical Examinations
Physical examinations will be performed by a physician and evaluate any clinically 
significant abnormalities within the following body systems: general appearance, skin 
(presence of rash), HEENT (head, eyes, ears, nose, throat), heart (auscultation for presence of 
murmurs, gallops, rubs), lungs (auscultation), abdomen (palpation and auscultation), lower 
extremities (peripheral edema), neurological (mental status, gait, reflexes, motor and sensory 
function, coordination), back/spinal and lymph nodes.

At the screening visit, the results of the physical examination will be recorded in the 
subject’s source documents and any significant findings will be recorded on the 
Medical History CRF and/or the appropriate AE CRF.

At the subsequent study visits, the results of the physical examination will be 
recorded in the subject’s source documents and any clinically significant changes 
from the physical performed at the screening visit will be recorded on the appropriate 
AE CRF.

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7.5.2. Vital Signs/Height/Weight
Vital signs consist of sitting blood pressure and pulse rate.  Blood pressure and pulse will be 
measured at every visit.  The blood pressure and pulse rate should be obtained while the 
subject is sitting.  Blood pressure will be measured in the subject’s arm and recorded to the 
nearest mm Hg.  It is preferable to take the blood pressure in the same arm at each visit, 
using an appropriate cuff size.  Every effort should be made to take the blood pressure 
reading after the subject rests for at least 5 minutes.  If possible, a different arm should be 
used for the collection of blood samples
Height and weight will be recorded at the screening visit, Week 24 visit as well as the final 
study visit (either Week 64, Week R12 or early discontinuation).
7.5.3. Chest X-ray and TB Testing
Local country guidelines should be followed for appropriate screening and prophylaxis in the 
setting of anti-TNF therapy, including a chest radiograph and objective TB testing, such as 
purified protein derivative (PPD) or Quantiferon.  If the subject is known to be PPD positive, 
the test need not be repeated if documentation is available to show the subject meets local 
criteria for anti-TNF therapy and has not had active TB in the last 2 years.  If the subject has 
a documented negative PPD or Quantiferon test within 3 months prior to the screening visit, 
the test need not be repeated.
7.5.4. IBD, Psoriasis, Uveitis Assessment
Subjects will be assessed to determine if they have experienced an episode of IBD, psoriasis 
and uveitis since the last visit.
7.5.5. Adverse Events and Serious Adverse Events
Refer to Section 8 for details.
7.5.6. Clinical Laboratory Evaluations 
Clinical laboratory evaluations include hematology, blood chemistry and urinalysis (see 
Section 7.6 Laboratory Evaluations).
7.6. Laboratory Evaluations
As much as possible, only one central laboratory will be used by each investigator for all 
determinations.  Laboratory certification and laboratory normal ranges must be provided to 
the sponsor for all laboratories used, excluding the sponsor-designated central laboratory.
All laboratory tests that become abnormal to a clinically significant degree after 
investigational product administration must be repeated and the investigator must continue to 
follow up as medically indicated until values have returned to baseline or until the condition 
stabilizes.  If laboratory values do not return to normal or baseline within a reasonable 
period, the etiology must be identified and the sponsor notified.  In the judgment of the 
investigator, all clinically significant abnormal laboratory tests will be recoded on the 

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appropriate AE CRF.  Additional laboratory testing may be performed according to local 
guidelines or standard of care and for follow-up of abnormal laboratory test results.
All laboratory tests will be performed by the central laboratory with the exception of the ESR 
and urine pregnancy testing, which will be performed by the investigative site.  The ESR will 
be performed at the investigative site using an ESR kit supplied by the central laboratory.  A 
locally supplied ESR kit should not be used for this study.  The urine pregnancy testing will 
use a urine pregnancy kit supplied by the central laboratory.
All laboratory samples should be collected at the subject’s scheduled visit, however, to 
accommodate rare instances when a subject is unable to fast (or did not fast), all scheduled 
lab samples for the visit may be drawn within 4 days of the visit.  Unscheduled clinical labs 
may be obtained at any time during the study to assess any perceived safety concerns.
Sample collection, storage, and shipping information can be found in the laboratory manual 
supplied by the sponsor-designated central laboratory.  Laboratory evaluations will include 
the following (see the Schedule of Activities for specific time points):

Blood Chemistry: sodium, potassium, chloride, carbon dioxide (or bicarbonate), 
blood urea nitrogen (or urea), creatinine, ALT, AST, alkaline phosphatase, total direct 
bilirubin, albumin and total protein.

Hematology: white blood cell count with differential, red blood cell (RBC) with 
morphology, RBC indices (mean corpuscular volume [MCV], mean corpuscular 
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], red cell 
distribution width [RDW]), platelets, hemoglobin and hematocrit.

Urinalysis: glucose, albumin and hemoglobin.

Other Serum Blood Tests: serum pregnancy test, high sensitivity C-reactive protein, 
Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody and
Human Leukocyte antigen B27 (HLA-B27). 
7.7. Imaging

X-ray SIJ – this x-ray is obtained at the screening visit to determine eligibility.  The 
reading of this x-ray is performed by the central imaging vendor.  If it is necessary to 
repeat the x-ray of the SIJ to determine eligibility, the screening period may be 
extended to 6 weeks.  Results of historical x-rays that have been obtained within 
4 months prior to the screening visit could be used in lieu of performing screening 
x-rays.  If historical x-rays are used, the original films, or a copy, must be on site and 
a copy should be sent to the central reader.  If the results are considered unevaluable 
by the central reader, the x-ray must be repeated.  The original films or digital images 
will be sent to the central imaging vendor for digitization, masking of any personal 
identifying information and archiving.  Copies of the original films and/or digital 
images may be made and kept at the sites. In Germany only: historical x-rays of 
pelvis taken within 12 months prior to the screening could be used in lieu of the 

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screening x-ray.  This can only occur if the x-rays are deemed to be evaluable by the 
central reader for the presence of and/or degree of sacroiliitis.

MRI – the initial MRI takes place at the screening visit, but should not be performed 
until the SIJ x-ray has been read and the results communicated to the investigator as 
the x-ray results may determine non-eligibility.  The first MRI should be performed 
prior to the initial dosing with the investigational product.  This first MRI will 
evaluate for the presence of inflammation of sacroiliac joints.  If it is necessary to 
repeat the MRI, the screening period may be extended to 6 weeks.  MRI evaluation 
will be repeated at Weeks 24, 48, 64, R0, R12, or early discontinuation.  When the 
subject enters the retreatment period (Period 3), if it has been <8 weeks since their 
previous MRI, there is no need to conduct the MRI at the first retreatment visit 
(Visit R0).
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered AEs regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all AEs, the investigator must pursue and obtain information adequate both to determine 
the outcome of the AE and to assess whether it meets the criteria for classification as a 
serious adverse event (SAE) requiring immediate notification to Pfizer or its designated 
representative.  For all AEs, sufficient information should be obtained by the investigator to 
determine the causality of the AE.  The investigator is required to assess causality.  
Follow-up by the investigator may be required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Pfizer concurs with that assessment.
As part of ongoing safety reviews conducted by the sponsor, any nonserious AE that is 
determined by the sponsor to be serious will be reported by the sponsor as an SAE.  To assist 
in the determination of case seriousness, further information may be requested from the 
investigator to provide clarity and understanding of the event in the context of the clinical 
study. 
8.2. Reporting Period
For SAEs, the active reporting period to Pfizer or its designated representative begins from 
the time that the subject provides informed consent, which is obtained prior to the subject’s 
participation in the study, ie, prior to undergoing any study-related procedure and/or 
receiving investigational product, through and including 28 calendar days after the last 
administration of the investigational product.  SAEs occurring to a subject after the active 
reporting period has ended should be reported to the sponsor if the investigator becomes 
aware of them; at a minimum, all SAEs that the investigator believes have at least a 
reasonable possibility of being related to investigational product are to be reported to the 
sponsor.

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AEs (serious and nonserious) should be recorded on the case report form (CRF) from the 
time the subject has taken at least 1 dose of investigational product through the subject’s last
visit.
8.3. Definition of an Adverse Event
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
product or medical device; the event need not necessarily have a causal relationship with the 
treatment or usage.  Examples of AEs include but are not limited to: 

Abnormal test findings;

Clinically significant symptoms and signs;

Changes in physical examination findings;

Hypersensitivity;

Progression/worsening of underlying disease 

Drug abuse;

Drug dependency.
Additionally, they may include the signs or symptoms resulting from:

Drug overdose;

Drug withdrawal;

Drug misuse; 

Drug interactions;

Extravasation;

Exposure during pregnancy (EDP);

Exposure via breastfeeding;

Medication error;

Occupational exposure.

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8.4. Medication Errors
Medication errors may result, in this study, from the administration or consumption of the 
wrong product, by the wrong subject, at the wrong time, or at the wrong dosage strength.  
Such medication errors occurring to a study participant are to be captured on the medication 
error CRF which is a specific version of the AE page, and on the SAE form when 
appropriate.  In the event of medication dosing error, the sponsor should be notified 
immediately.
Medication errors are reportable irrespective of the presence of an associated AE/SAE, 
including:

Medication errors involving subject exposure to the investigational product;

Potential medication errors or uses outside of what is foreseen in the protocol that do 
or do not involve the participating subject;

Administration of a dose other than that specified in the protocol, Note: Missed doses 
of investigational product are not considered to be a medication error;

Administration of investigational product in which deviations from the 
protocol-specified storage and refrigeration requirements have been noted (except 
those approved by the Pfizer study team);

Administration of ETN from a commercial supply rather than ETN labeled for 
investigational use (unless specifically instructed to do so by the Pfizer study team);

Administration of the investigational product to anyone other than the subject.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is captured on the medication error version of the AE page 
and, if applicable, any associated AE(s) are captured on an AE CRF page.
8.5. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an AE 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 AE by the investigator or sponsor.

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Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an AE.  Any abnormal test result that is determined to be an error does not require 
reporting as an AE.
8.6. Serious Adverse Events
A serious adverse event is any untoward medical occurrence at any dose that:

Results in death;

Is life-threatening (immediate risk of death);

Requires inpatient hospitalization or prolongation of existing hospitalization;

Results in persistent or significant disability/incapacity (substantial disruption of the 
ability to conduct normal life functions);

Results in congenital anomaly/birth defect;

Lack of efficacy should be reported as an AE when it is associated with an SAE.
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 subject or may require intervention to prevent one of the other AE outcomes, 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.
8.6.1. Protocol-Specified Serious Adverse Events 
There are no protocol-specified SAEs in this study. All SAEs will be reported by the 
investigator as described in previous sections, and will be handled as SAEs in the safety 
database (see the section on Serious Adverse Event Reporting Requirements).
8.6.2. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in AST and/or ALT levels concurrent with abnormal elevations in total 
bilirubin level that meet the criteria outlined below in the absence of other causes of liver 
injury are considered potential cases of drug-induced liver injury (potential Hy’s law cases) 
and should always be considered important medical events. 
The threshold of laboratory abnormalities for a potential case of drug-induced liver injury 
depends on the subject’s individual baseline values and underlying conditions.  Subjects who 
present with the following laboratory abnormalities should be evaluated further to 
definitively determine the etiology of the abnormal laboratory values:

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
Subjects with AST or ALT and total bilirubin baseline values within the normal range 
who subsequently present with AST or ALT values 3 times the upper limit of 
normal (x ULN) concurrent with a total bilirubin value 2 x ULN with no evidence of 
hemolysis and an alkaline phosphatase value 2 x ULN or not available;

For subjects with preexisting ALT OR AST OR total bilirubin values above the 
ULN, the following threshold values should be used in the definition mentioned 
above:

For subjects with preexisting AST or ALT baseline values above the normal 
range: AST or ALT values 2 times the baseline values and 3 x ULN, or 
8 x ULN (whichever is smaller).
Concurrent with

For subjects with preexisting values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 x ULN or
if the value reaches 3 x ULN (whichever is smaller).
The subject should return to the investigational site and be evaluated as soon as possible, 
preferably within 48 hours from awareness of the abnormal results.  This evaluation should 
include laboratory tests, detailed history, and physical assessment. 
In addition to repeating measurements of AST and ALT, laboratory tests should include 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, gamma-glutamyl 
transferase, prothrombin time (PT)/ international normalized ratio (INR), and alkaline 
phosphatase.  A detailed history, including relevant information, such as review of ethanol, 
acetaminophen, recreational drug and supplement consumption, family history, occupational 
exposure, sexual history, travel history, history of contact with a jaundiced person, surgery, 
blood transfusion, history of liver or allergic disease, and work exposure, should be collected.  
Further testing for acute hepatitis A, B, or C infection and liver imaging (eg, biliary tract) 
may be warranted.  All cases confirmed on repeat testing as meeting the laboratory criteria 
defined above, with no other cause for liver function test (LFT) abnormalities identified at 
the time, should be considered potential Hy’s law cases irrespective of availability of all the 
results of the investigations performed to determine etiology of the abnormal LFTs.  Such 
potential Hy’s law cases should be reported as SAEs.
8.7. Hospitalization
Hospitalization is defined as any initial admission (even less than 24 hours) in a hospital or 
equivalent healthcare facility or any prolongation of an existing admission.  Admission also 
includes transfer within the hospital to an acute/intensive care unit (eg, from the psychiatric 
wing to a medical floor, medical floor to a coronary care unit, or neurological floor to a 
tuberculosis unit).  An emergency room visit does not necessarily constitute a hospitalization; 
however, the event leading to the emergency room visit should be assessed for medical 
importance.

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Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;

Nursing homes;

Same-day surgeries (as outpatient/same-day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
AE is not in itself an SAE.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, for 
workup of persistent pre-treatment laboratory abnormality);

Social admission (eg, subject has no place to sleep);

Administrative admission (eg, for yearly physical examination);

Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol);

Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery);

Hospitalization for observation without a medical AE;

Preplanned treatments or surgical procedures.  These should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject;
Diagnostic and therapeutic noninvasive and invasive procedures, such as surgery, should not 
be reported as AEs.  However, the medical condition for which the procedure was performed 
should be reported if it meets the definition of an AE.  For example, an acute appendicitis 
that begins during the AE reporting period should be reported as the AE, and the resulting 
appendectomy should be recorded as treatment of the AE.

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8.8. Severity Assessment
If required on the AE CRFs, the investigator will use the adjectives MILD, MODERATE, or 
SEVERE to describe the maximum intensity of the AE.  For purposes of consistency, these 
intensity grades are defined as follows:
MILD
Does not interfere with subject's usual function.
MODERATE
Interferes to some extent with subject's usual function.
SEVERE
Interferes significantly with subject's usual function.
Note the distinction between the severity and the seriousness of an AE.  A severe event is not 
necessarily an SAE.  For example, a headache may be severe (interferes significantly with 
the subject's usual function) but would not be classified as serious unless it met one of the 
criteria for SAEs, listed above.
8.9. Causality Assessment
The investigator’s assessment of causality must be provided for all AEs (serious and 
nonserious); the investigator must record the causal relationship in the CRF, as appropriate, 
and report such an assessment in accordance with the SAE reporting requirements if 
applicable.  An investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the investigational product caused or contributed to an 
AE; generally the facts (evidence) or arguments to suggest a causal relationship should be 
provided.  If the investigator does not know whether or not the investigational product caused 
the event, then the event will be handled as “related to investigational product” for reporting 
purposes, as defined by the sponsor (see the section on Reporting Requirements).  If the 
investigator's causality assessment is "unknown but not related to investigational product," 
this should be clearly documented on study records. 
In addition, if the investigator determines that an SAE is associated with study procedures, 
the investigator must record this causal relationship in the source documents and CRF, as 
appropriate, and report such an assessment in accordance with the SAE reporting 
requirements, if applicable.
8.10. Exposure During Pregnancy
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy occurs if:
1. A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes, or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;
An example of environmental exposure would be a case involving direct contact with 
a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant and has 
been exposed to chemotherapeutic products).

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2. A male has been exposed (eg, because of treatment or environmental exposure) to the 
investigational product prior to or around the time of conception and/or is exposed 
during his partner’s pregnancy.
If a study subject or study subject’s partner becomes or is found to be pregnant during the 
study subject’s treatment with the investigational product, the investigator must submit this 
information to the Pfizer drug safety unit on an SAE Report Form and Exposure During 
Pregnancy (EDP) supplemental form, regardless of whether an SAE has occurred.  In 
addition, the investigator must submit information regarding environmental exposure to a 
Pfizer product in a pregnant woman (eg, a subject reports that she is pregnant and has been 
exposed to a cytotoxic product by inhalation or spillage) using the EDP supplemental form.  
This must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the exposure. The 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 and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer of the outcome as a follow-up 
to the initial EDP supplemental form.  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 preprocedure 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 (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported as SAEs follows: 

Spontaneous abortion includes miscarriage and missed abortion;

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 when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product.
Additional information regarding the EDP may be requested by the investigator.  Further 
follow-up of birth outcomes will be handled on a case-by-case basis (eg, follow-up on 
preterm infants to identify developmental delays). In the case of paternal exposure, the 
investigator will provide the study subject with the Pregnant Partner Release of Information 
Form to deliver to his partner. The investigator must document in the source documents that 
the subject was given the Pregnant Partner Release of Information Form to provide to his 
partner.

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8.11. Occupational Exposure
An occupational exposure occurs when, during the performance of job duties, a person 
(whether a healthcare professional or otherwise) gets in unplanned direct contact with the 
product, which may or may not lead to the occurrence of an AE.
An occupational exposure is reported to the drug safety unit within 24 hours of the
investigator’s awareness, using the SAE report form, regardless of whether there is an 
associated AE/SAE.  Since the information does not pertain to a subject enrolled in the study, 
the information is not reported on a CRF; however a copy of the completed SAE report form 
is maintained in the investigator site file.
8.12. Withdrawal Due to Adverse Events (See Also the Section on Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of AE noted earlier, and recorded on the appropriate AE CRF 
page. 
When a subject withdraws because of an SAE, the SAE must be reported in accordance with 
the reporting requirements defined below.
8.13. Eliciting Adverse Event Information
The investigator is to report all directly observed AEs and all AEs spontaneously reported by 
the study subject.  In addition, each study subject will be questioned about AEs.
8.14. Reporting Requirements
Each AE is to be assessed to determine if it meets the criteria for SAEs.  If an SAE occurs, 
expedited reporting will follow local and international regulations, as appropriate.
8.14.1. Serious Adverse Event Reporting Requirements
If an SAE occurs, Pfizer is to be notified within 24 hours of investigator awareness of the 
event.
In particular, if the SAE is fatal or life-threatening, notification to Pfizer must be made 
immediately, irrespective of the extent of available AE information.  This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports as 
well as to the initial and follow-up reporting of EDP, exposure via breastfeeding, and 
occupational exposure cases. 
In the rare event that the investigator does not become aware of the occurrence of an SAE
immediately (eg, if an outpatient study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours after learning of it and document the time 
of his or her first awareness of the AE.
For all SAEs, the investigator is obligated to pursue and provide information to Pfizer in 
accordance with the time frames for reporting specified above.  In addition, an investigator 
may be requested by Pfizer to obtain specific additional follow-up information in an 

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expedited fashion.  This information collected for SAEs is more detailed than that captured 
on the AE CRF.  In general, this will include a description of the AE in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Information on other possible causes of the event, such as concomitant 
medications, vaccines, and/or illnesses, must be provided.  In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Pfizer or its 
designated representative. 
8.14.2. Nonserious Adverse Event Reporting Requirements
All AEs will be reported on the AE page(s) of the CRF.  It should be noted that the form for 
collection of SAE information is not the same as the AE CRF.  Where the same data are 
collected, the forms must be completed in a consistent manner.  For example, the same AE
term should be used on both forms.  AEs should be reported using concise medical 
terminology on the CRFs as well as on the form for collection of SAE information.
8.14.3. Sponsor’s Reporting Requirements to Regulatory Authorities
AE reporting, including suspected unexpected serious adverse reactions, will be carried out 
in accordance with applicable local regulations.
9. DATA ANALYSIS/STATISTICAL METHODS
Detailed methodology for summary and statistical analyses of the data collected in this study 
will be documented in a Statistical Analysis Plan (SAP), which will be maintained by the 
sponsor.  This document may modify the plans outlined in the protocol; however, any major 
modifications of the primary endpoint definition and/or its analysis will also be reflected in a 
protocol amendment.
9.1. Sample Size Determination
The focus of this open label study is estimation.  The sample size for this study was 
determined based on both the primary and key secondary endpoints.  For the primary 
endpoint, 70% of subjects are expected to flare following treatment withdrawal.  With an 
enrollment of approximately 200 subjects, approximately 96 subjects are expected to enter 
the treatment withdrawal period.  If 70% of subjects with treatment withdrawn flare, the half 
width of the 95% confidence interval on flare rate estimate will be approximately 10%.  For 
the key secondary endpoint of retreatment response, it is anticipated that 60% of the subjects 
who flare and are retreated will recover the initial ASDAS less than 1.3 response.  The 
half-width confidence interval on this estimate will be approximately 12%.
9.2. Efficacy Analysis
9.2.1. Analysis of the Primary Endpoint
The primary endpoint, the occurrence of flare (ASDAS ESR greater than or equal to 2.1) in 
Period 2 will be summarized descriptively as the percent with flare with 95% confidence 
interval.  This estimate will include all subjects who qualify for the retreatment interval and 
have at least one evaluation after treatment is withdrawn.

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ASDAS is calculated from the following parameters4: 
1. Total back pain (BASDAI question 2);
2. Subject global assessment of disease activity;
3. Peripheral pain/swelling (BASDAI question 3);
4. Duration of morning stiffness (BASDAI question 6);
5. C-reactive protein (CRP) in mg/litre or ESR in mm/h.
The ASDAS score is then calculated as follows: 
ASDAS CRP = (0.121 x total back pain) + (0.110 x subject global) + (0.073 x peripheral 
pain/swelling) + (0.058 x duration of morning stiffness) + (0.579 x Ln(CRP+1)).
ASDAS ESR = (0.08 x total back pain) + (0.11 x subject global) + (0.09 x peripheral 
pain/swelling) + (0.07 x duration of morning stiffness) + (0.29 x √(ESR).
9.2.2. Analysis of Secondary Endpoints
For the key secondary endpoint of time to flare, descriptive statistics will include median 
time to flare and 95% confidence interval using the Kaplan-Meier approach.  In addition an 
estimate of the relative flare rates in the current study and that seen in those subjects in 
protocol B1801031 who met the treatment withdrawal criteria for the current protocol will 
also be obtained; subjects in B1801031 did not discontinue treatment and will serve as a 
reference population.  For this estimate a Cox Proportional Hazards model will be used.  A 
99% confidence interval will be calculated for the Hazard Ratio.  Additional sensitivity 
analyses evaluating the impact of covariates may be performed, details will be provided in 
the statistical analysis plan.
The efficacy upon retreatment will be assessed descriptively as the proportion of subjects 
who achieve an ASDAS CRP inactive disease less than 1.3; this will be expressed as a 
percent with 95% confidence interval.
Dichotomous clinical and subject rated endpoints measured during Periods 1 and 2 will be 
summarized as number evaluated, percent with response of interest and 95% confidence 
intervals.
For continuous clinical and subject rated endpoints measured during Periods 1 and 2, both 
raw and change values will be summarized with the following descriptive statistics: n, mean, 
standard deviation, min and max, median and the 25th and 75th percentiles (quartiles).

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9.3. Safety Analysis
The safety data will be summarized in accordance with Pfizer data standards.  The safety 
analysis set will include all randomized subjects who have taken at least one dose of 
investigational product.
Listings and summary tabulations of AEs and treatment-emergent AEs will be generated.  
AEs will be classified by body system and preferred term and summaries of the number of 
subjects with events will be provided for each treatment group.
Listings and summary tables will be produced for vital signs (sitting blood pressure and pulse 
rate), weight, laboratory evaluations (hematology, blood chemistry, and urinalysis).
9.4. Interim Analysis
Descriptive analyses of Period 1 will be performed when all subject data for Period 1 is 
complete.  No interim analysis with the aim of stopping or modifying the trial in any way is 
planned.
9.5. Data Monitoring Committee 
This study will not use a data monitoring committee.
10. QUALITY CONTROL AND QUALITY ASSURANCE
Pfizer or its agent will conduct periodic monitoring visits during study conduct to ensure that 
the protocol and Good Clinical Practices (GCPs) are being followed.  The monitors may 
review source documents to confirm that the data recorded on CRFs are accurate.  The 
investigator and institution will allow Pfizer monitors/auditors or its agents and appropriate 
regulatory authorities direct access to source documents to perform this verification.  This 
verification may also occur after study completion.
During study conduct and/or after study completion, the study site may be subject to review 
by the IRB/EC, and/or to quality assurance audits performed by Pfizer, or companies 
working with or on behalf of Pfizer, and/or to inspection by appropriate regulatory 
authorities.
The investigator(s) will notify Pfizer or its agents immediately of any regulatory inspection 
notification in relation to the study.  Furthermore, the investigator will cooperate with Pfizer 
or its agents to prepare the study site for the inspection and will allow Pfizer or its agent, 
whenever feasible, to be present during the inspection.  The investigator will promptly 
provide copies of the inspection findings to Pfizer or its agent.  Before response submission 
to the regulatory authorities, the investigator will provide Pfizer or its agents with an 
opportunity to review and comment on responses to any such findings.
It is important that the investigator(s) and their relevant personnel are available during the 
monitoring visits and possible audits or inspections and that sufficient time is devoted to the 
process.

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11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term CRF should be understood to refer to either a paper form or 
an electronic data record or both, depending on the data collection method used in this study.
A CRF is required and should be completed for each included subject.  The completed 
original CRFs are the sole property of Pfizer and should not be made available in any form to 
third parties, except for authorized representatives of Pfizer or appropriate regulatory 
authorities, without written permission from Pfizer.
The investigator has ultimate responsibility for the collection and reporting of all clinical, 
safety, and laboratory data entered on the CRFs and any other data collection forms (source 
documents) and ensuring that they are accurate, authentic/original, attributable, complete, 
consistent, legible, timely (contemporaneous), enduring, and available when required.  The 
CRFs must be signed by the investigator or by an authorized staff member to attest that the 
data contained on the CRFs are true. Any corrections to entries made in the CRFs or source 
documents must be dated, initialed, and explained (if necessary) and should not obscure the
original entry. 
In most cases, the source documents are the hospital's or the physician's subject chart.  In 
these cases, data collected on the CRFs must match the data in those charts. 
In some cases, the CRF, or part of the CRF, may also serve as source documents.  In these 
cases, a document should be available at the investigative site as well as at Pfizer and clearly 
identify those data that will be recorded in the CRF, and for which the CRF will stand as the 
source document.
11.2. Record Retention
To enable evaluations and/or audits from regulatory authorities or Pfizer, the investigator 
agrees to keep records, including the identity of all participating subjects (sufficient 
information to link records, eg, CRFs and hospital records), all original signed informed 
consent documents, copies of all CRFs, safety reporting forms, source documents, and 
detailed records of treatment disposition, and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, and telephone call reports).  The records should 
be retained by the investigator according to the ICH guidelines, according to local 
regulations, or as specified in the clinical study agreement (CSA), whichever is longer.
If the investigator becomes unable for any reason to continue to retain study records for the 
required period (eg, retirement, relocation), Pfizer should be prospectively notified.  The 
study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or an independent third party arranged by Pfizer. 
Investigator records must be kept for a minimum of 15 years after completion or 
discontinuation of the study or for longer if required by applicable local regulations. 

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The investigator must obtain Pfizer's written permission before disposing of any records, 
even if retention requirements have been met.
12. ETHICS
12.1. Institutional Review Board/Ethics Committee 
It is the responsibility of the investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent documents, and other relevant documents, 
eg, recruitment advertisements, if applicable, from the IRB/EC.  All correspondence with the 
IRB/EC should be retained in the investigator file.  Copies of IRB/EC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/EC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/EC and Pfizer in writing immediately after 
the implementation.
12.2. Ethical Conduct of the Study
The study will be conducted in accordance with legal and regulatory requirements, as well as 
the general principles set forth in the International Ethical Guidelines for Biomedical 
Research Involving Human Subjects (Council for International Organizations of Medical 
Sciences 2002), Guidelines for GCP (ICH 1996), and the Declaration of Helsinki (World 
Medical Association 1996 & 2008). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline 
on GCP, and applicable local regulatory requirements and laws.
12.3. Subject Information and Consent
All parties will ensure protection of subject personal data and will not include subject names 
or other identifiable data in any reports, publications, or other disclosures, except where
required by law.
When study data are compiled for transfer to Pfizer and other authorized parties, subject 
names, addresses, and other identifiable data will be replaced by a numerical code based on a 
numbering system provided by Pfizer in order to de-identify study subjects. The study site 
will maintain a confidential list of subjects who participated in the study, linking each 
subject’s numerical code to his or her actual identity.  In case of data transfer, Pfizer will 
maintain high standards of confidentiality and protection of subjects’ personal data consistent 
with applicable privacy laws.
The informed consent documents must be in compliance with ICH GCP, local regulatory 
requirements, and legal requirements, including applicable privacy laws.
The informed consent documents used during the informed consent process must be 
reviewed and approved by the sponsor, approved by the IRB/EC before use, and available for 
inspection.

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The investigator must ensure that each study subject 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 subject before any study-specific activity is performed. The investigator 
will retain the original of each subject's signed consent document.
12.4. Subject Recruitment
Advertisements approved by IRBs/ECs and investigator databases may be used as 
recruitment procedures.
Pfizer will have an opportunity to review and approve the content of any study recruitment 
materials directed to potential study subjects before such materials are used.
12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP
In the event of any prohibition or restriction imposed (ie, clinical hold) by an applicable 
competent authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
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 subjects against any immediate hazard, and of 
any serious breaches of this protocol or of ICH GCP that the investigator becomes aware of.
13. DEFINITION OF END OF TRIAL
13.1. End of Trial in a Member State 
End of trial in a Member State of the European Union is defined as the time at which it is 
deemed that a sufficient number of subjects have been recruited and completed the study as 
stated in the regulatory application (ie, clinical trial application [CTA]) and ethics application 
in the Member State.  Poor recruitment (recruiting less than the anticipated number in the 
CTA) by a Member State is not a reason for premature termination but is considered a 
normal conclusion to the study in that Member State.
13.2. End of Trial in All Other Participating Countries 
End of trial in all other participating countries is defined as last subject last visit (LSLV).
14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/EC, or investigational product safety problems, or at the 
discretion of Pfizer.  In addition, Pfizer retains the right to discontinue development of ETN
at any time.
If a study is prematurely terminated or discontinued, Pfizer will promptly notify the 
investigator.  After notification, the investigator must contact all participating subjects and 

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the hospital pharmacy (if applicable) within one week.  As directed by Pfizer, all study 
materials must be collected and all CRFs completed to the greatest extent possible.
15. PUBLICATION OF STUDY RESULTS
15.1. Communication of Results by Pfizer
Pfizer fulfills its commitment to publicly disclose clinical trial results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations. 
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies conducted in patients that evaluate the safety and/or efficacy of a Pfizer 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are submitted for posting within 1 year of the primary completion date for studies in 
adult populations or within 6 months of the primary completion date for studies in pediatric 
populations.
Primary completion date is defined as the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary outcome, 
whether the clinical study concluded according to the prespecified protocol or was 
terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the primary completion date for studies in adult populations or 
within 6 months of the primary completion date for studies in pediatric populations.
www.pfizer.com
Pfizer posts Public Disclosure Synopses (clinical study report synopses in which any data 
that could be used to identify individual patients has been removed) on www.pfizer.com for 
Pfizer-sponsored interventional studies at the same time the US Basic Results document is 
posted to www.clinicaltrials.gov.
15.2. Publications by Investigators
Pfizer supports the exercise of academic freedom and has no objection to publication by 
principal investigator of the results of the study based on information collected or generated 
by principal investigator, whether or not the results are favorable to the Pfizer product.

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However, to ensure against inadvertent disclosure of confidential information or unprotected 
inventions, the investigator will provide Pfizer an opportunity to review any proposed 
publication or other type of disclosure of the results of the study (collectively, “Publication”) 
before it is submitted or otherwise disclosed.
The investigator will provide any publication to Pfizer at least 30 days before they are 
submitted for publication or otherwise disclosed. If any patent action is required to protect 
intellectual property rights, the investigator agrees to delay the disclosure for a period not to 
exceed an additional 60 days.
The investigator will, on request, remove any previously undisclosed confidential 
information before disclosure, except for any study- or Pfizer product-related information 
necessary to the appropriate scientific presentation or understanding of the study results.
If the study is part of a multicenter study, the investigator agrees that the first publication is 
to be a joint publication covering all study sites, and that any subsequent publications by the 
principal investigator will reference that primary publication. However, if a joint manuscript 
has not been submitted for publication within 12 months of completion or termination of the 
study at all participating sites, the investigator is free to publish separately, subject to the 
other requirements of this section.
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors.
Publication of study results is also provided for in the CSA between Pfizer and the 
institution.  In this section entitled Publications by Investigators, the defined terms shall have 
the meanings given to them in the CSA.
If there is any conflict between the CSA and any Attachments to it, the terms of the CSA 
control.  If there is any conflict between this protocol and the CSA, this protocol will control 
as to any issue regarding treatment of study subjects, and the CSA will control as to all other 
issues.

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16. REFERENCES
1.
Kelly’s Textbook of Rheumatology. Van Der Linden in Elsevier Saunders, 7th edition 
2005, Vol II pg 1133.
2.
Symptomatic Efficacy of Etanercept and Its Effects on Objective Signs of Inflammation 
in Early Nonradiographic Axial Spondyloarthritis. Dougados, M, et al: Arthritis & 
Rheumatology, 2014; Vol 66, No 8, pp 2091-2102.
3.
Frequency and Duration of Drug-free Demission After 1 Year of Treatment with 
Etanercept versus Sulfasalazine in Early Axial Spondyloarthritis: 2 Year Data of the 
ESTHER Trial. IH Song et al, Ann Rheum Dis 2012;71:1212-1215.
4.
Ankylosing Spondylitis Disease Activity Score (ASDAS): Defining Cut-off Values for 
Disease Activity States and Improvement Scores. Machado, P, et al: Ann Rheum Dis 
2011;7047-53.

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Appendix 1. Abbreviations
This is a list of abbreviations that may or may not be used in the protocol.  
Abbreviation
Term
AE
adverse event
ALT
alanine aminotransferase 
ASAS
Assessment of SpondyloArthritis Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
AST
aspartate aminotransferase
ax SpA
axial spondyloarthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BAS-G
Bath Ankylosing Spondylitis Patient Global Assessment Score
BL
baseline
BP
blood pressure
CDS
core data sheet
CM
centimeter
CRF
case report form
CSA
clinical study agreement
CRP
c-reactive protein
CTA
clinical trial application
DAI
dosage and administration instructions
DMARD
disease modifying anti-rheumatic drug
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DU
dispensable unit
EC
ethics committee
EDP
exposure during pregnancy
EDTA
edetic acid (ethylenediaminetetraacetic acid)
EQ-5D
EuroQoL-5D Health Questionnaire
ESR
erythrocyte sedimentation rate
ETN
etanercept
EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration (United States)
FDAAA
Food and Drug Administration Amendments Act (United States)
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HLA-B27
Human Leucocyte Antigen B27
hsCRP
high sensitivity c-reactive protein
IB
investigator’s brochure
IBD
inflammatory bowel disease
IBP
inflammatory back pain
ICH
International Conference on Harmonisation

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ID
identification
IND
investigational new drug application
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
IUD
intrauterine device
IVR
interactive voice response
IWR
interactive web response
KG
kilogram
LFT
liver function test
LOCF
last observation carried forward
LSLV
last subject last visit 
MASES
Maastricht Anklyosing Spondylitis Enthesitis
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCS
mental component summary
MCV
mean corpuscular volume
MM
millimeter
MRI
magnetic resonance imaging
N/A
not applicable
nr-ax SpA
non-radiographic axial spondyloarthritis
NSAID
non-steroidal anti-inflammatory drug
PCD
primary completion date
PCS
physical component summary
PFS
pre-filled syringe
PPD
purified protein derivative
PT
prothrombin time
RDW
red cell distribution width
RNA
ribonucleic acid
SADA
Subject’s Assessment of Disease Activity
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SCL
Supply Chain Lead
SF-36
Short-Form 36
SIJ
sacroiliac joint
SOP
standard operating procedure
SpA
spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
SPC
summary of product characteristics
SRSD
single reference safety document
TB
tuberculosis

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TNFα
tumor necrosis factor alpha
ULN
upper limit of normal
US
United States
USPI
United States package insert
UTN
Universal Trial Number
VAS
visual analogue scale
WPAI
Work Productivity and Activity Impairment

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Appendix 2. ASAS Classification Criteria for Axial Spondyloarthritis (ax SpA) in 
Patients with 3 Months of Back Pain and Age at Onset <45
                        OR 
# SpA Features
*Sacroiliitis on Imaging
Inflammatory back pain
Active inflammation on MRI highly 
suggestive of sacroiliitis associated with SpA
Arthritis
Defined radiographic sacroiliitis according to 
the Modified New York criteria
Enthesitis (heel)
Uveitis
Dactylitis
Psoriasis
Crohn’s or Colitis
Good response to NSAIDs
Family history of SpA
HLA-B27
Elevated CRP
Reference: Assessment of SpondyloArthritis International Society (ASAS) handbook: A guide to Assess 
spondyloarthritis.. J Sieper, M Rudwaleit, X Baraliakos, J Brandt, J Braun, R Burgos-Vargas,et al. Ann Rheum 
Dis 2009;68(Suppl II):ii1– ii44. doi:10.1136/ard.2008.104018.
Positive HLA-B27
Plus 
2 other SpA
Features #
Sacroiliitis on imaging*
Plus
1 SpA
Feature #

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Appendix 3. Radiographic Criterion in the Modified New York Criteria for Ankylosing 
Spondylitis
Radiographic criterion: Sacroiliitis Grade 2 bilaterally or Grade 3 4 unilaterally.
Grade 0: 
normal
Grade 1: 
suspicious changes
Grade 2: 
minimal abnormality – small localized areas with erosion or sclerosis, without 
alteration in the joint width.
Grade 3: 
unequivocal abnormality – moderate or advanced sacroiliitis with one or more 
erosions, evidence of sclerosis, widening, narrowing, or partial ankylosis.
Grade 4: 
severe abnormality – total ankylosis.
Reference: 
Assessment of SpondyloArthritis International Society (ASAS) handbook: A guide to Assess spondyloarthritis.  
J Sieper, M Rudwaleit, X Baraliakos, J Brandt, J Braun, R Burgos-Vargas ,et al.  Ann Rheum Dis 
2009;68(Suppl II):ii1– ii44. doi:10.1136/ard.2008.104018.

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Appendix 4. Definition of Parameters Applied in the Classification Criteria for Ax SpA
Inflammatory 
back pain
At least 4 out of 5 parameters present:
1. age at onset <40;
2. insidious onset;
3. improvement with exercise;
4. no improvement with rest;
5. pain at night (with improvement upon getting up).
Arthritis 
Past or present synovitis diagnosed by a physician.
Enthesitis (heel) Heel enthesitis: past or present spontaneous pain or tenderness at 
examination of the site of the insertion of the Achilles tendon or plantar 
fascia at the calcaneus.
Uveitis anterior
Past or present uveitis anterior confirmed by an ophthalmologist.
Dactylitis 
Past or present dactylitis, diagnosed by a physician.
Psoriasis 
Past or present psoriasis diagnosed by a physician.
Inflammatory 
bowel disease
Past or present Crohn disease or ulcerative colitis diagnosed by a 
physician.
Good response 
to NSAID
24-48 hours after a full dose of NSAID the back pain is not present any 
more or has improved.
Family History 
of SpA 
Presence in a first degree relative (mother, father, sister , brother or 
children) or second degree relative (maternal or paternal grandparent, 
aunt, uncle, niece or nephew) of any of the following : 
1. AS;
2. psoriasis;
3. uveitis;
4. reactive arthritis;
5. inflammatory bowel disease
Elevated CRP
CRP above upper normal limits in the presence of backache, after 
exclusion of other causes for elevated CRP.
HLA-B27
Positive testing according to standard laboratory techniques.
Sacroiliitis by 
radiographs
Bilateral grade 2-4 or unilateral grade 3-4 sacroiliitis on plain x-ray 
according to the New York criteria.
Sacroiliitis by 
MRI 
Active inflammatory lesions of sacroiliac joint with defined marrow 
oedema/osteitis, suggestive of sacroiliitis associated with SpA. 
Reference: The Development of Assessment of Spondyloarthritis International Society Classification criteria for 
Axial Spondyloarthritis (Part II): validation for Final Selection.  M Rudwaleit, D. van der Heijde et al.  Annual 
Rheum Dis. 2009 68(6):777-783.

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Appendix 5. Grades of Adverse Events
The following scale should be used to grade the event when determining whether a subject 
should be discontinued from investigational product, as outlined in Section 6.8 Subject 
Withdrawal:
0 = No adverse event or within normal limits
1 = Mild adverse event
2 = Moderate adverse event
3 = Severe and undesirable adverse event
4 = Life-threatening or disabling adverse event
5 = Death related to adverse event
Reference: National Cancer Institute (NCI) Common Toxicity Manual.  Common toxicity Criteria Version 2.0 
June 1st, 1999.  http://www.rtog.org/members/toxicity/ctcmanual6-1-99.pdf.

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Appendix 6. ASAS Eligibility Flowchart
ASAS Eligibility Flowchart
•
Duration of symptoms >3months and < 5 years at time of consent.
•
Diagnosis of axial spondyloarthritis, as defined by ASAS  criteria.
•
In order to meet imaging criteria for ASAS, subjects must have positive Sacroiliitis on MRI based on readings performed at 
BioClinica. Subjects negative for Sacroiliitis on MRI must have positive HLA-B27 plus 2 SpA features (one SpA feature must be 
elevated hsCRP). Conversely, subjects that are HLA-B27 negative must have positive Sacroiliitis on MRI plus 1 SpA feature.
Please note this is a portion of the overall eligibility criteria and these criteria alone do not make the
subjects eligible for randomization! Subjects must meet eligibility requirements for radiological 
sacroiliitis. They are not eligible if the centrally read x-ray of the SI joint meets modified NY criteria.
HLA-B27
HLA-B27
+
-
HLA-B27
Sacroiliitis
on MRI
+
Sacroiliitis
on MRI
-
+
Subject does not meet 
ASAS criteria and should not 
be randomized
1 SpA
Feature
Subject meets 
ASAS criteria
Subject meets 
ASAS criteria
Subject meets 
ASAS criteria
2 SpA
Features
One feature must 
be elevated hsCRP
1 SpA
Feature
Sacroiliitis
on MRI
-
+
+
+