Clinical trial NCT01421069
Conditions: Juvenile Idiopahtic Arthritis
Keywords: Use of etanercept to treat pediatric subjects with extended oligoarticular JIA enthestitis related arthritis (ERA) or psoriatic arthritis (PsA).
Sponsor: Pfizer
Start date: 2011-10-10; Completion date: 2021-02-04
Enrollment: 109 participants; Allocation: NA; Intervention model: 

Brief summary:
This is a 8-year extension study in pediatric subjects who have been diagnosed with one of 3 subtypes of Juvenile Idiopathic Arthritis (JIA) \[extended oligoarticular JIA, enthestitis related arthritis (ERA), or psoriatic arthritis (PsA)\] who have completed approximately 96 weeks of participation in study 0881A1-3338 (B1801014). The study contains an active treatment period, withdrawal/re-treatment period and a observational period (non-treatment).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: etanercept
Intervention descriptions: intervention 1: Subjects aged \<18 years and less than or equal to 62 kg will receive etanercept SC at a dose of 0.8 mg/kg QW (up to a maximum dose of 50 mg QW).

Subjects aged greater than or equal to 18 years or \>62 kg will receive etanercept SC at a dose of 50 mg QW.

Protocol documents:
Prot_000.pdf: 
Etanercept
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Page 1
AN OPEN-LABEL EXTENSION STUDY TO ASSESS THE LONG-TERM SAFETY 
AND CLINICAL BENEFIT OF ETANERCEPT IN CHILDREN AND 
ADOLESCENTS WITH EXTENDED OLIGOARTICULAR JUVENILE 
IDIOPATHIC ARTHRITIS, ENTHESITIS-RELATED ARTHRITIS, OR PSORIATIC 
ARTHRITIS WHO WERE PREVIOUSLY ENROLLED IN PROTOCOL 
0881A1-3338-WW(B1801014)
Compound:
PF-05208752
Compound Name (if applicable):
Etanercept
US IND Number (if applicable):
N/A
European Clinical Trial Database 
(EudraCT) Number (if applicable):
2010-023802-10
Protocol Number:
B1801023
Phase:
3b
This document contains confidential information belonging to Pfizer.  Except as otherwise 
agreed to in writing, by accepting or reviewing this document, you agree to hold this 
information in confidence and not copy or disclose it to others (except where required by 
applicable law) or use it for unauthorized purposes.  In the event of any actual or suspected 
breach of this obligation, Pfizer must be promptly notified.


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Document History
Document
Version Date
Summary of Changes
Amendment 2
09 March 2015
Updated 1.2 Background and Rationale
Added 4.4 Sponsor’s Qualified Medical Personnel
5.3.2.1 Medication Error

Modified medication error language
6.1.2.2 Withdrawal Period 

“Re-treatment” has been removed given that it 
is not applicable in this section.
6.1.6 Observational Period Follow-up Visits for 
Subjects Who Participated in the Active Treatment 
Period and/or Withdrawal/Re-treatment Period

Added “active treatment” for clarity
8.0 AE Reporting

Modified Adverse Event Reporting section
15.1 Communication of Results by Pfizer

Modified United States Basic Results 
information

Added European Clinical Trials Database 
information
Amendment 1
20 July 2012
Title 

Added ‘Clinical Benefit’ to study title. 
Schedule of Activities – Active Treatment Period
Added the following assessments throughout:  

Temperature, pain assessment, duration of 
morning stiffness, joint assessment, overall 
back pain and nocturnal pain (ERA only), 


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BASMI (ERA only), BSA (PsA only), and 
PGA of Psoriasis (PsA only).
•
Added review of inclusion and exclusion 
criteria for the withdrawal/re-treatment.
•
Added Informed consent/assent for the 
Withdrawal/Re-treatment period or 
Observational Period, as appropriate.
Schedule of Activities – Withdrawal/Re-Treatment 
Period 
•
Added a separate withdrawal period and 
re-treatment period schedule of activities for the 
new withdrawal/re-treatment period.
Introduction
•
Changed age 4 to 2 given that etanercept is 
approved to treat pediatric patients with 
polyarticular JIA aged 2 years and above.
•
Added information & rationale for amending 
the protocol to include a 
withdrawal/re-treatment period.
Study Objectives 
•
Added a secondary objective regarding the 
evaluation of clinical benefit and physical 
function. 
 
 
 
 
 
Endpoints
•
Clarified primary and secondary endpoints for 
all subjects.
•
Added additional endpoints for subjects in the 
CCI


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active treatment period.
•
Added endpoints for subjects in the 
withdrawal/re-treatment period. 
•
Added additional endpoints for subject with 
ERA & PsA.
 
 
Study Design
•
Added a withdrawal/re-treatment period.
•
Clarified and added additional information to 
the observational period study design to allow 
for subjects who participate in the 
withdrawal/re-treatment period.
Subject Selection
•
Added the wording “withdrawal/re-treatment 
period”.
Inclusion and Exclusion Criteria 
•
Clarified inclusion & exclusion criteria for 
subjects in the active treatment period. 
•
Added inclusion & exclusion criteria for 
subjects entering in the withdrawal/re-treatment 
period. 
Life Style Guidelines and Pregnancy Testing
•
Added specific information regarding the 
withdrawal/re-treatment period.
•
Added language regarding subjects may need to 
continue using highly effective method of 
contraception beyond 30 days after last dose of 
IP for subjects entering into the observational 
period. 
CCI


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Study Treatment 

Added wording for re-treatment period. 

Clarified if more than 4 missed doses of IP are 
missed and added wording that tapering of IP is 
not allowed. 
Administration

Added/clarified administration of IP throughout 
this section. 
Medication Errors

Added wording to state that medication errors 
are reportable events and must be documented 
accordingly in the CRF.

Added examples of medication errors.
Compliance 

Clarified if more than 4 missed doses of IP are 
missed and added wording that tapering of IP is 
not allowed. 
Drug Storage and Drug Accountability 

Clarified section throughout on when to return 
IP.
Concomitant Medications

Add permitted and prohibited medications for 
withdrawal/re-treatment period.

Added more instructions/clarification for 
receipt of live vaccines.

Added information regarding planned surgical 
procedures.

Changed permitted medication/dosing 
information allowed in the active treatment 
period and withdrawal/re-treatment period for 
corticosteroids (Oral, IM or IV injections).


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Study Procedures

Add study procedures and assessments for the 
active treatment period, 
withdrawal/re-treatment period, including the 
withdrawal visits. 
Subject Withdrawal

Added withdrawal/re-treatment language.

Added guidance for contacting the Clinical 
team if a subject is planning to undergo or has 
undergone any surgical procedure.

Clarified if more than 4 missed doses of IP are 
missed and added wording that tapering of IP is 
not allowed. 

Added language around lack of compliance 
with protocol. 

Added language regarding infection meeting 
seriousness criteria other than hospitalization.
Assessments

Added wording for withdrawal/re-treatment 
period throughout section. 

Added efficacy assessments in the active 
treatment period and withdrawal/re-treatment 
period.
Adverse Event Reporting

Clarified adverse event information around 
ongoing safety reviews conducted by the 
Sponsor, any non-serious adverse event that is 
determined by the Sponsor to be serious will be 
reported by the Sponsor as an SAE. 

Added withdrawal/re-treatment wording 
throughout section. 


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Reporting Period
•
Added adverse event reporting period for the 
withdrawal/re-treatment period.
Definition of Adverse Event
•
Added examples of drug abuse and drug 
dependency.
•
Added medication error to signs and symptoms 
of an adverse event.
Serious Adverse Event
•
Expanded the bullet ‘Results in persistent or 
significant disability/incapacity’.
Potential Cases of Drug-Induced Liver Injury 
•
Clarified the criteria for laboratory 
abnormalities that require further evaluation n 
the context of potential cases of drug-induced 
liver injury. 
Causality Assessment 
•
Clarified that generally the facts (evidence) or 
arguments to suggest a causal relationship 
should be provided by the investigator.
Exposure During Pregnancy
•
Added to this section to improve clarity. 
Data Analysis/Statistical Methods
Efficacy
•
Added an analysis for additional efficacy 
assessments.
 
CCI


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Safety

Clarified safety analysis for all subjects.

Added safety analysis for subjects in the 
withdrawal/re-treatment period.
Interim Analysis

Clarified language around interim analysis.
Data Monitoring Committee

Clarified internal review committee language.
Subject Information and Consent

Clarified informed consent process language. 
Communication of Results by Pfizer

Clarified the communication of results.
Original 
protocol
25 February 
2011
N/A
This amendment incorporates all revisions to date including amendments made at the request 
of country health authorities, institutional review boards/ethics committees (IRBs/ECs), etc. 


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SCHEDULE OF ACTIVITIES – ACTIVE TREATMENT PERIOD 
For subjects who enter into the active treatment period and receive investigational product in study B1801023
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol. 
Protocol Activity
Day 1a
Baseline
Months
3, 15, 
27, 39, 
51, 63, 
75, 87b
Months
6, 18, 
30, 42, 
54, 66, 
78, 90b
Months
9, 21, 
33, 45, 
57, 69, 
81, 93b
Months
12, 24, 
36, 48, 
60, 72, 
84b
Month
96b
Active 
Treatment 
Early 
Withdrawalc
Follow-upd
Observational Periode
Active Treatment Period
1st 
Visitf
Subsequent 
Visitsg
Final Visit 
(Month 
96)h
Informed Consent/Assent for the 
Active Treatment Period
Xa
Review Inclusion and Exclusion 
Criteria for the Active Treatment 
Period
Xa
Collect/update contact 
information
Xa
X
X
X
X
X
X
X
X
Prior and concomitant 
medications/non-drug treatments
Xa
Xi
Xi
Xi
Xi
Xi
Xi
Xi
Xj
Xj
Xj
Height (cm)
Xa
X
X
X
Weight (kg)k
Xa
X
X
X
X
X
X
Blood Pressure (mmHg), Pulse 
(Beats/min), Temperature 
Xa
X
X
X
X
X
X
Physical examination
Xa
X
X
X
Tanner Stage Assessmentl
Xa
X
X
X
Hematology, Blood chemistry, 
C-reactive proteinm
Xa
X
X
X
X
Evaluate childbearing potential 
(females)n
X
X
X
X
X
X
X
Urine pregnancy testo
X
X
X
X
X
X
X
Discuss sexual activity and use of 
contraception, as appropriatep
X
X
X
X
X
X
X
PGA of Disease Activity
Xa
X
X
X
X
Parent/Patient Global Assessmentq
Xa
X
X
X
X


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Protocol Activity
Day 1a
Baseline
Months
3, 15, 
27, 39, 
51, 63, 
75, 87b
Months
6, 18, 
30, 42, 
54, 66, 
78, 90b
Months
9, 21, 
33, 45, 
57, 69, 
81, 93b
Months
12, 24, 
36, 48, 
60, 72, 
84b
Month
96b
Active 
Treatment 
Early 
Withdrawalc
Follow-upd
Observational Periode
Active Treatment Period
1st 
Visitf
Subsequent 
Visitsg
Final Visit 
(Month 
96)h
CHAQ/HAQr
Xa
X
X
X
X
Pain Assessmentq
Xa
X
X
X
X
Duration of Morning Stiffnessq
Xa
X
X
X
X
Joint Assessment
Xa
X
X
X
X
Overall Back Pain and Nocturnal 
Pain (ERA only)q
Xa
X
X
X
X
BASMI (ERA only)
Xa
X
X
X
X
BSA (PsA only)
Xa
X
X
X
X
PGA of Psoriasis (PsA only)
Xa
X
X
X
X
Adverse eventss
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xt
Xu
Xu
Xu
Dispense visit reminder card
X
X
X
X
X
X
X
X
X
Dispense IP, and subject diary
X
X
X
X
X
Collect returned IP and subject 
diary
X
X
X
X
X
X
Registration/ Randomization
X
Review inclusion and exclusion 
criteria for the Withdrawal/
Re-treatment Period
X
Informed consent/assent for the 
Withdrawal/Re-treatment period 
or Observational Period, as 
appropriate
X
End of Treatment Subject 
Summary 
X
X
End of Study Subject Summary 
X
X
a.
Every attempt should be made to complete the study B1801023 baseline visit on the same day as the study 0881A1-3338 week 96 visit.  For subjects planning to continue 
investigational product, the baseline visit (day 1) of study B1801023 must occur within 6 weeks of the last dose of investigational product received in study 0881A1-3338.  
For subjects with 14 days between the study 0881A1-3338 week 96 visit and the study B1801023 baseline visit, the indicated procedures do not need to be repeated. 
b.
All visits during the active treatment period (month 3 to month 96) must occur at the study site within a window of 14 days of the projected visit date based on the baseline 
visit date.


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c.
Subjects in the active treatment period of study B1801023 who withdraw from investigational product before completion of the month 96 visit are required to complete the 
early withdrawal visit at the study site. Subjects in the active treatment period who meet Wallace definition for clinically inactive disease for at least 6 months on 
investigational product or who, in the investigators judgment, have had a good clinical response and would benefit from withdrawal from investigational product and are 
otherwise eligible will be asked to participate in the withdrawal/re-treatment period. Subjects in the active treatment period who are ineligible for the withdrawal/re-treatment 
period will be asked to participate in the observational period.
d.
The follow-up visit will only be completed for those subjects who are receiving investigational product in either the active treatment period or re-treatment period 
approximately 96 months after the baseline visit in study B1801023 and will occur 30 days (7 days) after the Month 96 visit.
e.
Subjects who receive at least 1 dose of investigational product in the active treatment period of study B1801023 and withdraw from the active treatment period before 
completion of the month 96 visit and do not participate in the withdrawal/re-treatment period will be asked to participate in the observational period.
f.
For subjects who consent to participate in the observational period, the first observational visit will occur at the study site and will be scheduled 30 days (7 days) after the 
early active treatment withdrawal visit.
g.
Subsequent observational visits will occur by telephone every 6 months (4 weeks) after the first observational visit.  For subjects <18 years of age, telephone contacts will be 
conducted with the subject’s parent or legal representative/guardian.  For subjects aged 18 years, telephone contacts will be conducted with the subject or the subject’s parent 
or legal representative/guardian. The number of telephone contacts will be adjusted based on when the subject enters the observational period. 
h.
The final observational visit will occur by telephone contact 96 months (4 weeks) after the baseline visit of study B1801023.
i.
For subjects in the active treatment period, the following concomitant medications will be collected: DMARDs, corticosteroids, NSAIDs, and anti-infective agents. Only 
non-drug treatments received due to an adverse event will be collected.
j.
For subjects in the observational period, the following concomitant medications will be collected: DMARDs, including any immunosuppressives or anti-TNFs and/or other 
immunosuppressive biologic agents; corticosteroids; and anti-infective agents taken for medically important infections.  Only non-drug treatments received due to an adverse 
event will be collected.
k.
Weight will be measured at every visit for subjects who are <18 years of age and who weigh 62 kg.  For those subjects who are 18 years of age or weigh >62 kg, weight 
will be measured annually as part of the physical examination.
l.
Tanner Stage Assessment will be performed annually for subjects <18 years of age or who have a score of <5 on 1 or more applicable domain(s). The Tanner Stage 
Assessment does not need to be repeated at the early withdrawal visit if it was performed within 2 months before the visit.
m.
Additional laboratory testing may be performed according to local guidelines or standard of care and for follow-up of abnormal laboratory test results.
n.
The evaluation of childbearing potential in female subjects must be documented in the subject’s source documents.
o.
Urine pregnancy tests will be performed at each of the visits in the active treatment period for all female subjects who, in the opinion of the investigator, are of childbearing 
potential; this includes subjects who are menstruating at the time of the visit.  The baseline pregnancy test must be performed within 7 days before the baseline visit.  
Pregnancy tests will also be done whenever a menstrual cycle is missed during the active treatment period or when potential pregnancy is otherwise suspected.  Pregnancy 
tests may also be repeated as per request of IRB/IECs or if required by local regulations.
p.
Discussion of sexual activity and use of contraception must be documented in the subject’s source documents. 
q.
Assessment will be completed by the subject’s parent or legal representative/guardian for subjects aged <18 years, or directly by subjects aged 18 years at the time of the 
assessment.
r.
Childhood Health Assessment Questionnaire (CHAQ) will be completed by the subject’s parent or legal representative/guardian for subjects aged <18 years at the time of the 
assessment; Health Assessment Questionnaire (HAQ) will be completed directly by subjects aged 18 years at the time of the assessment.
s.
Adverse events will be collected from the signing of the informed consent document through 96 months after the baseline visit of study B1801023.  For subjects who 
complete the Month 96 visit in either the active treatment period or the re-treatment period of study B1801023, adverse events will be collected until 30 days after the last 


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dose of investigational product.  Events reported as ongoing at the final study 0881A1-3338 visit as well as events starting between the final study 0881A1-3338 visit and the 
baseline visit of study B1801023 must be recorded on the appropriate eCRF. 
t.
For subjects in the active treatment period, all adverse events, malignancies, serious adverse events, infections, medically important infections (ie, an infection requiring 
parenteral [IV, IM] anti-infective agent(s) and/or hospitalization), and injection site reactions, will be collected.
u.
For subjects in the observational period, only serious adverse events, malignancies and medically important infections (ie, an infection requiring parenteral [IV, IM] 
anti-infective agent(s) and/or hospitalization), will be collected.
Abbreviations: CHAQ=Childhood Health Assessment Questionnaire; DMARD=Disease-Modifying Antirheumatic Drug; eCRF=electronic Case Report Form; HAQ=Health
Assessment Questionnaire; IRB=Internal Review Board; IWR/IVR=interactive web response/interactive voice response; NSAID= Nonsteroidal Anti-inflammatory Drug; 
PGA=physician’s global assessment; TNF=tumor necrosis factor


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SCHEDULE OF ACTIVITIES – WITHDRAWAL PERIOD
For subjects who enter into the withdrawal period in study B1801023
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol.
Protocol Activity
Withdrawal Period
Observational Periode
Day 1a
Baseline
Months
1b,3,6,9
Months 
12, 24, 36, 48, 
60, 72, 84c
Months
18,  30,  42,  
54, 66, 78, 90c
Month
96c
Re-Treatmen
t 
Assessmentd
1st Visitf
Subsequent 
Visitsg
Final Visit 
(Month 96)h
Informed Consent/Assent 
for 
Withdrawal/Re-treatment 
Period
X
X
Review Inclusion and 
Exclusion Criteria for 
Withdrawal/Re-treatment 
Period
X
Collect/update contact 
information
X
X
X
X
X
X
X
Prior and concomitant 
medications/non-drug 
treatments
Xi
Xi
Xi
Xi
Xi
Xi
Xj
Xj
Xj
Height (cm)
Xa
X
X
X
Weight (kg)
Xa
Xk
Xk
Xk
X
X
Temperature, Blood 
Pressure (mmHg), Pulse 
(Beats/min)
Xa
X
X
X
X
X
Physical examination
Xa
X
X
X
Tanner Stage Assessmentl
Xa
X
X
X
Hematology, Blood 
chemistry, C-reactive 
proteinm
Xa
X
X
X
X
X
Evaluate childbearing 
potential (females)n
X
X
X
X
X
X
Urine pregnancy testo
X
X
X
X
X
X


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Protocol Activity
Withdrawal Period
Observational Periode
Day 1a
Baseline
Months
1b,3,6,9
Months 
12, 24, 36, 48, 
60, 72, 84c
Months
18,  30,  42,  
54, 66, 78, 90c
Month
96c
Re-Treatmen
t 
Assessmentd
1st Visitf
Subsequent 
Visitsg
Final Visit 
(Month 96)h
Discuss sexual activity 
and use of contraception, 
as appropriatep
X
X
X
X
X
X
PGA of Disease Activity
Xa
X
X
X
X
X
Parent/Patient Global 
Assessmentq
Xa
X
X
X
X
X
CHAQ/HAQr
Xa
X
X
X
X
X
Pain Assessmentq
Xa
X
X
X
X
X
Duration of Morning 
Stiffnessq
Xa
X
X
X
X
X
Joint Assessment
Xa
X
X
X
X
X
Overall Back Pain and 
Nocturnal Pain (ERA 
only) q
Xa
X
X
X
X
X
BASMI (ERA only)
X
X
X
X
X
X
BSA (PsA only)
Xa
X
X
X
X
X
PGA of Psoriasis (PsA 
only)
Xa
X
X
X
X
X
Adverse eventss
Xt
Xt
Xt
Xt
Xt
Xt
Xu
Xu
Xu
Dispense visit reminder 
card 
X
X
X
X
X
X
X
Dispense IP and subject 
diary
X
Registration/ 
Randomization
X
Review inclusion and 
exclusion criteria for the 
Re-treatment Period
X
Informed consent/assent 
for the Observational 
Period, if appropriate
X
End of Phase Subject 
Summary 
X
X
End of Study Subject 
Summary 
X
X


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a.
The baseline visit is only for subjects who enter directly into the withdrawal/re-treatment period.  Every attempt should be made to complete the study B1801023 baseline 
visit on the same day as the study 0881A1-3338 week 96 visit.  The baseline (Day 1) visit must occur within 14 days of the last dose of investigational product received in 
study 0881A-3338.  For subjects with 14 days between the study 0881A1-3338 week 96 visit and the study B1801023 baseline visit, the indicated procedures do not need to 
be repeated.
b.
The month 1 visit will occur at the study site 1 month (7 days) after the baseline visit or active treatment early withdrawal visit.
c.
The month 3 to month 96 visits must occur at the study site within 14 days of the projected visit date based on the actual date of the baseline or active treatment early 
withdrawal visit.  Subjects who do not experience disease relapse will continue in the withdrawal period for a total of 96 months (14 days) after the baseline visit of study 
B1801023.
d.
Subjects in the withdrawal period who experience disease relapse or discontinue from the withdrawal period for any reason (eg, for adverse events) will be seen for a 
re-treatment assessment visit.  For subjects experiencing disease relapse, the re-treatment assessment visit should occur as soon as possible after disease relapse.  Those 
subjects requiring re-treatment per the investigator’s clinical judgment and who are otherwise eligible will be offered the option to re-start treatment with investigational 
product. Subjects who participate in the withdrawal period and are ineligible for the re-treatment period will be asked to participate in the observational period. 
e.
Subjects who participate in the withdrawal period, and discontinue from the withdrawal period before completion of the month 96 visit, and do not participate in the 
re-treatment period will be asked to be followed in the observational period for a total of 96 months from the time of the baseline visit in study B1801023. Once the subject is 
in the observational period, he or she cannot resume investigational product for the remaining time in the study.
f.
For subjects who agree to participate in the observational period, the first observational visit will occur at the study site 30 days (±7 days) after the re-treatment assessment 
visit. This visit may be waived if the subject had already been seen at the study site 30 days after the most recent dose of investigational product in either study 
0881A1-3338 or B1801023. 
g.
Subsequent observational visits will occur by telephone every 6 months (4 weeks) after the first observational visit (if conducted) or after the re-treatment assessment visit.  
For subjects <18 years of age, telephone contacts will be conducted with the subject’s parent or legal representative/guardian.  For subjects aged ≥18 years, telephone contacts 
will be conducted with the subject or the subject’s parent or legal representative/guardian.  The number of telephone contacts will be adjusted based on when the subject 
enters the observational period. 
h.
The final observational visit will occur by telephone contact 96 months (4 weeks) after the baseline visit of study B1801023. 
i.
For subjects in the withdrawal period, the following concomitant medications will be collected: DMARDs, corticosteroids, NSAIDs, and anti-infective agents. Only non-drug 
treatments received due to an adverse event will be collected.
j.
For subjects in the observational period, the following concomitant medications will be collected: DMARDs, including any immunosuppressives or anti-TNFs and/or other 
immunosuppressive biologic agents; corticosteroids; and anti-infective agents taken for medically important infections.  Only non-drug treatments received due to an adverse 
event will be collected.
k.
Weight will be measured at every visit for subjects who are <18 years of age and who weigh 62 kg.  For those subjects who are 18 years of age or weigh >62 kg, weight 
will be measured annually as part of the physical examination. 
l.
Tanner Stage Assessment will be performed annually for subjects <18 years of age or who have a score of <5 on 1 or more applicable domain(s). The Tanner Stage 
Assessment does not need to be repeated at the re-treatment assessment visit if it was performed within 2 months before the visit.
m.
Additional laboratory testing may be performed according to local guidelines or standard of care and for follow-up of abnormal laboratory test results.
n.
The evaluation of childbearing potential in female subjects must be documented in the subject’s source documents.
o.
Urine pregnancy tests will be performed at each of the visits in the withdrawal period for all female subjects who, in the opinion of the investigator, are of childbearing 
potential; this includes subjects who are menstruating at the time of the visit.  For subjects entering directly into the withdrawal/re-treatment period, the baseline pregnancy 
test must be performed within 7 days before the baseline visit.  Pregnancy tests will also be done whenever a menstrual cycle is missed during the withdrawal/re-treatment 
period or when potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.


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p.
Discussion of sexual activity and use of contraception must be documented in the subject’s source documents. 
q.
Assessment will be completed by the subject’s parent or legal representative/guardian for subjects aged <18 years, or directly by subjects aged 18 years at the time of the 
assessment.
r.
Childhood Health Assessment Questionnaire (CHAQ) will be completed by the subject’s parent or legal representative/guardian for subjects aged <18 years at the time of the 
assessment; Health Assessment Questionnaire (HAQ) will be completed directly by subjects aged 18 years at the time of the assessment.
s.
Adverse events will be collected from the signing of the informed consent document through 96 months after the baseline visit of study B1801023.  For subjects who 
complete the Month 96 visit in either the active treatment period or the re-treatment period of study B1801023, adverse events will be collected until 30 days after the last 
dose of investigational product.  Events reported as ongoing at the final study 0881A1-3338 visit as well as events starting between the final study 0881A1-3338 visit and the 
baseline visit of study B1801023 must be recorded on the appropriate eCRF. 
t.
For subjects in the withdrawal period, all adverse events including malignancies, serious adverse events, infections, medically important infections (ie, an infection requiring
parenteral [IV, IM] anti-infective agent(s) and/or hospitalization), and injection site reactions will be collected. 
u.
For subjects in the observational period, only serious adverse events, malignancies and medically important infections (ie, an infection requiring parenteral [IV, IM] 
anti-infective agent(s) and/or hospitalization), will be collected.
Abbreviations: CHAQ=Childhood Health Assessment Questionnaire; DMARD=Disease-Modifying Antirheumatic Drug; eCRF=electronic Case Report Form; HAQ=Health 
Assessment Questionnaire; IRB=Internal Review Board; IWR/IVR=interactive web response/interactive voice response; NSAID= Nonsteroidal Anti-inflammatory Drug; 
PGA=physician’s global assessment; TNF=tumor necrosis factor


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SCHEDULE OF ACTIVITIES – RE-TREATMENT PERIOD
For subjects who enter into the re-treatment period and receive investigational product in study B1801023
The Schedule of Activities table provides an overview of the protocol visits and procedures.  Refer to Study Procedures (Section 6) 
and Assessments (Section 7) for detailed information on each procedure and assessment required for compliance with the protocol.
Protocol Activity 
Re-Treatment Period
Observational Periode
Months 
3,6,
9a
Months
12, 24, 36, 
48, 60, 72, 
84a
Months
15, 27, 
39, 51,
63, 75, 
87a
Months
18, 30, 
42, 54, 
66,78, 
90a
Months 
21, 33, 
45, 57, 
69, 81, 
93a
Month 
96b
Re-treatment 
Early 
Withdrawalc
Follow-
upd
1st 
Visitf
Subsequent 
Visitsg
Final Visit 
(Month 
96)h
Ensure the most recent version(s) 
of the informed consent/assent for 
withdrawal/re-treatment period 
has been signed and dated
Xi
Ensure that the subject meets the 
inclusion/exclusion criteria that 
apply to the re-treatment period
Xi
Collect/update contact information
X
Xi
X
X
X
X
X
X
Prior and concomitant 
medications/non-drug treatments
Xj
X
Xj
Xj
Xj
Xj
Xj
Xj
Xk
Xk
Xk
Height (cm)
X
X
Weight (kg)l
X
X
X
X
X
X
X
Temperature, Blood Pressure 
(mmHg), Pulse (Beats/min)
X
X
X
X
X
X
X
Physical examination
X
X
X
Tanner Stage Assessmentm
X
X
X
Hematology, Blood chemistry, 
C-reactive proteinn
X
X
X
X
X
Evaluate childbearing potential 
(females)o
X
X
X
X
X
X
X
Urine pregnancy testp
X
X
X
X
X
X
X
Discuss sexual activity and use of 
contraception, as appropriateq
X
X
X
X
X
X
X
PGA of Disease Activity
X
X
X
X
X
Parent/Patient Global Assessmentr
X
X
X
X
X
CHAQ/HAQs
X
X
X
X
X
Pain Assessmentr
X
X
X
X
X
Duration of Morning Stiffnessr
X
X
X
X
X


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Protocol Activity 
Re-Treatment Period
Observational Periode
Months 
3,6,
9a
Months
12, 24, 36, 
48, 60, 72, 
84a
Months
15, 27, 
39, 51,
63, 75, 
87a
Months
18, 30, 
42, 54, 
66,78, 
90a
Months 
21, 33, 
45, 57, 
69, 81, 
93a
Month 
96b
Re-treatment 
Early 
Withdrawalc
Follow-
upd
1st 
Visitf
Subsequent 
Visitsg
Final Visit 
(Month 
96)h
Joint Assessment
X
X
X
X
X
Overall Back Pain and Nocturnal 
Pain (ERA only) r
X
X
X
X
X
BASMI (ERA only)
X
X
X
X
X
BSA (PsA only)
X
X
X
X
X
PGA of Psoriasis (PsA only)
X
X
X
X
X
Adverse eventst
Xu
Xu
Xu
Xu
Xu
Xu
Xu
Xv
Xv
Xv
Xv
Dispense visit reminder card
X
X
X
X
X
X
X
X
X
Dispense IP and subject diary
X
X
X
X
X
Collect returned IP and subject 
diary
X
X
X
X
X
X
X
End of Treatment Subject 
Summary 
X
X
End of Study Subject Summary 
X
X
a.
The Month 3 to Month 96 visits must occur at the study site within 14 days of the projected visit date based on the actual date of the re-treatment assessment visit.
b.
Subjects who remain eligible for re-treatment will continue in the re-treatment period for a total of 96 months (14 days) from the time of the baseline visit in study 
B1801023.
c.
Subjects in the re-treatment period who withdraw from investigational product for any reason before completion of the Month 96 visit are required to complete the retreatment 
early withdrawal visit at the study site.  At that time, the subject will be asked to participate in the observational period.  Subjects may not enter the withdrawal/re-treatment 
period more than once during the study.
d.
The follow-up visit will only completed for subjects who are receiving investigational product in either the active treatment period or the re-treatment period approximately 
96 months after the baseline visit in study B1801023 and will occur at the study site 30 days (7 days) after the Month 96 visit. 
e.
Subjects who receive at least 1 dose of investigational product in the re-treatment period of study B1801023 and withdraw from the re-treatment period before completion of 
the month 96 visit will be asked to be followed in the observational period for a total of 96 months from the time of the baseline visit in study B1801023. Once the subject is 
in the observational period, he or she cannot resume investigational product for the remaining time in the study.
f.
For subjects who agree to participate in the observational period, the first observational visit will occur at the study site and will be scheduled 30 days (±7 days) after the 
retreatment early withdrawal visit.
g.
Subsequent observational visits will occur by telephone every 6 months (4 weeks) after the first observational visit. For subjects <18 years of age, telephone contacts will be 
conducted with the subject’s parent or legal representative/guardian.  For subjects aged 18 years, telephone contacts will be conducted with the subject or the subject’s parent 
or legal representative/guardian.  The number of telephone contacts will be adjusted based on when the subject enters the observational period. 
h.
The final observational visit will occur by telephone contact 96 months (±4 weeks) after the baseline visit of study B1801023.
i.
Applies to the Month 3 visit.


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j.
For subjects in the re-treatment period, the following concomitant medications will be collected: DMARDs, corticosteroids, NSAIDs, and anti-infective agents. Only 
non-drug treatments received due to an adverse event will be collected.
k.
For subjects in the observational period, the following concomitant medications will be collected: DMARDs, including any immunosuppressives or anti-TNFs and/or other 
immunosuppressive biologic agents; corticosteroids; and anti-infective agents taken for medically important infections.  Only non-drug treatments received due to an adverse 
event will be collected.
l.
Weight will be measured at every visit for subjects who are <18 years of age and who weigh 62 kg.  For those subjects who are 18 years of age or weigh >62 kg, weight 
will be measured annually as part of the physical examination. 
m.
Tanner Stage Assessment will be performed annually for subjects <18 years of age or who have a score of <5 on 1 or more applicable domain(s). The Tanner Stage 
Assessment does not need to be repeated at the re-treatment assessment visit if it was performed within 2 months before the visit.
n.
Additional laboratory testing may be performed according to local guidelines or standard of care and for follow-up of abnormal laboratory test results.
o.
The evaluation of childbearing potential in female subjects must be documented in the subject’s source documents.
p.
Urine pregnancy tests will be performed at each of the visits in the re-treatment period for all female subjects who, in the opinion of the investigator, are of childbearing 
potential; this includes subjects who are menstruating at the time of the visit.  Pregnancy tests will also be done whenever a menstrual cycle is missed during the re-treatment 
period or when potential pregnancy is otherwise suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if required by local regulations.
q.
Discussion of sexual activity and use of contraception must be documented in the subject’s source documents. 
r.
Assessment will be completed by the subject’s parent or legal representative/guardian for subjects aged <18 years, or directly by subjects aged 18 years at the time of the 
assessment.
s.
Childhood Health Assessment Questionnaire (CHAQ) will be completed by the subject’s parent or legal representative/guardian for subjects aged <18 years at the time of the 
assessment; Health Assessment Questionnaire (HAQ) will be completed directly by subjects aged 18 years at the time of the assessment.
t.
Adverse events will be collected from the signing of the informed consent document through 96 months after the baseline visit of study B1801023.  For subjects who 
complete the Month 96 visit in either the active treatment period or the re-treatment period of study B1801023, adverse events will be collected until 30 days after the last 
dose of investigational product.  Events reported as ongoing at the final study 0881A1-3338 visit as well as events starting between the final study 0881A1-3338 visit and the 
baseline visit of study B1801023 must be recorded on the appropriate eCRF. 
u.
For subjects in the withdrawal period, all adverse events including malignancies, serious adverse events, infections, medically important infections(ie, an infection requiring 
parenteral [IV, IM] anti-infective agent(s) and/or hospitalization), and injection site reactions will be collected. 
v.
For subjects in the observational period, only serious adverse events, malignancies and medically important infections (ie, an infection requiring parenteral [IV, IM] 
anti-infective agent(s) and/or hospitalization), will be collected.
Abbreviations: CHAQ=Childhood Health Assessment Questionnaire; DMARD=Disease-Modifying Antirheumatic Drug; eCRF=electronic Case Report Form; HAQ=Health 
Assessment Questionnaire; IRB=Internal Review Board; IWR/IVR=interactive web response/interactive voice response; NSAID= Nonsteroidal Anti-inflammatory Drug; 
PGA=physician’s global assessment; TNF=tumor necrosis factor


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SCHEDULE OF ACTIVITIES – OBSERVATIONAL PERIOD
For subjects who enter directly into the observational period and do not receive 
investigational product in study B1801023
The Schedule of Activities table provides an overview of the protocol visits and procedures.  
Refer to Study Procedures (Section 6) and Assessments (Section 7) for detailed information 
on each procedure and assessment required for compliance with the protocol.
Protocol Activity
Day 1 
(Baseline)
Months 6, 12, 18, 24, 
30, 36, 42, 48, 54, 60, 
66, 72, 78, 84, 90a
Month 96a
Observational Period
Informed Consent/Assent
X
Review inclusion and exclusion 
criteria
X
Collect/update contact information
X
X
Prior and concomitant 
medications/non-drug treatmentsb
X
X
X
Serious adverse events, 
malignancies, and medically 
important infectionsc
X
X
X
Dispense visit reminder card
X
X
End of Study Subject Summary 
X
a.
The Month 6 to Month 96 visits will occur every 6 months (±4 weeks) after the baseline visit.  For subjects <18 years 
of age, telephone contact will be conducted with the subject's parent or legal representative/guardian. For subjects aged 
18 years, telephone contact will be conducted with the subject or the subject's parent or legal representative/guardian.
b.
Prior and concomitant medications (DMARDs, including any immunosuppressives or anti-TNFs and other 
immunosuppressive biologic agents; corticosteroids; and anti-infective agents taken for medically important infections) 
and non-drug treatments received due to an adverse event.
c.
Serious adverse events, malignancies, and medically important infections (ie, an infection requiring parenteral [IV, IM] 
anti-infective agent(s) and/or hospitalization) will be collected from the signing of the informed consent document
through 96 months after the baseline visit of study B1801023.  Events reported as ongoing at the final study 
0881A1-3338 visit as well as events starting between the final study 0881A1-3338 visit and the baseline visit of study 
B1801023 must be recorded on the appropriate eCRF.
Abbreviations: DMARD=Disease-Modifying Antirheumatic Drug; eCRF=electronic Case Report Form; TNF= tumor 
necrosis factor 


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TABLE OF CONTENTS
1. INTRODUCTION ...............................................................................................................26
1.1. Indication.................................................................................................................26
1.2. Background and Rationale ......................................................................................26
1.2.1. Disease Information....................................................................................28
1.2.1.1. Extended Oligoarticular JIA......................................................28
1.2.1.2. Enthesitis-Related Arthritis.......................................................29
1.2.1.3. Psoriatic Arthritis ......................................................................29
2. STUDY OBJECTIVES AND ENDPOINTS.......................................................................30
2.1. Objectives................................................................................................................30
2.2. Endpoints.................................................................................................................30
2.2.1. Primary Endpoint for All Subjects .............................................................30
2.2.2. Secondary Endpoints for Subjects in the Observational Period .................30
2.2.3. Secondary Endpoints for Subjects in the Active Treatment Period, 
and Withdrawal/Re-treatment Period ..............................................................30
2.2.3.1. Additional Secondary Endpoints for ERA Subjects .................32
2.2.3.2. Additional Secondary Endpoints for PsA Subjects...................32
2.2.4. Health Outcomes Assessment for Subjects in the Active Treatment 
Period, and Withdrawal/Re-treatment Period..................................................32
 
3. STUDY DESIGN.................................................................................................................32
4. SUBJECT SELECTION......................................................................................................34
4.1. Inclusion Criteria.....................................................................................................34
4.1.1. Inclusion Criteria for All Subjects at Baseline ...........................................34
4.1.2. Additional Inclusion Criteria for Subjects Planning to Continue 
Investigational Product in the Active Treatment Period..................................35
4.1.3. Additional Inclusion Criteria for Subjects Planning to Enter in the 
Withdrawal/Re-treatment Period .....................................................................35
4.1.3.1. Additional Inclusion Criteria for Subjects Planning to 
Restart Investigational Product in the Re-treatment Period ..............36
4.2. Exclusion Criteria....................................................................................................36
4.2.1. Exclusion Criteria for All Subjects at Baseline ..........................................36
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4.2.2. Additional Exclusion Criteria for Subjects Planning to Continue 
Investigational Product in the Active Treatment Period..................................36
4.2.3. Additional Exclusion Criteria for Subjects Planning to Enter in the 
Withdrawal/Re-treatment Period .....................................................................37
4.2.3.1. Additional Exclusion Criteria for Subjects Planning to 
Restart Investigational Product in the Re-treatment Period ..............37
4.3. Life Style Guidelines...............................................................................................39
4.3.1. Pregnancy Testing ......................................................................................39
4.3.2. Sexually Active Female Subjects ...............................................................39
4.3.3. Sexually Active Male Subjects...................................................................40
4.4. Sponsor’s Qualified Medical Personnel..................................................................40
5. STUDY TREATMENT.......................................................................................................41
5.1. Allocation to Treatment ..........................................................................................41
5.2. Drug Supplies..........................................................................................................42
5.2.1. Formulation and Packaging........................................................................42
5.2.2. Preparation and Dispensing........................................................................42
5.2.3. Administration............................................................................................42
5.2.3.1. Medication Errors......................................................................43
5.2.4. Compliance.................................................................................................44
5.2.5. Drug Storage and Drug Accountability......................................................44
5.3. Concomitant Medication(s).....................................................................................45
5.3.1. Prohibited and/or Permitted Medication(s) ................................................46
6. STUDY PROCEDURES .....................................................................................................49
6.1. Study Procedures for Subjects in the Active Treatment Period or 
Withdrawal/Re-treatment Period...............................................................................49
6.1.1. Active Treatment Period.............................................................................49
6.1.1.1. Baseline Procedures for Subjects Planning to Participate 
in the Active Treatment Period..........................................................49
6.1.1.2. Active Treatment Period – Month 3 to Month 96 Visits...........52
6.1.2. Withdrawal/Re-treatment Period................................................................54
6.1.2.1. Baseline Procedures for Subjects Planning to Enter 
Directly into the Withdrawal/Re-treatment Period............................54
6.1.2.2. Withdrawal Period.....................................................................56
6.1.2.3. Re-Treatment Period .................................................................58


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6.1.3. Active Treatment Period Follow-up Visit ..................................................61
6.1.4. Active Treatment Period and Re-Treatment Period Early Withdrawal 
Visits ................................................................................................................61
6.1.5. Re-Treatment Assessment Visit for Subjects in the Withdrawal 
Period...............................................................................................................64
6.1.6. Observational Period Follow-up Visits for Subjects Who Participated 
in the Active Treatment Period and/or Withdrawal/Re-treatment Period .......66
6.2. Study Procedures for Subjects Entering Directly into the Observational 
Period.........................................................................................................................67
6.2.1. Baseline Procedures for Subjects Entering Directly into the 
Observational Period........................................................................................67
6.2.2. Observational Period – Month 6 to Month 96............................................68
6.3. Subject Withdrawal.................................................................................................69
7. ASSESSMENTS..................................................................................................................71
7.1. Safety Assessments .................................................................................................71
7.2. Laboratory Evaluations ...........................................................................................72
7.3. Efficacy Assessments..............................................................................................73
7.4. Health Outcome Assessments .................................................................................75
7.4.1. Childhood Health Assessment Questionnaire (CHAQ) .............................75
7.4.2. Health Assessment Questionnaire (HAQ)..................................................76
8. ADVERSE EVENT REPORTING......................................................................................76
8.1. Adverse Events........................................................................................................76
8.2. Reporting Period .....................................................................................................76
8.3. Definition of an Adverse Event...............................................................................78
8.4. Abnormal Test Findings..........................................................................................79
8.5. Serious Adverse Events...........................................................................................79
8.5.1. Other Reportable Information.....................................................................80
8.5.2. Protocol-Specified Serious Adverse Events ...............................................80
8.5.3. Potential Cases of Drug-Induced Liver Injury............................................80
8.6. Hospitalization ........................................................................................................81
8.7. Severity Assessment................................................................................................82
8.8. Causality Assessment..............................................................................................83
8.9. Exposure During Pregnancy....................................................................................83


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8.10. Occupational Exposure .........................................................................................84
8.11. Withdrawal Due to Adverse Events (See Also the section Subject 
Withdrawal)...............................................................................................................85
8.12. Eliciting Adverse Event Information ....................................................................85
8.13. Reporting Requirements........................................................................................85
8.13.1. Serious Adverse Event Reporting Requirements .....................................85
8.13.2. NonSerious Adverse Event Reporting Requirements...............................86
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities ................86
9. DATA ANALYSIS/STATISTICAL METHODS...............................................................86
9.1. Sample Size Determination.....................................................................................86
9.2. Efficacy Analysis ....................................................................................................86
9.2.1. Analysis of Primary Endpoint ....................................................................86
9.2.2. Analysis of Secondary Endpoints for Subjects in the Active 
Treatment Period, and Withdrawal/Re-treatment Period.................................86
9.3. Analysis of Health Outcomes Assessments for Subjects in the Active 
Treatment, and Withdrawal/Re-treatment Period......................................................87
9.4. Safety Analysis........................................................................................................87
9.4.1. Safety Analysis All Subjects ......................................................................87
9.4.2. Safety Analysis for Subjects in the Active Treatment Period, and 
Withdrawal/re-treatment Period: .....................................................................88
9.5. Interim Analysis ......................................................................................................88
9.6. Data Monitoring Committee ...................................................................................88
10. QUALITY CONTROL AND QUALITY ASSURANCE.................................................88
11. DATA HANDLING AND RECORD KEEPING .............................................................89
11.1. Case Report Forms/Electronic Data Record .........................................................89
11.2. Record Retention...................................................................................................89
12. ETHICS..............................................................................................................................90
12.1. Institutional Review Board (IRB)/Independent Ethics Committee (IEC) ............90
12.2. Ethical Conduct of the Study ................................................................................90
12.3. Subject Information and Consent..........................................................................90
12.4. Subject Recruitment ..............................................................................................91
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12.5. Reporting of Safety Issues and Serious Breaches of the Protocol or ICH 
GCP ...........................................................................................................................91
13. DEFINITION OF END OF TRIAL...................................................................................91
13.1. End of Trial in a Member State.............................................................................91
13.2. End of Trial in all Participating Countries ............................................................91
14. SPONSOR DISCONTINUATION CRITERIA ................................................................92
15. PUBLICATION OF STUDY RESULTS..........................................................................92
15.1. Communication of Results by Pfizer ....................................................................92
15.2. Publications by Investigators ................................................................................93
16. REFERENCES ..................................................................................................................94
APPENDICES
Appendix 1. Abbreviations......................................................................................................96
Appendix 2. Sample of Childhood Health Assessment Questionnaire....................................97
Appendix 3. Sample of Health Assessment Questionnaire .....................................................99
Appendix 4. Joint Assessment...............................................................................................101


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1. INTRODUCTION
Juvenile idiopathic arthritis (JIA) is the most common autoimmune-autoinflammatory 
disease in childhood and affects approximately 1 in 1,000 children. Despite advances in 
diagnosis and treatment options, JIA remains a chronic condition for most affected children.  
Etanercept is approved by both the US Food and Drug Administration (FDA) and the
European Medicines Agency (EMA) to treat pediatric patients with polyarticular JIA aged
2 years and above, who have had an inadequate response to, or who have proved intolerant 
of, methotrexate.  In addition, etanercept is approved by the EMA for use in pediatric patients 
with severe plaque psoriasis from the ages of 6 to 17 years.
Etanercept binds specifically to tumor necrosis factor (TNF) and blocks its interaction with 
cell surface TNF receptors. TNF is a naturally occurring cytokine that is involved in normal 
inflammatory and immune responses. It plays an important role in the inflammatory 
processes of rheumatoid arthritis (RA), polyarticular JIA, and the resulting joint pathology.
Elevated levels of TNF are found in the synovial fluid of RA patients and in both the 
synovium and psoriatic plaques of patients with psoriatic arthritis.1
1.1. Indication
Etanercept is a TNF inhibitor that is being developed for the treatment of extended 
oligoarticular JIA, enthesitis related arthritis (ERA) or psoriatic arthritis (PsA) in pediatric 
patients. 
1.2. Background and Rationale
JIA is a clinically heterogeneous group of several disease types that are characterized by 
arthritis beginning before the age of 16 years with symptoms persisting for more than 
6 weeks.  The International League Associations for Rheumatology (ILAR) classification 
defines 7 distinct subtypes of JIA: systemic arthritis, oligoarthritis (persistent oligoarthritis, 
extended polyarticular), polyarthritis rheumatoid factor (RF) positive, polyarthritis RF 
negative, PsA, ERA, and undifferentiated arthritis. 
Protocol 0881A1-3338 (B1801014) was designed to assess the clinical benefit and the 
long-term safety of etanercept for 2 years in pediatric subjects with extended oligoarticular 
JIA, ERA or PsA.  Protocol B1801023 is an 8-year extension study designed to further 
characterize the long-term safety profile, including malignancy and other serious adverse 
events, and clinical benefit for those pediatric subjects who received at least one dose of 
etanercept and completed 96 weeks of investigational product and/or follow-up in study 
0881A1-3338. 
At the time of the original approved B1801023 protocol, the product label allowed for the use 
of etanercept in polyarticular JIA, regardless of JIA onset type (refer to the current version of 
the Summary of Product Characteristics of etanercept for the latest approved indications).2  
The approval of etanercept in this indication was based on a controlled study which mainly 
enrolled subjects with polyarticular-onset JIA.  Because of the relative paucity of data in 
other JIA subtypes, this study is being conducted to assess the long-term safety and clinical 
benefit of etanercept in subjects with extended oligoarticular JIA, ERA, or PsA.  In 


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August 2012, the sponsor was granted approval to extend the indication for JIA to include 
three new subtypes of the disease and to include long-term safety information for the JIA 
population, together with reclassification of the licensed indication of polyarticular JIA into 
the International League of Associations for Rheumatology (ILAR) classification of 
polyarthritis (rheumatoid factor positive) and polyarthritis (rheumatoid factor negative). 
Although the risk-benefit profile of etanercept in JIA has been well characterized, little is 
known about when or how to discontinue etanercept treatment in patients with JIA after a 
good clinical response has been achieved, nor are there guidelines from recognized bodies to 
define criteria for discontinuing treatment of etanercept.3  Thus, the decision to temporarily 
hold or completely stop therapy is currently a clinical one made between the health care 
provider and the patient, and is not based on clinical practice guidelines.  The criteria for 
clinically inactive disease in oligoarticular (persistent and extended), polyarticular (RF 
positive and negative), and systemic JIA have recently been revised by Wallace.  Clinically 
inactive disease is defined as 1) no joints with active arthritis; 2) fever, rash, serositis, 
splenomegaly, or generalized lymphadenopathy attributable to JIA; 3) erythrocyte 
sedimentation rate (ESR) or C-reactive protein (CRP) level within normal limits; 
4) Physician Global Assessment (PGA) of disease activity score of best possible on scale 
used; 5) duration of morning stiffness of ≤ 15 minutes; and 6) no active uveitis.4
There are some limited data from retrospective studies in the literature regarding 
discontinuation of etanercept during disease remission.  These data provide some support for 
the concept that etanercept can be withdrawn during remission, and in the event of relapse, 
restarted with a good clinical response.  Remesal et al analyzed the progress of patients with 
JIA after discontinuation of etanercept and the clinical response to re-introduction of the drug 
in those who relapsed.5  This retrospective chart review of patients between 2004 to 
2009 revealed that therapy with etanercept had been discontinued in 26 patients with JIA 
who had achieved inactive disease using the original definition from Wallace et al for 
clinically inactive disease.6  They note that the majority of patients (69%) relapsed after 
discontinuation of etanercept, the probability of remaining symptom-free at 6 months was 
50%, and the response to re-introduction of treatment was satisfactory.  They concluded that 
etanercept can be discontinued after an “as-yet undetermined period of disease inactivity,” 
given that even if there is a relapse of disease patients will respond to re-introduction of 
etanercept.  Prince et al found similar results in 9 patients with JIA who experienced relapse 
after withdrawal of etanercept.7 Unlike Remesal et al, they found the period of remission 
after discontinuation of etanercept was not associated with the duration of inactive disease 
before the withdrawal of treatment nor the method of withdrawal used (i.e., tapering of 
treatment versus abrupt cessation), and all 8 patients re-treated with etanercept achieved 
subsequent remission of disease activity “promptly”.  Finally, a retrospective chart review of 
171 JIA patients receiving anti-TNF agents, between 1998 and 2009 has recently been 
reported by Baszis et al.8 Of the 171 patients included in the review, 75% received
etanercept.  Similar to the findings of Prince et al, no correlation between the risk of flare and 
the length of anti-TNF therapy after inactive disease was achieved was observed in this 
study.  The median time to withdrawal of anti-TNF therapy after inactive disease was 
achieved was 6.1 months.  Of the 136 patients with inactive disease at the time of cessation 
of TNF treatment, 25% experienced a disease flare within 3 months of the withdrawal of 


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Etanercept 0.8 mg/kg once weekly (QW, up to a maximum dose of 50 mg QW) will be 
studied in this clinical trial.  Based on a previous pediatric plaque psoriasis study, which used 
etanercept 0.8 mg/kg QW (up to a maximum dose of 50 mg QW), this dose was found to 
have similar pharmacokinetic and safety profiles to etanercept 0.4 mg/kg twice-weekly 
(BIW, up to a maximum dose of 25 mg BIW), which was used in the pediatric JIA studies.  
In the pediatric plaque psoriasis study using etanercept 0.8 mg/kg QW (up to a maximum 
dose of 50 mg QW) and in adult RA studies using etanercept 50 mg QW, etanercept was well 
tolerated and efficacious.  In addition, the etanercept 0.8 mg/kg QW dose is generally more 
convenient for pediatric patients and their caregivers.  In August 2012, the sponsor was
granted approval of etanercept dosage regimen of 0.8 mg/kg (up to a maximum of 50 mg per 
dose) once weekly for the treatment of JIA.
Complete information for etanercept may be found in the Single Reference Safety Document, 
which for this study is the Investigator’s Brochure (IB).
The names, title, address and telephone number(s) of the sponsor's medical expert (Physician 
Clinician) for the trial is documented in the study contact list in the Study Reference Manual.
1.2.1. Disease Information 
1.2.1.1. Extended Oligoarticular JIA
This subtype presents in children as young as 2 to 4 years of age and affects female patients 
more often than male patients.9  The most commonly affected joints are the ankles and knees, 
with the knees being most affected.  Children with this disease generally have a poorer 
prognosis than children with persistent oligoarthritis and 50% have active arthritis or 
disability as adults.10
In order to be diagnosed with extended oligoarticular JIA per the ILAR criteria, a patient 
must have arthritis affecting 1 to 4 joints during the first 6 months of the disease that 
progresses to affect more than 4 joints after the first 6 months of disease.
Given the positive effect of etanercept on both polyarticular-onset JIA as well as 
oligoarticular-onset JIA with polyarticular course, it is expected that etanercept will also be 
effective in extended oligoarticular JIA.  This is further supported by sparse reports in the 
literature of extended oligoarticular JIA patients successfully treated with anti-TNF agents.11
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1.2.1.2. Enthesitis-Related Arthritis
Ankylosing spondylitis (AS) in adults and ERA in children share a number of important 
features, including a key role for TNF-α in disease pathogenesis.  These conditions in both 
adults and children appear to be immune mediated and unfold at the interface where articular 
cartilage and ligaments attach to bone.13  ERA mainly affects male patients after the age of 
6 years and is characterized by the association of enthesitis and arthritis.  In some patients, 
arthritis may progress to affect the spine and the sacroiliac joint, as in adult AS.14  ERA may 
be present with oligo or polyarthritis, affecting large or small joints as well as enthesitis.  
Compared with adult AS, ERA involves more peripheral joint involvement and less axial 
disease at disease onset.10
In order to be diagnosed with ERA per the ILAR criteria, a patient must have arthritis and 
enthesitis, or arthritis or enthesitis plus 2 of the following: 1) presence of or a history of 
sacroiliac joint tenderness and/or inflammatory lumbosacral pain; 2) the presence of human 
leukocyte antigen, subtype B, number 27 antigen (HLA-B27); 3) onset of arthritis in a male 
over 6 years of age; 4) acute (symptomatic) anterior uveitis; 5) a history of AS, ERA, 
sacroiliitis with inflammatory bowel disease, Reiter’s syndrome, or acute anterior uveitis in a 
first-degree relative.
Based upon the pathophysiology of the disease and the mechanism of action for etanercept, it 
is expected that etanercept will be effective in children with ERA.  This is supported by 
sparse reports in the literature of juvenile subjects with ERA successfully treated with 
anti-TNF agents.11, 15
1.2.1.3. Psoriatic Arthritis
PsA in adults and children share a number of important features, including an 
immune-mediated mechanism and a key role for TNF-α in disease pathogenesis.16  PsA 
mainly affects children over the age of 9, with males and females equally affected.17  This 
disease is rare in children but the long-term outcome may be unfavorable and reports suggest 
that the need for disease-modifying anti-rheumatic drug (DMARD)/anti-TNF agents is 
frequent in this JIA subcategory.18
In order to be diagnosed with PsA per the ILAR criteria, a patient must have arthritis and 
psoriasis, or arthritis plus at least 2 of the following: 1) dactylitis; 2) nail pitting or 
onycholysis; 3) psoriasis in a first-degree relative.
Based upon the pathophysiology of the disease and the mechanism of action for etanercept, it 
is expected that etanercept will be effective in children with PsA.  One (1) literature report of 
a small number of subjects with juvenile PsA successfully treated with etanercept was 
identified.


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2. STUDY OBJECTIVES AND ENDPOINTS
2.1. Objectives
Primary 
•
To monitor the occurrence of malignancy in pediatric subjects with extended 
oligoarticular JIA, ERA, or PsA.
Secondary 
•
To assess the long-term safety profile of etanercept;
•
To evaluate the long-term effect of etanercept on clinical benefit and physical 
function.
 
 
2.2. Endpoints
•
Multiple endpoints will be evaluated in the overall population and in each of the JIA 
subpopulations during the study to meet the stated objectives.
2.2.1. Primary Endpoint for All Subjects
•
Occurrence of malignancy over the course of the study.
2.2.2. Secondary Endpoints for Subjects in the Observational Period
•
Occurrence of serious adverse events, including serious infections;
•
Occurrence of medically important infections (ie, an infection requiring
hospitalization and /or parenteral [intravenous (IV), intra-muscular (IM)] 
anti-infective agents).
2.2.3. Secondary Endpoints for Subjects in the Active Treatment Period, and 
Withdrawal/Re-treatment Period
•
Occurrence of serious adverse events, including serious infections;  
•
Occurrence of medically important infections (ie, an infection requiring 
hospitalization and /or parenteral [intravenous (IV), intra-muscular (IM)] 
anti-infective agents);
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
Occurrence of all adverse events, including infections, infections considered 
preventable by vaccination, and injection site reactions;

Occurrence of withdrawals from investigational product due to adverse events;

Laboratory evaluations;

Growth parameters;

Tanner Stage Assessment for selected subjects;

ACR Pediatric 30, 50, 70, 90, and 100, defined as ≥ 30% (and 50%, 70%, 90%, 
100%, respectively) improvement from baseline in at least 3 of the 6 following 
variables, with no more than 1 of the remaining variables worsening by > 30 %:

Physician’s Global Assessment (PGA) of Disease Activity on a 21-circle 
visual analogue scale (VAS);

Patient/Parent Global Assessment on a 21-circle VAS;

Childhood Health Assessment Questionnaire (CHAQ)/Health Assessment 
Questionnaire (HAQ);

Number of joints with active arthritis, defined as joints that are swollen or, in 
the absence of swelling, joints with limited range of motion accompanied by 
pain and/or tenderness;

Number of joints with limited range of motion;

Laboratory measure of inflammation, c-reactive protein (CRP);

Individual components of the ACR Pediatric Assessments;

Pain Assessment on a 21-circle VAS;

Duration of morning stiffness in minutes;

Clinically inactive disease defined as follows per Wallace Criteria:12

No joints with active arthritis (defined as joints that are swollen or, in the 
absence of swelling, joints with limited range of motion accompanied by pain 
and/or tenderness);

No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy 
attributable to JIA;

No active uveitis;


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•
CRP level within normal limits in the laboratory where tested or, if elevated, 
not attributable to JIA;
•
PGA of disease activity score of best possible on the scale used;
•
Duration of morning stiffness of ≤ 15 minutes;
•
The Juvenile Arthritis Disease Activity Score (JADAS), using 4 components (PGA of 
Disease Activity, Patient/Parent Global Assessment, number of joints with active
arthritis and CRP).20
2.2.3.1. Additional Secondary Endpoints for ERA Subjects 
•
Overall Back Pain and Nocturnal Back Pain on a 100 mm VAS;
•
Bath Ankylosing Spondylitis Metrology Index (BASMI) and its components 
(Intermalleolar Distance, Cervical Rotation, Modified Schober’s Test, Lateral 
Flexion, and Tragus to Wall Distance).
2.2.3.2. Additional Secondary Endpoints for PsA Subjects 
•
Body Surface Area (BSA);
•
PGA of Psoriasis.
2.2.4. Health Outcomes Assessment for Subjects in the Active Treatment Period, and 
Withdrawal/Re-treatment Period
•
Childhood Health Assessment Questionnaire (CHAQ): for subjects aged <18 years at 
the time of assessment;
•
Health Assessment Questionnaire (HAQ): for subjects aged ≥18 years at the time of 
assessment.
 
3. STUDY DESIGN
This is an open-label, single treatment, multi-center, 8-year extension study in pediatric 
subjects who have been diagnosed with one of 3 subtypes of JIA (extended oligoarticular 
JIA, ERA, or PsA), have received at least one dose of etanercept and completed 
approximately 96 weeks of participation in study 0881A1-3338.  These subjects will be 
asked to participate in study B1801023. 
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It is anticipated that approximately 100 subjects will be enrolled in study B1801023.  This 
96-month study contains 3 periods: an active treatment period, a withdrawal/re-treatment 
period, and an observational period. 
Active treatment period:

Subjects who completed approximately 96 weeks of active treatment with 
investigational product (etanercept) in study 0881A1-3338 and are eligible to 
continue investigational product in study B1801023 will enter directly into the 
active treatment period.  These subjects may continue to receive investigational 
product for up to 8 additional years (96 months). 
Withdrawal/Re-treatment period:

Withdrawal: Subjects who have either completed approximately 96 weeks of 
treatment in study 0881A-3338 or were enrolled in the active treatment period of 
study B1801023 and who have either met the Wallace definition for clinically
inactive disease for at least 6 months on investigational product (etanercept) or 
who, in the investigators judgment, have had a good clinical response and would 
benefit from withdrawal from investigational product and are otherwise eligible 
can enter the withdrawal/re-treatment period.  However, the 
withdrawal/re-treatment period is optional and it is ultimately up to the 
investigator and subject to determine when the subject should be withdrawn from 
treatment. 

Re-treatment: Subjects requiring re-treatment per the investigator’s clinical 
judgment and who are otherwise eligible will be offered the option to re-start 
treatment with investigational product.
Subjects may not enter the withdrawal/re-treatment period more than once during the study.
Observational period: 
All subjects will be followed for a total of 8 years from the time of initial entry into the study 
as follows:

Subjects who discontinued investigational product prior to completing 96 weeks 
of active treatment in study 0881A1-3338 for any reason or who are not eligible 
to continue investigational product in study B1801023 will not be permitted to 
re-start investigational product in study B1801023 and will be asked to enter the 
observational period. 

Subjects who participate in the active treatment period of study B1801023 and 
subsequently discontinue use of investigational product at any time before 
completion of the study and do not participate in the withdrawal/re-treatment 
period for any reason (i.e., ineligible or subject declined participation) will be
asked to participate in the observational period. 


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
Subjects who participate in the withdrawal period and are ineligible for 
re-treatment with investigational product for any reason will be asked to 
participate in the observational period. 

Subjects who participate in the re-treatment period and subsequently discontinue 
investigational product prior to the completion of the study will be asked to 
participate in the observational period.
Once a subject enters into the observational period, he or she cannot resume investigational 
product for the remaining time in the study.  Subjects participating in the observational 
period of study B1801023 may receive standard of care including any anti-TNF agents (eg, 
commercial etanercept) and/or other immunosuppressive biologic agents for treatment of 
their disease at the discretion of the investigator.
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 surveillance in the observational 
period or receipt of investigational product in the active treatment period and/or 
withdrawal/re-treatment period is considered appropriate.  All relevant medical and 
non-medical conditions should be taken into consideration when deciding whether this 
protocol is suitable for a particular subject.
4.1. Inclusion Criteria
4.1.1. Inclusion Criteria for All Subjects at Baseline
Subject eligibility should be reviewed and documented by an appropriately qualified member 
of the investigator’s study team before subjects are included in the study.  Subjects must meet 
all of the following inclusion criteria to be eligible for enrollment into the study:
1. Evidence of a personally signed and dated informed consent document (and assent 
document, as applicable) indicating that the subject (and/or a legal
representative/guardian(s) as applicable according to subject age and local guidelines) 
has been informed of all pertinent aspects of the period of the study in which 
participation is being considered. 
2. Subjects who are willing and able to comply with all applicable aspects of the period 
of the study in which participation is being considered, including scheduled visits, 
treatment plan, laboratory tests, and other study procedures.
3. Receipt of at least 1 dose of investigational product and participation for 
approximately 96 weeks in study 0881A1-3338.
4. The subject and/or the parent or legal representative/guardian of the subject must be 
able to provide contact information, including primary care physician or other treating 
physician.


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4.1.2. Additional Inclusion Criteria for Subjects Planning to Continue Investigational 
Product in the Active Treatment Period
Subjects must meet the following additional inclusion criteria at the baseline visit to be 
eligible to continue investigational product in study B1801023:
1. Have completed approximately 96 weeks of investigational product in study 
0881A1-3338 and, in the investigator’s judgment, is appropriate to continue treatment 
with etanercept.
2. Either the subject or an available adult must be capable (according to the 
investigator’s judgment) of reconstituting and administering injections of 
subcutaneous (SC) etanercept.
3. The subject, parent, or legal representative/guardian of the subject must be able to 
read and complete the protocol-specified efficacy assessments.
4. The first dose of investigational product in study B1801023 must be administered 
within 6 weeks of receiving the last dose of investigational product in the study 
0881A1-3338.
4.1.3. Additional Inclusion Criteria for Subjects Planning to Enter in the 
Withdrawal/Re-treatment Period
1. Evidence of a personally signed and dated informed consent document (and assent 
document, as applicable) indicating that the subject (and/or a legal
representative/guardian(s) as applicable according to subject age and local guidelines) 
has been informed of all aspects of the withdrawal/re-treatment period of the study.  
Only one informed consent document/assent will be signed and dated for the 
withdrawal/re-treatment period. 
2. The subject is willing and able to comply with all applicable aspects of the 
withdrawal/re-treatment period of the study, including scheduled visits, treatment 
plan, laboratory tests, and other study procedures.
3. The subject and/or the parent or legal representative/guardian of the subject must be 
able to provide contact information, including primary care physician or other treating 
physician.
4. For subjects entering directly into the withdrawal/re-treatment period, have completed 
approximately 96 weeks of investigational product in study 0881A1-3338. 
5. For subjects entering directly into the withdrawal/re-treatment period, the baseline 
visit in study B1801023 must be completed within 14 days of the last dose of 
investigational product in study 0881A1-3338. 
6. The subject has met the Wallace definition for clinically inactive disease for at least 
6 months on investigational product (etanercept) or, in the investigator’s judgment, 


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has had a good clinical response and would benefit from withdrawal from 
investigational product.
7. The subject, parent, or legal representative/guardian of the subject must be able to 
read and complete the protocol-specified efficacy assessments.
4.1.3.1. Additional Inclusion Criteria for Subjects Planning to Restart Investigational 
Product in the Re-treatment Period
1. Re-treatment with investigational product should be based on the investigator’s 
clinical judgment as long as all other inclusion/exclusion criteria for re-treatment 
period are met.
2. Either the subject or an available adult must be capable (according to the
investigator’s judgment) of reconstituting and administering injections of 
subcutaneous (SC) etanercept. 
4.2. Exclusion Criteria
4.2.1. Exclusion Criteria for All Subjects at Baseline
Subjects presenting with any of the following will not be included in the study:
1. Subjects who are investigational site staff members or subjects who are Pfizer 
employees directly involved in the conduct of the trial.
4.2.2. Additional Exclusion Criteria for Subjects Planning to Continue Investigational 
Product in the Active Treatment Period
Subjects who completed approximately 96 weeks of investigational product in study 
0881A1-3338 and present with any of the following will not be allowed to continue 
investigational product in study B1801023:
1. Withdrawal from investigational product in study 0881A1-3338 for any reason.
2. History of malignancy other than squamous cell, basal cell carcinoma or cervical 
carcinoma in situ.
3. Participation in other clinical studies of investigational drugs or investigational 
combinations of approved drugs between the week 96 visit in study 0881A1-3338 and 
the baseline visit in study B1801023 or during participation in the active treatment 
period of study B1801023.
4. Pregnant or breastfeeding female subjects. 
5. Receipt of any of the following between the week 96 visit in study 0881A1-3338 and 
the baseline visit in study B1801023:


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
Any immunosuppressive biologic drugs, including but not limited to TNF 
inhibitors (other than etanercept), abatacept, rituximab, anakinra and 
tocilizumab;

Immunosuppressive drugs (excluding corticosteroids) (eg, cyclophosphamide, 
cyclosporine, azathioprine);

Leflunomide;

Use of more than 1 of the non-biologic DMARDs permitted in study 
0881A1-3338 (ie, methotrexate, hydroxychloroquine, chloroquine, 
sulfasalazine) in subjects <18 years of age;

Use of more than 2 of the non-biologic DMARDs permitted in study 
0881A1-3338 (ie, methotrexate, hydroxychloroquine, chloroquine, 
sulfasalazine) or hydroxychloroquine and chloroquine taken at the same time
in subjects ≥18 years of age;

Non-biologic DMARDs other than those permitted in study 0881A1-3338 (ie, 
methotrexate, hydroxychloroquine, chloroquine, sulfasalazine), or those not 
listed under other exclusion criteria;

Any live (attenuated) vaccines.
6. 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.
7. Signs and symptoms or suspicion of active tuberculosis.
4.2.3. Additional Exclusion Criteria for Subjects Planning to Enter in the 
Withdrawal/Re-treatment Period
1. Withdrawal from investigational product in study 0881A1-3338 for any reason.
2. Prior and/or current participation in the observational period of study B1801023. 
3. Prior and/or current participation in the withdrawal/re-treatment period of study 
B1801023. 
4.2.3.1. Additional Exclusion Criteria for Subjects Planning to Restart Investigational 
Product in the Re-treatment Period
1. History of malignancy other than squamous cell, basal cell carcinoma or cervical 
carcinoma in situ.


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2. Participation in other clinical studies of investigational drugs or investigational 
combinations of approved drugs during participation in study B1801023.
3. Pregnant or breastfeeding female subjects. 
4. Receipt of any of the following during participation in study B1801023:

Any immunosuppressive biologic drugs, including but not limited to TNF 
inhibitors (other than etanercept), abatacept, rituximab, anakinra and 
tocilizumab;

Immunosuppressive drugs (excluding corticosteroids) (eg, cyclophosphamide, 
cyclosporine, azathioprine);

Leflunomide;

Use of more than 1 of the non-biologic DMARDs permitted in study 
B1801023 (ie, methotrexate, hydroxychloroquine, chloroquine, sulfasalazine) 
in subjects <18 years of age;

Use of more than 2 of the non-biologic DMARDs permitted in study 
B1801023 (ie, methotrexate, hydroxychloroquine, chloroquine, sulfasalazine) 
or hydroxychloroquine and chloroquine taken at the same time in subjects 
≥18 years of age; 

Non-biologic DMARDs other than those permitted in study B1801023 (ie, 
methotrexate, hydroxychloroquine, chloroquine, sulfasalazine), or those not 
listed under other exclusion criteria;
5. Receipt of any live (attenuated) vaccine within 4 weeks after the last dose of 
investigational product in active treatment period and within 8 weeks prior to the first 
dose of investigational product in the re-treatment period. 
6. Any of the following laboratory abnormalities based on the most recent laboratory 
results:

White blood cell (WBC) count <3.50 x 103/mm3 (SI units: <3.50 x 109/L) and 
neutrophils < 1x109/L;

Hemoglobin < 8.5 g/dL (SI units: <85 g/L);

Platelet Count < 125,0000/mm3 or ≥1,000,000/mm3 (SI units: <125 x 109/L or 
≥1,000 x 109/L);

Aspartate aminotransaminase (AST) or alanine aminotransaminase (ALT) ≥ 
2.0 x upper limit of normal (ULN);


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
Should the laboratory results drawn at the time of re-treatment shows that the 
subject has met any of the above laboratory exclusions, the subject may be 
withdrawn from investigational product at that time (refer to Section 6.1.4). 
7. 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 the re-treatment period of this study.
8. Signs and symptoms or suspicion of active tuberculosis.
4.3. Life Style Guidelines 
4.3.1. Pregnancy Testing
At the baseline visit and each subsequent visit in the active treatment period, and the
withdrawal/re-treatment period, including the early withdrawal visit(s) and the re-treatment 
assessment visit, childbearing potential must be evaluated in female subjects and the 
evaluation must be documented in the subject’s source documents.  Female subjects who, in 
the opinion of the investigator, are biologically capable of having children (of childbearing 
potential) must have a urine pregnancy test performed within 7 days prior to the baseline 
(day 1) visit and at each of the visits while participating in the active treatment period, and 
the withdrawal/re-treatment period; including the early withdrawal visit(s) and the 
re-treatment assessment visit; this includes subjects who are menstruating at the time of the 
visit.  A negative urine pregnancy test must be obtained prior to administration and/or
dispensing of investigational product at each visit in the active treatment period, and 
re-treatment period.
Pregnancy tests will also be done whenever one menstrual cycle is missed during the active
treatment period and withdrawal/re-treatment period or when potential pregnancy is 
otherwise suspected.  Pregnancy tests may also be repeated as per request of Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) or if required by local regulations.
4.3.2. Sexually Active Female Subjects
As appropriate, sexual activity must be discussed with subjects at the baseline visit and each 
subsequent visit in the active treatment period, and in the withdrawal/re-treatment period, 
including the early withdrawal visit(s) and the re-treatment assessment visit.  For those 
subjects who either plan on becoming sexually active or who are sexually active, the 
requirement for highly effective methods of contraception outlined below must also be 
discussed.  The discussion must be documented in the subject’s source documents.
All female subjects who, in the opinion of the investigator, are biologically capable of having 
children and are sexually active, must agree and commit to the use of a highly effective 
method of birth control (failure rate less than 1% when used consistently and correctly) for 
the duration of the active treatment period, and withdrawal/re-treatment period of the study 
and for 30 days after the last dose of investigational product for those subjects entering into 


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the observational period.  According to investigator judgment, subjects may need to continue 
using a highly effective method of contraception beyond 30 days after the last dose of 
investigational product for those subjects entering into the observational period based on 
concomitant medications (eg, MTX) or local guidelines.
Medically-approved methods of contraception for this study include the following:

Properly used barrier contraception with spermicide;

Hormonal contraceptive; either oral, injectable, implanted or patch delivery 
systems;

Intrauterine device (IUD);

Documented surgical sterilization, such as tubal ligation, hysterectomy or bilateral 
oophorectomy.
4.3.3. Sexually Active Male Subjects
As appropriate, sexual activity must be discussed with subjects at the baseline visit and each 
subsequent visit in the active treatment period, and in the withdrawal/re-treatment period, 
including the early withdrawal visit(s) and the re-treatment assessment visit.  For those 
subjects who either plan on becoming sexually active or who are sexually active, the 
requirement for highly effective methods of contraception outlined below must also be 
discussed.  The discussion must be documented in the subject’s source documents.
Sexually active male subjects must agree to use highly effective method contraception 
(failure rate <1% when used consistently and correctly, such as properly used barrier 
contraception with spermicide or surgical sterilization and appropriately confirmed absence 
of sperm in the post vasectomy ejaculate) to protect his partner from becoming pregnant 
during the active treatment period, and in the withdrawal/re-treatment period of the study and 
for at least 30 days after the last dose of investigational product for those subjects entering 
into the observational period.  According to investigator judgment, subjects may need to 
continue using a highly effective method of contraception beyond 30 days after the last dose 
of investigational product for those subjects entering into the observational period based on 
concomitant medications (eg, MTX) or local guidelines.
4.4. 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 MyTrials 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 


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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. For sites other 
than a Pfizer Clinical Research Unit, 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.
5. STUDY TREATMENT
The following only applies to those subjects who are in the active treatment period, or the 
re-treatment period in this study:

Etanercept will be provided as investigational product by the sponsor throughout the 
course of the subject’s participation in this study for up to 8 years (96 months) unless 
early withdrawal of treatment is warranted.

Subjects aged <18 years and 62 kg will receive etanercept SC at a dose of 0.8 mg/kg 
QW (up to a maximum dose of 50 mg QW).

Subjects aged 18 years or >62 kg will receive etanercept SC at a dose of 50 mg QW.

No dose reductions of etanercept are permitted, except those due to changes in the 
subject’s weight (ie, for subjects aged <18 years and weighing 62 kg).

If more than 4 consecutive doses are missed due to AEs, infections, or surgeries, 
or if more than 2 consecutive doses are missed due to reasons other than AEs, 
infections, or surgery (eg, subject forgot to take investigational product or away 
from home without enough investigational product), the Pfizer Clinical Team
must be consulted in order to determine whether the subject should continue 
taking investigational product.

Tapering of the investigational product (ie, prescription or receipt of a dose lower 
than that described in Section 5 or less than once-weekly on an average basis) is 
not allowed.
5.1. Allocation to Treatment
Enrollment and assignment to investigational product will be accomplished using interactive 
web response/interactive voice response (IWR/IVR, an automated web/telephone 
randomization system provided by the sponsor).  At the baseline visit, the investigative site 
will contact the IWR/IVR (online or by telephone call).  The site will enroll the subject into 
the IWR/IVR by indicating minimal information sufficient to distinguish one subject from 
another (eg, date of birth) and receive the Subject ID number. 


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For subjects entering into the active treatment period, or re-treatment period, the IWR/IVR 
system will allocate investigational product according to the subject’s age and weight and 
assign a randomization number.  Sites must access the IWR/IVR system each time 
investigational product is dispensed. 
The use of the IWR/IVR allows for proper drug coverage by monitoring enrollment, 
inventory and drug shipments.
5.2. Drug Supplies
5.2.1. Formulation and Packaging
Investigational product will be provided by the sponsor: 

Subjects aged <18 years and 62 kg will be provided with vials containing 
lyophilized etanercept 25 mg with pre-filled syringes of sterile water for injection. 

Subjects aged ≥18 years or >62 kg will be provided with pre-filled syringes 
containing etanercept 50 mg diluted in 1.0 ml of sterile water for injection or vials 
containing lyophilized etanercept 25 mg with pre-filled syringes of sterile water for 
injection. 
5.2.2. Preparation and Dispensing
Refer to separate instructions regarding the preparation, and administration of the 
investigational product. 
At each dispensing visit in the active treatment period and the re-treatment period, subjects 
will receive sufficient quantities of investigational product to last until the next scheduled 
visit.  Investigational product will not be dispensed at the early withdrawal or month 96 visit.
5.2.3. Administration
The dose of etanercept will be based on the subject’s weight and age at the previous visit.  
Therefore, if the subject’s weight or age changes then the dose will be increased or decreased 
accordingly.  The investigational product should be administered QW on the same day of the 
week throughout the study.  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 regularly scheduled day (eg, 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 may be taken as soon 
as possible and the subsequent dose must not be given sooner than 4 days later. 
All doses will either be self-administered or given by a designated person at the subject’s 
home.  Study personnel will provide training to the person designated to administer the 
investigational product on how to store the investigational product at home and how and 
when to administer the investigational product.  The individual administering the 
investigational product must demonstrate competency to the site staff regarding their ability 
to correctly administer the SC dose.  The subject or person designated to administer the 


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investigational product and the site’s assessment of this person will be documented in the 
subject’s source documents.  If necessary, doses may be given at the study site until the 
person designated to administer the investigational product feels comfortable administering 
the dose. 
Subjects will also be given a diary card on which their subject number and the date of their 
next appointment will be written.  For subjects in the active treatment period and re-treatment 
period, the diary will also be used by the person designated to administer the investigational 
product to record the date of each of the SC injection(s), the volume (mL) delivered from 
each syringe, the injection site location, and the reason for change from the 
protocol-specified dose (if applicable). 
5.2.3.1. Medication Errors
A medication error is any preventable event that may cause or lead to inappropriate 
investigational use or subject harm while the investigational product is in control of the 
healthcare professional, subject, or consumer.  Such events may be related to professional 
practice, health care products, procedures, and systems, including prescribing, order 
communication, product labeling, packaging, nomenclature, compounding, dispensing, 
distribution, administration, education, monitoring, and use. 
Medications errors are to be captured on the medication error CRF page irrespective of the 
presence of an associated adverse event/serious adverse event, including, but not limited to 
the following: 

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, including doses that 
differ from the calculated dose based on the subject’s age and weight by >20%. 

(([administered dose, mg] – [expected dose, mg])/[expected dose]) X 100% is 
greater than 20% for an overdose or less than -20% for an underdose. 

Note: missed doses of investigational product are not considered to be a 
medication error.

Errors in the reconstitution of the investigational product, including use of the wrong 
diluents, and deviations from the protocol-specified timeframe in which the 
investigational product should be used after reconstitution (see Drug Storage and 
Accountability section).

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 as outlined in Section 5.2.5).


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
Administration of etanercept from a commercial supply rather than etanercept 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 adverse event, as determined by the 
investigator, the medication error is captured on the medication error CRF and, if applicable, 
any associated adverse event(s) is captured on an adverse event CRF page (refer to adverse 
event reporting section for further details). 
In the event of a medication error involving investigational product, a site staff member 
(ie, Investigator, Study Coordinator) must inform the sponsor’s site monitor of the incident.
5.2.4. Compliance
Compliance will be monitored by study personnel at each study visit using diary cards, and 
verbal information from the parent and/or subject.  Reasons for missed doses must be 
recorded in the subject’s source documents and CRF. 
Subjects provided with vials will be instructed to return all investigational product packages 
and vials (including used, empty, and unused vials).  Subjects provided with pre-filled 
syringes will be instructed to return the empty investigational product packages and unused 
prefilled syringes in order to review drug accountability and subject compliance. 
If more than 4 consecutive doses are missed due to AEs, infections, or surgeries, or if more 
than 2 consecutive doses are missed due reasons other than AEs, infections, or surgery 
(eg, subject forgot to take investigational product or away from home without enough 
investigational product), the Pfizer Clinical team must be consulted in order to determine 
whether the subject should continue taking investigational product.
Tapering of the investigational product (i.e., prescription or receipt of a dose lower than that 
described in Section 5 or less than once-weekly on an average basis) is not allowed.
5.2.5. Drug Storage and Drug Accountability 
The investigational product must be stored under refrigerated conditions (2C - 8C).  The 
investigational product must not be frozen.  For subjects using lyophilized vials of 
etanercept, after reconstitution of the investigational product, the solution may be stored 
upright in a refrigerator (2C – 8C) for up to 6 hours.  Storage conditions stated in the IB
and/or local product package insert will be superseded by the storage conditions stated on the 
investigational product label.
The investigational product must be stored as indicated.  Deviations from the storage 
requirements, including any actions taken, must be documented and reported to the sponsor’s
site monitor. Once a deviation is identified, the investigational product must be quarantined 
and not used until the sponsor provides documentation of permission to use the 
investigational product. 


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The subject or the designated person will be given instructions regarding the reconstitution 
and storage of etanercept.
The investigator, or approved representative (eg, pharmacist) must maintain adequate records 
documenting the receipt, use, loss, or other disposition of the investigational product.  Pfizer 
may supply drug accountability forms to be used or may approve use of standard institution 
forms.  In either case, the forms must identify the investigational product, including batch or 
package numbers, and account for its disposition on a subject-by-subject basis, including 
specific dates and quantities dispensed. The forms must be signed by the individual who 
dispensed the drug, and copies must be provided to Pfizer.
All unused investigational product must be returned to the study site.  Subjects must return 
all investigational product packages and vials (including used, empty, and unused etanercept 
vials); subjects provided with pre-filled syringes will be instructed to return the empty 
investigational product packages and unused pre-filled syringes to the investigative site.  
Drug accountability will be reviewed by the monitor during routine monitoring visits.
Returned and/or used investigational product can be destroyed only after the monitor has 
verified the accuracy of the dispensing and inventory record.  The monitor must verify that 
site staff follows instructions regarding the return of investigational product to the Supply 
Chain Organization or vendor for destruction.
Pfizer will provide instructions as to disposition of any unused investigational product.  If 
Pfizer authorizes destruction 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.  Destruction must be adequately 
documented.
5.3. Concomitant Medication(s)
Any medication that the subject takes other than investigational product specified in the 
protocol after signing the informed consent document is considered concomitant medication.
Active treatment period: Concomitant DMARDs, corticosteroids (including intra-articular 
injections), nonsteroidal anti-inflammatory drugs (NSAIDs), and anti-infective agents will be 
reported on the appropriate eCRF up to the final follow-up visit. 
Withdrawal/re-treatment period: Concomitant DMARDs, corticosteroids (including 
intra-articular injections), NSAIDs, and anti-infective agents will be reported on the 
appropriate eCRF up to the final follow-up visit. 
Observational period: Concomitant DMARDs (including any immunosuppressives or 
anti-TNFs and other immunosuppressive biologic agents), corticosteroids (including 
intra-articular injections), and anti-infective agents taken for medically important infections 
will be reported on the appropriate eCRF up to the month 96 visit. 


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The start date, stop date (if applicable), dose, unit, frequency, route of administration, and 
indication for use for concomitant DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents will be recorded on separate CRFs.
Concomitant medications other than those listed above will not be recorded on the study 
eCRFs, but must be maintained in the subject’s source documents. 
The start date and stop date (if applicable) of non-drug treatments received due to an adverse 
event will be reported on a separate CRF throughout all periods up to the month 96 visit or 
the final follow-up visit, as applicable.
5.3.1. Prohibited and/or Permitted Medication(s)
Subjects who are participating in the observational period may receive standard of care 
medications including any anti-TNF agents (eg, commercial etanercept) and other 
immunosuppressive biologic agents for treatment of their disease at the discretion of the 
investigator.  However, subjects entering the observational period are not permitted to 
receive any live (attenuated) vaccines within 4 weeks after the last dose of investigational 
product in the active treatment period or re-treatment period. 
The following prohibited and/or permitted medications/treatments will only apply to subjects 
while they are in the active treatment period and withdrawal/re-treatment period of this study.
Prohibited medications and/or treatments during active treatment period and 
withdrawal/re-treatment period:
1. Use of more than 1 permitted non-biologic DMARD (ie, methotrexate, 
hydroxychloroquine, chloroquine, sulfasalazine) in subjects <18 years of age.
2. Use of more than 2 of the permitted non-biologic DMARDs (ie, methotrexate, 
hydroxychloroquine, chloroquine, sulfasalazine) or hydroxychloroquine and 
chloroquine taken at the same time in subjects ≥18 years of age.
3. Non-biologic DMARDs (other than methotrexate, hydroxychloroquine, chloroquine, 
or sulfasalazine), immunosuppressive agents (including azathioprine, cyclosporine, 
cyclophosphamide), TNF inhibitors (other than investigational product) or other 
immunosuppressive biologic agents.
4. Chronic use of more than 1 NSAID.
5. Any other investigational drugs or investigational combinations of approved drugs.
6. Plasma exchange therapy.
7. Any live (attenuated) vaccines:

At any time while receiving investigational product in the active treatment period 
or the re-treatment period;


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
Within 4 weeks after the last dose of investigational product in active treatment 
period and within 8 weeks before the last dose of investigational product in the 
re-treatment period.
8. The 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 (See 
Withdrawal Section).
Additional prohibited medications and/or treatment for subjects with PsA:
9. Receipt of psoralen + ultraviolet A (PUVA), ultraviolet A (UVA), or ultraviolet B 
(UVB) therapy, including narrow band UVB and excimer laser.
10. Oral retinoids.
Permitted medications and/or treatments during active treatment period and 
withdrawal/re-treatment period:
1. Subjects <18 years of age may take no more than 1 of the 4 following permitted 
non-biologic DMARDs at the same time.  Subjects ≥18 years of age may take no 
more than 2 of the 4 following permitted non-biologic DMARDs at the same time 
(hydroxychloroquine and chloroquine must not be taken at the same time).  Subjects 
may either start a permitted non-biologic DMARD, continue at same dose, reduce the 
dose, stop taking the permitted non-biologic DMARD, or switch to a different 
permitted non-biologic DMARD; subjects ≥18 years may also add 1 of the permitted 
DMARDs to the existing DMARD.

Hydroxychloroquine (maximum recommended dose per local product 
information);

Chloroquine (maximum recommended dose per local product information);

Sulphasalazine (maximum recommended dose per local product 
information);

Methotrexate (15 mg/m2/week not to exceed 20 mg/week in subjects aged 
<18 years or 25 mg/week in subjects aged 18 years).
2. The following treatments may be adjusted at the discretion of the investigator using 
the lowest possible dose:
a.
Oral corticosteroids (0.2 mg/kg/day up to a maximum dose of 10 mg/day of 
prednisone or equivalent). 
b. No more than a total of 3 administrations per calendar year for any of the 
following corticosteroid regimens:


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
Oral corticiosteriods: The dose may be increased to no more than 40 mg 
prednisone/day (or equivalent) for no more than 3 days and then dose 
tapered over no more than 2 weeks to a stable daily dose that is 
0.2 mg/kg/day up to a maximum dose of 10 mg/day of prednisone or 
equivalent.

IV or IM corticosteroid injections: The dose of corticosteroid injected at 
each time point should not exceed the anti-inflammatory equivalent dose 
of methylprednisolone suspension (up to 60 mg).
c.
No more than 6 intra-articular (IA) or soft tissue corticosteroid injections may 
be administered per calendar year.  The dose of corticosteroid injected at each 
time point should not exceed the anti-inflammatory equivalent dose of 
methylprednisolone suspension (up to 40 mg). 
d. No more than 1 NSAID may be used on a chronic basis (maximum 
recommended dose per local product information or local guidelines);  

An additional NSAID may be given as needed for acute conditions 
(maximum recommended dose per local product information or local 
guidelines).

Subjects may switch to a different NSAID at the discretion of the 
investigator.
e.
Folic acid prophylaxis is recommended for all subjects receiving 
methotrexate;
f.
Simple short-acting analgesics without anti-inflammatory action and/or short 
acting oral narcotic analgesics (such as acetominophen/paracetamol, codeine, 
dihydrocodeine, or tramadol, alone or in combination) may be used at the 
discretion of the investigator (≤ maximum recommended dose per local 
product information or local guidelines);
g. Physical therapy and therapeutic exercise;
h. Medications and treatments for acute or chronic conditions not listed under 
the prohibited treatments.
Additional permitted medications for subjects with PsA:
3. The dose and type of the following may be adjusted at the discretion of the 
investigator:
a.
Topical steroids and tar-based shampoos on all regions;
b. Topical vitamin A or D analog preparations;


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c.
Anthralin.
6. STUDY PROCEDURES 
6.1. Study Procedures for Subjects in the Active Treatment Period or 
Withdrawal/Re-treatment Period 
Whenever possible, every effort must be made to ensure that the same investigator performs 
the investigator assessments (ie, physical assessment, Tanner Assessment, PGA of Disease 
Activity, Joint Assessment, BASMI, PGA of Psoriasis, Body Surface Area) for a subject 
throughout the study.  Worksheets will be provided to the site to record the results of the 
assessments and must be maintained with the subject’s source documents.
Throughout the study, the Patient/Parent Global Assessment, Pain Assessment, Duration of 
morning stiffness, Overall Back Pain and Nocturnal Pain will be completed by the subject’s 
parent or legal representative/guardian for subjects aged <18 years at the time of the 
assessment; these will be completed directly by subjects aged 18 years at the time of the 
assessment.  The CHAQ will be completed by the subject’s parent or legal 
representative/guardian for subjects aged <18 years at the time of the assessment; the HAQ 
will be completed directly by subjects aged 18 years at the time of the assessment.
The health outcomes assessments (ie, CHAQ/HAQ) are for the purpose of exploring the 
subject’s own perceptions about his/her quality of life.  The investigator must not influence 
the subject’s assessment.  Every effort should be made by site personnel to maintain an 
unbiased assessment.
Refer to the Schedule of Activities flowchart of the protocol.
6.1.1. Active Treatment Period
6.1.1.1. Baseline Procedures for Subjects Planning to Participate in the Active 
Treatment Period
Baseline procedures may not commence until after the informed consent and assent (as 
applicable) have been signed.  The study investigator or a sub-investigator will discuss with 
each subject and parent(s) (as applicable according to subject age and local guidelines) the 
nature of the study, its requirements, and its restrictions.
Every attempt should be made to complete the study B1801023 baseline visit on the same 
day as the study 0881A1-3338 Week 96 visit.  For subjects planning to continue 
investigational product, the baseline visit (Day 1) of study B1801023 must occur within 
6 weeks of the last dose of investigational product received in study 0881A1-3338. 
The following baseline procedures and assessments must be completed for all subjects in the 
active treatment period:
1. Sign and date informed consent/assent for active treatment period.


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2. Review inclusion/exclusion criteria that apply to all subjects and that apply to 
subjects planning to continue investigational product in study B1801023.

Those subjects who do not meet entry criteria for continuing investigational 
product in study B1801023 will be asked to participate in the observational period 
in study B1801023.
3. Collect/update contact information, including primary care physician or other treating 
physician. 
4. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents. 
5. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test, which must be preformed within 7 days before the 
baseline visit; this includes subjects who are menstruating at the time of the visit.  If a 
pregnancy test was collected at the week 96 visit in study 0881-3338, and the visit 
occurred within 7 days of the baseline visit, a urine pregnancy test does not have to be 
repeated as long as the test result was negative.  For these subjects, a negative test 
result must be available before dispensing and administration of investigational 
product.  Pregnancy tests will also be done whenever one menstrual cycle is missed 
during the active treatment period or when potential pregnancy is otherwise 
suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
6. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss requirement for highly 
effective methods of contraception (refer to Section 4.3.2 for female subjects and 
Section 4.3.3 for male subjects). The discussion must be documented in the subject’s 
source documents. 
7. BASMI and its components (Intermalleolar Distance, Cervical Rotation, Modified 
Schober’s Test, Lateral Flexion, and Tragus to Wall Distance) only for ERA subjects. 
8. Prior and concomitant medications (DMARDs, corticosteroids, NSAIDs, and 
anti-infective agents) and non-drug treatments received due to an adverse event.  
Medications reported as ongoing at the final study 0881A1-3338 visit as well as 
events starting between the final study 0881A1-3338 visit and baseline visit of study 
B1801023 must be recorded on the appropriate CRF.
9. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.  Events reported as ongoing at the 
final study 0881A1-3338 visit as well as events starting between the final study 
0881A1-3338 visit and baseline visit of study B1801023 must be recorded on the 
appropriate CRF. 


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The following additional baseline procedures and assessments must be completed for 
subjects in the active treatment period with >14 days between the study 0881A1-3338 week 
96 visit and the study B1801023 baseline visit:
10. Physical examination (performed by a physician).

The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).
11. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
12. Height (cm).
13. Weight (kg):
14. Laboratory evaluations (ie, hematology, blood chemistry, and CRP).
15. PGA of Disease Activity.
16. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment.
17. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment. 
18. Duration of Morning Stiffness.
19. Joint Assessment including joints with limitation of motion.
20. Overall Back Pain and Nocturnal Back Pain (ERA subjects only).
21. BSA (PsA subjects only).
22. PGA of Psoriasis (PsA subjects only).
23. CHAQ or HAQ, according to the subject’s age at the time of the assessment.
24. Randomization/Registration.
Once all baseline procedures have been completed and it has been confirmed that the subject 
is eligible to enter the active treatment period, the study staff will use the IWR/IVR to 
allocate investigational product packages.  The investigational product, investigational 
product instructions, subject diary and reminder card for their next scheduled visit will then 
be dispensed to the subject.


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For subjects with 7 days since the previous dose of investigational product in study 
0881A1-3338, the first dose of investigational product in study B1801023 may be 
administered at the study site to maintain the QW dosing schedule.
6.1.1.2. Active Treatment Period – Month 3 to Month 96 Visits
For subjects in the active treatment period, study visits will be scheduled at the study site at 
Months 3, 6, 9, 12, 15, 18, 21, 24, 27, 30, 33, 36, 39, 42, 45, 48, 51, 54, 57, 60, 63, 66, 69, 
72, 75, 78, 81, 84, 87, 90, 93, and 96 (within 14 days of the projected visit date based on the 
actual baseline visit date).
The following safety and efficacy evaluations will be performed at all visits during the active 
treatment period unless otherwise indicated:  
1. Collect/update contact information, including primary care physician or other treating 
physician.
2. Concomitant medications (DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents) and non-drug treatments received due to an adverse event.
3. Physical examination (performed by a physician at months 12, 24, 36, 48, 60, 72, 84, 
and 96 only).

The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).
4. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
5. Height (cm, at months 12, 24, 36, 48, 60, 72, 84, and 96 only).
6. Weight (kg):

For subjects who are <18 years of age and who weigh 62 kg (at all visits). 

For subjects who are 18 years of age or weigh >62 kg (at months 12, 24, 36, 48, 
60, 72, 84, and 96 only).
7. Laboratory evaluations (ie, hematology, blood chemistry, and CRP, at months 6, 12, 
18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 only).  Additional testing may 
be performed according to local guidelines or standard of care and for follow-up of 
abnormal laboratory test results. 
8. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents. 
9. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test at each visit; this includes subjects who are 


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menstruating at the time of the visit.  For these subjects, a negative test result must be 
available before dispensing and/or administration of investigational product.  
Pregnancy tests will also be done whenever one menstrual cycle is missed during the 
active treatment period or when potential pregnancy is otherwise suspected.  
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by 
local regulations.
10. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss highly effective methods 
of contraception (refer to Section 4.3.2 for female subjects and Section 4.3.3 for male 
subjects).  The discussion must be documented in the subject’s source documents.
11. PGA of Disease Activity (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 
84, 90, and 96 only).
12. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 
96 only).
13. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 
only).
14. Duration of Morning Stiffness (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72,
78, 84, 90, and 96 only).
15. Joint Assessment (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 
and 96 only).
16. Overall Back Pain and Nocturnal Back Pain (at months 6, 12, 18, 24, 30, 36, 42, 48, 
54, 60, 66, 72, 78, 84, 90, and 96 only [ERA subjects only]).
17. BASMI Assessments (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 
90, and 96 only [ERA subjects only]).
18. BSA (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 only 
[PsA subjects only]).
19. PGA of Psoriasis (at months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, 
and 96 only [PsA subjects only]).
20. CHAQ or HAQ, according to the subject’s age at the time of the assessment (at 
months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 only).
21. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.


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22. Perform drug accountability.
23. Collect and review diary card dispensed at the previous visit. 

For each dose, the site personnel will calculate the total volume (mL) delivered 
from the syringe(s) and the total dose (mg). 
24. Use the IWR/IVR to allocate investigational product packages (except at month 96).
25. Dispense investigational product, investigational product instructions, and the subject 
diary (except at month 96).
26. Dispense the reminder card for next scheduled visit. 
27. Complete the End of Treatment Subject Summary CRF (only at month 96).
6.1.2. Withdrawal/Re-treatment Period
6.1.2.1. Baseline Procedures for Subjects Planning to Enter Directly into the 
Withdrawal/Re-treatment Period
The following section is only applicable to subjects who enter directly into the 
withdrawal/re-treatment period at the baseline visit of study B1801023.
Baseline procedures may not commence until after the informed consent and assent (as 
applicable) have been signed.  The study investigator or a sub-investigator will discuss with 
each subject and parent(s) (as applicable according to subject age and local guidelines) the 
nature of the study, its requirements, and its restrictions.
Every attempt should be made to complete the study B1801023 baseline visit on the same 
day as the study 0881A1-3338 week 96 visit.  The baseline visit (day 1) must occur within 
14 days of the last dose of investigational product received in study 0881A1-3338. 
The following baseline procedures and assessments must be completed for all subjects 
entering into the withdrawal/re- treatment period:
1. Sign and date informed consent/assent for withdrawal/re-treatment period.
2. Review inclusion/exclusion criteria that apply to all subjects and that apply to 
subjects planning to enter the withdrawal/re-treatment period.

Those subjects who do not meet entry criteria for withdrawal/re-treatment period 
may be evaluated to determine whether participation in the active treatment 
period or observational period is appropriate. 
3. Collect/update contact information, including primary care physician or other treating 
physician every. 


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4. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents. 
5. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test, which must be performed within 7 days before the 
baseline visit; this includes subjects who are menstruating at the time of the visit.  If a 
pregnancy test was collected at the week 96 visit in study 0881-3338, and the visit 
occurred within 7 days of the baseline visit, a urine pregnancy test does not have to be 
repeated as long as the test result was negative.  For these subjects, a negative test 
result must be available before dispensing and administration of investigational 
product.  Pregnancy tests will also be done whenever one menstrual cycle is missed 
during the active treatment period or when potential pregnancy is otherwise 
suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
6. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss requirement for highly 
effective methods of contraception (refer to Section 4.3.2 for female subjects and 
Section 4.3.3 for male subjects).  The discussion must be documented in the subject’s 
source documents. 
7. BASMI and its components (Intermalleolar Distance, Cervical Rotation, Modified 
Schober’s Test, Lateral Flexion, and Tragus to Wall Distance) only for ERA subjects. 
8. Prior and concomitant medications (DMARDs, corticosteroids, NSAIDs, and 
anti-infective agents) and non-drug treatments received due to an adverse event.  
Medications reported as ongoing at the final study 0881A1-3338 visit as well as 
events starting between the final study 0881A1-3338 visit and baseline visit of study 
B1801023 must be recorded on the appropriate CRF.
9. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.  Events reported as ongoing at the 
final study 0881A1-3338 visit as well as events starting between the final study 
0881A1-3338 visit and baseline visit of study B1801023 must be recorded on the 
appropriate CRF. 
10. Registration/Randomization.
11. Dispense reminder card for next scheduled visit.
The following additional baseline procedures and assessments do not need to be completed 
for subjects in the withdrawal/re-treatment period as long as the each procedure was 
completed within 14 days of the study 0881A1-3338 week 96 visit and the study 
B1801023 baseline visit:
12. Physical examination (performed by a physician).


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
The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).
13. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
14. Height.
15. Weight (kg).
16. Laboratory evaluations (ie, hematology, blood chemistry, and CRP).
17. PGA of Disease Activity.
18. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment.
19. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment. 
20. Duration of Morning Stiffness.
21. Joint Assessment including joints with limitation of motion.
22. Overall Back Pain and Nocturnal Back Pain (ERA subjects only).
23. BSA (PsA subjects only).
24. PGA of Psoriasis (PsA subjects only).
25. CHAQ or HAQ, according to the subject’s age at the time of the assessment.
6.1.2.2. Withdrawal Period 
Subjects who are eligible and consent to participate in the withdrawal period will have the 
following visits conducted:

Subjects who enter directly into the withdrawal period will have the first post baseline 
visit conducted at the study site 1 month (7 days) after the baseline visit. 

Subjects who participated in the active treatment period of study B1801023 will have 
the first withdrawal visit conducted at the study site 1 month (7 days) after the active 
treatment early withdrawal visit. 

Subsequent visits will occur at the study site every 3 months after the baseline or 
active treatment early withdrawal visit for up to a year and then every 6 months 
thereafter.  Subsequent visits must be scheduled within 14 days of the projected visit 
date based on the actual date of the baseline or active treatment period early 


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withdrawal visit.  Subjects who do not experience disease relapse will continue in the 
withdrawal period for a total of 96 months from the time of the baseline visit in study 
B1801023.
The following assessments will be performed at all visits during the withdrawal period unless
otherwise indicated:
1. Ensure that the subject meets inclusion/exclusion criteria that apply to the withdrawal 
period.
2. Those subjects who do not meet entry criteria for the withdrawal period will be asked 
to participate in the observational period.
3. Ensure the most recent version(s) of the informed consent/assent for 
withdrawal/re-treatment period has been signed and dated.
4. Collect/update contact information, including primary care physician or other treating 
physician.
5. Concomitant medications (DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents) and non-drug treatments received due to an adverse event.
6. Physical examination (performed by a physician and conducted at months 12, 24, 36, 
48, 60, 72, 84, and 96 only).

The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).
7. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
8. Height (cm, at months 12, 24, 36, 48, 60, 72, 84, and 96 only).
9. Weight (kg):

For subjects who are <18 years of age and who weigh 62 kg (at all visits). 

For subjects who are 18 years of age or weigh >62 kg (at months 12, 24, 36, 48, 
60, 72, 84, and 96 only).
10. Laboratory evaluations (ie, hematology, blood chemistry, and CRP).
11. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents.
12. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test; this includes subjects who are menstruating at the 
time of the visit.  Pregnancy tests will also be done whenever one menstrual cycle is 


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missed during the withdrawal period or when potential pregnancy is otherwise 
suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
13. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss highly effective methods 
of contraception (refer to Section 4.3.2 for female subjects and Section 4.3.3 for male 
subjects).  The discussion must be documented in the subject’s source documents.
14. PGA of Disease Activity.
15. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment.
16. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment.
17. Duration of Morning Stiffness.
18. Joint Assessment.
19. Overall Back Pain and Nocturnal Back Pain (ERA subjects only).
20. BASMI Assessments (ERA subjects only).
21. BSA (PsA subjects only).
22. PGA of Psoriasis (PsA subjects only).
23. CHAQ or HAQ, according to the subject’s age at the time of the assessment.
24. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.
25. Dispense reminder card for next scheduled visit (except at month 96).
26. Complete the End of Phase Subject Summary CRF for the withdrawal period (at the 
month 96 visit only).
27. Complete the End of Study Summary CRF (at the month 96 visit only). 
6.1.2.3. Re-Treatment Period
Subjects who are eligible for re-treatment with investigational product will have study visits 
conducted at the study site every 3 months after the re-treatment assessment visit.  Visits 
must be scheduled within 14 days of the projected visit date based on the actual date of the 
re-treatment assessment visit.  Subjects who remain eligible for re-treatment will continue in 


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the re-treatment period for a total of 96 months (14 days) from the time of the baseline visit 
in study B1801023. 
The following assessments will be performed at all visits during the re-treatment period:
1. Ensure that the subject meets the inclusion/exclusion criteria that apply to the 
re-treatment period.
2. Those subjects who do not meet entry criteria for the re-treatment period will be 
asked to participate in the observational period.
3. Ensure the most recent version(s) of the informed consent/assent for 
withdrawal/re-treatment period has been signed and dated.
4. Collect/update contact information, including primary care physician or other treating 
physician.
5. Concomitant medications (DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents) and non-drug treatments received due to an adverse event.
6. Physical examination (performed by a physician and conducted at months 12, 24, 36, 
48, 60, 72, 84, and 96 months only).

The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).
7. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
8. Height (cm, at months 12, 24, 36, 48, 60, 72, 84, and 96 only).
9. Weight (kg):

For subjects who are <18 years of age and who weigh 62 kg (at all visits). 

For subjects who are 18 years of age or weigh >62 kg (at months 12, 24, 36, 48, 
60, 72, 84, and 96 only).
10. Laboratory evaluations (ie, hematology, blood chemistry, and CRP) at months 3, 6, 9, 
12, and every 6 months thereafter. 
11. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents.
12. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test; this includes subjects who are menstruating at the 
time of the visit.  Pregnancy tests will also be done whenever one menstrual cycle is 


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missed during the active treatment period or when potential pregnancy is otherwise 
suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
13. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss highly effective methods 
of contraception (refer to Section 4.3.2 for female subjects and Section 4.3.3 for male 
subjects).  The discussion must be documented in the subject’s source documents.
14. PGA of Disease Activity at months 3, 6, 9, 12, and every 6 months thereafter.
15. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment at months 3, 6, 9, 12, and every 6 months thereafter.
16. Joint Assessment at months 3, 6, 9, 12, and every 6 months thereafter.
17. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment at months 3, 6, 9, 12, and every 6 months thereafter. 
18. Duration of Morning Stiffness at months 3, 6, 9, 12, and every 6 months thereafter. 
19. Overall Back Pain and Nocturnal Back Pain (ERA subjects only) at months 3, 6, 9, 
12, and every 6 months thereafter. 
20. BASMI Assessments (ERA subjects only) at months 3, 6, 9, 12, and every 6 months 
thereafter. 
21. BSA (PsA subjects only) at months 3, 6, 9, 12, and every 6 months thereafter. 
22. PGA of Psoriasis (PsA subjects only) at months 3, 6, 9, 12, and every 6 months 
thereafter. 
23. CHAQ or HAQ, according to the subject’s age at the time of the assessment at 
months 3, 6, 9, 12, and every 6 months thereafter.
24. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions. 
25. Perform drug accountability.
26. Collect and review diary card dispensed at the previous visit. 

For each dose, the site personnel will calculate the total volume (mL) delivered 
from the syringe(s) and the total dose (mg). 
27. Use the IWR/IVR to allocate investigational product packages (except at month 96).


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28. Dispense investigational product, investigational product instructions, and the subject 
diary (except at month 96).
29. Dispense the reminder card for next scheduled visit. 
30. End of treatment subject summary (month 96 only). 
6.1.3. Active Treatment Period Follow-up Visit 
The follow-up visit will only be completed for subjects who are receiving investigational 
product in either the active treatment period or the re-treatment period approximately 
96 months after the baseline visit in study B1801023.  The follow-up visit will occur at the 
study site 30 days (7 days) after the month 96 visit. 
The following information will be collected at the follow-up visit:
1. Concomitant medications (DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents) and non-drug treatments received due to an adverse event.
2. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.
3. Complete the End of Study Subject Summary CRF.
6.1.4. Active Treatment Period and Re-Treatment Period Early Withdrawal Visits
Active Treatment Period Early Withdrawal Visit: 

Subjects in the active treatment period who receive at least 1 dose of investigational 
product in the active treatment period of study B1801023 and withdraw before 
completion of the month 96 visit are required to complete the active treatment early 
withdrawal visit at the study site.  The active treatment early withdrawal visit should 
occur as soon as possible after the decision has been made to withdraw the subject
from investigational product.  At the active treatment early withdrawal visit, the 
subject will be asked to participate in either the withdrawal/re-treatment period or the 
observational period as appropriate
Re-Treatment Period Early Withdrawal Visit:

Subjects in the re-treatment period who withdraw from investigational product before 
completion of the month 96 visit are required to complete the re-treatment early 
withdrawal visit at the study site.  At the early withdrawal visit, the subject will be 
asked to participate in the observational period. Subjects may not enter the 
withdrawal/re-treatment period more than once during the study.  Once the subject is 
in the observational period, he or she cannot resume investigational product for the 
remaining time in the study.


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The following safety and efficacy evaluations will be performed at the early withdrawal visit: 
1. Collect/update contact information, including primary care physician or other treating 
physician.
2. Concomitant medications (DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents) and non-drug treatments received due to an adverse event.
3. Physical examination (performed by a physician).

The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).  
The Tanner Assessment does not need to be repeated if it was performed within 
2 months before the early withdrawal visit.
4. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
5. Height (cm).
6. Weight (kg).
7. Laboratory evaluations (ie, hematology, blood chemistry, and CRP).
8. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents.
9. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test; this includes subjects who are menstruating at the 
time of the visit.  Pregnancy tests will also be done whenever one menstrual cycle is 
missed during the active treatment period or when potential pregnancy is otherwise 
suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
10. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss highly effective methods 
of contraception (refer to Section 4.3.2 for female subjects and Section 4.3.3 for male 
subjects). The discussion must be documented in the subject’s source documents.
11. PGA of Disease Activity.
12. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment.
13. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment. 
14. Duration of Morning Stiffness.


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15. Joint Assessment.
16. Overall Back Pain and Nocturnal Back Pain (ERA subjects only).
17. BASMI Assessments (ERA subjects only).
18. BSA (PsA subjects only).
19. PGA of Psoriasis (PsA subjects only).
20. CHAQ or HAQ, according to the subject’s age at the time of the assessment.
21. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.
22. Perform drug accountability.
23. Collect and review diary card dispensed at the previous visit.

For each dose, the site personnel will calculate the total volume (mL) delivered 
from the syringe(s) and the total dose (mg). 
24. Dispense reminder card for next scheduled visit. 
25. Review inclusion/exclusion and discuss the option of entering into the observational 
period or the withdrawal/re-treatment period as appropriate.

For subjects being withdrawn from the active treatment period who are being 
considered for participation in the withdrawal/re-treatment period, review 
inclusion/exclusion criteria that apply to the withdrawal/re-treatment period.

Those subjects who do not meet entry criteria for the withdrawal/re-treatment 
period will be asked to participate in the observational period.  This includes 
subjects who have previously or are currently participating in the 
withdrawal/re-treatment period.

Sign and date informed consent/assent for the observational period or the 
withdrawal/re-treatment period, as appropriate.  There will be separate informed 
consents for participation in the observational and withdrawal/re-treatment 
periods. 
26. Complete the appropriate End of Phase Subject Summary CRF.  Separate subject 
summaries will be completed at the time of withdrawal from each of the active 
treatment period, and/or re-treatment period.


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6.1.5. Re-Treatment Assessment Visit for Subjects in the Withdrawal Period 
Subjects in the withdrawal period who experience disease relapse will be seen for a 
re-treatment assessment visit at the study site, which should occur as soon as possible after 
disease relapse.  Subjects requiring re-treatment per the investigator’s clinical judgment and 
who are otherwise eligible will be offered the option to re-start treatment with investigational 
product.
Subjects who are in the withdrawal period and discontinue (eg, for adverse events) or are 
ineligible for re-treatment with investigational product for any reason will be seen for a 
re-treatment assessment visit at the study site and asked to participate in the observational 
period.   Once the subject is in the observational period, he or she can not resume 
investigational product for the remaining time in the study.
The following safety and efficacy evaluations will be performed at the re-treatment 
assessment visit: 
1. Collect/update contact information, including primary care physician or other treating 
physician.
2. Concomitant medications (DMARDs, corticosteroids, NSAIDs, and anti-infective 
agents) and non-drug treatments received due to an adverse event.
3. Physical examination (performed by a physician).

The physical examination will include completion of the Tanner Assessment for 
subjects <18 years or who have a score of <5 on 1 or more applicable domain(s).  
The Tanner Assessment does not need to be repeated if it was performed within 
2 months before the re-treatment assessment visit.
4. Vital signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after 
sitting for at least 5 minutes).
5. Height (cm).
6. Weight (kg):
7. Laboratory evaluations (ie, hematology, blood chemistry, and CRP).

For subjects entering the re-treatment period, all laboratory evaluations must be 
completed before administration of the first dose of the investigational product.  
Results of the re-treatment assessment visit laboratory tests are not required for 
investigational product administration, but must be reviewed as soon as possible 
after the re-treatment assessment visit and before the first visit in the re-treatment 
period.  If the re-treatment assessment visit laboratory results are consistent with 
the laboratory abnormalities described in the exclusion criteria in Section 4.2.3.1
or the results are determined to be clinically significant by the investigator, the 


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tests should be repeated and decisions regarding continuation of investigational 
product must be discussed with the sponsor’s Clinical team. 
8. For female subjects, evaluate childbearing potential.  The evaluation must be 
documented in the subject’s source documents.
9. Female subjects who, in the opinion of the investigator, are of childbearing potential 
will have a urine pregnancy test; this includes subjects who are menstruating at the 
time of the visit.  Pregnancy tests will also be done whenever one menstrual cycle is 
missed during the active treatment period or when potential pregnancy is otherwise 
suspected.  Pregnancy tests may also be repeated as per request of IRB/IECs or if 
required by local regulations.
10. As appropriate, discuss sexual activity.  For those subjects who either plan on 
becoming sexually active or who are sexually active, discuss highly effective methods 
of contraception (refer to Section 4.3.2 for female subjects and Section 4.3.3 for male 
subjects).  The discussion must be documented in the subject’s source documents. 
11. PGA of Disease Activity.
12. Patient/Parent Global Assessment, according to the subject’s age at the time of the 
assessment.
13. Pain Assessment.  The Pain Assessment should be completed before the Joint 
Assessment. 
14. Duration of Morning Stiffness.
15. Joint Assessment.
16. Overall Back Pain and Nocturnal Back Pain (ERA subjects only).
17. BASMI Assessments (ERA subjects only).
18. BSA (PsA subjects only).
19. PGA of Psoriasis (PsA subjects only).
20. CHAQ or HAQ, according to the subject’s age at the time of the assessment.
21. Adverse events, including malignancies, serious adverse events, infections, medically 
important infections, and injection site reactions.
22. Review inclusion/exclusion criteria and discuss the option of entering into the 
observational period or the re-treatment period as appropriate. 


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
For subjects experiencing disease relapse who are being considered for 
participation in the re-treatment period, review inclusion/exclusion criteria that 
apply to the re-treatment period.

Those subjects who do not meet entry criteria for the re-treatment period will be 
asked to participate in the observational period.

For subjects entering into the observational period, sign and date informed 
consent/assent for the observational period.

For subjects entering the re-treatment period, assure that the most recent version 
of the withdrawal/re-treatment period informed consent/assent has been signed. 
23. Dispense reminder card for next scheduled visit. 
24. Complete the End of Phase Subject Summary CRF for the withdrawal period. 
For subjects who will be participating in the re-treatment period: Once all of the re-treatment 
assessment visit procedures have been completed and it has been confirmed that the subject 
is eligible to enter the re-treatment period, the study staff will use the IWR/IVR to allocate 
investigational product packages.  Investigational product, investigational product 
instructions, and subject diary will then be dispensed to the subject.  The first dose of 
investigational product in the re-treatment period may be administered at the study site.
6.1.6. Observational Period Follow-up Visits for Subjects Who Participated in the 
Active Treatment Period and/or Withdrawal/Re-treatment Period
Subjects who participate in the active treatment period and/or withdrawal/re-treatment period 
and are no longer eligible to participate in one of these periods will be asked to continue to be 
followed in the observational period for a total of 96 months from the time of the baseline 
visit in study B1801023: 

The first observational period follow-up visit will occur at the study site and will be 
scheduled 30 days (7 days) after the active treatment early withdrawal visit or the 
re-treatment assessment visit or re-treatment early withdrawal visit. For subjects who 
enter the observational period after discontinuing from the withdrawal period, this 
visit may be waived as long as the subject had already been seen at the study site 
30 days after the most recent dose of investigational product in either study 
0881A1-3338 or study B1801023.

The subsequent follow-up visits will occur by telephone every 6 months (4 weeks) 
after the first follow-up visit.  For subjects who enter the observational period after 
discontinuing from the withdrawal period and are eligible to waive the first 
observational period follow-up visit, the subsequent observational period follow-up 
visits will occur by telephone every 6 months (4 weeks) after the re-treatment 
assessment visit.


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
For subjects <18 years of age, telephone contacts will be conducted with the 
subject’s parent or legal representative/guardian. 

For subjects aged 18 years, telephone contacts may be conducted with the 
subjects or the subject’s parent or legal representative/guardian. 

The number of telephone contacts will be adjusted based on when the subject 
enters the observational period.

The final observational period follow-up visit will occur by telephone 96 months 
(4 weeks) after the baseline visit of study B1801023.
The following safety evaluations will be performed at the follow-up visits:
1. Ensure the informed consent/assent for observational period is signed and dated. 
2. Collect/update contact information, including primary care physician or other treating 
physician (except at the final month 96 follow-up visit).
3. Concomitant medications (DMARDs, including any immunosuppressives or 
anti-TNFs and/or other immunosuppressive biologic agents; corticosteroids; and 
anti-infective agents taken for medically important infections) and non-drug 
treatments received due to an adverse event.
4. Serious adverse events, malignancies, and medically important infections.
5. Complete the End of Study Subject Summary CRF (at the final follow-up visit or 
upon early withdrawal from the study).
6.2. Study Procedures for Subjects Entering Directly into the Observational Period
Subjects who discontinue investigational product prior to completing 96 weeks of active 
treatment in study 0881A1-3338 or do not meet eligibility criteria for continuing 
investigational product in study B1801023 will be asked to participate in the observational 
period of study B1801023.  The initial baseline visit will be conducted at the study site, and 
subsequent study visits will be conducted via telephone at Months 6, 12, 18, 24, 30, 36, 42, 
48, 54, 60, 66, 72, 78, 84, 90, and 96.  The month 6 to month 96 visits must occur within a 
window of 4 weeks of the projected visit date based on the actual baseline visit date.
6.2.1. Baseline Procedures for Subjects Entering Directly into the Observational Period
Baseline procedures may not commence until after the informed consent and assent (as 
applicable) have been signed.  The study investigator or a sub-investigator will discuss with 
each subject and parent(s) (as applicable according to the subject’s age and local guidelines) 
the nature of the study, its requirements, and its restrictions.
The following baseline procedures and assessments must be completed for all subjects in the 
observational period:


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1. Sign and date informed consent/assent.
2. Review inclusion/exclusion criteria that apply to all subjects.
3. Collect/update contact information, including primary care physician or other treating 
physician.
4. Prior and concomitant medications (DMARDs, including any immunosuppressives or 
anti-TNFs and other immunosuppressive biologic agents; corticosteroids; and 
anti-infective agents taken for medically important infections) and non-drug 
treatments received due to an adverse event.
5. Serious adverse events, malignancies, and medically important infections (ie, an 
infection requiring parenteral [IV, IM] anti-infective agent(s) and/or hospitalization). 
Events reported as ongoing at the final study 0881A1-3338 visit as well as events 
starting between the final study 0881A1-3338 visit and baseline visit of study 
B1801023 must be recorded on the appropriate CRF. 
6.2.2. Observational Period – Month 6 to Month 96
For subjects in the observational period, study visits will be conducted via telephone at 
Months 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, 84, 90, and 96 (within ±4 weeks of 
the projected visit date based on the actual baseline visit date).  Subjects should receive 
reminder cards for their next scheduled telephone visit. 

For subjects <18 years of age, telephone contact will be conducted with the subject's 
parent or legal authorized representative/guardian. 

For subjects aged 18 years, telephone contact may be conducted with the subject or 
the subject's parent or legal representative/guardian. 
The following safety evaluations will be performed at all visits unless otherwise indicated:
1. Collect/update contact information, including primary care physician or other treating 
physician (except at month 96).
2. Concomitant medications (DMARDs, including any anti-TNFs and/or other 
immunosuppressive biologic agents; corticosteroids; and anti-infective agents taken 
for medically important infections) and non-drug treatments received due to an 
adverse event.
3. Serious adverse events, malignancies, and medically important infections.
4. Complete the End of Study Subject Summary CRF (at month 96 or upon early 
withdrawal from the study).


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6.3. Subject Withdrawal 
The Pfizer Clinical team must be consulted as soon as possible if any of the following occur 
during the active treatment period, or the withdrawal/re-treatment period in order to 
determine whether the subject should continue receiving investigational product or for 
consideration of whether re-treatment with investigational product should be allowed: 

Any medically important infection (ie, an infection requiring parenteral [IV, IM] 
anti-infective agent(s), and/or hospitalization).

Subjects with clinical signs and symptoms suggestive of active tuberculosis should 
have investigational product withheld until a diagnosis can be confirmed.  If 
diagnosis of tuberculosis is confirmed, investigational product must be discontinued.

The 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 other than surgical joint interventions (open or 
arthroscopic), investigational product should be withheld for a period of time 
prior to the procedure; the specific duration should be determined according to the 
investigator’s clinical judgment.

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 more than 4 consecutive doses of investigational product are missed due to AEs, 
infections, or surgery or if more than 2 consecutive doses are missed due reasons
other than AEs, infections, or surgery (eg, subject forgot to take investigational 
product or away from home without enough investigational product).  Note: Tapering 
of the investigational product (ie, prescription or receipt of a dose lower than that 
described in Section 5 or less than once-weekly on an average basis) is not allowed. 

Lack of compliance with the protocol, including protocol required schedule of study 
visits and/or procedures.
Subjects MUST be withdrawn from investigational product if any of the following occurs 
during the active treatment period or withdrawal/re-treatment period:

Pregnancy;

Suspected Sepsis;

Any infection meeting seriousness criteria other than hospitalization (refer to serious 
adverse event Section 8.5);


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
Confirmed blood dyscrasia, demyelinating disorders (such as multiple sclerosis or 
optic neuritis), lupus-like syndrome or development of hypersensitivity to etanercept;

Confirmed malignancy other than squamous cell, basal cell carcinoma or cervical 
carcinoma in situ;

Receipt of any live (attenuated) vaccines:

At any time while receiving investigational product in the active treatment period 
or the re-treatment period;

Within 4 weeks after the last dose of investigational product in the active 
treatment period and within 8 weeks after the last dose of investigational product 
in the re-treatment period;

Surgical joint intervention (open or arthroscopic);

Tapering of the investigational product (ie, prescription or receipt of a dose lower 
than that described in Section 5 or less than once-weekly on an average basis);

Withdrawal of consent;

Principal investigator’s decision;

Sponsor decision.
Subjects may withdraw from the study at any time (active, withdrawal/re-treatment or 
observational period) 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 site. 
If a subject does not return for a scheduled visit in the active treatment period, or the 
withdrawal/re-treatment period, or cannot be reached for a scheduled observational period 
phone call every effort should be made to contact the subject.  The number and type 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 the subject to return all 
unused investigational product(s), request the subject to return for a final visit, if applicable, 
and follow-up with the subject regarding any unresolved adverse events.
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.


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Refer to Section 6.1.4 for procedures to be performed for subjects in the active treatment 
period or re-treatment period and withdraw from investigational product before completion 
of the Month 96 visit.
Refer to Section 6.1.5 for procedures to be performed for subjects in the withdrawal period 
who experience disease relapse before completion of the Month 96 visit and are being 
considered for participation in the re-treatment period.
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 
which he/she has taken to ensure that normal processes are adhered to as soon as possible.  
The study team must be informed of these incidents in a timely fashion.
7.1. Safety Assessments
For subjects in the active treatment period, and the withdrawal/re-treatment period, safety 
will be assessed using the following measures:
1. Physical examinations will be performed by a physician.  Any clinically significant 
abnormalities or worsening of medical history conditions should be recorded on the 
source documents and the appropriate adverse event CRF. 

The physical examination will include the Tanner Stage Assessment for subjects 
<18 years of age or who have a score of <5 on 1 or more applicable domain(s).  
The sexual maturity rating of each subject will be determined according to the 
criteria adapted from Tanner.  Female subjects will be classified on a scale of 1 to 
5 across the following 2 maturity domains: breast and pubic hair characteristics.  
Male subjects will be classified on a scale of 1 to 5 across the following 
3 maturity domains: pubic hair, penis and testes characteristics.
2. Vital sign measurements will include temperature, blood pressure and pulse rate (after 
sitting for at least 5 minutes).

A sitting blood pressure will be obtained by qualified site personnel and should be 
taken using the same arm throughout the study.  If possible, a different arm should 
be used for the collection of blood samples. 
3. Height and Weight. 
4. Subjects will be evaluated for adverse events (infectious and noninfectious), serious 
adverse events, malignancy, and medically important infections. 


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
Infectious and noninfectious adverse events will be recorded on separate CRFs.

Medically important infections are defined as infections that require parenteral 
anti-infective agents (IV, IM) and/or hospitalization.

Infections considered preventable by vaccination will be reported on the 
infectious adverse event CRF.
5. Injection site reactions (symptoms, action taken, number, and frequency) will be 
monitored throughout the study and will be graded for intensity according to the 
Symptom Occurrence Scale (Itching, Redness, Swelling, Pain, Ulceration).  Injection 
site reactions need to be clearly differentiated from symptoms associated with the 
technique of administering subcutaneous injections (eg, physical injury to blood 
vessels). 
6. Clinical laboratory evaluations including blood chemistry, hematology, and 
urinalysis.
For subjects in the observational period, safety will be assessed through collection of the 
following information via telephone contact:
1. Subjects will be evaluated for serious adverse events, malignancy, and medically 
important infections. 

Infectious and noninfectious serious adverse events will be recorded on separate 
CRFs.

Medically important infections are defined as infections that require parenteral 
anti-infective agents (IV, IM) and/or hospitalization. 
7.2. Laboratory Evaluations
As much as possible, only one 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 laboratory ranges and certifications for the 
sponsor designated central laboratory.
All laboratory tests with values 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 recorded on the 
appropriate adverse event CRF.  In addition, additional laboratory testing may be performed 
according to local guidelines or standard of care and for follow-up of abnormal laboratory 
test results.


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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:
1. Pregnancy test (performed locally with material provided by the central laboratory): 
For female subjects, who in the opinion of the investigator are biologically capable of 
having children, a urine pregnancy test must be performed within 7 days prior to the 
baseline (day 1) visit and at each of the visits in the active treatment period during the
withdrawal/re-treatment period, including the early withdrawal visit(s) and the 
re-treatment assessment visit; this includes subjects who are menstruating at the time 
of the visit.  A negative urine pregnancy test must be obtained prior to administration 
and dispensing of investigational product at each of the visits in the active treatment 
period and the re-treatment period.  Pregnancy tests will also be done whenever one 
menstrual cycle is missed during the active treatment period and 
withdrawal/re-treatment period or when potential pregnancy is otherwise suspected.  
Pregnancy tests may also be repeated as per request of IRB/IECs or if required by 
local regulations.
2. Serum chemistry: alkaline phosphatase, alanine aminotransferase (ALT)/serum 
glutamic pyruvic transaminase (SGPT), aspartate aminotransferase (AST)/serum 
glutamic oxaloacetic transaminase (SGOT), and total bilirubin.
3. Hematology: white blood cell (WBC) count including differential, red blood cell 
(RBC) count, hemoglobin, and platelet count.
4. CRP evaluation.
5. Evaluation of potential Hy’s Law cases: Repeat testing will include AST, ALT, 
albumin, creatine kinase, total bilirubin, direct and indirect bilirubin, 
gamma-glutamyl transferase (GGT), prothrombin time (PT)/international normalized 
ratio (INR), and alkaline phosphatase.  At the discretion of the investigator, additional 
testing for acute hepatitis A, hepatitis B, or hepatitis C may also be performed at the 
site’s local laboratory.
7.3. Efficacy Assessments
For subjects in the active treatment period, and in the withdrawal/re-treatment period, 
efficacy will be assessed. 
1. The following assessments will be completed by the subject’s parent or legal 
representative/guardian for subjects aged <18 years; these will be completed directly 
by subjects aged 18 years at the time of the assessment. 

Patient/Parent Global Assessment: The subject or parent will assess all the ways 
that arthritis affects the subject using a scale between 0 and 10 on a 21-circle VAS 
with 0 = Very Well and 10 = Very Poor.  This is to be completed in a manner that 
does not bias the investigator’s assessment of the subject. 


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
Pain Assessment: The subject or parent will assess how much pain the subject has 
had because of his/her illness in the past week (0-10 on a 21-circle VAS with 
0= no pain and 10=very severe pain).  The Pain Assessment should be completed 
before the joint assessment. 

Duration of morning stiffness: Based on the investigator questioning the subject 
or parent, the time elapsed when the subject awoke in the morning and was able to 
resume normal activities without stiffness will be provided in minutes and cannot 
exceed 1440 minutes within 24 hours; If morning stiffness was continuing at the 
time of assessment or was unusual compared to the recent past, the average 
duration of stiffness over the past 3 days should be reported. 

Overall Back Pain and Nocturnal Back Pain ([0-100 mm VAS with 0= no pain 
and 100= most severe pain], ERA subjects only).
2. PGA of Disease Activity: The investigator will estimate the subject’s overall disease 
activity for the current day by using a scale between 0 and 10 on a 21-circle VAS 
with 0 = No Activity and 10 = Maximum Activity.  This is to be completed in a 
manner that does not bias the Patient/Parent Global Assessment
3. Number of active joints, defined as joints with swelling or, in the absence of swelling, 
joints with limitation of motion with pain and /or tenderness.  Joint assessors will 
assess 68 joints for swelling, 69 joints for limitation of motion, and 75 joints for pain 
and/or tenderness on motions as follows: 0=no swelling, limitation of motion, or pain 
and/or tenderness on motion; 1=any swelling, limitation of motion, or pain and/or 
tenderness on motion; JR = joint replacement; NE=not evaluable 
4. Number of joints with limited range of motion.  Joint assessors will assess 69 joints 
for limited range of motion as follows: 0=no limited range of motion; 1=any limited 
range of motion; JR = joint replacement; NE=not evaluable 
5. Laboratory measure of inflammation (CRP)
6. BASMI consists of 5 clinical measurements to reflect axial status (ERA subjects 
only):

Intermalleolar Distance: The subject should lie supine with the knees straight and 
feet pointing straight up.  The subject is asked to separate the legs as far as 
possible and the distance between the medial malleoli is measured (in cm to the 
nearest tenth of a cm).  Measure two tries.

Cervical Rotation: The subject should be in the neutral position.  The subject is
then asked to turn the head as far as possible to the right and then to the left.  Use
a inclinometer to measure two tries on the right side and two tries on the left side
in degrees (to the nearest degree).

Modified Schober's Test: With the subject standing erect, place a mark in the 
midpoint of a line that joins the posterior superior iliac spines (baseline mark).  


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Place another mark 10 cm above the first (baseline mark).  Then, have the subject
maximally bend forward, keeping the knees fully extended.  With the subject’s
spine in full flexion, re-measure the distance between the two marks.  The full 
measurement between the two lines should be recorded to the nearest tenth of a 
centimeter.

Lateral Flexion: The subject should stand as close to the wall as possible with 
shoulders level and outer edges of feet 30 cm apart and feet parallel (neutral 
position). The distance between the subject’s middle fingertip and the floor is 
measured in cm (to the nearest tenth of a cm). The patient is asked to bend 
sideways without bending the knees or lifting the heels while attempting to keep 
the shoulders in the same place (flexion position). The distance between the 
subject’s middle fingertip and the floor is re-measured.  Measure two tries on the 
right side and two tries on the left side.

Tragus to Wall Distance: Place the subject standing with his/her back against the 
wall; knees straight; scapulae, buttocks, and heels against wall; and head in as 
neutral position as possible.  Measure the distance between the tragus and wall in 
cm (to the nearest tenth of a cm) from both the right side and left side.  Measure 
two tries on the right side and two tries on the left side.
7. BSA will be measured as the percentage of BSA affected by psoriasis using the palm 
method; the subject’s palm will be used for the calculation, with 1 of the subject’s 
palms to PIP and thumb equal to 1% of BSA (PsA subjects only). 
8. PGA of Psoriasis will assess the amount of induration, erythema, and scaling 
averaged over all psoriatic lesions on a scale of 0-5 (PsA subjects only).
7.4. Health Outcome Assessments
Health outcomes will be assessed using the CHAQ and HAQ. 
The CHAQ will be completed by the subject’s parent or legal representative/guardian for 
subjects aged <18 years at the time of the assessment; HAQ will be completed directly by 
subjects aged 18 years at the time of the assessment.
The health outcomes assessments (ie, CHAQ/HAQ) are for the purpose of exploring the 
subject’s own perceptions about his/her quality of life.  The investigator must not influence 
the subject’s assessment.  Every effort should be made by site personnel to maintain an 
unbiased assessment.
7.4.1. Childhood Health Assessment Questionnaire (CHAQ)
The CHAQ, derived from the adult HAQ, is a parent-administered, reliable and valid 
assessment of functional disability and discomfort in pediatric subjects with rheumatic
diseases.  The parent of the pediatric subject is asked to report the subject’s ability to perform 
activities of daily living, over the past week, in the following eight domains: dressing, 
arising, eating, walking, hygiene, reach, grip, and common activities distributed among a 


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total of 30 items.  Each item within a domain is scored on a 4-point Likert scale from 0 to 3: 
0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do.  Not Applicable is 
also included as an option.  The highest score reported for a domain determines the score for 
that domain.  If aids or devices are used, or assistance is required, the minimum score for that 
functional area is 2.  The Disability Index is calculated as the mean of the eight functional 
areas.19 The English version of the CHAQ is included in Appendix 2. The appropriate 
language form will be used for each participating country.
7.4.2. Health Assessment Questionnaire (HAQ)
The HAQ assesses the degree of difficulty a subject has experienced during the past week in 
8 domains of daily living activities: dressing and grooming, arising, eating, walking, hygiene, 
reach, grip, and other activities.  Each activity category consists of 2-3 items.  For each 
question in the questionnaire, the level of difficulty is scored from 0-3 with 0 representing 
“no difficulty,” 1 as “some difficulty,” 2 as “much difficulty,” and 3 as “unable to do.”  Any 
activity that required assistance from another individual or requires the use of an assistive 
device adjusts to a minimum score of 2 to represent a more limited functional status.  The 
English version of the HAQ is included in Appendix 3. The appropriate language form will 
be used for each participating country.
8. ADVERSE EVENT REPORTING
8.1. Adverse Events
All observed or volunteered adverse events regardless of treatment group or suspected causal 
relationship to the investigational product(s) will be reported as described in the following 
sections. 
For all adverse events, the investigator must pursue and obtain information adequate both to 
determine the outcome of the adverse event and to assess whether it meets the criteria for 
classification as a serious adverse event requiring immediate notification to Pfizer or its 
designated representative.  For all adverse events, sufficient information should be obtained 
by the investigator to determine the causality of the adverse event.  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 adverse event 
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 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 


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receiving investigational product, through at least 96 months after the baseline visit in study 
B1801023.  In addition, for subjects who are either in the active treatment period or the 
re-treatment period at Month 96, serious adverse events will be collected until 30 days after 
the last dose of 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.
AEs (serious and nonserious) should be recorded on the CRF from the time the subject enters 
either the active treatment period or withdrawal/re-treatment period at the baseline visit of 
study B1801023 through the subject’s last visit in the active treatment period and/or the 
withdrawal/re-treatment period of the study and for 30 days after the last dose of 
investigational product for those subjects who are in either the active treatment period or the 
re-treatment period at Month 96.
For subjects in the active treatment period: 
All adverse events (serious and non-serious), including infections, medically important 
infections, injection site reactions, and malignancy must be recorded on the CRF from the 
time the informed consent is signed through the Month 96 visit or upon early withdrawal 
from the study.  All adverse events will be collected for the duration of the active treatment 
period and for 30 days after the last dose of investigational product for those subjects who are 
either in the active treatment period or the re-treatment period at Month 96.
Events reported as ongoing at the final study 0881A1-3338 visit as well as events starting 
between the final study 0881A1-3338 visit and baseline visit of study B1801023 must also be 
recorded on the appropriate CRF.
For subjects in the withdrawal/re-treatment period:  
All adverse events (serious and non-serious), including infections, medically important 
infections, injection site reactions, and malignancy must be recorded on the CRF from the 
time the informed consent is signed through the duration of the withdrawal/re-treatment 
period.  All adverse events will be collected for the duration of the withdrawal/re-treatment 
period and for 30 days after the last dose of investigational product for those subjects who are 
in either the active treatment period or the re-treatment period at Month 96. 
For subjects entering directly into the withdrawal/re-treatment period at the baseline visit of 
study B1801023, events reported as ongoing at the final study 0881A1-3338 visit as well as 
events starting between the final study 0881A1-3338 visit and baseline visit of study 
B1801023 must also be recorded on the appropriate CRF. 
For subjects in the observational period:
All serious adverse events (including serious infections), malignancy and medically 
important infections must be recorded on the CRF from the time the informed consent is 
signed or when the subject enters the observational period through the Month 96 visit. 


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For subjects entering into the observational period at the baseline visit of study 
B1801023, events reported as ongoing at the final study 0881A1-3338 visit as well as events 
starting between the final study 0881A1-3338 visit and baseline visit of study 
B1801023 must also be recorded on the appropriate CRF.
8.3. Definition of an Adverse Event
An adverse event 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 adverse events 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. Abnormal Test Findings
The criteria for determining whether an abnormal objective test finding should be reported as 
an adverse event are as follows: 

Test result is associated with accompanying symptoms, and/or

Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or

Test result leads to a change in study dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the study, significant additional concomitant 
drug treatment, or other therapy, and/or

Test result is considered to be an adverse event by the investigator or sponsor.
Merely repeating an abnormal test, in the absence of any of the above conditions, does not 
constitute an adverse event.  Any abnormal test result that is determined to be an error does 
not require reporting as an adverse event.
8.5. 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 adverse event when it is associated with a 
serious adverse event.
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 adverse event 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.


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8.5.1. Other Reportable Information
If a subject experiences any of the following events, the event must be reported to Pfizer in 
the same manner and time frame as a serious adverse event:  

Amyotrophic lateral sclerosis;

Demyelination and multiple sclerosis;

Guillain-Barré Syndrome;

Malignancy, including lymphoma (excluding squamous cell or basal cell carcinoma 
or cervical carcinoma in situ);

Cutaneous T-cell lymphoma, including mycosis fungoides; 

Progressive Multifocal Leukoencephalopathy (PML).
8.5.2. 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).
8.5.3. Potential Cases of Drug-Induced Liver Injury 
Abnormal values in aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)
concurrent with abnormal elevations in total bilirubin 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:

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 concurrent with a total bilirubin value 2 times the upper limit of normal with 
no evidence of hemolysis and an alkaline phosphatase value 2 times the upper limit 
of normal or not available.

For subjects with preexisting ALT or AST or total bilirubin values above the upper 
limit of normal, the following threshold values should be used in the definition 
mentioned above:


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
For subjects with preexisting AST or ALT baseline values above the normal 
range, AST or ALT values 2 times the baseline values and 3 times the upper 
limit of normal, or 8 times the upper limit of normal (whichever is smaller).
Concurrent with

For subject with pre-existing values of total bilirubin above the normal range: 
Total bilirubin level increased from baseline by an amount of at least 1 time the 
upper limit of normal or if the value reaches 3 times the upper limit of normal 
(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 (GGT), 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 serious adverse events.
8.6. 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.

Hospitalization does not include the following:

Rehabilitation facilities;

Hospice facilities;

Respite care (eg, caregiver relief);

Skilled nursing facilities;


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
Nursing homes;

Same day surgeries (as outpatient/same day/ambulatory procedures).
Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical 
adverse event is not in itself a serious adverse event.  Examples include: 

Admission for treatment of a preexisting condition not associated with the 
development of a new adverse event or with a worsening of the preexisting condition 
(eg, for work-up of persistent pretreatment 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 adverse event (eg, for 
elective cosmetic surgery);

Hospitalization for observation without a medical adverse event;

Pre-planned 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 non-invasive and invasive procedures, such as surgery, should not 
be reported as adverse events.  However, the medical condition for which the procedure was 
performed should be reported if it meets the definition of an adverse event.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as 
the adverse event, and the resulting appendectomy should be recorded as treatment of the 
adverse event.
8.7. Severity Assessment
If required on the adverse event case report forms, the investigator will use the adjectives 
MILD, MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  
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 adverse event.  A severe 
event is not necessarily a serious event.  For example, a headache may be severe (interferes 


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significantly with subject's usual function) but would not be classified as serious unless it met 
one of the criteria for serious adverse events, listed above.
8.8. Causality Assessment
The investigator’s assessment of causality must be provided for all adverse events (serious 
and nonserious); the investigator must record the causal relationship in the CRF, as 
appropriate, and report such an assessment in accordance with the serious adverse 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 adverse event; 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 a serious adverse event 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 serious adverse 
event reporting requirements, if applicable.
8.9. 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).
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 EIU 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 EIU Form.  This must be done irrespective of whether an adverse event 
has occurred and within 24 hours of awareness of the exposure.  The information submitted 


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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 EIU 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 congental 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 serious adverse events.
Additional information about pregnancy outcomes that are reported as serious adverse events 
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 serious adverse events.  In addition, infant deaths after 1 month should 
be reported as serious adverse events when the investigator assesses the infant death 
as related or possibly related to exposure to the investigational product. 
Additional information regarding the exposure during pregnancy 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.
8.10. 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 nvestigative site file.


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8.11. Withdrawal Due to Adverse Events (See Also the section Subject Withdrawal)
Withdrawal due to AEs should be distinguished from withdrawal due to other causes, 
according to the definition of adverse event noted earlier, and recorded on the appropriate 
adverse event CRF page. 
When a subject withdraws because of a serious adverse event, the serious adverse event must 
be reported in accordance with the reporting requirements defined below.
8.12. Eliciting Adverse Event Information
The investigator is to report all directly observed adverse events and all adverse events 
spontaneously reported by the study subject.  In addition, each study subject will be 
questioned about adverse events.  In addition to recording observed or spontaneously 
volunteered adverse events, certain additional data will be solicited from the subjects in this 
study via questionnaires. These additional data will be collected and evaluated in a different 
manner than the observed or volunteered adverse events as detailed in the statistical analysis 
section. Given these differences, no attempt will be made to resolve any apparent 
discrepancies between or volunteered adverse events and the questionnaire data collected.  
Questionnaire data will be presented in separate tables, figures, and data listings, and will be 
reviewed in the final study report. Adverse event incidence rates will not be calculated from 
these solicited data.
8.13. Reporting Requirements
Each adverse event is to be assessed to determine if it meets the criteria for serious adverse 
events.  If a serious adverse event occurs, expedited reporting will follow local and 
international regulations, as appropriate.
8.13.1. Serious Adverse Event Reporting Requirements
If a serious adverse event occurs, Pfizer is to be notified within 24 hours of investigator 
awareness of the event.  In particular, if the serious adverse event is fatal or life-threatening, 
notification to Pfizer must be made immediately, irrespective of the extent of available 
adverse event information.  This timeframe also applies to additional new information 
(follow-up) on previously forwarded serious adverse event 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 a serious 
adverse event 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 adverse event.
For all serious adverse events, the investigator is obligated to pursue and provide information 
to Pfizer in accordance with the timeframes for reporting specified above.  In addition, an 
investigator may be requested by Pfizer to obtain specific additional follow-up information in 
an expedited fashion.  This information collected for serious adverse events is more detailed 
than that captured on the adverse event case report form.  In general, this will include a 
description of the adverse event in sufficient detail to allow for a complete medical 


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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. 
8.13.2. NonSerious Adverse Event Reporting Requirements
All adverse events will be reported on the adverse event page(s) of the CRF.  It should be 
noted that the form for collection of serious adverse event information is not the same as the 
adverse event CRF.  Where the same data are collected, the forms must be completed in a 
consistent manner.  For example, the same adverse event term should be used on both forms.  
Adverse events should be reported using concise medical terminology on the eCRFs as well 
as on the form for collection of serious adverse event information.
8.13.3. Sponsor’s Reporting Requirements to Regulatory Authorities
Adverse events 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, 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 sample size for this safety extension protocol, as agreed upon with regulatory authorities, 
is not based on efficacy considerations; rather, all eligible subjects who either complete or 
discontinue from study 0881A1-3338 will be asked to participate in study B1801023.  The 
anticipated enrollment is approximately 100 subjects. 
9.2. Efficacy Analysis
9.2.1. Analysis of Primary Endpoint 
The primary endpoint in this study are are related to safety.  Efficacy endpoints are 
secondary. 
9.2.2. Analysis of Secondary Endpoints for Subjects in the Active Treatment Period, 
and Withdrawal/Re-treatment Period
The secondary efficacy endpoints will be analyzed in the active treatment period and the 
withdrawal/re-treatment period.  For the overall population as well as each of the JIA 
subpopulations, descriptive statistics will be provided for each study endpoint at all time 
points in the study.  For categorical endpoints, the summary statistics will contain the 
frequency, percentage, and 95% confidence interval (CI) for the percentage.  For continuous 
endpoints, the summary statistics will contain the number of observations, mean, standard 


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deviation, median, minimum, maximum, and 95% CI of the mean for both raw data and the 
change from baseline.  The observed data analysis, ie, without imputation for missing data, 
will be the focus of the efficacy summaries. The baseline visit from study 0881A1-3338 will 
be used for the calculation of change from baseline results where applicable. Summaries 
with last observation carried forward (LOCF) imputation may also be provided.
 
 
 
 
 
 
 
 
 
 
9.3. Analysis of Health Outcomes Assessments for Subjects in the Active Treatment, 
and Withdrawal/Re-treatment Period
The CHAQ and HAQ will be summarized in the same way as the efficacy endpoints.  CHAQ 
and HAQ results will be summarized separately as well as for the combined CHAQ/HAQ 
results for subjects who switch to the adult version over the course of the trial.
9.4. Safety Analysis
9.4.1. Safety Analysis All Subjects
The incidence of malignancies, serious adverse events and medically important infections
will be summarized as frequency and percentage, as well as adjusted rate per 
100 subject-years of exposure to etanercept along with 95% confidence intervals.  In addition 
to showing cumulative rates over the entire study period (including both 0881A1-3338 and 
B1801023), rates will also be categorized by year for each year from 1 to 10.  Safety 
presentations will be provided for overall populations and by each JIA subpopulations; 
separate summaries for subjects in the active treatment period, withdrawal/re-treatment 
period and the observational period will also be provided.
Incidence of malignancies may be compared to external data sources to generate standardized 
incidence ratios (SIRs) to aid interpretation. Due to the small sample size and expected rarity 
of the events, this approach may be of limited value.
CCI


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9.4.2. Safety Analysis for Subjects in the Active Treatment Period, and 
Withdrawal/re-treatment Period:
The occurrence of all adverse events (infectious and noninfectious), infections considered 
preventable by vaccination, and injection site reactions as well as treatment-emergent adverse 
events, potentially clinically important laboratory measurements, and premature 
discontinuations during the study will be summarized as using frequency and percentage, as 
well as adjusted rate per 100 subject-years of exposure to etanercept. 
For laboratory data, vital sign measurements, and other continuous safety data, the number of 
observations, mean, standard deviation, median, minimum, maximum, and 95% CI of the 
mean will be summarized by visit for raw data and the change from baseline. Height, 
weight, BMI, and Tanner scores will be summarized using the number of observations, 
mean, standard deviation, median, minimum, and maximum by age group.  Height, weight
and BMI will also be compared with data from standardized growth charts.
9.5. Interim Analysis
No formal statistical interim analyses are planned.  However, a descriptive analysis will be 
performed at a minimum of every 2 years after subjects have either completed or withdrawn 
from the study at the corresponding time point based on the time of initial entry into study 
B1801023.  In addition, summaries of safety and efficacy assessments will be produced at 
intervals to satisfy regulatory obligations and the requirements of the Data Monitoring 
Committee.
9.6. Data Monitoring Committee 
This study will use an Internal Review Committee (IRC) to help assure the safety of study 
participants.  The IRC will be responsible for ongoing monitoring of the efficacy and safety 
of subjects in the study according to the Charter which describes and governs the IRC’s 
activities.  The recommendations made by the IRC to alter the conduct of the study will be 
forwarded to the appropriate Pfizer team member as identified in the IRC Charter for final 
decision.  Pfizer will forward such decisions, which may include summaries of aggregate 
analyses of safety and/or efficacy data to regulatory authorities, as appropriate.  In this 
instance, such disease-related efficacy endpoints are not reported individually as SAEs. 
10. QUALITY CONTROL AND QUALITY ASSURANCE
During study conduct, Pfizer or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Global Clinical Practices (GCPs) are being followed.  The monitors 
may review source documents to confirm that the data recorded on eCRFs is accurate.  The 
investigator and institution will allow Pfizer monitors or its agents and appropriate regulatory 
authorities direct access to source documents to perform this verification.
The study site may be subject to review by the IRB/IEC, 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.


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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.
11. DATA HANDLING AND RECORD KEEPING
11.1. Case Report Forms/Electronic Data Record
As used in this protocol, the term Case Report Form (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 is true. Any corrections to entries made in the CRFs, 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 investigator’s 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, telephone calls reports).  The records should be 
retained by the investigator according to ICH, local regulations, or as specified in the Clinical 
Study Agreement, 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 


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study records must be transferred to a designee acceptable to Pfizer, such as another 
investigator, another institution, or to 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 longer if required by applicable local regulations. 
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 (IRB)/Independent Ethics Committee (IEC)
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/IEC.  All correspondence with the 
IRB/IEC should be retained in the Investigator File.  Copies of IRB/IEC approvals should be 
forwarded to Pfizer.
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects.  In 
that event, the investigator must notify the IRB/IEC 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 Good Clinical Practice (International Conference on 
Harmonization 1996), and the Declaration of Helsinki (World Medical Association 
1996 and/or 2008 as mandated by local law). 
In addition, the study will be conducted in accordance with the protocol, the International 
Conference on Harmonisation guideline on Good Clinical Practice, 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 
on any sponsor forms, reports, publications, or in any other disclosures, except where 
required by laws. 
Subject names, address, birth date and other identifiable data will be replaced by an 
alpha-numerical code consisting of a numbering system provided by Pfizer and year of birth.  
In case of data transfer, Pfizer will maintain high standards of confidentiality and protection 
of subject personal data.


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The informed consent and assent forms must be in compliance with ICH GCP, local 
regulatory requirements, and legal requirements. 
The informed consent documents(s) used during the informed consent process must be 
reviewed by the sponsor, approved by the IRB/IEC, and available for inspection.
At the baseline visit, the following must occur according to local regulatory guidelines before 
any study specific activity is performed:

The investigator must ensure that each study subject and/or his/her legal
representative/guardian, 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 and/or the subject's legal representative/guardian. 

The investigator will retain the original of each subject's signed consent and assent 
forms.
12.4. Subject Recruitment
Only subjects who were previously enrolled in study 0881A1-3338 will be included in 
B1801023.  Therefore advertisements will not be used for this study. 
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 which 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 sufficient 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 Participating Countries
End of Trial in all participating countries is defined as Last Subject Last Visit in the study.


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14. SPONSOR DISCONTINUATION CRITERIA
Premature termination of this study may occur because of a regulatory authority decision, 
change in opinion of the IRB/IEC, drug safety problems, or at the discretion of Pfizer.  In 
addition, Pfizer retains the right to discontinue the development of Etanercept 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 
the hospital pharmacy (if applicable) within 7 days.  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 the results of studies through posting the 
results of this study 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 United States (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 pre-specified 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 


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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 has no objection to publication by Investigator of any information collected or 
generated by Investigator, whether or not the results are favorable to the Investigational 
Drug.  However, to ensure against inadvertent disclosure of Confidential Information or 
unprotected Inventions, Investigator will provide Pfizer an opportunity to review any 
proposed publication or other type of disclosure before it is submitted or otherwise disclosed.
Investigator will provide manuscripts, abstracts, or the full text of any other intended 
disclosure (poster presentation, invited speaker or guest lecturer presentation, etc.) 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, Investigator agrees to delay 
the disclosure for a period not to exceed an additional 60 days.
Investigator will, on request, remove any previously undisclosed Confidential Information 
(other than the Study results themselves) before disclosure.
If the Study is part of a multi-centre study, Investigator agrees that the first publication is to 
be a joint publication covering all centers.  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, Investigator is free to publish separately, subject to the other requirements 
of this Section.
For all publications relating to the Study, 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 Clinical Study Agreement between 
Pfizer and the institution.  In this section entitled Publications by Investigators, the defined 
terms shall have the meanings given to them in the Clinical Study Agreement.


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16. REFERENCES
1.
Saxne T, Palladino Jr. MA, Heinegard D, et al. Detection of tumor necrosis factor alpha 
but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. 
Arthritis Rheum. 1988;31:1041-1045.
2.
EMEA EPARs for authorised medicinal products for human use (Enbrel): 
http://www.emea.europa.eu/humandocs/Humans/EPAR/enbrel/enbrel.htm
3.
Ringold A, Wallace CA.  Measuring clinical response and remission in juvenile 
idiopathic arthritis.  Curr Opin Rheumatol 2007;19(5):471-6.
4.
Wallace CA, Giannini EH, Huang B, et al.  American College of Rheumatology 
provisional criteria for defining clinically inactive disease in select categories of 
juvenile idiopathic arthritis.  Arthritis Care Res (Hoboken) 2011;63(7);929-36.
5.
Remesal A, De Inocencio J, Merino R, et al. Discontinuation of etanercept after 
successful treatment in patients with juvenile idiopathic arthritis. J Rheumatol 
2010;37(9):1970-1.
6.
Wallace CA, Ruperto N, Giannini E. Preliminary criteria for clinical remission for 
select categories of juvenile idiopathic arthritis. J Rheumatol 2004;31(11): 2290–4.
7.
Prince FH, Twilt M, Simon SC, et al.  When and how to stop etanercept after successful 
treatment of patients with juvenile idiopathic arthritis. Ann Rheum Dis 
2009;68(7):1228-9.
8.
Baszis K, Garbutt J, Toib D, et al. Clinical outcomes after withdrawal of anti–tumor 
necrosis factor α therapy in patients with juvenile idiopathic arthritis: a twelve-year 
experience. Arthritis Rheum 2011;63(10):3163-8..
9.
Ravelli A, Martini A. Juvenile idiopathic arthritis. Lancet. 2007;369:767-778.
10.
Jordan A, McDonagh JE. Juvenile idiopathic arthritis: the paediatric perspective. 
Pediatr Radiol. 2006;36:734-742.
11.
Prince FH, Twilt M, ten Cate R, et al. Long-term follow-up on effectiveness and safety 
of etanercept in JIA: the Dutch national register. Ann Rheum Dis. 2009;68:635–641.
12.
Wallace CA, Giannini EH, Huang B, et al.  American College of Rheumatology 
provisional criteria for defining clinically inactive disease in select categories of 
juvenile idiopathic arthritis.  Arthritis Care Res (Hoboken) 2011;63(7);929-36
13.
Verjans GM, Brinkman BM, Van Doornik CE, Kijlstra A, Verweij CL. Polymorphism 
of tumour necrosis factor-alpha (TNF-alpha) at position -308 in relation to ankylosing 
spondylitis.  Clin Exp Immunol. 1994;97: 45-47.


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14.
Gensler LS, Ward MM, Reveille JD, Learch TJ, Weisman MH, Davis JC Jr. Clinical, 
radiographic and functional differences between juvenile-onset and adult-onset 
ankylosing spondylitis: results from the PSOAS cohort. Ann Rheum Dis. 2008;67: 233-
237.
15.
Burgos-Vargas R, Casasola J. A twelve-week, randomized, double-blind, placebo-
controlled trial to determine the efficacy and safety of infliximab in juvenile-onset 
spondyloarthropathies (JO-SPA).  Ann Rheum Dis. 2008;67(Suppl II):69
16.
Choy E. T cells in psoriatric arthritis. Curr Rheumatol Rep. 2007;9:437-441.
17.
Saurenmann RK, Rose JB, Tyrrell BM, et al.  Epidemiology of juvenile idiopathic 
arthritis in a multiethnic cohort.  Arthritis Rheum. 2007;56:1974-1984.
18.
Flato B, Lien G, Smerdel-Ramoya A, Vinje O. Juvenile psoriatic arthritis: Longterm 
outcome and differentiation from other subtypes of juvenile idiopathic arthritis. J 
Rheumatol. 2009;36:642-650
19.
Duffy CM.  Assessing outcome in juvenile idiopathic arthritis. J Can Rheum Assoc. 
2000;10(2):4-7.
20.
Development and validation of a composite disease activity score for juvenile idiopathic 
arthritis. Consolaro A, Ruperto N, Bazso A, Pistorio A, Magni-Manzoni S, Filocamo G, 
Malattia C, Viola S, Martini A, Ravelli A; Paediatric Rheumatology International Trials 
Organisation. Arthritis Rheum. 2009 May 15;61(5):658-66.


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Appendix 1. Abbreviations
Abbreviation
Term
ACR
American College of Rheumatology 
ALT
alanine aminotransferase
AS
ankylosing spondylitis
AST
aspartate aminotransferase
BASMI
Bath Ankylosing Spondylitis Metrology Index
BSA
Body Sure Area
CHAQ
Childhood Health Assessment Questionnaire
CRP
c-reactive protein
CSR
clinical study report
CTA
clinical trial application
DMARD
disease-modifying antirheumatic drug
eCRF
electronic case report form
EIU
Exposure in-utero 
EMA
European Medicines Agency
ERA
enthesitis-related arthritis
FDA
US Food and Drug Administration
FDAAA
US Food and Drug Administration Amendments Act
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HAQ
Health Assessment Questionnaire
IB
investigator’s brochure
IEC
independent ethics committee
ILAR
International League of Associations for Rheumatology
IRC
Internal Review Committee
IV
intravenous
IM
intra-muscular
IND
investigational new drug application
INR
international normalized ratio
IRB
institutional review board
IUD
intrauterine device
IWR/IVR
interactive web response/interactive voice response
JIA
juvenile idiopathic arthritis
LFT
liver function test
LOCF
last observation carried forward
LSLV
last subject last visit
NSAID
nonsteroidal anti-inflammatory drug
PCD
primary outcome completion date
Pedi
pediatric
PGA
Physician’s Global Assessment
PhRMA
Pharmaceutical Research and Manufacturers of America
PsA
psoriatic arthritis
PUVA
psoralen + ultraviolet A
QW
once weekly
RA
rheumatoid arthritis
RBC
red blood cell
RF
rheumatoid factor
SAE
serious adverse event
SC
subcutaneous
SGOT
serum glutamic pyruvic transaminase
SGPT
serum glutamic oxaloacetic transaminase
TNF
tumor necrosis factor
TNF-α
tumor necrosis factor alpha
UVA
ultraviolet A
UVB
ultraviolet B
VAS
visual analogue scale
WBC
white blood cell


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Appendix 2. Sample of Childhood Health Assessment Questionnaire


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Sample of Childhood Health Assessment Questionnaire cont.


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Appendix 3. Sample of Health Assessment Questionnaire


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Sample of Health Assessment Questionnaire cont.


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Appendix 4. Joint Assessment
Please enter one of the following four codes for each of the joints:
0 = No swelling; No pain and/or tenderness on motion; No limitation of motion
1 = Any swelling; Any pain and/or tenderness on motion; Any limitation of motion
JR = Joint replacement
NE = Not evaluable
Swell
Pain
LOM
JOINTS
Swell
Pain
LOM
Temporo-mandibular
Sterno-clavicular
Acromion-clavicular
Shoulder
Elbow
Wrist
MCP I
MCP II
MCP III
MCP IV
MCP V
PIP I
PIP II
PIP III
PIP IV
PIP V
DIP II
DIP III
DIP IV
DIP V
Hip
Knee
Ankle
Talocalcaneal joints
Intertarsal joints
MTP I
MTP II
MTP III
MTP IV
MTP V
TOE I
TOE II
TOE III
TOE IV
TOE V
Sacroiliac joints
Cervical spine
Thoracic spine
Lumbar spine
Abbreviations:
MCP=metacarpophalangeal; PIP=proximal interphalangeal; DIP=distal interphalangeal; MTP=metatarsophalangeal
Assessor’s Signature:_______________________________________________
Legend:
Swell: swelling
Pain: pain &/or 
tenderness on 
motion
LOM: limitation 
of motion
RIGHT
SIDE
LEFT
SIDE

SAP_001.pdf: 
Statistical Analysis Plan B1801023 Version 4.0
Page 1 of 19
Protocol B1801023
AN OPEN-LABEL EXTENSION STUDY TO ASSESS THE LONG-TERM SAFETY AND 
CLINICAL BENEFIT OF ETANERCEPT IN CHILDREN AND ADOLESCENTS WITH 
EXTENDED OLIGOARTICULAR JUVENILE IDIOPATHIC ARTHRITIS, 
ENTHESITIS-RELATED ARTHRITIS, OR PSORIATIC ARTHRITIS WHO WERE 
PREVIOUSLY ENROLLED IN PROTOCOL 0881A1-3338-WW (B1801014)
Statistical Analysis Plan (SAP)
Version: 4.0
Author:  
Date:
22 March 2017
PPD
CCI


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Revision History
Version
Date
Author(s)
Summary of Changes/Comments
1
2Dec2011
First version based on original protocol
(25 Feb 2011)
2
08Apr2013
Based on Protocol Amendment 1 (20 Jul 
2012), the following changes were made:
Title:
•
Added “AND CLINICAL 
BENEFIT”
Section 2.1: 
•
Added an additional secondary 
objective.
•
Added the withdrawal/Re-
treatment period
Section 3:
•
FAAS, OAAS, and OOAS were 
removed.
Section 3.2:
•
Added Withdrawal Analysis Set
Section 3.3:
•
Added Re-treatment Analysis Set
Section 4.2.2:
•
Added additional endpoints for 
subjects in the active treatment 
period, withdrawal/re-treatment 
period.
Section 5.2:
•
Treatment-emergent event 
definition was added.
Section 5.4:
•
Added additional baseline disease 
characteristics. Section 5.8:
Added analysis method for categorical 
endpoints.
Section 5.16 was added.
PPD
PPD
PPD
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3
14-Apr-2015
Section 4.0.1 added to address site 
specific data exclusion for 1 subject to 
address lost source documents
4.0
8-Mar-2017
 
 
PPD
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TABLE OF CONTENTS
1. INTRODUCTION .................................................................................................................6
2. STUDY OBJECTIVES AND STUDY DESIGN..................................................................6
2.1. Objectives..................................................................................................................6
2.2. Study Design .............................................................................................................7
2.2.1. Basic Features of the Study Design..............................................................7
2.2.2. Interim Analysis............................................................................................8
2.2.3. Sample Size Rationale..................................................................................8
3. ANALYSIS SETS .................................................................................................................8
3.1. Full Analysis Set .......................................................................................................8
3.1.1. Site specific exclusion from full analysis set................................................9
3.2. Withdrawal Analysis Set...........................................................................................9
3.3. Re-treatment Analysis Set.........................................................................................9
4. SPECIFICATION OF ENDPOINTS AND VARIABLES ...................................................9
4.1. Demography and Baseline Characteristics................................................................9
4.2. Endpoints...................................................................................................................9
4.2.1. Primary .........................................................................................................9
4.2.2. Secondary Endpoints ....................................................................................9
5. ANALYSIS METHODS .....................................................................................................13
5.1. Data Analysis Intervals ...........................................................................................13
5.2. Treatment-emergent Events ....................................................................................13
5.3. Subject Disposition .................................................................................................13
5.4. Demography and Baseline Characteristics..............................................................13
5.5. Malignancies, SAE and Medically Important Infections........................................14
5.6. General Adverse Events..........................................................................................14
5.7. Laboratory, Vital Signs, Tanner Stage Assessment ................................................14
5.8. Growth Parameters..................................................................................................15
5.9. Efficacy Endpoints ..................................................................................................15
5.10. Health Outcomes Assessments..............................................................................16
5.11. Exposure................................................................................................................16
5.12. Nonstudy Medications...........................................................................................16
5.13. Hospitalizations.....................................................................................................16


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5.14. Deaths....................................................................................................................16
5.15. Data Monitoring Committee .................................................................................17
5.16. Data Derivation and Missing Data Handling ........................................................17
5.16.1. Number of Active Joints...........................................................................17
5.16.2. Number of Joints with Limited Range of Motion ....................................17
5.16.3. CHAQ/HAQ .............................................................................................17
5.16.4. ACR Pedi Response..................................................................................18
5.16.5. Juvenile Arthritis Disease Activity Score (JADAS).................................18
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1. INTRODUCTION
[Note: In this document, any text taken directly from the protocol is italicized.]  
The purpose of this document is to provide further details about the statistical analysis methods 
specified in the study protocol B1801023. Protocol B1801023 is an 8-year extension study designed 
to further characterize the long-term safety profile, malignancy and other serious adverse events, and 
clinical benefit for those pediatric subjects who received at least one dose of etanercept and 
completed 96 weeks of investigational product and/or follow-up in study 0881A1-3338-WW 
(B1801014).  The previous study was designed to assess the clinical benefit and the long-term safety 
of etanercept for 2 years (96 weeks) in pediatric subjects with extended oligoarticular juvenile 
idiopathic arthritis, enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). 
Based on the lack of information regarding when treatment with etanercept should be discontinued 
and the success of re-treatment if relapse occurs, this protocol is being amended to also explore 
clinical benefit and physical function after withdrawal of etanercept and after disease relapse occurs.
A brief description of the study objectives and the study design are given in Section 2.  Subsequent 
sections include the definitions of baseline, efficacy and safety endpoints, and analysis populations 
followed by details about statistical methods.  Any major deviations from the methods specified in 
this document and the protocol must be discussed in the clinical study report. 
In order to evaluate overall safety in the most meaningful way, data from the 8 year extension study 
should not be analyzed independent of the data collected during the preceding 2 year parent study.  
Therefore, most of the safety analyses will be based on the combined data from the parent study and 
the subsequent extension.  The resulting data summaries and analyses will cover the entire period of 
up to 10 years.  In some cases, in order to fully address the entire etanercept experience, data from 
subjects who were in the parent study but were never enrolled in the extension study will be included 
in determining overall rates.  Details will be provided in the following sections.  
2. STUDY OBJECTIVES AND STUDY DESIGN
2.1. Objectives
Primary 
To monitor the occurrence of malignancy in pediatric subjects with eoJIA, ERA, or PsA.
Secondary 
•
To assess the long-term safety profile of etanercept;
•
To evaluate the long-term effect of etanercept on clinical benefit and physical function.
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2.2. Study Design
2.2.1. Basic Features of the Study Design
This is an open-label, single treatment, multi-center, 8-year extension study in pediatric subjects who 
have been diagnosed with one of 3 subtypes of JIA (eoJIA, ERA, or PsA), have received at least one 
dose of etanercept and completed approximately 96 weeks of participation in study 0881A1-3338-
WW (B1801014). These subjects will be asked to participate in study B1801023.  It is anticipated that 
approximately 100 subjects will be enrolled in study B1801023. This 96-month study contains 3 
periods: an active treatment period, a withdrawal/re-treatment period, and an observational period.
Active treatment period 
Subjects who completed approximately 96 weeks of active treatment with investigational product 
(etanercept) in study 0881A1-3338-WW (B1801014) and are eligible to continue investigational 
product in study B1801023 will enter directly into the active treatment period.  These subjects may 
continue to receive investigational product for up to 8 additional years (96 months). 
Withdrawal/Re-treatment period
Withdrawal: Subjects who have either completed approximately 96 weeks of treatment in study 
0881A-3338 or were enrolled in the active treatment period of study B1801023 and who have either 
met the Wallace definition for clinically inactive disease for at least 6 months on investigational 
product (etanercept) or who, in the investigators judgment, have had a good clinical response and 
would benefit from withdrawal from investigational product and are otherwise eligible can enter the 
withdrawal/re-treatment period. However, the withdrawal/re-treatment period is optional and it is 
ultimately up to the investigator and subject to determine when the subject should be withdrawn from 
treatment.
Re-treatment: Subjects requiring re-treatment per the investigator’s clinical judgment and who are 
otherwise eligible will be offered the option to re-start treatment with investigational product.
Subjects may not enter the withdrawal/re-treatment period more than once during the study.


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Observational period
All subjects will be followed for a total of 8 years from the time of initial entry into the study as 
follows:
Subjects who discontinue investigational product prior to completing 96 weeks of active treatment in 
study 0881A1-3338-WW (B1801014) for any reason or who are not eligible to continue 
investigational product in study B1801023 will not be permitted to re-start investigational product in 
study B1801023 and will be asked to enter the observational period. Subjects who participate in the 
active treatment period of study B1801023 and subsequently discontinue use of investigational 
product at any time before completion of the study and do not participate in the withdrawal/re-
treatment period for any reason (i.e., ineligible or subject declined participation) will be asked to 
participate in the observational period.  Subjects who participate in the withdrawal period and are 
ineligible for re-treatment with investigational product for any reason will be asked to participate in 
the observational period.  Subjects who participate in the re-treatment period and subsequently 
discontinue investigational product prior to the completion of the study will be asked to participate in 
the observational period.
Once a subject enters into the observational period, he or she cannot resume investigational product 
for the remaining time in the study.  Subjects participating in the observational period of study 
B1801023 may receive standard of care including any anti-TNF agents (eg, commercial etanercept) 
and/or other biologic agents for treatment of their disease at the discretion of the investigator.
2.2.2. Interim Analysis
No formal statistical interim analyses are planned. However, a descriptive analysis will be performed 
at a minimum of every 2 years based on the time of last patient first visit.  In addition, summaries of 
safety and efficacy assessments will be produced at intervals to satisfy regulatory obligations and the 
requirements of the Internal Review Committee.
2.2.3. Sample Size Rationale
The sample size for this safety extension protocol, as agreed upon with regulatory authorities, is not 
based on efficacy considerations; rather, all eligible subjects who either complete or discontinue 
from study 0881A1-3338-WW (B1801014) will be asked to participate in study B1801023.  The 
anticipated enrollment is approximately 100 subjects.  
3. ANALYSIS SETS
3.1. Full Analysis Set
The full analysis set (FAS) will include all subjects in the parent study who received at least one dose 
of investigational product regardless of whether they received any investigational product during the 
extension study.


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3.1.1. Site specific exclusion from full analysis set.
Source data for three Study visits M6, M9 and M12 of Pt 10081010 in Hungary, were accidentally 
lost at site. Duplicate patient charts could be reconstituted from the computerized data base of the 
hospital, but outcome data and patient dosing diary data for the three patient visits were lost and could 
not be recovered. The team decided that data deletion from the system is not recommended.  
However, the decision was made that all patient safety data will be included in the study report but 
not the efficacy data for the three visits.
3.2. Withdrawal Analysis Set
The withdrawal analysis set (WAS) will include those subjects who entered the withdrawal period.  
Only data collected in the withdrawal period will be included.
3.3. Re-treatment Analysis Set
The re-treatment analysis set (RTAS) will include those subjects who entered the re-treatment period.  
Only data collected in the re-treatment period will be included.
4. SPECIFICATION OF ENDPOINTS AND VARIABLES
The primary endpoints in this study are related to safety.  Efficacy endpoints are secondary.
4.1. Demography and Baseline Characteristics 
The demographic data include age, sex, race, weight, height and BMI.  The baseline characteristics 
are: subtype of JIA, disease duration, number of prior DMARDS, use of the following medications: 
DMARDS, methotrexate, HCQ, chloroquine, SSZ, oral corticosteroids and oral NSAIDS. 
4.2. Endpoints
4.2.1. Primary
The occurrence of malignancy is the primary endpoint for all subjects. 
4.2.2. Secondary Endpoints
The secondary endpoints include

the occurrence of serious adverse events (SAE, infectious and non-infectious events will be 
summarized separately),

the occurrence of medically important infections (ie, an infection requiring hospitalization 
and /or parenteral [intravenous (IV), intra-muscular (IM)] anti-infective agents).

Hospitalization: For any hospitalizations, the admission date, discharge date and reason for 
hospitalization will be collected during the study.

Death: For any deaths, date of death and cause of death will be collected during the study.


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
Nonstudy medication: nonstudy medications are coded using the WHO Drug Dictionary 
(2006 Q3). The Prior, Concomitant, After (PCA) flag for nonstudy medications will be 
derived for both parent study and extension study (only for active treatment period):

Prior nonstudy medications are defined as any nonstudy medications taken before the 
first dose of investigational product taken at the start of the study,

Concomitant nonstudy medications are defined as any nonstudy medications taken 
during the treatment period (from the first dose to the last dose of the investigational 
product).

After nonstudy medications refer to any nonstudy medications taken after the last 
dose of the investigational product.(not applicable for observational period)

Exposure: the total number of doses taken and exposure time.
The above endpoints will be collected for all subjects. The following endpoints will be collected only 
for subjects in the active treatment period, or withdrawal/re-treatment period in the extension study:
Non-serious adverse Events (Adverse events that occur up to 30 days after the last dose of 
investigational product will be counted as having occurred during the treatment period) This is 
applied for active and retreatment periods. If an AE started in active or retreatment period and 
continued into withdrawal or observational period, it will be only counted in active or retreatment 
period, it will not be counted in withdrawal or observational period again. If an event started in 
withdrawal or observational period, and after 30 days of the last dose of investigational product of 
active period or re-treatment period, this event will not be counted.  
Occurrence of withdrawals from investigational product due to adverse events;
Laboratory evaluations (ie, hematology, blood chemistry, and CRP)
Tanner Stage Assessment for subjects <18 years of age or who have a score of <5 on 1 or more 
applicable domain(s). The Tanner Assessment does not need to be repeated if it was performed within 
2 months before the early withdrawal visit.
Vital Signs: Temperature, blood pressure (mmHg) and pulse rate (beats/min, after sitting for at least 
5 minutes);
Growth parameters: height, weight, BMI;

Efficacy:

ACR Pediatric 30, 50, 70, 90, and 100, defined as ≥ 30% (and 50%, 70%, 90%,100%, 
respectively) improvement from baseline in at least 3 of the 6 following variables, with no 
more than 1 of the remaining variables worsening by > 30 %:

Physician’s Global Assessment (PGA) of Disease Activity on a 21-circle visual 
analogue scale (VAS);

Patient/Parent Global Assessment on a 21-circle VAS;

Childhood Health Assessment Questionnaire (CHAQ


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
Number of joints with active arthritis, defined as joints that are swollen or, in the 
absence of swelling, joints with limited range of motion accompanied by pain and/or 
tenderness;

Number of joints with limited range of motion;

Laboratory measure of inflammation, c-reactive protein (CRP);
(Note: ACRPedi responses will be calculated based on parent study baseline. For subjects 
aged ≥18 years, CHAQ is missing)

Individual components of the ACR Pediatric Assessments;

Pain Assessment on a 21-circle VAS;

Duration of morning stiffness in minutes;

Clinically inactive disease defined as follows per 2011 Wallace Criteria:

No joints with active arthritis (defined as joints that are swollen or, in the 
absence of swelling, joints with limited range of motion accompanied by 
pain and/or tenderness);

No fever, rash, serositis, splenomegaly, or generalized lymphadenopathy 
attributable to JIA;

No active uveitis;

CRP level within normal limits in the laboratory where tested or, if 
elevated, not attributable to JIA;

PGA of disease activity score of best possible on the scale used;

Duration of morning stiffness of ≤ 15 minutes;

The Juvenile Arthritis Disease Activity Score (JADAS), using 4 components (PGA of 
Disease Activity, Patient/Parent Global Assessment, number of joints with active 
arthritis and CRP).


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•
Additional Secondary Endpoints for ERA Subjects
•
Overall Back Pain and Nocturnal Back Pain on a 100 mm VAS;
•
Bath Ankylosing Spondylitis Metrology Index (BASMI) components 
(Intermalleolar Distance, Cervical Rotation, Modified Schober’s Test, Lateral 
Flexion, and Tragus to Wall Distance. Note: Modified Schober’s Test is used for 
BASMI calculation. Schober’s Test, not Modified Schober’s Test, was collected 
for this study. So BASMI cannot be calculated for this study).
•
Additional Secondary Endpoints for PsA Subjects
•
Body Surface Area (BSA);
•
PGA of Psoriasis.
•
Health outcomes assessments for Subjects in the Active Treatment Period, and 
Withdrawal/Re-treatment Period:
•
Childhood Health Assessment Questionnaire (CHAQ): for subjects aged <18 years 
at the time of assessment;
•
Health Assessment Questionnaire (HAQ): for subjects aged ≥18 years at the time of 
assessment.  
•
Proportion of subjects with total CHAQ score improvement of >0.188 (decrease by 
>0.188) from baseline of 1014.
 
 
CCI


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5. ANALYSIS METHODS
All analyses will be performed for the overall population as well as each of the 3 JIA subtypes. 
5.1. Data Analysis Intervals
As shown in the study flowchart of the protocol, the visit time and the collection time of study 
endpoints are regularly scheduled.  However, these scheduled time points may not be followed 
exactly.  For the purpose of reporting clinical data results and satisfying the requirements of certain 
statistical analysis methods, it is necessary to window the actual observation time into data analysis 
intervals (DAIs).  Details regarding the DAIs will be provided in a separate programming 
specifications document. 
5.2. Treatment-emergent Events
An event is defined as a treatment-emergent event if the event occurred during the active period 
(either parent or extension studies) or re-treatment period with onset dates between the first dose date 
of investigational product and within 30 days after the last dose of investigational product. If a 
treatment-emergent event started in active or re-treatment period and continued to withdrawal or 
observational period, it will be only counted in active or re-treatment period, it will not be counted in 
withdrawal or observational period again. If an event started in the withdrawal or observational 
periods, and after 30 days of the last dose of investigational product of the active period or re-
treatment period, this event is not a treatment-emergent event. 
5.3. Subject Disposition
The numbers (and percentages) of subjects who were enrolled, who took at least one dose of 
investigational product, who discontinued from the parent study and who completed the parent study 
will be summarized from FAS.  The number who completed the parent study will be further broken 
down into the number who did and did not continue into the extension study.  The numbers (and 
percentages) of subjects who discontinued from the extension and who completed the extension will 
be summarized.  This will be done separately for all subjects in the extension, for all subjects who 
began the extension in the active treatment period, withdrawal/re-treatment period, and for subjects 
who began the extension in the observational period.  For those subjects who began in the active 
treatment period, the numbers who entered withdrawal/re-treatment period, who switched to the 
observational period, and reason for switching, will also be tabulated.  In addition, the proportion of 
subjects who discontinued from the extension study for any reason and for each specific reason will 
be tabulated.  The number and percentage of subjects who completed each year of the study may be 
provided.  
5.4. Demography and Baseline Characteristics
Demographic, baseline characteristics (eg, subtype of JIA) and baseline disease characteristics 
(physician global assessment, patient/parent global assessment, Number of joints with LOM, Number 
of painful joints, Number of swollen joints, Pain assessment, Morning stiffness, CRP, CHAQ and 
HAQ. Additionally, Tender entheseal score, Overall back pain VAS, Nocturnal back pain VAS, 
Modified Schober’s test for ERA subtype; BSA of psoriasis, Physician’s Global Assessment of 
Psoriasis for PsA subtype) data will be summarized. For continuous variables such as age, height, 
weight, the descriptive statistics will include the number of patients, mean, median, standard 
deviation, minimum, and maximum. For dichotomous variables such as sex and nominal variables 
such as race and ethnicity, the descriptive statistics will include the total number of patients, the count
and percentage in each category.  Baseline and demographic data will be summarized for subjects 
entered extension study (both parent study and extension study baselines), Withdrawal Analysis Set


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(WAS, withdrawal period baseline), and Re-treatment Analysis Set (RTAS, retreatment period 
baseline).
5.5. Malignancies, SAE and Medically Important Infections
The malignancies, serious adverse events and medically important infections will be summarized 
using the frequency and percentage of subjects reporting events.  The adjusted rate per 100 subject-
years of exposure to etanercept (defined as # of events/total exposure*100) will be summarized also.
The incidence of malignancies may be compared to external data sources to generate standardized 
incidence ratios (SIRs) to aid interpretation.  
In addition to showing cumulative rates over the entire study period (including both parent study and 
extension), incidences of subjects with malignancies, serious adverse events and medically important 
infections as well as exposure-adjusted rates will also be categorized by year for each year from 1 
through 10.
These summaries and analyses will be performed for:

FAS, all events in all periods;

FAS, treatment-emergent events in the on-drug period (active and retreatment periods
together).
5.6. General Adverse Events
The occurrence of all treatment-emergent adverse events (excluding infection and ISR), infections, 
infections considered preventable by vaccination, and injection site reactions will be separately 
summarized by incidence rate (proportion of subjects reporting events) and adjusted rate per 100 
subject-years of exposure to etanercept. Adverse events will also be summarized by severity and 
relationship to investigational product. Adverse events occurring in >1 subject in any of the subtypes 
may be summarized as well.  

Tabulations of withdrawals from investigational product due to adverse events will be 
provided.  

In addition to showing cumulative rates over the entire study period (including both parent 
study and extension), incidences of subjects with treatment-emergent event as well as 
exposure-adjusted event rates will also be categorized by year for each year from 1 through 
10. 
These summaries will be performed for FAS (treatment-emergent events in on-drug period (active 
and retreatment periods together)) and WAS.
5.7. Laboratory, Vital Signs, Tanner Stage Assessment
For laboratory data, vital sign measurements and other continuous safety data, the number of 
observations, mean, standard deviation, median, minimum, maximum will be summarized by visit. 
Height, weight, BMI, and Tanner scores will be summarized using the number of observations, mean, 
standard deviation, median, minimum, and maximum by age group (ages 2-4, 5-11 and 12-17 years at 
start of parent study). The visits shown in these reports will be the baseline visit from the parent 
study, weeks 12, 24, 48, and 96, from the parent study and all visits from the extension study where 


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the data is collected. Some additional analyses of the Tanner data that takes age at time of 
measurement into account may also be done.    
The Potentially Clinically Important (PCI) Flag is a derived flag value based on the PCI criteria 
defined for laboratory data captured in the study. The PCI criteria are based on NCI toxicity criteria. 
The number (%) of subjects with PCI events will also be provided for the lab data.  
These summaries will be performed for FAS (active period (both parent and extension studies)), 
WAS, and RTAS.
5.8. Growth Parameters
Height, weight, and body mass index (BMI) will also be compared with data from standardized 
growth charts. Height, weight, and BMI will be summarized using Z-scores. Z-score is calculated 
using the following formulation:
Or
0
,
/)
/
ln(


L
S
M
X
Z
where X is the physical measurement (eg, height, weight, BMI) and L, M, and S are the values from 
standardized growth charts provided by the US Centers for Disease Control website 
(http://www.cdc.gov/GrowthCharts/) by gender for children from birth to 240 months.  The Z-score 
cannot be calculated if age > 240 months.
These summaries will be performed for FAS (active period (both parent and extension studies)), 
WAS and RTAS.
5.9. Efficacy Endpoints
Descriptive summary statistics will be provided for efficacy endpoints.  For continuous endpoints, the 
summary statistics at each visit will include the number of observations, mean, standard deviation, 
median, minimum, maximum and 95% confidence interval for the mean.  These statistics will be 
provided for the observed value and change from baseline. The mean percent change from baseline
will be provided also.  For categorical endpoints, the summary statistics will contain the frequency, 
percentage, and 95% confidence interval (CI) for the percentage.
These summaries will be performed for:

FAS, active period data (both parent and extension studies. Baseline of parent study will be 
used for calculation of change from baseline). The reports will show the baseline (no baseline 
for ACRPedi responses), weeks 12, 24, 48, and 96 from the parent study and all visits from 
the extension study where data is collected.

WAS. The reports will show all visits where data is collected.
0
,
1
)
/
(



L
LS
M
X
Z
L


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
RTAS. Re-treatment period baseline will be used for calculation of change from baseline. 
The reports will show all visits where data is collected.
5.10. Health Outcomes Assessments
The CHAQ and HAQ will be summarized in the same way as the efficacy endpoints.  CHAQ and HAQ 
results will be summarized separately.  
5.11. Exposure 
The exposure time (years) to etanercept will be calculated for each subject each period using (the last 
dose date – the first dose date + 1)/365.25. If the gap is less than 28 days between two etanercept 
treatment periods, the cumulative exposure will includes the gap. Otherwise, the gap will be excluded 
from the cumulative exposure. Descriptive statistics will be provided to summarize the exposure time 
for:

FAS, on-drug period (active and re-treatment periods together);

FAS, all periods (includes commercial etanercept in withdrawal and observational periods).
The total number of doses of investigational product taken will be summarized for FAS (active and 
re-treatment periods together).
A table showing the number of subjects taking investigational product for 1 year, 2 years and so on 
through 10 years may be provided for FAS (active and re-treatment periods together). 
5.12. Nonstudy Medications
The number (%) of subjects using nonstudy medications will be reported by medication type 
(DMARD, NSAID, etc) for FAS (on-drug period (active and re-treatment periods together)) and 
WAS.
Separate tabulations will be provided for prior to, concomitant with or after investigational product 
will be provided for FAS (on-drug period (active and re-treatment periods together)).  
5.13. Hospitalizations
Listings of subjects who are hospitalized will be provided for FAS. 
5.14. Deaths
Listings of any deaths that occur will be provided for FAS. 
The incidence of death may be compared to external data sources to generate standardized incidence 
ratios (SIRs) for:

FAS, all periods;

FAS, on-drug period (active and re-treatment periods together).  


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5.15. Data Monitoring Committee
This study will use an Internal Review Committee (IRC) to help assess the safety of the study.  The 
IRC will be responsible for evaluation of periodic assessments of safety and efficacy data. A separate 
Charter will describe and govern the IRC’s activity.
5.16. Data Derivation and Missing Data Handling
The following rules will be used to derive the endpoints and handle the missing components. If an 
endpoint is missing after derivation, the missing value will not be imputed.
5.16.1. Number of Active Joints
The active joints are defined as joints that are swollen or, in the absence of swelling, joints with 
limited range of motion accompanied by pain and/or tenderness. Total number of active joints is the 
number of active joints prorated for missing joints. It is defined as 73*(total number of active joints
with score greater than zero)/number of non-missing active joints. Joint replacement (JR) and not 
evaluable (NE) are treated as missing. If more than 36 active joint scores are missing, then the total 
number of active joints will be defined as missing.
5.16.2. Number of Joints with Limited Range of Motion
Total number of joints with limited range of motion is the number of joints with limited range of 
motion prorated for missing limited range of motions. It is defined as 69*(total number of joints with 
score of limited range of motion greater than zero)/number of non-missing limited range of motions. 
Joint replacement (JR) and not evaluable (NE) are treated as missing. If more than 34 scores of 
limited range of motion are missing, then the total number of joints with limited range of motion will 
be defined as missing.
5.16.3. CHAQ/HAQ 
For subjects < 18 years of age, the CHAQ will be used and completed by the subject’s parent or legal 
representative/guardian. For subjects >= 18 years of age, he HAQ will be used and completed by the 
subject. CHAQ/HAQ contains eight domains: dressing, arising, eating, walking, hygiene, reach, grip, 
and common activities. Each item within a domain is scored on a 4-point Likert scale from 0 to 3: 
0=no difficulty; 1=some difficulty; 2=much difficulty; 3=unable to do. Not applicable is defined as 
missing. The highest score reported for a domain determines the score for that domain. In addition, a 
series of questions about use of aids or devices or help (e.g a cane for walking) are asked for each 
subscales. If the subscale score, based on the ordinal response, is missing, 0 or 1, but at least one of 
the aids or devices or help is used, the score is set to 2. The overall CHAQ/HAQ is computed as the 
sum of domain scores and divided by the number of domains answered. If 3 or more domains are 
missing, CHAQ/HAQ is defined as missing.


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5.16.4. ACR Pedi Response
Scoring algorithm including missing data handling for ACR Pedi 30, 50, 70, 90, and 100: First, if any 
of the components have a score of zero at baseline and the post baseline score is >0, that component 
will be treated as worsening >30% for scoring improvement; if the baseline score is 0 and the post 
baseline score is also zero, improvement will be set to 0%. Then the algorithm described in the table 
below will be applied, based on the number of components with worsening >30%, missing, and 
improvement >30% (or 50% for ACR Pedi 50, etc).
Worsening>=30%
Missing
Improvement>30%
Outcome
>=2
Non-responder
1
0
>=3
Responder
<3
Non-responder
1
>=2
Missing
<2
Non-responder
2
>=1
Missing
0
Non-responder
>=3
Missing
0
0
>=3
Responder
<3
Non-responder
1
>=3
Responder
2
Missing
<2
Non-responder
>=2
Missing
5.16.5. Juvenile Arthritis Disease Activity Score (JADAS)
JADAS consists of four components: physician global assessment of disease activity on a 10 cm VAS 
(0=no activity, 10=maximum activity); parent/patient global assessment of well-being on a 10 cm 
VAS (0=very well, 10=very poor); number of joints with active disease; and an inflammatory marker 
CRP. CRP was truncated to a 0–10 scale according to the following formula: 
(CRP (mg/l) −10)/10,
Before calculation, CRP values <10 mg/l were converted to 10 and CRP values >110 mg/l were 
converted to 110. JADAS was calculated as the simple linear sum of its four components. If one or 
more components are missing, JADAS score will be missing.
 
 
 
 
 
 
CCI


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CCI