Clinical trial NCT04230213
Conditions: Rheumatoid Arthritis
Sponsor: Pfizer
Start date: 2020-01-13; Completion date: 2021-06-22
Enrollment: 455 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study will assess the impact of pharmacokinetics (PK), safety and immunogenicity after switches between PF-06410293 and adalimumab and with continuous dosing with adalimumab in combination with methotrexate in subjects with moderately to severely active rheumatoid arthritis.

Detailed description:

Arms: arm 1: Subcutaneous (SC) injection given every other week arm 2: SC injection given every other week
Interventions: intervention 1: PF-06410293 intervention 2: adalimumab
Intervention descriptions: intervention 1: SC injection intervention 2: SC injection

Protocol documents:
Prot_000.pdf: 
PF-06410293
Protocol B5381012
Final Protocol Amendment 1, 19 May 2020
PFIZER CONFIDENTIAL
Page 1
CLINICAL PROTOCOL
A RANDOMIZED COMPARATIVE STUDY ASSESSING THE SWITCHING 
BETWEEN PF-06410293 AND HUMIRA® IN COMBINATION WITH
METHOTREXATE IN PARTICIPANTS WITH MODERATELY TO SEVERELY 
ACTIVE RHEUMATOID ARTHRITIS 
Investigational Product Number:
PF-06410293
Investigational Product Name:
Adalimumab-Pfizer
United States (US) Investigational New 
Drug (IND) Number:
European Clinical Trials Database 
(EudraCT) Number:
2019-000284-24
Protocol Number:
B5381012
Phase:
3
Short Title:
A Comparative Study Between PF-06410293 And Humira in Combination with 
Methotrexate in Participants with Active Rheumatoid Arthritis 
This document and accompanying materials contain confidential information belonging to Pfizer.  Except as 
otherwise agreed to in writing, by accepting or reviewing these documents, 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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Protocol Amendment Summary of Changes Table
Document History
Document
Version Date
Summary of Changes and Rationale
Original protocol
28 June 2019
Not applicable (N/A)
Amendment 1
19 May 2020
Protocol Administrative Clarification 
Letters (PACLs) were incorporated:

Women of Childbearing Potential 
(WOCBP) Contraceptive use after 
last study dose is updated from “a 
minimum of 28 days” to “at least 
5 months” to follow the study’s 
single reference safety document 
(SRSD), which is the Humira label
in Appendix 4.  

Typographic error corrected for 
white blood cell count, lymphocyte 
count and platelets lab tests listed 
in Exclusion Criteria 19.

Updated instruction on empty drug 
containers in Sections 6.1.1 and
6.2.  They need to be returned, not 
destroyed for investigational 
product accountability purpose.

Text update in the protocol title:
“interchangeability of” is replaced 
by “switching between”.

Week 22 injection site updated to 
abdomen instead of abdomen or 
either upper front thigh to support 
primary data analysis in Schedule 
of Activities (SoA), Table 1, 
Sections 6.1.1 and 6.1.2.

Alternative solutions that are only 
acceptable during the COVID-19 
pandemic language have been 
added in SoA, Sections 6.2.1, 6.4, 
7.1, 7.2 and Appendix 11.


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Final Protocol Amendment 1, 19 May 2020
PFIZER CONFIDENTIAL
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Document History
Document
Version Date
Summary of Changes and Rationale
Updated status of expecting PF-06410293 
approval as a biosimilar to Humira from 
Food and Drug Administration (FDA) and 
regulatory agencies to approval for
PF-06410293 as a biosimilar to Humira 
was received from the FDA in 
Sections 1.1, 2, 2.2 and 2.3.
•
Mention of marketing applications 
under review with other agency(s) 
is removed from Section 2.2.
Corrected participant’s age range from age 
of 18 and older to between age of 18 to 
70 years in Section 1.1.
Corrected definition for end of Treatment 
Period (TP) 4 to include Week 32 dose 
administration, and Safety Follow Up 
Period to begin after the last 
investigational dose at Week 32 in 
Sections 1.1 and 4.1.
Added clarification in Table 1, 
Sections 1.1, 4.1 and 8.5 that the 2-week 
pharmacokinetic (PK) sampling period 
starts with Week 30 predose PK collection 
and ends with predose PK collection at 
Week 32.
Added clarification in Section 1.1 that 
immune-related safety will be described 
for the safety population including 
injection site reactions, hypersensitivity, 
anaphylaxis and angioedema.
 
Added utilization of home healthcare 
service as an option during the 2 week PK 
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Document History
Document
Version Date
Summary of Changes and Rationale
sampling period in SoA, Table 1 and 
Section 8.5.
Clarified that only applicable adalimumab 
injection details will be recorded in the 
electronic Participant Dosing Log in SoA, 
Sections 6.1.1 and 6.4.
Clarifications made to the following 
inclusion/exclusion criteria to stay 
consistent with Humira label:

Removal of Inclusion Criterion 7 
as it is a duplication of Exclusion 
Criterion 14.  Additionally, 
clarification is made to Exclusion 
Criterion 14. 

Clarification provided to 
Section 5.2, Exclusion Criteria 4c
and Section 8.2.8 that confirmed 
positive HIV, Hepatitis B and 
Hepatitis C are excluded.  More 
specifically, Hepatitis B DNA test 
has been added.

Clarification provided on 
prohibited biologic therapy in 
Exclusion Criterion 13, Section 6.5 
and Appendix 9 (Prohibited 
Concomitant Medication and 
Procedures).

Added new Exclusion Criterion 18
that unstable dose of oral and 
intramuscular (IM) corticosteroid is 
prohibited.  Updated Sections 6.5.2 
and removed Appendix 9 (Oral 
Corticosteriod in FAP).
Add clarification to Exclusion Criterion 
(#3) that active significant infection, 


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Document History
Document
Version Date
Summary of Changes and Rationale
eg, SARS-CoV2 (COVID-19) infection 
and any active infection considered to be 
clinically significant by the investigator 
should be excluded.  Updates are also 
made in Sections 7.1.1 and 7.1.2.
Language in Section 7.2 has been updated 
to follow Pfizer’s latest protocol template.
Updated population for analysis in 
Section 9.3 and AE analysis in 
Section 9.4.2.1.
Updated contraceptive requirements to 
follow Humira label for male participants 
Section 10.4.1.  Additionally, removed text 
“highly” from highly effective 
contraceptive methods in Exclusion 
Criterion 24, Sections 5.3.1 and 10.4.4 to 
keep consistent with Humira label.
Additional typographic errors were
corrected and editorial changes provided,
as deemed necessary, throughout the 
protocol.
Blood sample volume was updated in 
Section 8.5
Section 8.9 Immunogenicity Assessments 
have been added to follow Pfizer’s 
protocol template, as a result Section 8.5.1 
in protocol (28 June 2019) has been 
reformatted to Section 8.9.1 in 
Amendment 1.


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TABLE OF CONTENTS
LIST OF TABLES...................................................................................................................10
1. PROTOCOL SUMMARY...................................................................................................11
1.1. Synopsis ..................................................................................................................11
1.2. Schema ....................................................................................................................16
1.3. Schedule of Activities (SoA)...................................................................................17
2. INTRODUCTION ...............................................................................................................21
2.1. Study Rationale .......................................................................................................22
2.2. Background .............................................................................................................22
2.2.1. Clinical Overview.......................................................................................22
2.3. Benefit/Risk Assessment.........................................................................................24
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS ...........................................................25
4. STUDY DESIGN.................................................................................................................26
4.1. Overall Design.........................................................................................................26
4.2. Scientific Rationale for Study Design.....................................................................27
4.3. Justification for Dose ..............................................................................................27
4.4. End of Study Definition ..........................................................................................27
5. STUDY POPULATION......................................................................................................28
5.1. Inclusion Criteria.....................................................................................................28
5.2. Exclusion Criteria....................................................................................................29
5.3. Lifestyle Considerations..........................................................................................33
5.3.1. Contraception..............................................................................................33
5.4. Screen Failures ........................................................................................................33
6. INVESTIGATIONAL PRODUCT......................................................................................34
6.1. Investigational Product(s) Administered.................................................................34
6.1.1. Administration............................................................................................34
6.1.2. Training for Adalimumab Subcutaneous Injections...................................36
6.1.3. Medical Devices .........................................................................................36
6.2. Preparation/Handling/Storage/Accountability ........................................................36
6.2.1. Preparation and Dispensing........................................................................38
6.3. Measures to Minimize Bias: Randomization and Blinding.....................................38
6.3.1. Allocation to Investigational Product .........................................................38


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6.3.2. Breaking the Blind (Not Applicable)..........................................................39
6.4. Investigational Product Compliance .......................................................................39
6.5. Concomitant Therapy..............................................................................................39
6.5.1. Stable Background Therapies.....................................................................41
6.5.1.1. Methotrexate..............................................................................41
6.5.1.2. Folic/Folinic Acid Supplements................................................41
6.5.1.3. Additional Background Therapies ............................................41
6.5.2. Pain or Other Arthritis Therapy..................................................................42
6.5.3. Rescue Medicine.........................................................................................43
6.6. Dose Modification...................................................................................................44
6.7. Intervention After the End of the Study..................................................................44
7. DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL................................................44
7.1. Discontinuation of Investigational product.............................................................44
7.1.1. Temporary Discontinuation........................................................................45
7.1.2. Permanent Discontinuation.........................................................................45
7.2. Participant Discontinuation/Withdrawal From the Study.......................................46
7.3. Lost to Follow-up....................................................................................................47
8. STUDY ASSESSMENTS AND PROCEDURES...............................................................47
8.1. Efficacy Assessments..............................................................................................48
8.2. Safety Assessments .................................................................................................48
8.2.1. Physical Examinations................................................................................48
8.2.2. Vital Signs ..................................................................................................48
8.2.3. Chest Radiograph........................................................................................49
8.2.4. Electrocardiograms.....................................................................................49
8.2.5. Clinical Safety Laboratory Assessments ....................................................49
8.2.6. QuantiFERON-TB Gold In-Tube Test.....................................................50
8.2.7. Pregnancy Testing ......................................................................................50
8.2.8. Viral Disease Screening..............................................................................50
8.3. Adverse Events and Serious Adverse Events..........................................................51
8.3.1. Time Period and Frequency for Collecting AE and SAE Information.......51
8.3.1.1. Reporting SAEs to Pfizer Safety...............................................52


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8.3.1.2. Recording Nonserious AEs and SAEs on the CRF...................52
8.3.2. Method of Detecting AEs and SAEs ..........................................................52
8.3.3. Follow-up of AEs and SAEs.......................................................................52
8.3.4. Regulatory Reporting Requirements for SAEs...........................................53
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational 
Exposure ..........................................................................................................53
8.3.5.1. Exposure During Pregnancy......................................................53
8.3.5.2. Exposure During Breastfeeding ................................................53
8.3.5.3. Occupational Exposure .............................................................54
8.3.6. Cardiovascular and Death Events...............................................................54
8.3.7. Medical Device Incidents (Including Malfunctions)..................................54
8.3.7.1. Time Period for Detecting Medical Device Incidents...............54
8.3.7.2. Follow-up of Medical Device Incidents....................................54
8.3.7.3. Prompt Reporting of Medical Device Incidents to Sponsor .....55
8.3.7.4. Regulatory Reporting Requirements for Medical Device 
Incidents ............................................................................................55
8.3.8. Medication Errors .......................................................................................55
8.4. Treatment of Overdose............................................................................................56
8.5. Pharmacokinetics ....................................................................................................57
8.6. Pharmacodynamics..................................................................................................58
8.7. Genetics...................................................................................................................58
8.7.1. Specified Genetics ......................................................................................58
8.7.2. Banked Biospecimens for Genetics............................................................58
8.8. Biomarkers ..............................................................................................................58
8.8.1. Specified Gene Expression (RNA) Research .............................................58
8.8.2. Specified Protein Research.........................................................................58
8.8.3. Specified Metabolomic Research ...............................................................58
8.8.4. Banked Biospecimens for Biomarkers .......................................................58
8.9. Immunogenicity Assessments.................................................................................58
8.9.1. Analysis of Anti-adalimumab Antibodies and Neutralizing 
Anti-adalimumab Antibodies...........................................................................58
 
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8.10. Health Economics .................................................................................................59
9. STATISTICAL CONSIDERATIONS ................................................................................59
9.1. Estimands and Statistical Hypotheses.....................................................................59
9.1.1. Estimands....................................................................................................59
9.2. Sample Size Determination.....................................................................................59
9.3. Populations for Analysis .........................................................................................60
9.4. Statistical Analyses .................................................................................................60
9.4.1. Efficacy Analyses .......................................................................................60
9.4.2. Safety Analyses ..........................................................................................61
9.4.2.1. Adverse Event ...........................................................................61
9.4.2.2. Laboratory Test Abnormalities .................................................61
9.4.2.3. Prior and Concomitant Mediations ...........................................62
9.4.3. Other Analyses............................................................................................62
9.4.3.1. Pharmacokinetics Analysis .......................................................62
9.4.3.2. ADA and NAb Analysis............................................................62
9.4.3.3. Other Endpoint Analysis ...........................................................62
9.5. Interim Analyses .....................................................................................................62
9.5.1. Data Monitoring Committee.......................................................................62
10. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS..........................................................................................................63
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations...............63
10.1.1. Regulatory and Ethical Considerations ....................................................63
10.1.1.1. Reporting of Safety Issues and Serious Breaches of the 
Protocol or ICH GCP.........................................................................63
10.1.2. Financial Disclosure .................................................................................64
10.1.3. Informed Consent Process ........................................................................64
10.1.4. Data Protection .........................................................................................65
10.1.5. Dissemination of Clinical Study Data ......................................................65
10.1.6. Data Quality Assurance ............................................................................67
10.1.7. Source Documents....................................................................................68
10.1.8. Study and Site Closure..............................................................................68
10.1.9. Sponsor’s Qualified Medical Personnel ...................................................69
10.2. Appendix 2: Clinical Laboratory Tests .................................................................70


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting ......................................................................71
10.3.1. Definition of AE .......................................................................................71
10.3.2. Definition of SAE.....................................................................................72
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs.......................73
10.3.4. Reporting of SAEs....................................................................................76
10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy 
Information................................................................................................................78
10.4.1. Male Participant Reproductive Inclusion Criteria....................................78
10.4.2. Female Participant Reproductive Inclusion Criteria.................................78
10.4.3. Woman of Childbearing Potential (WOCBP) ..........................................78
10.4.4. Contraception Methods.............................................................................79
10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments ........82
10.6. Appendix 6: ECG Findings of Potential Clinical Concern ...................................84
10.7. Appendix 7: Medical Device Incidents: Definition and Procedures for 
Recording, Evaluating, Follow-up, and Reporting....................................................86
10.8. Appendix 8: Country-Specific Requirements .......................................................88
10.9. Appendix 9: Prohibited Concomitant Medications and Procedures .....................89
10.10. Appendix 10: New York Heart Associated Functional Classification 
Criteria.......................................................................................................................90
10.11. Appendix 11: COVID-19 Pandemic Considerations ..........................................91
10.12. Appendix 12: Abbreviations ...............................................................................92
11. REFERENCES ..................................................................................................................97
LIST OF TABLES
Table 1.
PK Sampling Table...................................................................................21
Table 2.
Permitted Opioid/Narcotic Drugs.............................................................42
Table 3.
Additional Opioid Drugs for Rescue Therapy..........................................43
Table 4.
Protocol-Required Safety Laboratory Assessments .................................70


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1. PROTOCOL SUMMARY 
1.1. Synopsis 
Short Title: A Comparative Study Between PF-06410293 And Humira in Combination 
with Methotrexate in Participants with Active Rheumatoid Arthritis
Rationale
Regulatory approval for PF-06410293 as a biosimilar to Humira was received from United 
States (US) FDA.  The purpose of conducting this trial is to support the application for the 
interchangeability designation with the FDA, not to re-establish “PK equivalence” between 
licensed Humira and PF-06410293.  The objectives and design of this study are consistent 
with recommendations for establishing interchangeability (IC) found in the corresponding 
guidance.7
A designation of IC for an approved biosimilar drug is granted by the US FDA based on 
information demonstrating that ‘the risk in terms of safety or diminished efficacy of 
alternating or switching between use of the biological product and the reference product is 
not greater than the risk of using the reference product without such alternation or switch’ 
(FDA Guidance, 2019).7  In reference to a biological product, interchangeability means that 
“the biological product may be substituted for the reference product without the intervention 
of the health care provider who prescribed the reference product”.7  This study has been 
designed with input from FDA to deliver sufficient information to support the 
interchangeability of PF-06410293 with the reference product, Humira. 
Objectives, Estimands, and Endpoints
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To evaluate 
interchangeability of 
PF-06510293 and Humira 
by examining adalimumab 
steady-state 
pharmacokinetics in a 
switching arm (following
3 switches between Humira 
and PF-06410293) as 
compared to a 
non-switching arm 
(receiving only Humira).

Evaluate the equivalence of 
primary endpoints (maximum 
observed concentration (Cmax) 
and area under the 
concentration-time curve over 
the dosing interval (AUC) 
obtained during the intensive 
PK sampling interval) between 
the switching arm and 
non-switching arm in 
participants who meet the PK 
population criteria,that include 
criteria for the number and 
timing of missing doses, 
availability of PK data, 
adherence to background 
therapy, and major protocol 

Cmax and AUCobtained 
during the intensive PK 
sampling interval.


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deviations related to PK 
assessment.
Objectives
Estimands
Endpoints
Secondary: 
Secondary:
Secondary: 

To evaluate other serum 
adalimumab PK parameters 
in the switching arm and the 
non-switching arm.

To evaluate the overall 
safety and tolerability of the 
switching arm and the 
non-switching arm.

To evaluate
immunogenicity of the 
switching arm and the non-
switching arm.

Summarize other serum 
adalimumab PK parameters, 
including time at which Cmax
occurs (Tmax), average 
concentration over the dosing 
interval (Cav), and apparent 
clearance (CL/F) obtained 
during the intensive PK 
sampling interval in participants 
who meet the PK population 
criteria, and predose 
concentration during multiple 
dosing (Ctrough) obtained at 
scheduled PK sample 
timepoints in participants who 
meet the safety population 
criteria, for the switching arm 
and non-switching arm.

Summarize safety endpoints for 
the switching arm and 
non-switching arm in 
participants who meet the safety 
population criteria.

Summarize percent of 
participants with antidrug 
antibodies (ADA), and 
neutralizing antibodies (NAb) 
and ADA/NAb titers over time 
for the switching arm and 
non-switching arm in 
participants who meet the 
Safety population criteria.

Other serum adalimumab PK 
parameters, including Tmax, 
Cav, and CL/F obtained during 
the intensive PK sampling 
interval and Ctrough obtained at 
scheduled PK sample 
timepoints.

Safety measures characterized 
by type, incidence, severity, 
timing, seriousness and 
relatedness of 
treatment-emergent AEs and 
laboratory test abnormalities. 

Percent of participants with 
ADA/NAb and ADA/NAb 
titers over time. 
Overall Design
This is an open-label, 2-arm, randomized, parallel-group study conducted to assess the 
impact of multiple switches between Humira and PF-06410293 on steady state adalimumab 
PK compared to the steady state PK of adalimumab following continuous dosing with 
Humira. This study is also designed to evaluate safety and immunogenicity after 
investigational product (IP) switching between the switching arm (Humira and 
PF-06410293), as compared with non-switching arm (Humira). For purposes of this 


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protocol, the treatment arm that includes switches between PF-06410293 and Humira will be 
referred to as the “switching” arm, while the treatment arm that comprises continuous 
Humira treatment will be referred to as the “non-switching” arm.
The study will include adult participants between the age of 18 and 70 years with moderate to 
severe rheumatoid arthritis (RA) who are on background methotrexate (MTX).  This study 
has two arms and comprises 3 switches in the switching arm, which has a total of four 
treatment periods (TP).  

TP1 (Lead In Period) will begin with the first dose of investigational product Humira
on Week 0 (Day 1) and conclude with the completion of Week 10 pre-dose 
assessments. 

TP2 will begin with the 1:1 randomization of the participants to either the switching 
arm or the non-switching arm at Week 10.  Investigational product dosing for 
Week 10 will begin after the randomization process in the respective treatment arms 
and will conclude with the completion of Week 16 pre-dose assessments.  

TP3 will begin with investigational product dosing on Week 16, and conclude with 
the completion of Week 22 pre-dose assessments.  

TP4 will begin with investigational product dosing on Week 22 and continue through 
Week 30, where onsite investigational product dosing is scheduled at Weeks 22, 24, 
26, 28, and 30, followed by a 2-week PK sampling period from Week 30 to Week 32. 
TP4 will conclude with end of treatment (EoT) assessments and final dose 
administration at Week 32.  

The 2-week PK sampling period starts with Week 30 predose PK collection and ends 
with predose PK collection on Week 32.

Safety Follow-Up Period begins after the last investigational product dosing on 
Week 32, and concludes at completion of the Week 36 assessments. All participants 
(including early discontinuations) will be followed for at least 28 calendar days from 
the date of their last dosed investigational product. Week 36 safety follow up may be 
conducted via phone.
Number of Participants
A maximum of approximately 420 participants will be enrolled into the study such that 
approximately 314 evaluable participants complete the study. 
Intervention Groups and Duration
The total duration of study participation is 36 weeks.  Participants will receive investigational 
product for the first 30 weeks over 4 treatment periods, followed by a 2-week intense 
PK sample collection period, last investigational product dosing at the end of the PK 
sampling period and a 4 week safety follow up.  The duration and details of each treatment 
period are described in the previous section.  


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Every participant will receive adalimumab 40 mg to be administered subcutaneously (SC) 
every 2 weeks; on-site injections will occur at the clinic during scheduled visits. The first 
injection is to be administered at the site under the supervision of the investigator or 
designee, where the participant and/or care giver will be assessed for their ability to 
administer adalimumab. Any issues may be reviewed at that time. The first injection should 
be an abdominal injection. Subsequently, the injection location may be the abdomen or 
upper front of either thigh, unless otherwise specified in the Schedule of Activities (SoA).
Following the first injection at the site, the participant should select a day of the week to 
administer their investigational product injections at home every other week, on the same 
day, except on the weeks where an onsite visit is scheduled.  Injections will occur during the 
scheduled visits under the supervision of the site’s investigator or designee.  Every effort 
should be made for participants to return for the scheduled visits and investigational product 
administration within the visit windows outlined in the SoA to support the PK endpoints of 
this study.
Please refer to Section 6 for additional investigational product information.
Data Monitoring Committee: 
This study will not use a data monitoring committee (DMC).
Statistical Methods
Pharmacokinetics
The serum concentrations between Week 30 and Week 32 will be analyzed for the PK 
population using standard non-compartmental analysis to estimate the PK parameters for 
each individual participant. The PK parameters: maximum observed concentration (Cmax), 
area under the concentration - time curve over the dosing interval (AUC), time at which Cmax
occurs (Tmax), average concentration (Cav), predose concentration during multiple dosing
(Ctrough), and apparent clearance (CL/F), and the serum concentrations will be summarized 
descriptively. 
Interchangeability will be assessed by constructing the point estimate and the 
90% confidence intervals (CIs) for the geometric mean ratio (GMR) for the primary 
endpoints Cmax and AUC.  Interchangeability will be established statistically if the 90% CI 
for the GMR is within (80.00%, 125.00%) for both endpoints.  The GMR and CI will be 
obtained using analysis of variance (ANOVA) applied to log-transformed data, with terms 
for treatment and randomization stratification factors (weight categories).
Safety
Adverse Events will be summarized descriptively using Safety-TP1 population for Humira 
group in TP1 and using Safety-Randomized populations for switching arm and 
non-switching arm during TP2 through TP4.  


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Immunogenicity
For the ADA (antidrug antibodies) and NAb (neutralizing antibodies) data, the percentage of 
participants with positive ADA and NAb will be summarized for the safety-randomized 
population by each visit in each Treatment Period.  For participants with positive ADA and 
NAb, the magnitude (titer), time of onset, and duration of ADA and NAb response will also 
be described.  In addition, immune-related safety will be described for the safety population 
including injection site reactions (ISR), hypersensitivity, anaphylaxis, and angioedema.  
Efficacy
This study will not evaluate efficacy.  


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1.2. Schema
TP = Treatment Period.
TP 3
6 weeks
30
PF-06410293   
PF-06410293   
Humira 
Humira
Last dose before
2 week PK sampling
Last dose in 
the study
Humira
Safety 
Follow-Up
36
32
TP 1 (Lead In Period)
10 Weeks
TP 4
10 Weeks
Week
0
10
22
TP 2
6 weeks
Adalimumab Switches in Switching Arm
Randomize
1:1 Ratio
16
PK
PK


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1.3. Schedule of Activities (SoA)
The SoA table provides an overview of the protocol visits and procedures.  Refer to the STUDY ASSESSMENTS AND 
PROCEDURES section of the protocol for detailed information on each procedure and assessment required for compliance with the 
protocol. 
The investigator may schedule visits (unplanned visits) in addition to those listed in the SoA table, in order to conduct evaluations or 
assessments required to protect the well-being of the participant. 
Study related visits and procedures may be disrupted during the Coronavirus Disease 2019 (COVID-19) pandemic, please see 
Appendix 11 for alternative solutions, if applicable.
Study Period
Scree
n
Treatment 
Period 1 
(Lead In)
Treatment
Period 2
Treatmen
t
Period 3
Treatment
Period 4
Safety Follow up 
Visit Identifier
1
2
(BL)
3
4
5
6
7
8
9
10
PK Profile 
Phlebotomy14
11 (EOT
/ET)16
1218
Study Week1
-6 to -1
0
4
10
16
22
24
26
28
30
30, 31
32
36
Study Day
-42 to -1
1
29
71
113
155
169
183
197
211
211 - 224
225
253
Visit Window in Days
+7
7
7
7
7
7
7
7
[1]
1
+14
Informed Consent
X
Inclusion/Exclusion Criteria
X
X
Contraception check
X
Medical History
X
Demography
X
Prior Treatments for RA
X
HIV, Hepatitis B & C2
X
FSH3
X
Tuberculosis Test4
X
Chest Radiography5
X
Single ECG (12-Lead)
X
Participant ID number (IWRS)6
X
Randomization (IWRS)7
X
Complete Physical Examination8
X
X16
Vital Signs9
X
X
X
X
Body Weight10
X
X
X10
X


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Study Period
Scree
n
Treatment 
Period 1 
(Lead In)
Treatment
Period 2
Treatmen
t
Period 3
Treatment
Period 4
Safety Follow up 
Visit Identifier
1
2
(BL)
3
4
5
6
7
8
9
10
PK Profile 
Phlebotomy14
11 (EOT
/ET)16
1218
Study Week1
-6 to -1
0
4
10
16
22
24
26
28
30
30, 31
32
36
Study Day
-42 to -1
1
29
71
113
155
169
183
197
211
211 - 224
225
253
Visit Window in Days
+7
±7
±7
±7
±7
±7
±7
±7
[±1]
±1
+14
Pregnancy Test11
X
X
X
Contraception Verification
X
Safety Laboratory
Hematology
X
X
X
X
Chemistry
X
X
X
X
Urinalysis
X
X
X
X
Urine Drug screen
X
ADA/NAb Samples12
X
X
X
X
X
X
X
X
X
 
Drug Concentration Samples14
X
X
X
X
X
X
X
X
X14
(7 samples)
X
Adalimumab SC Injection15
X
X
X
X
X
X
X
X
X
X
Background Methotrexate and 
folic/folinic acid
X
X
X
X
X
X-----------------------------------------------------------------------------------------------X
Assessment of AEs17
X
X
X
X
X
X-----------------------------------------------------------------------------------------------X
Assessment of Concomitant 
Medications18
X
X
X
X
X
X-----------------------------------------------------------------------------------------------X
Abbreviations: ADA = Anti-drug Antibody; AE = Adverse Event; BL = Baseline; ECG = Electrocardiogram; EOT = End of Treatment Period; ET = Early Termination; 
FSH = follicle stimulating hormone; HCG = human chorionic gonadotropin; HIV = Human Immunodeficiency Virus; ID = Identification; IWRS = InteractiveWeb-based response 
system; NAb = Neutralizing antibody; PK = Pharmacokinetics; 
; SC = Subcutaneous. 
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Footnotes:
1.
Visits should occur when scheduled, within the time window indicated in the column headings. When a visit does not happen on the scheduled day within or outside the 
window, the next visit should still be on the initially scheduled calendar date to restore the original calendar. On investigational product dosing days, assessments and lab 
tests are to be performed prior to dosing unless otherwise stated. This will require special attention to ensure participants do not administer the corresponding visit’s 
adalimumab injection prior to the clinic visit. Additional unscheduled assessments should be performed as clinically indicated.
2.
Viral disease screening, including hepatitis screening (HBsAg, HBcAb, HBsAb, HCVAb and HCV RNA) and HIV screening (HIV-1 Ab and HIV-2 Ab).  HIV screening 
(HIV-1 Ab and HIV-2 Ab) may be performed by the central lab or a local lab (if required by local regulations) at screening or within 6 weeks prior to the first dose of 
investigational product on Day 1. 
3.
Screening test for female participants who are amenorrheic for at least 12 consecutive months at the time of study screening with no alternative pathological or physiological 
cause.  A serum FSH level within the central laboratory’s reference range will confirm the participant’s non-childbearing status.
4.
Tuberculosis test will use QuantiFERON® (QFT) – TB Gold In-Tube Test and must be performed within 6 weeks prior to the first dose of investigational product on Day 1.  
Participants with positive or indeterminate screening QFT result must be re-tested with QFT – TB Gold In-Tube Test and referred to a specialist (eg, pulmonologist, TB 
specialist or infectious disease specialist) for further evaluation of latent or active TB or false positive QFT test result, unless they have past history of having been adequately 
treated with appropriate chemoprophylaxis for latent TB or have completed treatment for active TB previously, in which case re-testing is not required.  Participants who test 
positive and are considered to have current latent TB can enroll in the study if they are on chemophrophylaxis for at least 4 weeks.  
5.
Chest radiography (lateral and posterior-anterior views) must be performed within a 12-week window prior to Screening.  If a chest computed tomography (CT) exam (or an 
alternative chest imaging) is performed within 12 weeks prior to Screening, a chest x-ray is not required.
6.
Individuals who do not meet the criteria for participation in this study (screen failure) within the 6 week screening period may be rescreened.
7.
Participants completing Treatment Period 1 will be randomized into switching or non-switching treatment arms in a 1:1 ratio prior to dosing on Week 10, stratified based on 
3 weight groups (Week 10 weight).  Participants randomized to the non-switching arm will continue on Humira for the remainder of the study, and participants randomized to 
the switching arm will continue switching in each TP (TP2: PF-06410293; TP3: Humira; TP4: PF-06410293).
8.
Complete physical exam (PE) of major body systems.  Additional targeted PE may be performed during the study at the investigator’s discretion, as indicated by signs and 
symptoms of ongoing AEs. 
9.
Vital signs include blood pressure, respiratory and pulse rate, body temperature, body weight, with height measured at Screening only.  Blood pressure and pulse rate should 
be taken from the participant in the supine position after the participant has been resting quietly for at least 5 minutes. 
10. Body weight (BW) for Randomization should use the one collected at Week 10.  Every effort should be made to obtain BW at Week 10 prior to randomization, however, if 
the Week 10 BW is not available, Screening or Baseline BW (whichever is closest to Week 10 visit) may be used to randomize.
11. Pregnancy testing at Screening in female participants of childbearing potential by central lab serum HCG test. Pregnancy testing (HCG) after Screening will be performed 
locally using urine samples. Pregnancy testing may be repeated more frequently if required by IRB/ECs or local regulations, or if potential pregnancy is suspected.
12. Blood samples should be collected for ADA and NAb testing at the time when PK samples are also collected and prior to the next investigational product administration. 
 
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14. Please refer to Table 1 (PK Sampling Table). ALL PK samples will be collected prior to study dose (pre-dose) at visits where onsite injection is scheduled.  Blood 
samples for determination of adalimumab trough drug concentrations will be collected within 6 hours prior to the investigational product administration on Weeks 22, 24, 26, 
28, and on Day 1 (time 0), Weeks 10 and 16 at a maximum of 48 hours prior to, but as close as possible prior to the next investigational product administration (ie, pre-dose).
The 2-week PK sampling period starts with Week 30 predose PK collection and ends with Week 32 predose PK collection.  Blood samples for determination of adalimumab 
drug concentrations for the 2-week PK profile will be collected starting with the Week 30 injection of investigational product (PK Profile Day 1): blood will be collected 
within 6 hours prior to investigational product administration. For the subsequent PK Profile Days, post-Week 30 dosing times for serum collections are 48 (4) hrs on PK 
Profile Day 3, 72 (6) hrs on PK Profile Day 4, 96 (8) hrs on PK Profile Day 5, 144 (8) hrs on PK Profile Day 7, 240 (24) hrs on PK Profile Day 11, and 336 (24) hrs on 
PK Profile Day 15. Every effort should be made to draw samples within the scheduled time points.  The 2-week PK Profile collections may be completed using home 
health care service.
15. Investigational product will be administered by the participant, care giver or site personnel every other week using pre-filled syringes provided by the sponsor; on-site 
injections will occur during every scheduled visits after PK and ADA/NAb sample collection.  The first SC injection should be administered by the participant while at the 
clinic under the supervision of the site’s investigator or designee.  Any issues may be reviewed at that time.  The first injection must be an abdominal injection.  Subsequently, 
the injection location may be the abdomen or upper front of either thigh.  The first TP4 injection at Week 22 and injections at Weeks 24, 26, 28 and 30 (before starting the PK 
profile) must also be administered in the abdomen under the supervision of the site’s investigator or designee.  Applicable injection details (eg, date) will be recorded in the 
electronic Participant Dosing Log.  Investigational product will be dispensed to the participant at each visit.
16. After 30 weeks of investigational product plus 2 weeks of PK profile participants are required to return for an end of treatment (EOT) visit at Week 32 where the last 
investigational product dose is scheduled, then will be followed up for final safety evaluation at Week 36, which may be a phone visit. Early terminated (ET) participants are 
required to return to the clinic as soon as possible after the last investigational product dose for an ET visit and safety phone follow up is also required at least 28 calendar 
days after the last investigational product. Additional targeted PE may be performed at the ET and/or post-treatment follow up visits at the investigator’s discretion, as 
indicated by signs and symptoms of ongoing AEs. 
17. The time investigational product period for actively eliciting and collecting AEs and SAEs (“active collection period”) for each participant begins from the time the
participant provides informed consent, through and including a minimum of 28 calendar days after the last administration of the investigational product. Week 36 safety 
follow up may be conducted via phone. 
18. Concomitant medications will be routinely collected from the time the consent form is signed through the final study visit/contact.  If a participant discontinues early, 
concomitant medications must be followed for 28 calendar days after last dose of investigational product.  Week 36 safety follow up may be conducted via phone. 


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Table 1.
PK Sampling Table
Study 
Period
Treatment 
Period 1
Treatment 
Period 2
Treatment 
Period 3
Treatment Period 4
Visit ID
Day 1 
Abd 
Inj
Wk 
10
Abd 
Inj
Wk 16
Abd Inj
Wk 22
Abd Inj
Wk 24
Abd 
Inj
Wk 26 
Abd 
Inj
Wk 
28 
Abd 
Inj
Wk 
30 
Abd 
Inj
PK 
Day 
3
PK 
Day 
4
PK 
Day 
5
PK 
Day 
7
PK 
Day 
11
Wk 
32
PK Profile 
Day
1
3
4
5
7
11
15
Time (h) 
Post-Dose
0a,b
0a,b
0a,b
0a,b
0a,b
0a,b
0a,b
0a,b
48
72
96
144
240
336a
PK 
Tolerance 
Window 
(h)d
-48
-48
-48
-6
-6
-6
-6
-6c
4c
6c
8c
8c
24c
24c
a.
Predose PK sample.
b.
Injection on-site. 
c.
PK sample must fall within the PK sampling time window for the participant to be Per Protocol (for the primary 
endpoint).
d.
Blood samples for determination of adalimumab trough drug concentrations will be collected within 6 hours prior to 
the investigational product administration on Weeks 22, 24, 26, 28, and on Day 1 (time 0), Weeks 10 and 16 at a 
maximum of 48 hours prior to, but as close as possible prior to the next investigational product administration
(ie, pre-dose). The 2-week PK sampling period starts with Week 30 predose PK collection and end with Week 32 
predose PK collection.  Blood samples for determination of adalimumab drug concentrations for the 2-week PK profile 
will be collected starting with the Week 30 injection of investigational product (PK Profile Day 1): blood will be 
collected within 6 hours prior to investigational product administration. For the subsequent PK Profile Days, 
post-Week 30 dosing times for serum collections are 48 (+4) hrs on PK Profile Day 3, 72 (+6) hrs on PK Profile Day 4, 
96 (+8) hrs on PK Profile Day 5, 144 (+8) hrs on PK Profile Day 7, 240 (+24) hrs on PK Profile Day 11, and 336 (+24) 
hrs on PK Profile Day 15. Every effort should be made to draw samples within the specified time windows.  The 
2-week PK Profile collections may be completed using home health care service 
Abbreviations: Abd = abdominal; h = hour; Inj = injection; PK = pharmacokinetic; Wk = week.
2. INTRODUCTION
Adalimumab (marketed under the brand name HUMIRA®) is a recombinant fully human 
Immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that specifically binds to TNFα and 
blocks its interaction with the p55 and p75 cell surface TNF receptors, thereby neutralizing 
the effect of TNF in inflammatory conditions.  HUMIRA is approved for use in both the 
United States (US) and European Union (EU) for the treatment of rheumatoid arthritis (RA), 
ankylosing spondylitis (AS), psoriatic arthritis (PSA), polyarticular juvenile idiopathic 
arthritis, Crohn's disease (CD), pediatric CD, ulcerative colitis (UC), plaque psoriasis (PS), 
adult and adolescent hidradenitis suppurativa (HS), and pediatric and adult uveitis (UV); it is 
also approved in the EU for axial spondyloarthropathy (radiographic-negative), pediatric 
plaque psoriasis, and juvenile enthesitis-related arthritis. 
PF-06410293 is a fully human IgG1 monoclonal antibody (mAb) and has been approved by 
the FDA as a biosimilar of adalimumab, also referred by the brand name HUMIRA in this 
protocol.  The general term “adalimumab” is sometimes used for convenience when 
discussing the treatments in the 2 arms: switching and non-switching.  


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2.1. Study Rationale 
The purpose of the trial is to support obtaining the FDA’s interchangeability designation, not 
to re-establish “PK equivalence” between licensed Humira and PF-06410293.  The objectives 
and design of this study are generally consistent with recommendations found in the 
corresponding FDA Interchangeability guidance.7  In reference to a biological product, 
interchangeability means that “the biological product may be substituted for the reference 
product without the intervention of the health care provider who prescribed the reference 
product”.7  This study has been designed with input from FDA to deliver sufficient 
information to support the interchangeability of PF-06410293 with the reference product, 
Humira.
2.2. Background 
Pfizer is developing PF-06410293 as a biosimilar and interchangeable product to Humira.  
Biosimilarity has been established through quality, nonclinical, and clinical assessments.  
Regulatory approval for PF-06410293 as a biosimilar to Humira was received from United 
States (US) Food and Drug Administration (FDA).  Pfizer seeks to demonstrate that 
PF-06410293 is interchangeable under Section 351(k)(4) of the PHS Act (FDA Guidance 
2015).8  A designation of interchangeability means that ‘the risk in terms of safety or 
diminished efficacy of alternating or switching between use of the biological product and the 
reference product is not greater than the risk of using the reference product without such 
alternation or switch’ (FDA Guidance, 2019).7
This IC study has been designed to support the FDA interchangeability designation. 
Humira is approved for use in both the United States (US) (first licensed on 31 December 
2002) and European Union (EU) (first authorized on 8 September 2003).  
2.2.1. Clinical Overview
The clinical development program for PF-06410293 consisted of 4 completed clinical 
studies: 3 single-dose PK studies (B5381001, B5381007, and B5381005) in healthy subjects 
using a pre-filled syringe (PFS) and a pre-filled pen (PFP) and 1 multidose safety and 
efficacy study (B5381002) in patients with moderately to severely active RA using a PFS, 
which included a device substudy using PFP.  This program demonstrated the clinical 
similarity between PF-06410293 and Humira that supported the extrapolation to the Humira 
indications. 
The safety profile of PF-06410293 is consistent with that reported in the US Prescribing 
Information (USPI) and Summary of Product characteristics (SmPC) of Humira.1,2  Data 
from the PF-06410293 clinical development program did not reveal any new safety risks for 
PF-06410293.  A summary of the clinical safety in the USPI is shown below: 


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Serious Infections1

Increased risk for developing serious infections. 

Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, 
parasitic, or other opportunistic pathogens have been reported with TNF blockers. 
Patients have frequently presented with disseminated rather than localized disease.

Treatment should not be initiated in patients with an active infection, including 
localized infections. 

Patients greater than 65 years of age, patients with co-morbid conditions and/or 
patients taking concomitant immunosuppressants, may be at greater risk of infection. 
Tuberculosis1

Reactivation of tuberculosis and new onset tuberculosis infections have been 
reported. 

Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents 
has been shown to reduce the risk of tuberculosis reactivation during therapy. 

Consider anti-tuberculosis therapy prior to initiation of treatment. 
Invasive Fungal Infections1

Consider appropriate empiric antifungal therapy, taking into account both the risk for 
severe fungal infection and the risks of antifungal therapy.

Consider consultation with a physician with expertise in the diagnosis and treatment 
of invasive fungal infections. 
Hepatitis B Virus Reactivation1

Use of TNF blockers may increase the risk of reactivation of hepatitis B virus.
Malignancies1

Non-Melanoma Skin Cancer (NMSC): The rate (95% confidence interval) was 
0.8 (0.52, 1.09) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.10, 
0.59) per 100 patient-years among control-treated patients. 

Lymphoma and Leukemia: The observed rate of lymphomas was approximately 
3-fold higher than expected in the general U.S. population according to the 
Surveillance, Epidemiology, and End Results (SEER) database (adjusted for age, 
gender, and race).  Post-marketing cases of acute and chronic leukemia have been 
reported in association with TNF-blocker use in RA and other indications.  Even in 
the absence of TNF-blocker therapy, patients with RA may be at a higher risk 
(approximately 2-fold) than the general population for the development of leukemia. 


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
Malignancies in Pediatric Patients and Young Adults: Malignancies, some fatal, have 
been reported among children, adolescents, and young adults who received treatment 
with TNF-blockers (initiation of therapy ≤18 years of age).  These cases were 
reported post-marketing and are derived from a variety of sources including registries 
and spontaneous postmarketing reports. 
Hypersensitivity Reactions1

Anaphylaxis and angioneurotic edema have been reported following HUMIRA 
administration. 

Allergic reactions (eg, allergic rash, anaphylactoid reaction, fixed drug reaction, non-
specified drug reaction, urticaria) have been observed. 
Neurologic Reactions1

Rare cases of new onset or exacerbation of clinical symptoms and/or radiographic 
evidence of central nervous system, and peripheral demyelinating disease. 
Hematological Reactions1

Rare reports of pancytopenia including aplastic anemia, medically significant 
cytopenia. 
Heart Failure1

Worsening congestive heart failure (CHF) and new onset CHF. 
Autoimmunity1

HUMIRA treatment may result in the formation of autoantibodies. 

Development of a lupus-like syndrome.
2.3. Benefit/Risk Assessment
PF-06410293 has been approved by the US FDA as a biosimilar to Humira. The clinical 
benefit of adalimumab (Humira®) is well established and applies to both drugs used in this 
trial: PF-06410293 and Humira.
The safety profile of adalimumab is well established.  The most common adverse reaction to 
adalimumab are injection site reactions, while the important identified risks include serious 
infections, malignancies, hypersensitivity reactions, hematologic disorders, gastrointestinal 
disorders, heart failure and demyelinating disorders. 
PF-06410293 is approved by US FDA with the same safety profile as described in the 
adalimumab (Humira®) USPI and SmPC.  Appropriate risk evaluation and mitigation 
strategies have been incorporated into this protocol.


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More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events (AEs) of adalimumab may be found in the Humira label, which is 
the SRSD for this study. 
3. OBJECTIVES, ESTIMANDS, AND ENDPOINTS
Objectives
Estimands
Endpoints
Primary: 
Primary:
Primary: 

To evaluate 
interchangeability of 
PF-06510293 and Humira by 
examining adalimumab 
steady-state 
pharmacokinetics in a 
switching arm (following 
3 switches between Humira 
and PF-06410293) as 
compared to a non-switching 
arm (receiving only Humira).

Evaluate the equivalence of 
primary endpoints (maximum 
observed concentration (Cmax) 
and area under the 
concentration-time curve over 
the dosing interval (AUC) 
obtained during the intensive 
PK sampling interval) between 
the switching arm and non-
switching arm in participants 
who meet the PK population 
criteria,that include criteria for 
the number and timing of 
missing doses, availability of 
PK data, adherence to 
background therapy, and major 
protocol deviations related to 
PK assessment.

Cmax and AUCobtained 
during the intensive PK 
sampling interval. 
Objectives
Estimands
Endpoints
Secondary: 
Secondary:
Secondary: 

To evaluate other serum 
adalimumab PK parameters 
in the switching arm and the 
non-switching arm.

To evaluate the overall safety 
and tolerability of the 
switching arm and the 
non-switching arm.

To evaluate immunogenicity 
of the switching arm and the 
non-switching arm.

Summarize other serum 
adalimumab PK parameters, 
including time at which Cmax
occurs (Tmax), average 
concentration over the dosing 
interval (Cav), and apparent 
clearance (CL/F) obtained 
during the intensive PK 
sampling interval in participants 
who meet the PK population 
criteria, and predose 
concentration during multiple 
dosing (Ctrough) obtained at 
scheduled PK sample 
timepoints in participants who 
meet the safety population 
criteria, for the switching arm 
and non-switching arm.

Other serum adalimumab PK 
parameters, including Tmax, 
Cav, and CL/F obtained 
during the intensive PK 
sampling interval and Ctrough
obtained at scheduled PK 
sample timepoints.

Safety measures 
characterized by type, 
incidence, severity, timing, 
seriousness and relatedness 
of treatment-emergent 
adverse events (AEs) and 
laboratory test abnormalities.

Percent of participants with 
ADA/NAb and ADA/NAb 
titers over time.


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
Summarize safety endpoints for 
the switching arm and 
non-switching arm in 
participants who meet the safety 
population criteria.

Summarize percent of 
participants with antidrug 
antibodies (ADA), and 
neutralizing antibodies (NAb) 
and ADA/NAb titers over time 
for the switching arm and 
non-switching arm in 
participants who meet the 
Safety population criteria.
4. STUDY DESIGN
4.1. Overall Design
This is an open-label, multi-national, 2-arm, randomized, parallel-group study designed to 
evaluate the interchangeability of the switching arm (PF-06410293 and Humira), compared 
to non-switching arm (Humira), in participants with moderately to severely active RA on 
background methotrexate (MTX).  For purposes of this protocol, the treatment arm that 
includes switches between PF-06410293 and Humira will be referred to as the “switching” 
arm, while the treatment arm that comprises continuous Humira treatment will be referred to 
as the “non-switching” arm.
This study will enroll a maximum of approximately 420 participants  such that approximately 
314 evaluable participants complete the study. 
Study treatment will be provided through 4 treatment periods.  For the first 10 weeks, all 
participants will receive Humira [Treatment Period (TP) 1].  Upon completion of TP1, 
participants will be randomized (1:1 ratio) into either the switching or the non-switching arm
prior to dosing on Week 10.  Randomization will be stratified by 3 body weight groups 
(Week 10 weight) (≥40 kg to <70 kg; 70 kg to <100 kg; 100 kg to ≤130 kg).  Participants 
randomized to the non-switching arm will continue on Humira for the remainder of the study, 
and participants randomized to the switching arm will continue switching in each TP (TP2: 
PF-06410293; TP3: Humira; TP4: PF-06410293).

TP1 (Lead In Period) will begin with the first dose of investigational product on 
Week 0 (Day 1) and conclude with the completion of Week 10 pre-dose assessments. 

TP2 will begin with the 1:1 randomization of the participants to either the switching 
arm or the non-switching arm at Week 10.  Investigational product dosing for 
Week 10 will begin after the randomization process in the respective treatment arms 
and will conclude with the completion of Week 16 pre-dose assessments.  


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
TP3 will begin with investigational product dosing on Week 16, and conclude with 
the completion of Week 22 pre-dose assessments.  

TP4 will begin with investigational product dosing on Week 22 and continue through 
Week 30, where onsite investigational product dosing is scheduled at Weeks 22, 24, 
26, 28, and 30, followed by a 2-week PK sampling period from Week 30 to Week 32. 
TP4 will conclude with end of treatment (EoT) assessments and final dose 
administration at Week 32.  

The 2-week PK sampling period starts with Week 30 predose PK collection and 
ends with predose PK collection on Week 32. 

Safety Follow-Up Period begins after the last investigational product dosing on 
Week 32, and concludes at completion of the Week 36 assessments.  All participants 
(including early discontinuations) will be followed for at least 28 calendar days from 
the date of their last dosed investigational product. Week 36 safety follow up may be 
conducted via phone.
4.2. Scientific Rationale for Study Design
This study design is consistent with recommendations outlined in the FDA Interchangeability 
guidance7 and FDA Clinical Pharmacology guidance 2016.9  These recommendations include 
lead-in period, switching and non-switching treatment arms, for which the switching arm 
should have at least 3 switches between the biosimilar and reference products.  Furthermore, 
the duration of each treatment period should be sufficient to establish PK steady state, with 
PK samples collected at the end of the last treatment period in both treatment arms for 
determination of steady state PK parameters.  PK parameters should be analyzed using a 
standard bioequivalence (BE) approach with acceptance margins of 80.00% to 125.00%.  
Specific details regarding statistical approaches to data analysis for this study are discussed 
further in Section 9.
This study is also designed to evaluate safety and immunogenicity after several 
investigational product switches between the switching and non-switching arms.
4.3. Justification for Dose
The 40 mg dose is the recommended dose for RA participants in the HUMIRA and 
PF-06410293 labels for moderately to severely active RA patients.  Dose modification is not 
allowed in this trial to avoid potential confounding factors that could impact ADA formation 
and PK, as well as safety (see Section 6.6).
4.4. End of Study Definition
A participant is considered to have completed the study if he/she has completed all treatment 
periods of the study, including the EoT visit (Week 32).  The final safety follow-up is at 
Week 36, which may be done by phone.  Early discontinuation from investigational product
requires participants to return as soon as possible after the last dose of investigational product


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for an EoT visit.  A safety follow-up (may be done by phone) at least 28 calendar days after 
the last investigational product is also required. 
The end of the study is defined when the last participant in the trial completes the date of last 
scheduled visit or contact as shown in the SoA.
5. STUDY POPULATION
This study can fulfill its objectives only if appropriate participants are enrolled.  The 
following eligibility criteria are designed to select participants for whom participation in the 
study is considered appropriate.  All relevant medical and nonmedical conditions should be 
taken into consideration when deciding whether a particular participant is suitable for this 
protocol. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1. Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age and Sex:
1. Male or female participants between the ages of 18 (or the minimum country-specific 
age of consent if >18) and 70 years, inclusive, at Visit 1 (Screen 1).

Refer to Appendix 4 for reproductive criteria for male (Section 10.4.1) and female 
(Section 10.4.2) participants.
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment 
plan, laboratory tests, lifestyle considerations, and other study procedures.
3. Diagnosis of rheumatoid arthritis (RA) based on 2010 American College of 
Rheumatology (ACR)/European League Against Rheumatism (EULAR) 
classification criteria for RA for at least a 4 month duration.
4. Moderately to severely active RA disease based on local standard of care.
5. Must have received oral, subcutaneous (SC), or IM methotrexate for at least 12 weeks 
and been on a stable dose for at least 4 weeks prior to first dose of investigational 
product on Day 1 of TP1.  The stable dose must be 10 to 25 mg per week, with the 
exception of 6 to 25 mg per week where 6 mg per week is a recommended initial dose 
by local guidance or standard of care. 


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6. Stable dose of oral folic acid (at least 1 mg/day on 5 days per week) or oral folinic 
acid (≥5 mg once per week) supplementation for at least 21 days prior to the first dose 
of investigational product on Day 1 of TP1. In countries which do not have approved 
folic acid 1 mg or folinic acid 5 mg presentations, a regimen of folic acid of 5 mg 
weekly is acceptable. 
Weight:
7. Body mass index (BMI) of 18 to 45 kg/m2 and a total body weight of ≥40 kg 
(88 pounds) to ≤130 kg (287 pounds). 
Informed Consent:
8. Capable of giving signed informed consent as described in Appendix 1, which 
includes compliance with the requirements and restrictions listed in the informed 
consent document (ICD) and in this protocol.
5.2. Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions:
1. Evidence or history of nervous system demyelinating diseases (including multiple 
sclerosis, optic neuritis, Guillain-Barré syndrome).  
2. History of seizure disorder requiring treatment in the previous 5 years prior to 
Screening.
3. History of or active significant infection defined by:
a.
History of recurrent (more than one episode) limited herpes simplex which 
requires current chronic antiviral therapy, or disseminated (a single episode) 
herpes simplex. 
b. History of disseminated or recurrent infection with Epstein Barr virus (EBV), 
human papilloma virus (HPV), or varicella zoster.  A single, limited episode in 
the past is not exclusionary. 
c.
Any infection requiring hospitalization or parenteral antimicrobial therapy judged 
clinically significant by the investigator within 6 months prior to first dose of 
investigational product.
d. History of an infected joint prosthesis at any time, with the prosthesis still in situ.
e.
SARS-CoV2 infection (COVID-19) should be considered clinically significant, 
local guidelines on COVID-19 and medical judgement should be followed.


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f.
Any other active infection considered to be clinically significant as assessed by 
the investigator.
4. Known or screen test confirmed positive for human immunodeficiency virus (HIV), 
hepatitis B virus, or hepatitis C (HCV) virus (please see Section 8.2.8 for details on 
testing). 
a.
Positive for HIV.
b. Positive hepatitis B surface antigen (HBsAg).
c.
Positive hepatitis B core antibody (HBcAb) without positive hepatitis B surface 
antibody (HBsAb) (unless it is documented that hepatitis B DNA test is negative).
d. Positive hepatitis C antibody (HCV Ab) results and positive confirmatory HCV 
riboneucleic acid (HCV RNA) results.
5. Evidence of current or recent history of uncontrolled, clinically significant 
hematological, renal, endocrine, pulmonary, gastrointestinal, hepatic, infectious, 
psychiatric, neurologic, allergic, or cardiovascular disease including evidence or 
history of moderate or severe heart failure (NYHA Class III/IV) or Screening 12-lead 
electrocardiogram (ECG) that demonstrates clinically relevant abnormalities which 
may affect participant safety, and participants who are contraindicated for treatment 
with adalimumab in accordance with the approved local label.
6. History of any lymphoproliferative disorder (eg, EBV related lymphoproliferative 
disorder, lymphoma, or leukemia).  Evidence or history of a malignancy within the 
past 5 years (with the exception of adequately treated or excised non-metastatic basal 
cell or squamous cell cancer of the skin, or cervical carcinoma in situ with no 
evidence of recurrence). 
7. History of recurrent inflammatory joint disease other than RA (eg, post infectious 
arthritis, gout, etc.) or history of any other autoimmune rheumatic diseases 
(eg, vasculopathies, spondyloarthropathies, etc.) other than Sjogren’s syndrome.
8. Significant trauma or surgical procedure within 4 weeks prior to first dose of 
investigational product.
9. History of severe allergic or hypersensitivity or anaphylactic reaction to a biologic 
drug or to active or inactive components of the investigational product.
10. Other acute or chronic medical or psychiatric condition including recent (within the 
past year) or active suicidal ideation or behavior 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 participant inappropriate for entry into 
this study.


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Prior/Concomitant Therapy:
11. Prior/Current treatment with adalimumab. 
12. More than 3 disease modifying anti-rheumatic drugs (DMARDs) in combination 
therapy; concomitant DMARD therapy including small molecules, biologics, and 
biosimilars, with the exception of methotrexate (as specified in Section 6.5.1.1) and
stable dose (at least 4 weeks) of leflunomide, anti-malarials and sulfasalazine (please 
reference Section 6.5 and Appendix 9).  
13. Prior lymphocyte depleting therapies (eg, rituximab, Campath) with remaining 
lymphocyte depletion.
14. Known requirement for treatment with prohibited concomitant medications during the 
study.
15. Exposure to any live vaccines within 4 weeks prior to administration of the first dose 
of investigational product, or lack of willingness to avoid exposure to any live 
vaccines during the trial and for at least 2 months after the last dose of investigational 
product.
16. Intra- articular (IA) corticosteroids administered within 4 weeks prior to Screening.
17. Unstable dose (less than 4 weeks) of oral and IM corticosteroid prior to first study 
dose.
Prior/Concurrent Clinical Study Experience:
18. Previous administration with an investigational drug within 30 days (or as determined 
by the local requirement) or within 5 half-lives preceding the first dose of 
investigational product used in this study (whichever is longer) is not permitted. 
Diagnostic Assessments:
19. Clinically significant laboratory abnormalities at Screening, including but not limited 
to inadequate bone marrow, liver, renal and immune system function as defined by 
the following lab criteria:
a.
Hemoglobin (Hgb) <9 g/dL.
b. Absolute neutrophil count (ANC) 1500 cells/mm3.
c.
White blood cell (WBC) count <3.0 x 109/L.
d. Lymphocyte count of <0.5 x 109/L
e.
Platelets <100 x 109/L.


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f.
Aspartate aminotransferase/alanine aminotransferase (AST/ALT) 2 times the 
upper limit of normal.
g. Total bilirubin 1.5 times the upper limit of normal.
h. Serum creatinine 1.5 mg/dL.
i.
Serum albumin <3.0 g/dL.
20. Evidence of untreated or inadequately treated latent or active tuberculosis (TB) 
infection as defined below (See Sections 6.5 and Section 8.2.6): 
a.
If screening QuantiFERON-TB test is positive or indeterminate in a participant 
without history of active or latent TB, a retest of QuantiFERON-TB is required 
and the participant should be referred to a specialist according to local practice
(eg, pulmonologist, TB specialist or infectious disease specialist) for further 
evaluation of latent or active TB or false positive QuantiFERON-TB test result.  
Participants who are determined to have a false positive QuantiFERON-TB test 
result by the specialist are eligible to enroll. 
b. Participants diagnosed with latent TB at Screening are required to receive at least 
4 weeks of chemprophylaxis according to local clinical guidelines and repeat 
aminotransferases (ALT/AST) within at least 4 weeks prior to receiving study 
dose on Day 1 to confirm participants still fulfill entry criteria.  Participants need 
to commit to completion of the chemoprophylaxis course.
c.
Participants previously treated for active TB must have completed a successful 
course of treatment in accordance with local guidelines. 
d. Participants previously treated for latent TB infection, must have completed a 
successful course of chemoprophylaxis in accordance with local guidelines; or if 
chemoprophylaxis is still ongoing, participants must have received at least 
4 weeks before receiving study dose on Day 1.  Participants need to commit to 
completion of the chemoprophylaxis course. 
21. Chest radiography (or alternative chest imaging, ie, chest computed tomography (CT)
scan) with evidence of active TB, fungal infections, or other clinically significant 
abnormalities taken within 12 weeks prior to Screening.  If the TB has been 
adequately treated as specified in Exclusion Criteria 20, a chest imaging result 
consistent with prior TB (active or latent) will not exclude the participant.  (See 
Section 8.2.3) 
22. Positive urine drug test at Screening for substances of abuse that is not due to 
prescribed medication, or past or current history of addiction to or dependence on 
non-prescribed substances within 12 months prior to Screening.


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Other Exclusions:
23. Investigator site staff members directly involved in the conduct of the study and their 
family members, site staff members otherwise supervised by the investigator, or 
Pfizer employees, including their family members, directly involved in the conduct of 
the study. 
24. Pregnant females and breastfeeding females, male participants with partners currently 
pregnant who are unwilling to use a condom, or male and female participants of 
childbearing potential who are unwilling or unable to use an effective method of 
contraception as outlined in this protocol for the duration of the study and for at least 
5 months after the last dose of investigational product. 
5.3. Lifestyle Considerations
No lifestyle restrictions are required.  
5.3.1. Contraception 
The investigator or his or her designee, in consultation with the participant, will confirm that 
the participant has selected an appropriate method of contraception for the individual 
participant and his or her partner(s) from the permitted list of contraception methods (see 
Appendix 4 and Section 10.4.4) and will confirm that the participant has been instructed in 
its consistent and correct use.  At time points indicated in the SoA, the investigator or 
designee will inform the participant of the need to use effective contraception consistently 
and correctly and document the conversation and the participant’s affirmation in the 
participant’s chart (participants need to affirm their consistent and correct use of at least 1 of 
the selected methods of contraception).  In addition, the investigator or designee will instruct 
the participant to call immediately if the selected contraception method is discontinued or if 
pregnancy is known or suspected in the participant or partner.
5.4. Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently enrolled to receive investigational product.  A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure participants to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements 
and to respond to queries from regulatory authorities.  Minimal information includes 
demography, screen failure details, eligibility criteria, and any SAE.
Participants who do not meet all eligibility criteria may be retested (under the same screening 
number) within the 6 week screening period, and if the retest result(s) meet the eligibility 
criteria, the participant will not be considered as a screen fail and may enroll into the study.  
Individuals who do not meet the criteria for participation in this study within the 6 week 
screening period will be considered as screen failure, they may be rescreened.  


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6. INVESTIGATIONAL PRODUCT
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
For the purposes of this protocol, the term investigational product may be used 
synonymously with investigational product.
6.1. Investigational Product(s) Administered
The following table outlines the two investigational products used in this protocol. For more 
detailed information please refer to the Investigational Product (IP) Manual.
Intervention Name
PF-06410293
Humira
Type
Biologic
Biologic
Dose Formulation
solution for injections/solution for 
injection
solution for injections/solution 
for injection 
Unit Dose Strength(s)
40 mg /0.8 mL
40 mg/0.4 mL
Dosage Level(s)
40 mg every 2 weeks
40 mg every 2 weeks
Route of Administration
Subcutaneous (SC)
Subcutaneous (SC)
Investigational Medicinal 
Product (IMP) and 
Noninvestigational 
Medicinal Product (NIMP)
IMP 
IMP 
Sourcing
Provided centrally by the sponsor 
Provided centrally by the 
sponsor 
Packaging and Labeling
Investigational product will be 
provided in an Open Labeled 
Carton. Each carton will contain 
one syringe and will be labeled as 
required per country requirement.
Investigational product will be 
provided in an Open Labeled 
Carton.  Each carton will contain 
one syringe and will be labeled 
as required per country 
requirement.
6.1.1. Administration
Investigational product will be administered by the participant, care giver or site personnel
every other week using pre-filled syringes provided by the sponsor.  All participants will 
receive instruction on administration of investigational product by SC injection and may only 
inject following the Instructions for Use (IFU) (see Section 6.1.2).  Participants who are not 
capable of, or choose not to administer investigational product, may have their injections 
administered by a care-giver following the IFU.  Onsite injections will occur at every 
scheduled visit, after the PK and ADA/NAb sample is collected (See SoA and Table 1.
PK 
Sampling Table).
The first SC injection should be administered at the site under the supervision of the site’s 
investigator or designee, and the participant will be assessed for their ability to inject 
adalimumab. Any issues may be reviewed at that time. The first injection must be an 
abdominal injection.  The first TP4 injection at Week 22 and injections at Weeks 24, 26, 28 
and 30 (before starting the PK profile) must also be administered in the abdomen under the 
supervision of the site’s investigator or designee.  All other injections may be administered in 


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the abdomen or upper front of either thigh.  Applicable injection details (eg, date) will be 
recorded in the electronic Participant Dosing Log.  Investigational product will be dispensed 
to the participant at each visit.
Following the first injection at the site, the participant should select a day of the week for 
their every other week injections at home. For example, if the first injection occurred on a 
Monday (study Day 1) the participant should continue every other week injections on a 
Monday (study Day 15). Participants should select a day of the week which will most likely 
ensure compliance (eg, no late or forgotten doses). On-site injections will occur under the 
supervision of the site’s investigator or designee during the scheduled visits (See SoA). Any 
participant found to be non-compliant for any reason other than safety should be instructed to 
administer the non-compliant dose as soon as he/she remembers, as long as the time elapsed 
following the intended dosing time is ≤7 days. He/she should inject the next dose as 
scheduled. Once 7 days passes from a regularly scheduled dose, the delayed dose in the 
previous 2 week dosing period will be considered missing (not delayed), and shall not be 
administered. It is critical for participants be compliant with the dosing schedule. In 
particular, participant dosing compliance during TP4 is critical in order to achieve the 
primary objective of this study. In order to support PK collection starting at Week 30, 
participants must have received (at a minimum) 3 doses, specifically those at Week 26, 
Week 28 and Week 30. These injections must be administered in the abdomen while at the 
clinic under the supervision of the site’s investigator or designee.  
Applicable adalimumab injection details (eg, dates) will be recorded in the electronic 
Participant Dosing Log by the participant.  Once the pre-filled syringe is used the empty 
investigational product container should be returned.  The drug will be injected into a 
quadrant of the abdominal wall, remaining 2” inches/5 cm away from the navel, or upper 
front of either thigh.  Participants should carefully inspect the adalimumab solution in the 
syringe for particulate matter and discoloration prior to SC administration.  If particulates or 
discolorations are noted, the product should not be used.  Participants should use the next 
available pre-filled syringe for the scheduled dose and contact the investigator.  Participants 
should rotate injection sites and not administer injections into areas where the skin is tender, 
bruised, red or hard.  If any unused portion of the drug remains in the syringe after the drug 
administration, the remaining drug should be discarded with no attempt to re-inject.  
Participants should call the study site to discuss any problems, issues, and concerns related to 
the drug administration.  Participants should return any dropped (while uncapped) or frozen 
unused syringes.  If a potential defect is noted in the prefilled syringe (or its labeling or 
packaging), or the syringe fails to perform, the syringe should be returned to the site and the 
site should file a Medical Device Complaint (Refer to the IP Manual for specific instructions 
related to the form).  Site staff should also follow the above described process to inspect the 
pre-filled syringe for onsite injections and report issues as noted. 
Participants will be instructed to dispose of their used needles and syringes in a FDA-cleared 
biohazard disposal container immediately after use. Participants must not dispose their used 
biohazard disposal container in their household trash but may return them to the site, or they 
may dispose of them locally according to local guidelines. 


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Reference the IP manual for further details.
6.1.2. Training for Adalimumab Subcutaneous Injections
All participants will be provided the Instruction For Use (IFU) and will be supervised for the 
administration of their first dose of investigational product on study Day 1.  As noted above, 
the first SC injection must be an abdominal injection.  The first TP4 injection at Week 22 and 
injections at Weeks 24, 26, 28 and 30 (before starting the PK profile) must also be 
administered in the abdomen under the supervision of the site’s investigator or designee
(please also refer to Section 6.1). All other injections may be administered in the abdomen or 
upper front of either thigh.  IFU of the investigational product will be provided to the 
participant on Day 1 by the investigator or designee, and explanations will be provided as 
necessary.  Study staff, caregivers, and participants should refer to the participant dosing 
instructions on the handling and administration of the investigational product.  
6.1.3. Medical Devices 
1. The Pfizer manufactured medical device (or device manufactured for Pfizer by a third 
party) provided for use in this study is the PF-06410293 solution for injection 
prefilled syringe.
2. Other medical device (not manufactured by or for Pfizer) provided for use in this 
study is the Humira solution for injection syringe. 
3. Instructions for medical device use are provided in the Instruction For Use.
4. Medical device incidents must be detected, documented, and reported by the 
investigator throughout the study (see Section 8.3.7).  For device incidents resulting 
from malfunctions of the device please also refer to the Investigational Product 
Manual for the device complaint process instructions.
6.2. Preparation/Handling/Storage/Accountability
1. The investigator or designee must confirm appropriate temperature conditions have 
been maintained during transit for all investigational product received and that any 
discrepancies are reported and resolved before use of the investigational product, as 
applicable for temperature-monitored shipments. 
2. Only participants enrolled in the study may receive investigational product and only
authorized site staff may supply or administer investigational product.  All 
investigational products must be stored in a secure, environmentally controlled, and 
monitored (manual or automated recording) area in accordance with the labeled 
storage conditions with access limited to the investigator and authorized site staff.  At 
a minimum, daily minimum and maximum temperatures for all site storage locations 
must be documented and available upon request.  Data for nonworking days must 
indicate the minimum and maximum temperature since previously documented for all 
site storage locations upon return to business.


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3. The investigator, institution, or the head of the medical institution (where applicable) 
is responsible for investigational product accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records).  All 
investigational products will be accounted for using an investigational product 
accountability form/record. Once the pre-filled syringe is used, the empty 
investigational product container should be returned.  
4. Further guidance and information for the final disposition of unused investigational 
products are provided in the IP manual.
5. Any storage conditions stated in the SRSD will be superseded by the storage 
conditions stated on the product label. 
6. Investigational products should be stored in their original containers and in 
accordance with the labels. 
7. Site staff will instruct participants on the proper storage requirements for take-home 
investigational product. 
8. Any excursions from the investigational product label storage conditions should be 
reported to Pfizer upon discovery along with any actions taken.  The site should 
actively pursue options for returning the investigational product to the storage 
conditions described in the labeling, as soon as possible.  Once an excursion is 
identified, the investigational product must be quarantined and not used until Pfizer 
provides permission to use the investigational product.  It will not be considered a 
protocol deviation if Pfizer approves the use of the investigational product after the 
temperature excursion. Use of the investigational product prior to Pfizer approval 
will be considered a protocol deviation. Specific details regarding the definition of an 
excursion and information the site should report for each excursion will be provided 
to the site in the IP manual.
9. The sponsor or designee will provide guidance on the destruction of unused 
investigational product (eg, at the site).  If destruction is authorized to take place at 
the investigator site, the investigator must ensure that the materials are destroyed in 
compliance with applicable environmental regulations, institutional policy, and any 
special instructions provided by Pfizer, and all destruction must be adequately 
documented.
Additional details about accountability, storage, destruction, and excursion reporting can be 
found in the IP manual.


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6.2.1. Preparation and Dispensing
No preparation is required for either investigational product prior to use.
Single use PF-06410293 and Humira will be provided to the participants in pre-filled syringe 
(PFS) which are individually packaged in containers with tamper evident seals.  The cartons 
should not be opened until the drug is to be administered.  The investigational product will be 
dispensed using an interactive response technology (IRT) drug management system at each 
visit from Week 0 to Week 32; investigational product will be given to the participants for 
the exact number of doses needed between visits from Week 0 to Week 22.  A qualified staff 
member will dispense the investigational product via unique container numbers in the cartons 
provided, and in quantities appropriate so that participants will receive enough PFSs to cover 
the exact number of doses until the next scheduled clinic visit.  Participants will receive a 
carry case and cool pack for transport of investigational product, which must remain cool but 
not frozen.
When handling investigational product at the site, it is important that the study personnel 
handle only one participant’s investigational product container(s) at a time, to avoid a mix up 
with another participant’s investigational product container(s).
If applicable, please reference Appendix 11 for alternative options on investigational product 
dispensing during the COVID-19 pandemic.
6.3. Measures to Minimize Bias: Randomization and Blinding
This is an open-label study.  
Upon successful completion of TP1, participants will be randomized (1:1 ratio) into either 
the switching arm (ie, to PF-06410293) or the non-switching arm (ie, continue to receive 
Humira).  Randomization will be stratified by 3 body weight groups (40 kg to <70 kg; 
70 kg to <100 kg; 100 kg to ≤130 kg).  Participants randomized to the Humira arm will 
continue on Humira for the remainder of the study, and participants randomized to switch to 
PF-06410293 will continue switching in each TP (TP2: PF-06410293; TP3: Humira; TP4: 
PF-06410293).
6.3.1. Allocation to Investigational Product
Allocation of participants to treatment groups will proceed through the use of an interactive 
response technology (IRT) system (interactive Web-based response [IWR]).  The site 
personnel (study coordinator or specified designee) will be required to enter or select 
information including but not limited to the user’s identification (ID) and password, the 
protocol number, and the participant number.  
This is an open-label study; however, the specific investigational product dispensed to the 
participant will be assigned using an IRT. The site will contact the IRT upon the completion 
of Screening assessments on Study Day 1, if the participant is found to be eligible for the 
study.  On Study Day 1 and throughout Treatment Period 1 all participants will receive 
Humira. Upon successful completion of TP1, the site will contact the IRT prior to the start 


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of Week 10 investigational product administration for each participant to randomize the 
participant into the study (see Section 6.3). The site will record the investigational product 
assignment on the applicable case report form. Potential bias will be reduced by central 
randomization.
The investigator’s knowledge of the treatment should not influence the decision to enroll a 
particular participant or affect the order in which participants are enrolled.
Investigational product will be dispensed at the study visits summarized in the SoA. 
The study-specific IRT reference manual and IP manual will provide the contact information 
and further details on the use of the IRT system.
6.3.2. Breaking the Blind (Not Applicable)
This is an open-label trial. 
6.4. Investigational Product Compliance
Participant compliance will be verified by the review of the electronic Participant Dosing 
Log (or relevant source document), the returned unused investigational product, and 
accounting for any unused investigational product by the participant. When investigational 
product is administered at the study center (eg, Day 1 dosing), it will be administered under 
the supervision of study personnel (see Section 6.1). Compliance will be evaluated at all 
study visits beginning at Week 4. Participants will be directed to record the applicable 
injection details (eg, date) in the electronic Participant Dosing Log, and site personnel will 
enter this information onto electronic case report form (eCRF). Any participant found to be 
non-compliant for a reason other than safety should be instructed to self-administer the 
missed dose as soon as possible, as long as the time elapsed following the intended dosing 
time is ≤7 days. He/she should inject the next dose as scheduled. Once 7 days passes from a 
regularly scheduled dose, the delayed dose in the previous 2 week dosing period will be 
considered missing (not delayed), and shall not be administered. The participant should be 
reeducated on the every other week dosing regimen, and to revert to the original calendar day 
scheduled after any single dose outside the original calendar schedule. The investigator or 
designee should assess potential factors leading to less than complete compliance and take 
steps to improve compliance (see Section 7.1.1). Compliance and non-compliance of study 
participants will be monitored by study personnel at the site by using the source documents 
including the electronic Participant Dosing Log as noted above. See Section 7.1 for 
discontinuation of participants with noncompliance.
If applicable, please reference Appendix 11 for alternative options on investigational product 
compliance during the COVID-19 pandemic.
6.5. Concomitant Therapy
Hormonal contraceptives that meet the requirements of this study are allowed to be used in 
participants who are WOCBP (see Appendix 4).


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Medications that are taken after informed consent is obtained, but before the first dose of
investigational product is received, will be documented as prior medications.  The dosage 
and duration of all background RA medications will also be recorded on the eCRF for 
documentation of study eligibility.  Medications taken after the first dose of investigational 
product has been administered will be documented as concomitant medications.  Use of any 
allowed concomitant medications must follow local standard of care practices and 
regulations for the treated indication.  
For participants who are on DMARD therapy (with the exception of methotrexate as 
specified in Section 6.5.1.1) and stable dose (at least 4 weeks) of leflunomide, anti-malarials 
and sulfasalazine the doses can be reduced or discontinued as per medical judgement.  In the 
case of suspected COVID-19 infection, continuation of concomitant DMARD therapy should 
be carefully evaluated following local guidance and medical judgement, until full clinical 
assessment is completed.  Initiation of additional DMARDs or an increase in the dose of 
current DMARD therapy during the study is prohibited.  A combination of no more than 
3 DMARDs is permitted during the study.
Participants are encouraged to bring their vaccinations up to date prior to initiating 
adalimumab; any live attenuated vaccine must have been administered at least 4 weeks prior 
to Day 1.
Participants previously treated for active TB infection, must have completed and documented 
a successful course of treatment in accordance with local guidelines.  Participants detected 
with latent TB at Screening are eligible providing they have received at least 4 weeks of 
chemoprophylaxis and commit to completion of the full course of treatment, in accordance 
with local standard of care, before starting the study treatment.  Participants whose chest 
radiography (or alternative chest imaging) and QuantiFERON-TB Gold In-Tube Test 
results indicate no evidence of TB infection, but who are considered by the investigator to be 
at high risk to develop tuberculosis (eg, residing in high-risk areas or travel to high-risk 
areas), may be started on a course of TB prophylaxis or treatment in accordance with local 
guidelines at the discretion of the investigator.  If TB prophylaxis treatment is started after 
the Screening visit, aminotransferases (ALT/AST) levels should be checked within at least 
4 weeks prior to first investigational product in TP1 to confirm results fulfill entry criteria.
It is recommended that participants avoid changing prescription or non-prescription drugs, 
vitamins, and dietary supplements within 7 days or 5 half-lives (whichever is longer) prior to 
the first dose of investigational product and prior to study visits unless otherwise noted 
below, throughout the study. 
Concomitant medications will be collected at each visit/contact from the time the consent 
form is signed to the final study visit/contact.  All concomitant medication taken during the 
study (prescription, non-prescription drugs, and non-drug therapy as appropriate) must be 
recorded on the eCRF with daily dose, and start and stop dates of administration.  If a 
participant discontinues early, concomitant medications must be followed at the EoT visit, 
the safety follow-up visit at least 28 calendar days after the last dose of investigational 
product, and any additional post-treatment phone contact and/or extended safety follow-up.


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Concomitant medications prohibited in the study are summarized in Appendix 10.
6.5.1. Stable Background Therapies
6.5.1.1. Methotrexate
Adalimumab must be administered concomitantly with a stable dose of MTX throughout the 
course of study treatment. 
The administration of MTX, including dosage, laboratory testing, follow-up care (including 
contraception requirements), and contraindications should be performed according to local 
standards of care throughout the study. 
At study entry, participants must have received oral or IM MTX for at least 12 weeks and 
have been on a stable dose of 10 to 25 mg per week for at least 4 weeks prior to first dose of 
investigational product.  In geographic regions where 6 mg per week is a recommended 
initial dose by local guidance or standard of care, a stable dose of as low as 6 mg per week 
for at least 4 weeks prior to first dose of investigational product will be permitted. 
Participants are required to continue their stable dose of MTX background therapy 
throughout the study.  Dose reduction of MTX therapy during the study treatment is not 
recommended, with the exception of significant intolerance, and the dose reduction must be 
documented with the investigator’s medical justification.  Participants will not be 
discontinued from study treatment following a justified dose reduction of MTX, unless the 
MTX is adjusted below the minimal required dosage level of 7.5 mg/week (or a dose as low 
as 6 mg/week in geographic regions where permitted by local guidance or standard of care). 
6.5.1.2. Folic/Folinic Acid Supplements
Participants are required to receive a stable background dose of oral folic/folinic acid 
supplementation throughout the study.  Participants must have received an adequate stable 
dose of oral folate (at least 1 mg/day on 5 days per week) or oral folinic acid (5 mg once 
per week) for at least 21 days prior to first dose of investigational product and will continue 
on the regimen throughout the study treatment.  In countries which do not have approved 
folic acid 1 mg or folinic acid 5 mg presentations, a regimen of folic acid of at least 5 mg 
weekly is acceptable.  
6.5.1.3. Additional Background Therapies
Participants may also continue additional concomitant therapies, including corticosteroids, a 
NSAID or Cyclooxygenase-2 (COX-2) inhibitor, and non-opioid and allowed opioid/narcotic 
analgesics (see Section 6.5.2, Section 6.5.3 and Appendix 9).  


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6.5.2. Pain or Other Arthritis Therapy
Participants may receive the following concomitant medications during the study under 
restricted conditions as specified below:
1. Participants may be taking one NSAID, including a COX-2 inhibitor.  At the 
discretion of the investigator, the dosage may be adjusted to protect a participant’s 
safety during the study.  
2. Participants may additionally be receiving low dose aspirin for cardiovascular use 
(325 mg per day).
3. Intra articular (IA) corticosteroids, oral and IM corticosteroids are allowed as rescue 
therapy, as described in Section 6.5.3.  Participants who enter the study with oral or
IM corticosteroids must be on stable dosing regimen for at least 4 weeks prior to the 
first study treatment dose.  At the discretion of the investigator, the corticosteroid 
dosage may be adjusted during the trial as per investigator’s medical judgment.  
Tapering or discontinuation of the corticosteroid treatment should be performed as 
per local standard of care.
4. Participants receiving regular daily doses of only one of the allowed 
immediate-release opioids/narcotics (including tramadol) as listed in Table 2, and/or a 
regular a daily dose of up to 2 grams/day (or maximal local label daily dosage) of 
acetaminophen or 3 grams/day of paracetamol (eg, not using analgesic medication ‘as 
needed’) according to local guidance, must be on stable doses for at least 2 weeks 
prior to Day 1.  Less frequent dosing or cessation of analgesic therapy should be 
performed as per investigator’s medical judgment. 
5. New or increased doses of following medications will be allowed as rescue therapy, 
as described in Section 6.5.3. 
Table 2.
Permitted Opioid/Narcotic Drugs
Drug
Example Trade Names
Maximum Allowed Total Daily 
Dose
Tramadol
Ultram, Zydol, Zamadol, 
Ultracet, Tramal
300 mg
Codeine
Tylenol #2 and #3, Paveral
200 mg
Hydrocodone
Vicodin, Lortab
30 mg
Oxycodone
Roxicodone, Percocet, 
Tylox (not: OxyContin®)
15 mg
Propoxyphene HCl or 
Propoxyphene napsylate
Darvon, Darvocet, 
Doloxene, Darvon-N, 
Darvocet-N 100
300 mg propoxyphene HCl
400 mg propoxyphene napsylate


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6.5.3. Rescue Medicine 
1. Analgesics: New or increased acetaminophen/paracetamol, current tramadol or other 
single opioid/narcotic drug (see Table 2), or another allowed opioid (see Table 3) are
allowed as rescue medications according to the local label.  
Table 3.
Additional Opioid Drugs for Rescue Therapy
Drug
Example Trade Names
Maximum Allowed Total Daily 
Dose
Morphine
Short acting formulations  
(not: MS Contin®)
30 mg
Hydromorphone
Dilaudid
7.5 mg
Meperidine
Demerol, Pethidine
300 mg
For participants who are receiving regular daily doses of one of the allowed 
opioids/narcotics:

If the opioid/narcotic is tramadol, hydrocodone, or oxycodone, the dosage may be 
increased up to the maximum total daily dosage limits for rescue purposes.  
However, participants can NOT add a second opioid/ narcotic agent for rescue; 
therefore, any original opioid should be discontinued if a new opioid/narcotic is 
started for rescue. 
For participants who are not on a regular daily opioid/narcotic therapy:

Sustained release morphine formulations (eg, MS Contin®), sustained release 
oxycodone formulations (eg, OxyContin®), and propoxyphene HCL/napsylate are 
not allowed for rescue medication.
2. IA corticosteroids may not be administered within 4 weeks prior to Screening visit.  
However, IA injections of corticosteroids are allowed as rescue therapy in this study 
in accordance with the local label.
The following restrictions will apply when the rescue injections are performed:

Rescue injections should be performed following the joint assessment after 
Screening visit.

Investigators should follow local standard of care where participants should 
receive no more than one injection per month and no more than three injections 
per year.

Arthrocentesis without injection of any IA medication is allowed. The joint 
having arthrocentesis will be considered as having its pre-injection status for the 
joint counts.


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3. Non-pharmacologic treatment, including application of heat and cold, massage, 
physical therapy, splinting, or ultrasound is allowed.
6.6. Dose Modification 
No dose adjustment (dosage or dosing frequency) will be allowed in the study. 
6.7. Intervention After the End of the Study
No intervention will be provided to study participants after the end of the study.
7. DISCONTINUATION OF INVESTIGATIONAL PRODUCT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL
7.1. Discontinuation of Investigational product
In rare instances, it may be necessary for a participant to permanently discontinue 
investigational product prior to completing the study. If investigational product is 
permanently discontinued, the participant will remain in the study to be evaluated for at least 
28 calendar days after last dose of investigational product for monitoring of AEs/SAEs and 
concomitant medications. 
Reasons for discontinuation from study treatment may include, but will not be limited to:

AE potentially attributable to investigational product that in the opinion of the 
investigator endangers participant health or safety, including but not limited to severe 
hypersensitivity reactions, serious infections (see Section 2.3 Benefit/Risk 
Assessment), active/latent tuberculosis, serious cardiac arrhythmias, or new or 
worsening congestive heart failure. 

Inadequate response to study treatment, in the judgment of the investigator (per local 
standard of care and/or guidelines).

Participant noncompliance.

Participant choice to withdraw from treatment (follow-up permitted by participant).

Participant choice to withdraw from study participation (cessation of follow-up).

Participant lost to follow-up.

Participant pregnancy.
Note that discontinuation of investigational product does not represent withdrawal from the 
study.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.


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7.1.1. Temporary Discontinuation
Temporary treatment discontinuation may be allowed in the case of an infectious AE or other 
potentially related AE occurring during the first 3 study Treatment Periods and the first 
2 doses of TP4.  Temporary treatment discontinuation should also be considered in the case 
of a known SARS-CoV2 exposure or suspected COVID-19 infection until full clinical 
assessment is completed.
Participants who experience a serious infectious AE (eg, life-threatening, requiring 
hospitalization, documented COVID-19 infection, etc.) or sepsis should be permanently 
discontinued from study treatment.  
Delayed treatment due to other non-medical reasons (eg, participant is out of town and 
forgets to take their investigational product container) should be prevented as much as 
possible by discussing the participant’s plans and educating him/her about the regular every 
other week dosing schedule. In TPs 1 – 3 and the first 2 doses in TP4, a participant who 
misses a dose should be instructed to take the missed dose as soon as he/she remembers, as 
long as the time elapsed following the intended dosing time is <7 days. He/she should take 
the next dose as scheduled. To be included in the PK analysis, it is critical for participants to 
not miss (see Section 9.3):

The last 3 doses in TP4;

The first dose of the study in TP1;

No more than 1 missed dose per TP;

No more than 2 missed doses allowed in TP1 through TP4;

Participants can only miss or have an  incomplete dose for either the first or second 
dose in TP4 (but not both).
A delayed treatment dose should be administered once the AE is resolved if the dose can be 
administered no later than 7 days before the next regularly scheduled dose of investigational 
product.  Once 7 days passes from a regularly scheduled dose, the delayed dose in the 
previous 2 week dosing period will be considered missing (not delayed), and shall not be 
administered.  For example, if the participant does not administer the investigational product
on Monday (July 1), but is able to resume treatment on Sunday (July 8), the delayed July 1 
dose may be administered on July 8.  If the participant cannot resume treatment on July 8, the 
July 1 dose will not be administered (recorded as a missed dose), and the participant will 
receive the next regularly scheduled dose on Monday (July 15). 
7.1.2. Permanent Discontinuation
Participants who experience a serious infectious AE (eg life-threatening, requiring 
hospitalization, documented COVID-19, etc.) or sepsis should be permanently discontinued
from study treatment.  


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Permanent discontinuation would be considered for safety reasons or when either the 
participant or the investigator deemed necessary to discontinue investigational product.  
7.2. Participant Discontinuation/Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request.
At the time of discontinuing from the study, if possible, an early discontinuation visit should 
be conducted.  See the SoA for assessments to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
The early discontinuation visit applies only to participants who are enrolled in the study or 
those who are randomized and then are prematurely withdrawn from the study.  Participants 
should be questioned regarding their reason for withdrawal.  The participant will be 
permanently discontinued both from the investigational product and from the study at that 
time.
If a participant withdraws from the study, he/she may request destruction of any remaining 
samples taken and not tested, and the investigator must document any such requests in the 
site study records and notify the sponsor accordingly.
If the participant withdraws from the study and also withdraws consent (see below) 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.
Lack of completion of all or any of the withdrawal/early termination procedures will not be 
viewed as protocol deviations so long as the participant’s safety was preserved.
Withdrawal of Consent: 
Participants who request to discontinue receipt of study treatment will be discontinued from 
the study.  The only exception to this is when a participant specifically withdraws consent for 
any further contact with him or her or persons previously authorized by the participant to 
provide this information.  Participants should notify the investigator in writing of the decision 
to withdraw consent from future follow-up, whenever possible.  The withdrawal of consent 
should be explained in detail in the medical records by the investigator, as to whether the 
withdrawal is only from further receipt of investigational product or also from study 
procedures and/or post treatment study follow-up, and entered on the appropriate CRF page.  
In the event that vital status (whether the participant is alive or dead) is being measured, 
publicly available information should be used to determine vital status only as appropriately 
directed in accordance with local law.
Please reference Appendix 11 for details on participants discontinuing during the COVID-19 
pandemic.


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7.3. Lost to Follow-up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing 
address or local equivalent methods).  These contact attempts should be documented 
in the participant’s medical record.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
Discontinuation of specific sites or of the study as a whole is handled as part of Appendix 1.
8. STUDY ASSESSMENTS AND PROCEDURES
The investigator (or an appropriate delegate at the investigator site) must obtain a signed and 
dated ICD before performing any study-specific procedures.  
Study procedures and their timing are summarized in the SoA.  Protocol waivers or 
exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
investigational product.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria.  The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICD may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.


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Every effort should be made to ensure that protocol-required tests and procedures are 
completed as described.  However, it is anticipated that from time to time there may be 
circumstances outside the control of the investigator that may make it unfeasible to perform 
the test.  In these cases, the investigator must take all steps necessary to ensure the safety and 
well-being of the participant.  When a protocol-required test cannot be performed, the 
investigator will document the reason for the missed test and any corrective and preventive 
actions that he or she has taken to ensure that required processes are adhered to as soon as 
possible.  The study team must be informed of these incidents in a timely manner.
For samples being collected and shipped, detailed collection, processing, storage, and 
shipment instructions and contact information will be provided to the investigator site prior 
to initiation of the study.
The total blood sampling volume for individual participants in this study is approximately 
350 mL.  The actual collection times of blood sampling may change.  Additional blood 
samples may be taken for safety assessments at times specified by Pfizer, provided the total 
volume taken during the study does not exceed 550 mL during any period of 60 consecutive 
days.
8.1. Efficacy Assessments
Efficacy measures are not included as endpoints in this study design. (see SoA).
8.2. Safety Assessments
Planned time points for all safety assessments are provided in the SoA.  Unscheduled clinical 
laboratory measurements may be obtained at any time during the study to assess any 
perceived safety concerns.
8.2.1. Physical Examinations
A complete physical examination will include assessments of general appearance, skin 
(including presence of rash), head, eyes, ears, nose and throat (HEENT), lymph nodes, 
cardiovascular, respiratory, gastrointestinal, musculoskeletal and neurological systems.  
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.2.2. Vital Signs
Body temperature, pulse rate, respiratory rate, and blood pressure will be assessed as detailed 
in the SoA table.  Height and body weight will also be measured and recorded.
Pulse rate and supine blood pressure (in the participant’s arm and recorded to the nearest 
mmHg) measurements will be assessed with an automated device.  Manual techniques will 
be used only if an automated device is not available.
Blood pressure and pulse rate measurements should be preceded by at least 5 minutes of rest 
for the participant in a quiet setting without distractions (eg, television, cell phones).


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When timing of these measurements coincides with blood collection, the blood pressure and 
pulse rate should be obtained first.  For visits with investigational product dosing, vital signs 
should be taken prior to adalimumab injection.  
8.2.3. Chest Radiograph
A chest radiograph (lateral and posterior-anterior view chest X-rays) will be obtained at the 
Screening Visit in all participants, unless it has been taken and documented within 12 weeks 
prior to Screening. The chest radiograph should be performed according to local health 
authority guidance. To be considered eligible for the study, the screening radiograph must be 
negative for active tuberculosis infection, fungal infection, or any other clinically significant 
abnormalities unless the TB infection (evident by scar or granuloma) has been successfully 
treated (see Section 5.2 Exclusion Criteria). If a chest CT exam (or an alternative chest 
imaging) is performed within 12 weeks prior to the Screening, a chest x-ray is not required at 
Screening.
8.2.4. Electrocardiograms
12-Lead ECG is only required at Screening to determine participant’s eligibility, see SoA
section of this protocol.  ECG should be performed after the participant has rested quietly for 
about 10 minutes in a supine position as deemed appropriate by the personnel acquiring ECG 
tracings. ECGs will be read locally. Participants with a screening 12-lead electrocardiogram 
that demonstrates clinically significant abnormalities requiring urgent treatment (eg, acute 
myocardial infarction, serious tachy- or bradyarrhythmias) or that is indicative of serious 
underlying heart disease (eg, cardiomyopathy, major congenital heart disease, low voltage in 
all leads) should not be enrolled in the study.  These participants should be referred to a 
specialist for further assessment.
ECG values of potential clinical concern are listed in Appendix 6.
8.2.5. Clinical Safety Laboratory Assessments
See Appendix 2 for the list of clinical safety laboratory tests to be performed and the SoA for 
the timing and frequency.
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF.  
Clinically significant abnormal laboratory findings are those which are not associated with 
the underlying disease, unless judged by the investigator to be more severe than expected for 
the participant's condition.
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 28 calendar days after the last dose of investigational 
product should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.
If such values do not return to normal/baseline within a period of time judged reasonable by 
the investigator, the etiology should be identified and the sponsor notified.


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All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA.
If laboratory values from non-protocol-specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the 
results must be recorded in the CRF.
8.2.6. QuantiFERON-TB Gold In-Tube Test 
QuantiFERON- TB Gold In-Tube test (QFT) is an in vitro indirect diagnostic test for 
M. tuberculosis infection (including disease) and is intended for use in conjunction with risk 
assessment, radiography (and or alternative imaging) and other medical and diagnostic 
evaluations. Screening QuantiFERON-TB Gold In-Tube test must be performed in every 
participant within 6 weeks prior to the first investigational product at Day 1 with the 
exception of participants with documented history of latent or active TB who completed TB 
chemoprophylaxis and treatment in accordance with local guidelines.  
In the case of a positive or indeterminate screening QuantiFERON-TB Gold In-Tube test 
result, the participant must receive a re-test with QFT-TB Gold In-Tube Test and referred to 
a specialist according to local practice (eg, pulmonologist or infectious disease specialist) for 
further evaluation of latent TB, active TB or false positive QFT test result, unless they have a 
past history of having been adequately treated with appropriate chemoprohylaxis for latent 
TB or have completed treatment for active TB previously, in which case re-testing is not 
required. Participants who test positive and are considered to have current latent TB can 
enroll in the study if they are on chemophrophylaxis for at least 4 weeks.  (see Section 5.2
and Section 6.5). 
8.2.7. Pregnancy Testing
Pregnancy tests may be urine or serum tests, but must have a sensitivity of at least 
25 mIU/mL.  Pregnancy tests will be performed in all WOCBP at the times listed in the SoA.  
Following a negative pregnancy test result at screening, appropriate contraception must be 
commenced and a second negative pregnancy test result will be required at the baseline visit 
prior the participant’s receiving the adalimumab.  Pregnancy tests will also be done whenever 
1 menstrual cycle is missed during the active treatment period (or when potential pregnancy 
is otherwise suspected) and at the end of the study.  Pregnancy tests may also be repeated if 
requested by institutional review boards (IRBs)/ethics committees (ECs) or if required by 
local regulations.  If a urine test cannot be confirmed as negative (eg, an ambiguous result), a 
serum pregnancy test is required.  In such cases, the participant must be excluded if the 
serum pregnancy result is positive.
8.2.8. Viral Disease Screening 
HBsAg, HBcAb, HBsAb and HCVAb testing is required to determine eligibility.  Hepatitis 
testing will be performed by the central lab.  Participants who are negative for all tests are 
eligible. Participants with positive HCVAb will be reflex tested for HCV RNA and will be 
eligible to participate if HCV RNA results are negative.  Participants with positive HBsAg or 


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HBcAb without positive HBsAb results are not eligible to participate in the study.  
Participants with negative HBcAb and HBsAg results but positive HBsAb are eligible to 
participate in the study. 
HIV (HIV-1 Ab and HIV-2 Ab) testing is also required to demonstrate eligibility unless not 
permitted by local regulations.  HIV testing will be performed by the central lab unless 
testing at a local lab is required per local regulations.  HIV testing will be completed at 
Screening unless testing has been performed within 8 weeks before study dosing on Day 1 
and results are available.  
In the event where a false positive test result is suspected, additional testing may be done in 
the central or local laboratory to confirm that participants are not positive for HIV, 
hepatitis B or hepatitis C.
8.3. Adverse Events and Serious Adverse Events
The definitions of an AE and an SAE can be found in Appendix 3.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or 
the participant's legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible to pursue 
and obtain adequate information both to determine the outcome and to assess whether it 
meets the criteria for classification as an SAE or that caused the participant to discontinue the 
study (see Section 7). 
In addition, the investigator may be requested by Pfizer Safety to obtain specific follow-up 
information in an expedited fashion.
8.3.1. Time Period and Frequency for Collecting AE and SAE Information
The time period for actively eliciting and collecting AEs and SAEs (“active collection 
period”) for each participant begins from the time the participant provides informed consent, 
which is obtained before the participant’s participation in the study (ie, before undergoing 
any study-related procedure and/or receiving investigational product), through and including 
a minimum of 28 calendar days after the last administration of the investigational product.
For participants who are screen failures, the active collection period ends when screen failure 
status is determined.
Follow-up by the investigator continues throughout and after the active collection period and 
until the event or its sequelae resolve or stabilize at a level acceptable to the investigator, and 
Pfizer concurs with that assessment.
Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study 
participation.  However, if the investigator learns of any SAE, including a death, at any time 
after a participant has been discharged from the study, and he/she considers the event to be 


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reasonably related to the investigational product or study participation, the investigator must 
promptly notify the sponsor.
8.3.1.1. Reporting SAEs to Pfizer Safety
All SAEs occurring in a participant during the active collection period are reported to Pfizer 
Safety on the CT SAE Report Form immediately and under no circumstance should this 
exceed 24 hours, as indicated in Appendix 3.  The investigator will submit any updated SAE 
data to the sponsor within 24 hours of it being available.
SAEs occurring in a participant after the active collection period has ended are reported to 
Pfizer Safety 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 must be reported to Pfizer Safety.
8.3.1.2. Recording Nonserious AEs and SAEs on the CRF
All nonserious AEs and SAEs occurring in a participant during the active collection period as 
described in Section 8.3.1.1 are recorded on the AE section of the CRF.  
The investigator is to record on the CRF all directly observed and all spontaneously reported 
AEs and SAEs reported by the participant.
8.3.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 3.
Care will be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended and 
nonleading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.
8.3.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each 
participant at subsequent visits/contacts.  For each event, the investigator must pursue and 
obtain adequate information until resolution, stabilization, the event is otherwise explained, 
or the participant is lost to follow-up (as defined in Section 7.3).
In general, follow-up information will include a description of the event in sufficient detail to 
allow for a complete medical assessment of the case and independent determination of 
possible causality.  Any information relevant to the event, such as concomitant medications 
and illnesses, must be provided.  In the case of a participant death, a summary of available 
autopsy findings must be submitted as soon as possible to Pfizer Safety. 
Further information on follow-up procedures is given in Appendix 3.


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8.3.4. Regulatory Reporting Requirements for SAEs
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of an
investigational product under clinical investigation are met.
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a investigational product under clinical investigation.  
The sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, institutional review boards (IRBs)/ethics committees 
(ECs), and investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSARs) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the investigator’s brochure and will notify the IRB/EC, if 
appropriate according to local requirements.
8.3.5. Exposure During Pregnancy or Breastfeeding, and Occupational Exposure
Exposure to the investigational product under study during pregnancy or breastfeeding and 
occupational exposure are reportable to Pfizer Safety within 24 hours of investigator 
awareness.
8.3.5.1. Exposure During Pregnancy
Details of all pregnancies in female participants and female partners of male participants will 
be collected after the start of investigational product and until (50 - 100 days) after the last 
dose that is at least 5 terminal half-lives.
If a pregnancy is reported, the investigator should inform the sponsor within [24 hours] of 
learning of the pregnancy and should follow the procedures outlined in Appendix 4.
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.3.5.2. Exposure During Breastfeeding
Scenarios of exposure during breastfeeding must be reported, irrespective of the presence of 
an associated SAE, to Pfizer Safety within 24 hours of the investigator’s awareness, using the 
CT SAE Report Form.  An exposure during breastfeeding report is not created when a Pfizer
drug specifically approved for use in breastfeeding women (eg, vitamins) is administered in 
accord with authorized use.  However, if the infant experiences an SAE associated with such 
a drug’s administration, the SAE is reported together with the exposure during breastfeeding.


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8.3.5.3. 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 Pfizer Safety within 24 hours of the investigator’s 
awareness, using the CT SAE Report Form, regardless of whether there is an associated 
SAE.  Since the information does not pertain to a participant enrolled in the study, the 
information is not recorded on a CRF; however, a copy of the completed CT SAE Report 
Form is maintained in the investigator site file.
8.3.6. Cardiovascular and Death Events
Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported 
with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA.
HUMIRA has not been formally studied in patients with CHF; however, in clinical trials of 
another TNF blocker, a higher rate of serious CHF-related adverse reactions was observed. 
Exercise caution when using HUMIRA in patients who have heart failure and monitor them 
carefully.
8.3.7. Medical Device Incidents (Including Malfunctions)
Medical devices are being provided for use in this study for the purposes self-administer 
adalimumab injections.  In order to fulfill regulatory reporting obligations worldwide, the 
investigator is responsible for the detection and documentation of events meeting the 
definitions of incident or malfunction that occur during the study with such devices.
The definition of a medical device incident can be found in Appendix 7.
NOTE: Incidents fulfilling the definition of an AE/SAE will also follow the processes 
outlined in Section 8.3.1 and Appendix 3 of the protocol.
8.3.7.1. Time Period for Detecting Medical Device Incidents
Medical device incidents or malfunctions of the device that result in an incident will be 
detected, documented, and reported during all periods of the study in which the medical 
device is used.
If the investigator learns of any incident at any time after a participant has been discharged 
from the study, and such incident is considered reasonably related to a medical device 
provided for the study, the investigator will promptly notify the sponsor.
The method of documenting medical device incidents is provided in Appendix 7.
8.3.7.2. Follow-up of Medical Device Incidents
All medical device incidents involving an AE will be followed and reported in the same 
manner as other AEs (see Section 8.3.3).  This applies to all participants, including those who 
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The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the incident.
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.3.7.3. Prompt Reporting of Medical Device Incidents to Sponsor
Medical device incidents will be reported to the sponsor within 24 hours after the investigator 
determines that the event meets the protocol definition of a medical device incident.
The Medical Device Incident Report Form will be sent to the sponsor by fax.  If fax is 
unavailable, then email should be utilized.
The same individual will be the contact for the receipt of medical device reports and SAEs.
8.3.7.4. Regulatory Reporting Requirements for Medical Device Incidents
The investigator will promptly report all incidents occurring with any medical device 
provided for use in the study in order for the sponsor to fulfill the legal responsibility to 
notify appropriate regulatory authorities and other entities about certain safety information 
relating to medical devices being used in clinical studies.
The investigator, or responsible person according to local requirements (eg, the head of the 
medical institution), will comply with the applicable local regulatory requirements relating to 
the reporting of incidents to the IRB/EC.
8.3.8. Medication Errors
Medication errors may result from the administration or consumption of the investigational 
product by the wrong participant, or at the wrong time, or at the wrong dosage strength.  
Additional examples of a medication error includes, but not limited to: outside the dosing 
window as per SoA, drug dispensing error, administration of two injections on the same day, 
incorrect route of administration, wrong medication type taken by participant.
Exposures to the investigational product under study may occur in clinical trial settings, such 
as medication errors.
Safety Event
Recorded on the CRF
Reported on the CT SAE Report 
Form to Pfizer Safety Within 
24 Hours of Awareness
Medication errors All (regardless of whether 
associated with an AE)
Only if associated with an SAE
Medication errors include:


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
Medication errors involving participant 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 study participant.
Such medication errors occurring to a study participant are to be captured on the medication 
error page of the CRF, which is a specific version of the AE page.
In the event of a medication dosing error, the sponsor should be notified immediately.
Whether or not the medication error is accompanied by an AE, as determined by the 
investigator, the medication error is recorded on the medication error page of the CRF and, if 
applicable, any associated AE(s), serious and nonserious, are recorded on an AE page of the 
CRF.
Medication errors should be reported to Pfizer Safety within 24 hours on a CT SAE Report 
Form only when associated with an SAE.
8.4. Treatment of Overdose
For this study, any injection of adalimumab with a dose greater than 10 mg/kg will be 
considered an overdose. This is based on information included in the Humira USPI1 which 
indicates that multiple doses of up to 10 mg/kg IV have been administered to patients in 
clinical trials without evidence of dose-limiting toxicities.  Based on an average absolute 
bioavailability estimate of 64% from three studies in which a single 40 mg SC dose was 
administered, this would conservatively (based on a body weight of 40 kg) equate to an 
approximately 15-fold higher dose than the 40 mg injection used in the protocol.  The 
investigational products used in this study will follow Humira’s USPI/SmPC. Pfizer does not 
recommend specific treatment for an overdose. 
In the event of an overdose, the investigator should:
1. Contact the medical monitor immediately.
2. Closely monitor the participant for any AEs/SAEs and laboratory abnormalities until 
adalimumab can no longer be detected systemically (at least 70 days).  Appropriate 
treatments to relieve the symptoms should be provided to the participant. 
3. Obtain a blood sample for pharmacokinetic (PK) analysis within 70 days from the 
date of the last dose of investigational product if requested by the medical monitor 
(determined on a case-by-case basis).
4. Document the quantity of the excess dose as well as the duration of the overdose in 
the CRF.
5. Overdose is reportable to Safety only when associated with an SAE.


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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the medical monitor based on the clinical evaluation of the participant.
8.5. Pharmacokinetics 
Blood samples of approximately 6 mL, to provide a minimum of 1 mL of serum per aliquot
(2 total), will be collected for measurement of serum concentrations of adalimumab as 
specified below.

Samples for determination of adalimumab trough drug concentrations will be 
collected within 6 hours prior to the investigational product administration on Weeks 
22, 24, 26, 28, and on Day 1 (time 0), Weeks 10 and 16 at a maximum of 48 hours 
prior to, but as close as possible prior to the next investigational product
administration (ie, pre-dose).

Primary endpoint data will be supported by the determination of adalimumab drug 
concentrations for the 2-week PK Profile.

The 2-week PK sampling period starts with Week 30 pre-dose PK collection and ends 
with Week 32 pre-dose PK collection.

Pre-dose PK collection at Week 30/PK Profile Day 1, the blood sample will be 
collected within 6 hours prior to investigational product administration.

For the subsequent PK Profile Days, post-Week 30 dosing times for serum 
collections are:

48 (+4) hrs on PK Profile Day 3, 

72 (+6) hrs on PK Profile Day 4, 

96 (+8) hrs on PK Profile Day 5, 

144 (+8) hrs on PK Profile Day 7, 

240 (+24) hrs on PK Profile Day 11, and 

336 (+24) hrs on PK Profile Day 15; before Week 32 dosing. 
The 2-week PK Profile collections may be completed using home health care service.  Please 
reference Table 1.
PK Sampling Table. In order for participant’s PK Profile to be 
included in the primary analysis every effort should be made to draw samples within the 
specified time windows.
Serum samples for PK assessment will be analyzed using a validated enzyme linked 
immunosorbent assay (ELISA) to quantitatively measure concentrations of Humira and 
PF-06410293.


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For detailed PK sample collection and processing instructions, please see the study 
laboratory manual.
8.6. Pharmacodynamics
Pharmacodynamic (PD) parameters are not evaluated in this study.
8.7. Genetics
8.7.1. Specified Genetics
Genetics are not evaluated in this study.
8.7.2. Banked Biospecimens for Genetics
There are no Banked Biospecimens for Genetics in this study as per all other Biosimilar 
programs.
8.8. Biomarkers
Biomarkers are not evaluated in this study.
8.8.1. Specified Gene Expression (RNA) Research
Specified gene expression ribonucleic acid (RNA) research is not included in this study.
8.8.2. Specified Protein Research
Specified protein research is not included in this study.
8.8.3. Specified Metabolomic Research 
Specified metabolomic research is not included in this study.
8.8.4. Banked Biospecimens for Biomarkers
There are no Banked Biospecimens for Biomarkers in this study.
8.9. Immunogenicity Assessments
8.9.1. Analysis of Anti-adalimumab Antibodies and Neutralizing Anti-adalimumab 
Antibodies
Blood samples will be collected at the time points specified in the SoA table to determine the 
presence of ADA and neutralizing antibodies (NAb), concurrently with samples for PK analysis in 
Treatment Periods 1 through 4.  For detailed ADA and NAb sample collection and processing 
instructions, please see the study lab manual.
Serum samples for ADA assessment will be analyzed using a validated 
electrochemoluminescent (ECL) immunoassay using PF-06410293 as a capture agent.  
Samples positive for ADA will be further tested for neutralizing activity using a validated 
cell-based NAb assay that utilizes PF-06410293 as the capture agent. 


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8.10. Health Economics
Health economics/medical resource utilization and health economics parameters are not 
evaluated in this study.
9. STATISTICAL CONSIDERATIONS
Detailed methodology for summary and statistical analyses of the data collected in this study 
is outlined here and further detailed in a statistical analysis plan (SAP), which will be 
maintained by the sponsor.  The SAP may modify what is outlined in the protocol where 
appropriate; however, any major modifications of the primary endpoint definitions or their 
analyses will also be reflected in a protocol amendment.
9.1. Estimands and Statistical Hypotheses
9.1.1. Estimands
The primary estimands are the geometric mean ratio (GMR) and 90% confidence interval 
(CI) for AUCτ and Cmax to evaluate the PK equivalence between the switching and 
non-switching arms, after 3 switches, in participants with RA who meet the PK population 
criteria, that include criteria for the number and timing of missing doses, availability of PK 
data, adherence to background therapy, and major protocol deviations related to PK 
assessment (Section 9.3).
9.2. Sample Size Determination
Assuming a GMR (switching arm vs non-switching arm) of 105% and a coefficient of 
variation (CV) of 55% for each of the PK parameters, AUCτ and Cmax, an anticipated 
non-evaluable rate of 25%, and a correlation of 0.5 between log-transformed AUCτ and log 
transformed Cmax, a total sample size of approximately 420 participants (314 evaluable 
participants) would provide 85% power to demonstrate that the 90% CI for the GMR is 
within 80.00% to 125.00% for both parameters. 
The %CV assumption for the power calculation was derived from data on 15 RA participants 
receiving MTX who participated in a PK substudy of an innovator study,3 with %CV of 
53% and 56% for AUCτ and Cmax, respectively,4 and from 21 RA participants (6 on MTX) 
who participated in a PK substudy of the innovator open-label extension study, where %CV 
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for all participants was 48% and 49%, and for MTX only was 46% and 44%, for AUCand 
Cmax, respectively.
9.3. Populations for Analysis
The PK Population is defined as all randomized participants who are dosed to initiate the 
Week 30 steady state PK profile, remain on background MTX with no major protocol 
deviations influencing the PK assessment, such as a missing dose (the first dose of the study 
in TP1 cannot be missed, no more than 1 missed dose allowed per TP except Week 32 dose, 
no more than 2 missed doses allowed in TP1 through TP4 except Week 32 dose, participants 
can only miss or have an incomplete dose for either the first or second dose in TP4 (but not 
both), and the study doses on Weeks 26, 28, and 30 cannot be missed or incomplete), and
have at least 1 primary endpoint (AUCor Cmax).  The last study dose in TP4 on week 32 
after the PK assessments is not included in the definition of the population for analyses and 
can be missed or be incomplete.  Subjects will be excluded from the PK population in case of 
missed PK sample(s) which significantly affect the calculation of PK parameters.  The PK 
population will be used for the primary PK analysis and other secondary PK endpoint 
analyses (Tmax, Cav, and CL/F).  
The Enrolled Population is defined as all participants who are enrolled in TP1.  This 
population will be used for participant accountability in TP1.
The Safety Population for TP1 (Safety-TP1) is defined as all participants who are enrolled in 
TP1 and receive at least one dose of investigational product in TP1.  This population will be 
used for the TP1 safety analyses.
The Intent-to-Treat Population (ITT-Randomized) is defined as all participants who are 
randomized to a study treatment group at Study Week 10.  This population will be used for 
participant accountability during TP2 through TP4. 
The Safety Population (Safety-Randomized) is defined as all participants who are 
randomized and receive at least one dose of investigational product following the 
randomization at Study Week 10.  The Safety Population will be used for the safety analyses
during TP2 through TP4, ADA and NAb analyses and the secondary PK endpoint (Ctrough).
9.4. Statistical Analyses
The SAP will be developed and finalized before database lock and will describe the 
participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data.  This section is a summary of the planned statistical 
analyses of the primary and secondary endpoints.
9.4.1. Efficacy Analyses
Efficacy measures are not included in this study design, therefore, efficacy analyses will not 
be performed.  


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9.4.2. Safety Analyses
Safety analyses for TP1 will be performed using the Safety-TP1 population for the Humira 
group.  Safety analyses for TP2 through TP4 will be performed using Safety-Randomized 
populations by treatment groups (switching arm vs non-switching arm).  
9.4.2.1. Adverse Event
Adverse events will be classified using the medical dictionary for regulatory activities 
(MedDRA) classification system.  
Adverse events (treatment-emergent adverse events; treatment-related adverse events; 
adverse events classified as Grade 3 or higher; and SAEs) will be summarized by body 
system and preferred term according to MedDRA terminology.  A treatment-emergent 
adverse event (TEAE) is defined as any adverse event that occurs after the beginning of the 
study treatment. 
Adverse events of special interest including opportunistic infections and immune-based 
adverse effects will be summarized using grouped Medical dictionary for regulatory 
activities (MedDRA) codes in addition to presentation of individual AE preferred terms. 
Immune-based adverse effects may be both acute and delayed and include injection-site 
reactions (ISRs), AEs that fulfill Sampson Criteria,4 and AEs identified as potential 
hypersensitivity/anaphylactic reactions using a System Medical Dictionary for Drug 
Regulatory Activities (MedDRA) standardized MedDRA query (SMQ) that occur in relation 
to the administration of the study drug.  Adverse events recorded on the CRF as ISRs will be 
summarized both as individual event symptoms and as a group for the purpose of comparing 
the overall incidence of ISRs.  Therefore, the following safety endpoints will be summarized 
for all participants, and for ADA positive and negative subgroups: 

Participants with ISRs (as per the investigators); 

Participants with AEs that fulfill Sampson’s Criteria;

Participants with AEs belonging to SMQ broad groupings of potential 
hypersensitivity / anaphylactic reactions.  
9.4.2.2. Laboratory Test Abnormalities
Hematology and chemistry laboratory data will be summarized at week 32 Shift table from 
baseline to week 32 will be provided for selected laboratory.  
Additionally, change from baseline to week 32 will be summarized.  For the TP1 summary, 
the baseline value is defined as the most recent measurement prior to the first dose of 
investigational product in TP1.  For the TP2 to TP4 summary, the baseline value is defined as 
the most recent measurement prior to the first dose of investigational product after 
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9.4.2.3. Prior and Concomitant Mediations
Prior medications and concomitant medications will be coded by WHO medical dictionary. 
Participants who received these medications will be listed and summarized.
9.4.3. Other Analyses 
9.4.3.1. Pharmacokinetics Analysis
The serum concentrations between Week 30 and Week 32 will be analyzed for the 
PK population using standard non-compartmental analysis to estimate the PK parameters for 
each individual participant. The PK parameters (Cmax, AUC, Tmax, Cav, and CL/F), and the 
serum concentrations will be summarized descriptively. 
Interchangeability will be assessed by constructing the point estimate (GMR) and the 
90% CIs for the GMR for the primary endpoints, Cmax and AUC.  Interchangeability will be 
established statistically if the 90% CI for the GMR is within 80.00% to 125.00% for both 
endpoints.  The GMR and CI will be obtained using analysis of variance (ANOVA) applied 
to log-transformed data, with terms for treatment and randomization stratification factor 
(body weight categories).
Additionally, adalimumab trough concentration data (Ctrough) will be summarized using 
descriptive statistics (mean, standard deviation, median, minimum, and maximum) by 
treatment arm for each TP.
9.4.3.2. ADA and NAb Analysis
For the ADA and NAb data, the percentage of participants with positive ADA and NAb will 
be calculated and summarized for the safety-randomized population by each visit in 
Treatment Periods.  For participants with positive ADA and NAb, the magnitude (titer), time 
of onset, and duration of ADA and NAb response will also be described.  In addition, the 
impact of ADA and NAb on PK over time will be assessed for each treatment arm.
9.4.3.3. Other Endpoint Analysis
Demographic and baseline characteristics, such as participant age, sex, height, weight, race, 
ethnicity, MTX dose, and medical history will be tabulated and summarized using descriptive 
statistics. Investigational product administration will be summarized.
9.5. Interim Analyses
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor will conduct ongoing reviews of the data during the course of the study for 
the purpose of safety.
9.5.1. Data Monitoring Committee 
This study will not use a data monitoring committee (DMC).


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10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines;

Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) guidelines;

Applicable laws and regulations, including applicable privacy laws.
The protocol, protocol amendments, ICD, investigator’s brochure (IB), and other relevant 
documents (eg, advertisements) must be reviewed and approved by the sponsor and 
submitted to an IRB/EC by the investigator and reviewed and approved by the IRB/EC 
before the study is initiated.
Any amendments to the protocol will require IRB/EC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/EC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/EC;

Notifying the IRB/EC of SAEs or other significant safety findings as required by 
IRB/EC procedures;

Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/EC, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations.
10.1.1.1. 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 
regulatory authority in any area of the world, or if the investigator is aware of any new 
information that might influence the evaluation of the benefits and risks of the investigational 
product, Pfizer should be informed immediately. 


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In addition, the investigator will inform Pfizer immediately of any urgent safety measures 
taken by the investigator to protect the study participants against any immediate hazard, and 
of any serious breaches of this protocol or of ICH GCP that the investigator becomes aware 
of.
10.1.2. Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
10.1.3. Informed Consent Process
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.
Participants must be informed that their participation is voluntary.  Participants or their 
legally authorized representative will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/EC 
or study center.
The investigator must ensure that each study participant or his or her legally authorized 
representative is fully informed about the nature and objectives of the study, the sharing of 
data related to the study, and possible risks associated with participation, including the risks 
associated with the processing of the participant’s personal data. 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the participant.
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/EC members, and by inspectors from regulatory authorities.
The investigator further must ensure that each study participant or his or her legally 
authorized representative is fully informed about his or her right to access and correct his or 
her personal data and to withdraw consent for the processing of his or her personal data.
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained.  
The authorized person obtaining the informed consent must also sign the ICD.
Participants must be reconsented to the most current version of the ICD(s) during their 
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A copy of the ICD(s) must be provided to the participant or the participant’s legally 
authorized representative.
10.1.4. Data Protection
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of participant data.
Participants’ personal data will be stored at the study site in encrypted electronic form and 
will be password protected to ensure that only authorized study staff have access.  The study 
site will implement appropriate technical and organizational measures to ensure that the 
personal data can be recovered in the event of disaster.  In the event of a potential personal 
data breach, the study site shall be responsible for determining whether a personal data 
breach has in fact occurred and, if so, providing breach notifications as required by law.
To protect the rights and freedoms of natural persons with regard to the processing of 
personal data, participants will be assigned a single, participant-specific numerical code.  
Any participant records or data sets that are transferred to the sponsor will contain the 
numerical code; participant names will not be transferred.  All other identifiable data 
transferred to the sponsor will be identified by this single, participant-specific code.  The 
study site will maintain a confidential list of participants who participated in the study, 
linking each participant’s numerical code to his or her actual identity.  In case of data 
transfer, the sponsor will protect the confidentiality of participants’ personal data consistent 
with the clinical study agreement and applicable privacy laws.
10.1.5. Dissemination of Clinical Study Data
Pfizer fulfills its commitment to publicly disclose clinical study results through posting the 
results of studies on www.clinicaltrials.gov (ClinicalTrials.gov), the European Clinical Trials 
Database (EudraCT), and/or www.pfizer.com, and other public registries in accordance with 
applicable local laws/regulations.  In addition, Pfizer reports study results outside of the
requirements of local laws/regulations pursuant to its standard operating procedures (SOPs).
In all cases, study results are reported by Pfizer in an objective, accurate, balanced, and 
complete manner and are reported regardless of the outcome of the study or the country in 
which the study was conducted.
www.clinicaltrials.gov
Pfizer posts clinical trial US Basic Results on www.clinicaltrials.gov for Pfizer-sponsored 
interventional studies (conducted in patients) that evaluate the safety and/or efficacy of a 
product, regardless of the geographical location in which the study is conducted.  US Basic 
Results are generally submitted for posting within 1 year of the primary completion date 
(PCD) for studies in adult populations or within 6 months of the PCD for studies in pediatric 
populations.


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PCD is defined as the date that the final participant was examined or received an intervention 
for the purposes of final collection of data for the primary outcome, whether the clinical 
study concluded according to the prespecified protocol or was terminated.
EudraCT
Pfizer posts European Union (EU) Basic Results on EudraCT for all Pfizer-sponsored 
interventional studies that are in scope of EU requirements.  EU Basic Results are submitted 
for posting within 1 year of the PCD for studies in adult populations or within 6 months of 
the PCD for studies in pediatric populations.
www.pfizer.com
Pfizer posts public disclosure synopses clinical study report (CSR) synopses in which any 
data that could be used to identify individual participants have been removed) on 
www.pfizer.com for Pfizer-sponsored interventional studies at the same time the US Basic 
Results document is posted to www.clinicaltrials.gov.
Documents within marketing authorization packages/submissions
Pfizer complies with the European Union Policy 0070, the proactive publication of clinical 
data to the European Medicines Agency (EMA) website.  Clinical data, under Phase 1 of this 
policy, includes clinical overviews, clinical summaries, CSRs, and appendices containing the 
protocol and protocol amendments, sample CRFs, and statistical methods.  Clinical data, 
under Phase 2 of this policy, includes the publishing of individual participant data.  Policy 
0070 applies to new marketing authorization applications submitted via the centralized 
procedure since 01 January 2015 and applications for line extensions and for new indications 
submitted via the centralized procedure since 01 July 2015.
Data Sharing
Pfizer provides researchers secure access to patient-level data or full CSRs for the purposes 
of “bona-fide scientific research” that contribute to the scientific understanding of the 
disease, target, or compound class.  Pfizer will make available data from these trials 
24 months after study completion.  Patient-level data will be anonymized in accordance with 
applicable privacy laws and regulations.  CSRs will have personally identifiable information 
redacted.
Data requests are considered from qualified researchers with the appropriate competencies to 
perform the proposed analyses.  Research teams must include a biostatistician.  Data will not 
be provided to applicants with significant conflicts of interest, including individuals 
requesting access for commercial/competitive or legal purposes.


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10.1.6. Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.
The investigator must ensure that the CRFs are securely stored at the study site in encrypted 
electronic form and are password protected to prevent access by unauthorized third parties.
The investigator must permit study-related monitoring, audits, IRB/EC review, and 
regulatory agency inspections and provide direct access to source data documents. This 
verification may also occur after study completion.  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.
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as risk management and mitigation strategies and analytical risk-based monitoring), 
methods, responsibilities, and requirements, including handling of noncompliance issues and 
monitoring techniques (central, remote, or on-site monitoring), are provided in the 
monitoring plan.
The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.
Records and documents, including signed ICDs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor.  The 
investigator must ensure that the records continue to be stored securely for as long as they are 
maintained.
When participant data are to be deleted, the investigator will ensure that all copies of such 
data are promptly and irrevocably deleted from all systems.


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The investigator(s) will notify the sponsor or its agents immediately of any regulatory 
inspection notification in relation to the study.  Furthermore, the investigator will cooperate 
with the sponsor or its agents to prepare the investigator site for the inspection and will allow 
the sponsor or its agent, whenever feasible, to be present during the inspection.  The 
investigator site and investigator will promptly resolve any discrepancies that are identified 
between the study data and the participant's medical records.  The investigator will promptly 
provide copies of the inspection findings to the sponsor or its agent.  Before response 
submission to the regulatory authorities, the investigator will provide the sponsor or its 
agents with an opportunity to review and comment on responses to any such findings.
10.1.7. Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator site.
Data reported on the CRF or entered in the electronic CRF (eCRF) that are transcribed from 
source documents must be consistent with the source documents or the discrepancies must be 
explained.  The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current medical records must be available.
Definition of what constitutes source data can be found in the Study Binder.
10.1.8. Study and Site Closure
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor.  Study sites will be closed upon 
study completion.  A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time upon notification to the contract 
research organization (CRO) if requested to do so by the responsible IRB/EC or if such 
termination is required to protect the health of study participants.
Reasons for the early closure of a study site by the sponsor may include but are not limited 
to:

Failure of the investigator to comply with the protocol, the requirements of the 
IRB/EC or local health authorities, the sponsor's procedures, or GCP guidelines;

Inadequate recruitment of participants by the investigator;

Discontinuation of further investigational product development.
Study termination is also provided for in the clinical study agreement.  If there is any conflict 
between the contract and this protocol, the contract will control as to termination rights.


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10.1.9. Sponsor’s Qualified Medical Personnel
The contact information for the sponsor's appropriately qualified medical personnel for the 
study is documented in the study contact list located in the Study Binder.  
To facilitate access to appropriately qualified medical personnel on study-related medical 
questions or problems, participants are provided with a contact card.  The contact card 
contains, at a minimum, protocol and investigational product identifiers, participant numbers, 
contact information for the investigator site, and contact details for a contact center in the 
event that the investigator site staff cannot be reached to provide advice on a medical 
question or problem originating from another healthcare professional not involved in the 
participant’s participation in the study.  The contact number can also be used by investigator 
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 investigator site 
and the study team are not available.  It is therefore intended to augment, but not replace, the 
established communication pathways between the investigator site and the study team for 
advice on medical questions or problems that may arise during the study.  The contact 
number is not intended for use by the participant directly, and if a participant calls that 
number, he or she will be directed back to the investigator site.


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10.2. Appendix 2: Clinical Laboratory Tests
The following safety laboratory tests will be performed by a central laboratory at times 
defined in the SoA section of this protocol.  Additional laboratory results may be reported on 
these samples as a result of the method of analysis or the type of analyzer used by the clinical 
laboratory; or as derived from calculated values.  These additional tests would not require 
additional collection of blood.  Unscheduled clinical laboratory measurements may be 
obtained at any time during the study to assess any perceived safety concerns.
Table 4.
Protocol-Required Safety Laboratory Assessments
Hematology
Chemistry
Urinalysis
Other
Hemoglobin
Hematocrit
RBC count
MCV
MCH
MCHC
Platelet count
WBC count
Total neutrophils 
(Abs)
Eosinophils (Abs)
Monocytes (Abs)
Basophils (Abs)
Lymphocytes (Abs)
BUN
creatinine
Calcium
Sodium
Potassium
Chloride
Total 
CO2 (bicarbonate)
AST, ALT
Total bilirubin
Alkaline phosphatase
Albumin
Total protein
pH
Glucose 
Protein 
Blood 
Ketones
Nitrites
Leukocyte esterase
Urobilinogen
Urine bilirubin
Microscopya
At screening only:

FSHb

Urine drug screening

Pregnancy test 
(β-hCG)c

Hepatitis B surface 
antigen

Hepatitis B core 
antibody

Hepatitis B surface 
antibody

Hepatitis C antibody

HCV RNAd

HIV-1 antibody

HIV-2 antibody

QuantiFERON-TB Gold 
In-Tube Test
Abbreviations: Abs = absolute; ALT = alanine aminotransferase; AST = aspartate aminotransferase; 
-hCG = beta-human chorionic gonadotropin; BUN = blood urea nitrogen; CO2 = carbon dioxide; 
FSH = follicle-stimulating hormone; MCH = mean corpuscular hemoglobin; MCHC = mean 
corpuscular hemoglobin concentration; MCV = mean corpuscular volume; qual = qualitative; 
RBC = red blood cell; WBC = white blood cell. 
a.
Only if urine dipstick is positive for blood, protein, nitrites, or leukocyte esterase.
b.
For confirmation of postmenopausal status only.
c.
Pregnancy testing at Screening in female participants of childbearing potential by central lab 
serum HCG test. Pregnancy testing (HCG) after Screening will be performed locally using 
urine samples. Pregnancy testing may be repeated more frequently if required by IRB/ECs or 
local regulations, or if potential pregnancy is suspected.
d.
Required only if HCVAb test result is positive.
Investigators must document their review of each laboratory safety report.


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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
10.3.1. Definition of AE
AE Definition

An AE is any untoward medical occurrence in a patient or clinical study 
participant, temporally associated with the use of investigational product, whether 
or not considered related to the investigational product.

NOTE: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of investigational product.
Events Meeting the AE Definition

Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) 
or other safety assessments (eg, ECG, radiological scans, vital sign measurements), 
including those that worsen from baseline, considered clinically significant in the 
medical and scientific judgment of the investigator (ie, not related to progression of 
underlying disease).

Exacerbation of a chronic or intermittent preexisting condition including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after investigational product administration 
even though it may have been present before the start of the study.

Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction.

Signs, symptoms, or the clinical sequelae of a suspected overdose of either 
investigational product or a concomitant medication.  Overdose per se will not be 
reported as an AE/SAE unless it is an intentional overdose taken with possible 
suicidal/self-harming intent.  Such overdoses should be reported regardless of 
sequelae.
Events NOT Meeting the AE Definition

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by the 
investigator to be more severe than expected for the participant’s condition.


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
The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE.

Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
10.3.2. Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious 
conditions are met (eg, hospitalization for signs/symptoms of the disease under study, death 
due to progression of disease).
An SAE is defined as any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
The term “life-threatening” in the definition of “serious” refers to an event in which the 
participant was at risk of death at the time of the event.  It does not refer to an event that 
hypothetically might have caused death if it were more severe.
c.
Requires inpatient hospitalization or prolongation of existing hospitalization
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
outpatient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen from 
baseline is not considered an AE.
d.
Results in persistent disability/incapacity

The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions.


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
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, 
influenza, and accidental trauma (eg, sprained ankle) which may interfere with or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Other situations:

Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that 
may not be immediately life-threatening or result in death or hospitalization but 
may jeopardize the participant or may require medical or surgical intervention to 
prevent one of the other outcomes listed in the above definition.  These events 
should usually be considered serious.

Examples of such events include invasive or malignant cancers, 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.
10.3.3. Recording/Reporting and Follow-up of AEs and/or SAEs
AE and SAE Recording/Reporting
The table below summarizes the requirements for recording adverse events on the CRF 
and for reporting serious adverse events on the Clinical Trial (CT) Serious Adverse Event 
(SAE) Report Form to Pfizer Safety.  These requirements are delineated for 3 types of 
events: (1) SAEs; (2) nonserious adverse events (AEs); and (3) exposure to the 
investigational product under study during pregnancy or breastfeeding, and occupational 
exposure. 
It should be noted that the CT SAE Report Form for reporting of SAE information is not 
the same as the AE page of the CRF.  When the same data are collected, the forms must be 
completed in a consistent manner.  AEs should be recorded using concise medical 
terminology and the same AE term should be used on both the CRF and the CT SAE 
Report Form for reporting of SAE information.
Safety Event
Recorded on the CRF
Reported on the CT SAE 
Report Form to Pfizer 
Safety Within 24 Hours of 
Awareness
SAE
All
All
Nonserious AE
All
None


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Exposure to the 
investigational product 
under study during 
pregnancy or 
breastfeeding, and 
occupational exposure
None
All (and exposure during 
pregnancy [EDP] 
supplemental form for 
EDP)  

When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostic 
reports) related to the event.

The investigator will then record all relevant AE/SAE information in the CRF.

It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Pfizer Safety in lieu of completion of the CT SAE Report 
Form/AE/SAE CRF page.

There may be instances when copies of medical records for certain cases are 
requested by Pfizer Safety.  In this case, all participant identifiers, with the 
exception of the participant number, will be redacted on the copies of the medical 
records before submission to Pfizer Safety.

The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information.  Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the AE/SAE.
Assessment of Intensity
The investigator will make an assessment of intensity for each AE and SAE reported 
during the study and assign it to 1 of the following categories: 
GRADE
Clinical Description of Severity
1
MILD adverse event
2
MODERATE adverse event
3
SEVERE adverse event
4
LIFE-THREATENING consequences; urgent intervention indicated
5
DEATH RELATED TO adverse event


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Assessment of Causality

The investigator is obligated to assess the relationship between investigational 
product and each occurrence of each AE/SAE.

A “reasonable possibility” of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out.

The investigator will use clinical judgment to determine the relationship.

Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to investigational 
product administration will be considered and investigated.

The investigator will also consult the investigator’s brochure (IB) and/or product 
information, for marketed products, in his/her assessment.

For each AE/SAE, the investigator must document in the medical notes that he/she 
has reviewed the AE/SAE and has provided an assessment of causality.

There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to the sponsor.  However, it is 
very important that the investigator always make an assessment of causality 
for every event before the initial transmission of the SAE data to the sponsor.

The investigator may change his/her opinion of causality in light of follow-up 
information and send an SAE follow-up report with the updated causality 
assessment.

The causality assessment is one of the criteria used when determining regulatory 
reporting requirements.

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.  In addition, if the investigator 
determines that an SAE is associated with study procedures, the investigator must 
record this causal relationship in the source documents and CRF, and report such 
an assessment in the dedicated section of the CT SAE Report Form and in 
accordance with the SAE reporting requirements.


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Follow-up of AEs and SAEs

The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the 
sponsor to elucidate the nature and/or causality of the AE or SAE as fully as 
possible.  This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other healthcare professionals.

If a participant dies during participation in the study or during a recognized 
follow-up period, the investigator will provide Pfizer Safety with a copy of any 
postmortem findings including histopathology.

New or updated information will be recorded in the originally completed CRF.

The investigator will submit any updated SAE data to the sponsor within 24 hours 
of receipt of the information.
10.3.4. Reporting of SAEs
SAE Reporting to Pfizer Safety via an Electronic Data Collection Tool

The primary mechanism for reporting an SAE to Pfizer Safety will be the 
electronic data collection tool.

If the electronic system is unavailable, then the site will use the paper SAE data 
collection tool (see next section) in order to report the event within 24 hours.

The site will enter the SAE data into the electronic system as soon as the data 
become available.

After the study is completed at a given site, the electronic data collection tool will 
be taken off-line to prevent the entry of new data or changes to existing data.

If a site receives a report of a new SAE from a study participant or receives updated 
data on a previously reported SAE after the electronic data collection tool has been 
taken off-line, then the site can report this information on a paper SAE form (see 
next section) or to Pfizer Safety by telephone.


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SAE Reporting to Pfizer Safety via CT SAE Report Form

Facsimile transmission of the CT SAE Report Form is the preferred method to 
transmit this information to Pfizer Safety.

In circumstances when the facsimile is not working, notification by telephone is 
acceptable with a copy of the CT SAE Report Form sent by overnight mail or 
courier service.

Initial notification via telephone does not replace the need for the investigator to 
complete and sign the CT SAE Report Form pages within the designated reporting 
time frames.


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10.4. Appendix 4: Contraceptive Guidance and Collection of Pregnancy Information
10.4.1. Male Participant Reproductive Inclusion Criteria
According to Humira label (SmPC), no specific male contraceptive measures are mandated 
with Humira use, although male participants with WOCBP partners should be familiar with 
the following Humira SmPC recommendation: “Women of childbearing potential are 
strongly recommended to use adequate contraception to prevent pregnancy and continue its 
use for at least 5 months after the last Humira treatment”.2
10.4.2. Female Participant Reproductive Inclusion Criteria
According to Humira label (SmPC), women of childbearing potential are strongly 
recommended to use adequate contraception to prevent pregnancy and continue its use for at 
least 5 months after the last Humira treatment.  
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at 
least 1 of the following conditions applies:

Is not a WOCBP (see definitions below in Section 10.4.3).
OR

Is a WOCBP and using an acceptable contraceptive method as described below 
during the intervention period (for at least 5 months after the last dose of 
investigational product).  The investigator should evaluate the effectiveness of the 
contraceptive method in relationship to the first dose of investigational product.  
The investigator is responsible for review of medical history, menstrual history, and recent 
sexual activity to decrease the risk for inclusion of a woman with an early undetected 
pregnancy. 
10.4.3. Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal 
unless permanently sterile (see below).
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot 
be confirmed before the first dose of investigational product, additional evaluation should be 
considered.
Women in the following categories are not considered WOCBP:
1. Premenopausal female with 1 of the following:

Documented hysterectomy;

Documented bilateral salpingectomy;


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
Documented bilateral oophorectomy.
For individuals with permanent infertility due to an alternate medical cause other than 
the above, (eg, mullerian agenesis, androgen insensitivity), investigator discretion 
should be applied to determining study entry.
Note: Documentation for any of the above categories can come from the site 
personnel’s review of the participant’s medical records, medical examination, or 
medical history interview.  The method of documentation should be recorded in the 
participant’s medical record for the study.
2. Postmenopausal female:

A postmenopausal state is defined as age 60 years or older or no menses for 
12 months without an alternative medical cause. 

A high follicle-stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormone replacement therapy (HRT). 

Females on HRT and whose menopausal status is in doubt will be required to 
use one of the nonestrogen hormonal highly effective contraception methods 
if they wish to continue their HRT during the study.  Otherwise, they must 
discontinue HRT to allow confirmation of postmenopausal status before study 
enrollment.
10.4.4. Contraception Methods
1. Implantable progestogen-only hormone contraception associated with inhibition of 
ovulation.
2. Intrauterine device (IUD).
3. Intrauterine hormone-releasing system (IUS).
4. Bilateral tubal occlusion.
5. Vasectomized partner:

Vasectomized partner is a highly effective contraceptive method provided that the 
partner is the sole sexual partner of the woman of childbearing potential and the 
absence of sperm has been confirmed.  If not, an additional effective method of 
contraception should be used.  The spermatogenesis cycle is approximately 
90 days.
6. Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation:


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
oral;

intravaginal;

transdermal;

injectable.
7. Progestogen-only hormone contraception associated with inhibition of ovulation:

oral;

injectable.
8. Sexual abstinence:

Sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the investigational product.  The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.
9. Progestogen-only oral hormonal contraception where inhibition of ovulation is not the 
primary mode of action.
10. Male or female condom with or without spermicide.
11. Cervical cap, diaphragm, or sponge with spermicide.
12. A combination of male condom with either cervical cap, diaphragm, or sponge with 
spermicide (double-barrier methods).
Collection of Pregnancy Information
For both unapproved/unlicensed products and for marketed products, an exposure during 
pregnancy (EDP) occurs if:

A female becomes, or is found to be, pregnant either while receiving or having been 
exposed (eg, because of treatment or environmental exposure) to the investigational 
product; or the female becomes or is found to be pregnant after discontinuing and/or 
being exposed to the investigational product;

An example of environmental exposure would be a case involving direct contact 
with a Pfizer product in a pregnant woman (eg, a nurse reports that she is pregnant 
and has been exposed to chemotherapeutic products).


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
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 participant or participant’s partner becomes or is found to be pregnant during the 
participant’s treatment with the investigational product, the investigator must report this 
information to Pfizer Safety on the CT SAE Report Form and an EDP supplemental form, 
regardless of whether an SAE has occurred.  In addition, the investigator must submit 
information regarding environmental exposure to a Pfizer product in a pregnant woman (eg, a 
participant reports that she is pregnant and has been exposed to a cytotoxic product by 
inhalation or spillage) to Pfizer Safety using the EDP supplemental form.  This must be done 
irrespective of whether an AE has occurred and within 24 hours of awareness of the 
exposure.  The information submitted should include the anticipated date of delivery (see 
below for information related to termination of pregnancy).
Follow-up is conducted to obtain general information on the pregnancy and its outcome for 
all EDP reports with an unknown outcome.  The investigator will follow the pregnancy until 
completion (or until pregnancy termination) and notify Pfizer Safety of the outcome as a 
follow-up to the initial EDP supplemental form.  In the case of a live birth, the structural 
integrity of the neonate can be assessed at the time of birth.  In the event of a termination, the 
reason(s) for termination should be specified and, if clinically possible, the structural 
integrity of the terminated fetus should be assessed by gross visual inspection (unless 
preprocedure test findings are conclusive for a congenital anomaly and the findings are 
reported).
If the outcome of the pregnancy meets the criteria for an SAE (ie, ectopic pregnancy, 
spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital anomaly [in a 
live-born baby, a terminated fetus, an intrauterine fetal demise, or a neonatal death]), the 
investigator should follow the procedures for reporting SAEs.
Additional information about pregnancy outcomes that are reported to Pfizer Safety as SAEs 
follows: 

Spontaneous abortion includes miscarriage and missed abortion;

Neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs.  In addition, infant deaths after 1 month should be reported as 
SAEs when the investigator assesses the infant death as related or possibly related to 
exposure to the investigational product. 
Additional information regarding the EDP may be requested by the sponsor.  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 participant with the Pregnant Partner Release of Information 
Form to deliver to his partner.  The investigator must document in the source documents that 
the participant was given the Pregnant Partner Release of Information Form to provide to his 
partner.


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10.5. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments 
Potential Cases of Drug-Induced Liver Injury
Humans exposed to a drug who show no sign of liver injury (as determined by elevations in 
transaminases) are termed “tolerators,” while those who show transient liver injury, but adapt 
are termed “adaptors.”  In some participants, transaminase elevations are a harbinger of a 
more serious potential outcome.  These participants fail to adapt and therefore are 
"susceptible" to progressive and serious liver injury, commonly referred to as drug-induced 
liver injury (DILI).  Participants who experience a transaminase elevation above 3 times the 
upper limit of normal (× ULN) should be monitored more frequently to determine if they are 
an “adaptor” or are “susceptible.”
In the majority of DILI cases, elevations in aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT) precede total bilirubin (TBili) elevations (>2 × ULN) by several 
days or weeks.  The increase in TBili typically occurs while AST/ALT is/are still elevated 
above 3 × ULN (ie, AST/ALT and TBili values will be elevated within the same laboratory 
sample).  In rare instances, by the time TBili elevations are detected, AST/ALT values might 
have decreased.  This occurrence is still regarded as a potential DILI.  Therefore, abnormal 
elevations in either AST OR ALT in addition to TBili that meet the criteria outlined below 
are considered potential DILI (assessed per Hy’s law criteria) cases and should always be 
considered important medical events, even before all other possible causes of liver injury 
have been excluded.
The threshold of laboratory abnormalities for a potential DILI case depends on the 
participant’s individual baseline values and underlying conditions.  Participants who present 
with the following laboratory abnormalities should be evaluated further as potential DILI 
(Hy’s law) cases to definitively determine the etiology of the abnormal laboratory values:

Participants with AST/ALT and TBili baseline values within the normal range who 
subsequently present with AST OR ALT values >3 × ULN AND a TBili value 
>2 × ULN with no evidence of hemolysis and an alkaline phosphatase value 
<2 × ULN or not available.

For participants with baseline AST OR ALT OR TBili values above the ULN, the 
following threshold values are used in the definition mentioned above, as needed, 
depending on which values are above the ULN at baseline:

Preexisting AST or ALT baseline values above the normal range: AST or ALT 
values >2 times the baseline values AND >3 × ULN; or >8 × ULN (whichever is 
smaller).

Preexisting values of TBili above the normal range: TBili level increased from 
baseline value by an amount of at least 1 × ULN or if the value reaches 
>3 × ULN (whichever is smaller).


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Rises in AST/ALT and TBili separated by more than a few weeks should be assessed 
individually based on clinical judgment; any case where uncertainty remains as to whether it 
represents a potential Hy’s law case should be reviewed with the sponsor.  
The participant should return to the investigator 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 and TBili for suspected cases of 
Hy’s law, additional laboratory tests should include albumin, creatine kinase (CK), direct and 
indirect bilirubin, gamma-glutamyl transferase (GGT), prothrombin time (PT)/international 
normalized ratio (INR), total bile acids, and alkaline phosphatase.  Consideration should also 
be given to drawing a separate tube of clotted blood and an anticoagulated tube of blood for
further testing, as needed, for further contemporaneous analyses at the time of the recognized 
initial abnormalities to determine etiology.  A detailed history, including relevant 
information, such as review of ethanol, acetaminophen (either by itself or as a coformulated 
product in prescription or over-the-counter medications), recreational drug, supplement 
(herbal) use and consumption, family history, sexual history, travel history, history of contact 
with a jaundiced person, surgery, blood transfusion, history of liver or allergic disease, and 
potential occupational exposure to chemicals, should be collected.  Further testing for acute 
hepatitis A, B, C, D, and E infection and liver imaging (eg, biliary tract) and collection of 
serum sample for acetaminophen drug and/or protein adduct levels may be warranted. 
All cases demonstrated on repeat testing as meeting the laboratory criteria of AST/ALT and 
TBili elevation defined above should be considered potential DILI (Hy’s law) cases if no 
other reason for the liver function test (LFT) abnormalities has yet been found.  Such 
potential DILI (Hy’s law) cases are to be reported as SAEs, irrespective of availability 
of all the results of the investigations performed to determine etiology of the LFT 
abnormalities.
A potential DILI (Hy’s law) case becomes a confirmed case only after all results of 
reasonable investigations have been received and have excluded an alternative etiology.


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10.6. Appendix 6: ECG Findings of Potential Clinical Concern
ECG Findings That May Qualify as Adverse Events (AEs)

Marked sinus bradycardia (rate <40 bpm) lasting minutes.

New PR interval prolongation >280 msec.

New prolongation of QTcF to >480 msec (absolute) or by 60 msec from baseline.

New-onset atrial flutter or fibrillation, with controlled ventricular response rate:
ie, rate <120 bpm.

New-onset type I second-degree (Wenckebach) AV block of >30 seconds’ 
duration.

Frequent premature ventricular complexes (PVCs), triplets, or short intervals 
(<30 seconds) of consecutive ventricular complexes.
ECG Findings That May Qualify as Serious Adverse Events (SAEs)

QTcF prolongation >500 msec.

New ST-T changes suggestive of myocardial ischemia.

New-onset left bundle branch block (QRS >120 msec).

New-onset right bundle branch block (QRS >120 msec).

Symptomatic bradycardia. 

Asystole:

In awake, symptom-free patients in sinus rhythm, with documented periods of 
asystole 3.0 seconds or any escape rate <40 bpm, or with an escape rhythm 
that is below the AV node; 

In awake, symptom-free patients with atrial fibrillation and bradycardia 
with 1 or more pauses of at least 5 seconds or longer; 

Atrial flutter or fibrillation, with rapid ventricular response rate: rapid = rate 
>120 bpm.

Sustained supraventricular tachycardia (rate >120 bpm) (“sustained” = short 
duration with relevant symptoms or lasting >1 minute).

Ventricular rhythms >30 seconds’ duration, including idioventricular rhythm (rate 
<40 bpm), accelerated idioventricular rhythm (40< x <100), and 


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monomorphic/polymorphic ventricular tachycardia >100 bpm (such as torsades de 
pointes).

Type II second-degree (Mobitz II) AV block.

Complete (third-degree) heart block.
ECG Findings That Qualify as Serious Adverse Events

Change in pattern suggestive of new myocardial infarction. 

Sustained ventricular tachyarrhythmias (>30 seconds’ duration).

Second- or third-degree AV block requiring pacemaker placement.

Asystolic pauses requiring pacemaker placement.

Atrial flutter or fibrillation with rapid ventricular response requiring cardioversion.

Ventricular fibrillation/flutter.

At the discretion of the investigator, any arrhythmia classified as an adverse 
experience.
The enumerated list of major events of potential clinical concern are recommended as “alerts” or 
notifications from the core ECG laboratory to the investigator and Pfizer study team, and not to be 
considered as all inclusive of what to be reported as AEs/SAEs.


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10.7. Appendix 7: Medical Device Incidents: Definition and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions of a Medical Device Incident
The detection and documentation procedures described in this protocol apply to all sponsor 
medical devices provided for use in the study (see Section 8.3.7 and Section 6.1.3) for the list 
of sponsor medical devices).
Medical Device Incident Definition

A medical device incident is any malfunction or deterioration in the characteristics 
and/or performance of a device as well as any inadequacy in the labeling or the 
instructions for use which, directly or indirectly, might lead to or might have led to 
the death of a participant/user/other person or to a serious deterioration in his/her 
state of health.

Not all incidents lead to death or serious deterioration in health.  The 
nonoccurrence of such a result might have been due to other fortunate 
circumstances or to the intervention of healthcare personnel.
It is sufficient that:

An incident associated with a device happened.
AND

The incident was such that, if it occurred again, might lead to death or a serious 
deterioration in health.
A serious deterioration in state of health can include any of the following:

Life-threatening illness;

Permanent impairment of body function or permanent damage to body structure;

Condition necessitating medical or surgical intervention to prevent one of the above;

Fetal distress, fetal death, or any congenital abnormality or birth defects.


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Examples of Incidents

A participant, user, caregiver, or healthcare professional is injured as a result of a 
medical device failure or its misuse.

A participant’s investigational product is interrupted or compromised by a medical 
device failure.

A misdiagnosis due to medical device failure leads to inappropriate treatment.

A participant’s health deteriorates due to medical device failure.
Documenting Medical Device Incidents
Medical Device Incident Documentation

Any medical device incident occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal 
clinical practice, and on the appropriate form of the CRF.

For incidents fulfilling the definition of an AE or an SAE, the appropriate 
AE/SAE CRF page will be completed as described in Appendix 3.

The CRF will be completed as thoroughly as possible and signed by the 
investigator before transmittal to the sponsor or designee.

It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the sponsor) at the time of the 
initial AE or SAE report and describes any corrective or remedial actions taken to 
prevent recurrence of the incident.

A remedial action is any action other than routine maintenance or servicing of a 
medical device where such action is necessary to prevent recurrence of an 
incident.  This includes any amendment to the device design to prevent 
recurrence.


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10.8. Appendix 8: Country-Specific Requirements
There is no country specific requirement of all the countries planned for this study.


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10.9. Appendix 9: Prohibited Concomitant Medications and Procedures
1. Any live attenuated vaccines.
2. DMARDs including small molecules, biologics and biosimilars with the exception of:

methotrexate (as specified in Section 6.5.1.1).

leflunomide, anti-malarials and sulfasalazine (stable dose of at least 4 weeks).
Participants who are on DMARD therapy with the exceptions noted above, the doses 
can be reduced or discontinued as per medical judgement. Initiation of additional 
DMARDs or increase dose of current DMARD therapy during the study is prohibited.  
A combination of no more than 3 DMARDs is permitted during the study. The 
following table list examples of prohibited medications but not an exhaustive list:  
Small molecule DMARDs prohibited:
Biologic/Biosimilar DMARDs prohibited:
azathioprine
Abatacept
cyclophosphamide
Anakinra
cyclosporine
TNF inhibitors
Janus kinase (JAK) inhibitors
Tocilizumab
tacrolimus (FK506)
Rituximab
6 mercaptopurine (6-MP)
3. Other investigational drugs or investigational biologics.
4. B-cell depleting therapy.
5. Plasma exchange therapy.
6. IV immunoglobulin (IVIG).
7. High potency, sustained release narcotics (see allowed opioids/ narcotics in 
Section 6.5.2).
8. Intra-articular (IA) Corticosteroid Injections (please also reference Rescue Therapy, 
Section 6.5.3):

Investigators should follow local standard of care where participants should 
receive no more than one injection per month and no more than three injections 
per year. 


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10.10. Appendix 10: New York Heart Associated Functional Classification Criteria 
The table below describes the most commonly used classification system for heart failure, the 
New York Heart Association (NYHA) Functional Classification.10  It places patients in one 
of four categories based on how much they are limited during physical activity. 
Class
Functional Capacity: How a patient with cardiac disease feels during physical
activity.
I
Patients with cardiac disease but resulting in no limitation of physical activity.  
Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea or 
anginal pain.
II
Patients with cardiac disease resulting in slight limitation of physical activity.  
They are comfortable at rest.  Ordinary physical activity results in fatigue, 
palpitation, dyspnea or anginal pain.
III
Patients with cardiac disease resulting in marked limitation of physical activity.  
They are comfortable at rest.  Less than ordinary activity causes fatigue, 
palpitation, dyspnea or anginal pain.
IV
Patients with cardiac disease resulting in inability to carry on any physical 
activity without discomfort.  Symptoms of heart failure or the anginal syndrome 
may be present even at rest.  If any physical activity is undertaken, discomfort 
increases.


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10.11. Appendix 11: COVID-19 Pandemic Considerations 
In response to the ongoing global pandemic COVID-19, and the increasing restrictions and 
concerns on public health, the following changes are being incorporated into the B5381012 
protocol to clarify alternative solutions to accommodate study procedures during the 
unprecedented time (eg the COVID-19 pandemic).  
The following alternative solutions are only acceptable during the COVID-19 pandemic:  

The PI should document the start and end date of the necessity to use alternative 
solutions as described herein. Local law and regulations may apply.

For participants who have received study treatment, scheduled study visits may be 
done remotely.

For study drug dispensation, study drugs may be dispensed via a courier arranged by
the investigational site, the home health care service or alternative transports as
agreed upon between site and study participant.  Please be sure alternative drug
dispensation is in accordance with applicable laws and regulations.  

A home health care service will be added as an option to scheduled study visits after 
the Day 1/Week 0 Visit to: provide investigational product to study participants, 
including administration of study treatment, collect vital signs and specimens and/or 
processing of laboratory tests as specified in the protocol.  In these cases, the 
investigator or designee must contact the study participants to collect adverse event 
(AE)/serious adverse event (SAE) information.  Investigator or designee should also 
confirm dosing data with the participant and record it in the site’s source or eDiary.  

Randomization at Week 10 may be done off-site:

Body weight is required to be taken at Day 1 or at Screening, whichever is closer
to the Week 10 visit,  and will be used to randomize as stated in the protocol.

Sites will need to call IWRS to randomize the study participant into either the
switching arm (PF-06410293) or non-switching arm (Humira) for treatment.  
Once treatment assignment is received, site may dispense the study medication
and deliver it to the participant as described below.

The home health care service may be used to collect specimens for safety
evaluation, PK, ADA/NAb, vital signs and possibly deliver study medication.

Dosing compliance confirmation should be recorded by study site investigator(s)/staff
remotely in site’s source documents or in eDiary at the time of the remote visit.  
Dosing data must be entered timely in the eCRF.

AEs, contraception use and concomitant medications will be collected by study site
investigator(s)/staff remotely, eg by phone for each remote visit and entered timely in
the eCRF.

For participant discontinuation reporting in the CRF: select the most appropriate 
status for discontinuation; if the discontinuation is associated with the current 
COVID-19 pandemic, enter “COVID-19” in the “Specify Status” field.


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10.12. Appendix 12: Abbreviations 
The following is a list of abbreviations that may be used in the protocol.
Abbreviation
Term
6-MP
6 mercaptopurine
ACR
American College of Rheumatology
Abd
Abdominal
Abs
Absolute
ACR
American College of Rheumatology
ADA
antidrug antibodies
AE
adverse event
ALT
alanine aminotransferase
ANC
Absolute neutrophil count
AS
ankylosing spondylitis
AST
aspartate aminotransferase
AUC
area under the concentration - time curve
AUC
area under the concentration - time curve over the dosing interval
AV
Atrioventricular
BA
Bioavailability
BBS
Biospecimen Banking System
BE
Bioequivalence
-hCG
beta-human chorionic gonadotropin
BMI
Body mass index
BP
blood pressure
Bpm
beats per minute
BUN
blood urea nitrogen
Cav
average concentration
CD
Crohn's disease
CFR
Code of Federal Regulations
CHF
congestive heart failure
COVID-19
Coronavirus Disease 2019
CIOMS
Council for International Organizations of Medical Sciences
CK
creatine kinase
CL/F
apparent clearance
Cmax
maximum observed concentration
CMC
Chemistry, Manufacturing, and Controls
CO2
carbon dioxide (bicarbonate)
CONSORT
Consolidated Standards of Reporting Trials
COX-2
Cyclooxygenase-2
CRF
case report form
CRO
contract research organization
CRU
clinical research unit
CSF
cerebrospinal fluid
CSR
clinical study report


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Abbreviation
Term
CT
clinical trial
CT
computed tomography
CTMS
clinical trial management system
Ctrough
predose concentration during multiple dosing
CV
Cardiovascular
CV
Coefficient of variation 
DCT
data collection tool
DILI
drug-induced liver injury
DMARD
Disease modifying anti-rheumatic drug
DMC
data monitoring committee
DNA
deoxyribonucleic acid
DRE
disease-related event
DU
dispensable unit
EBV
Epstein Barr virus
EC
ethics committee
ECL
Electrochemoluminescent
ECG
Electrocardiogram
eCRF
electronic case report form
E-DMC
external data monitoring committee 
EDP
exposure during pregnancy
EDR
extemporaneous dispensing record
ELISA
enzyme linked immunosorbent assay
EMA
European Medicines Agency
EoT
End of Treatment
ET
Early Termination
EU
European Union
EudraCT
European Clinical Trials Database
EULAR
European League Against Rheumatism
FAP
Final Approved Protocol
FDA
United States (US) Food and Drug Administration
FK506
Tacrolimus
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
gamma-glutamyl transferase
H
Hour
HbA1c
hemoglobin A1c
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBsAg 
hepatitis B surface antigen 
HCG
human chorionic gonadotropin
HCL
Hydrogen chloride
HCV
hepatitis C
HCVAb
hepatitis C antibody


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Abbreviation
Term
HCV RNA
HCV riboneucleic acid
HEENT
head, eyes, ears, nose and throat
Hgb
Hemoglobin
HIPAA
Health Insurance Portability and Accountability Act
HIV
human immunodeficiency virus
HPV
human papilloma virus
HRT
hormone replacement therapy
HS
hidradenitis suppurativa
IA
intra articular
IB
investigator’s brochure
IC
Interchangeability
ICD
informed consent document
ICH
International Council for Harmonisation
ID
Identification
IFU
Instruction for Use
IgG1
Immunoglobulin G1
IM
Intramuscular
IMP
investigational medicinal product
IND
investigational new drug application
Inj
injection 
INR
international normalized ratio
IP
investigational product
IP manual
investigational product manual
IRB
institutional review board
IRC
internal review committee
IRT
interactive response technology
ISR
injection-site reactions
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
IVIG
IV immunoglobulin
IWRS
interactive Web-based response system
JAK
janus kinase inhibitor
LBBB
left bundle branch block
LDAS
low disease activity state
LFT
liver function test
mAb
monoclonal antibody
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical dictionary for regulatory activities
MnB
Neisseria meningitidis serogroup B
Msec
Millisecond


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Abbreviation
Term
MTX
Methotrexate
N/A
not applicable
Nab
neutralizing antibodies
NIMP
noninvestigational medicinal product
NMSC
Non-Melanoma Skin Cancer
NOAEL
no-observed-adverse-effect level
NYHA
New York Heart Association
PACLs
Protocol Administrative Clarification Letters
PCD
primary completion date
PD
pharmacodynamic(s)
PFS
prefilled syringe
PFP
pre-filled pen
PI
principal investigator
PK
pharmacokinetic(s)
PS
plaque psoriasis
PSA
psoriatic arthritis
PT
prothrombin time
PVC
premature ventricular contraction/complex
QTc
corrected QT
QTcF
corrected QT (Fridericia method)
QFT
QuantiFERON® - TB Gold In-Tube test
Qual
qualitative
RA
rheumatoid arthritis
RBC
red blood cell
RNA
ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
SEER
Surveillance, Epidemiology, and End Results
SmPC
Summary of Product characteristics
SMQ
standardized MedDRA query
SoA
schedule of activities
SOP
standard operating procedure
SRSD
single reference safety document
SToD
study team on demand
SUSAR
suspected unexpected serious adverse reaction
TB
tuberculosis
TBili
total bilirubin
TEAE
treatment-emergent adverse event
Tmax
time at which Cmax occurs
TNF
Tumor necrosis factor
TP
treatment periods
CCI


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Abbreviation
Term
TP1
treatment period 1
TP2
treatment period 2
TP3
treatment period 3
TP4
treatment period 4
UC
ulcerative colitis
ULN
upper limit of normal
US
United States
USPI
US Prescribing Information
UV
uveitis
WBC
white blood cell
WHO
World Health Organization
Wk
week
WOCBP
woman of childbearing potential


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11. REFERENCES
1.
Humira US Prescribing Information (USPI). 16 Oct 2018. 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125057s409lbl.pdf 
Accessed on 12 Oct 2018.
2.
Humira (adalimumab) Summary of Product Characteristics (SmPC). 26 Jul 2018. 
http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/0004
81/human_med_000822.jsp&mid=WC0b01ac058001d124 Accessed on 31 Jul 2018.
3.
Weinblatt ME, Keystone EC, Furst DE, et al.  Adalimumab, a fully human anti–tumor
necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in
patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum
2003;48:35-45.
4.
Sampson HA, Munoz-Furlong A, Campbell RL, et al. Second symposium on the 
definition and management of anaphylaxis: summary report--Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. 
J Allergy Clin Immunol 2006;117(2)(Feb):391-7.
5.
CDER and Center for Evaluation and Research.  Clinical Pharmacology and 
Biopharmaceutics Review(s).  Application 125057/0, page 36. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/BLA_125057_S000_HUMI
RA_BIOPHARMR.PDF Accessed 18 Oct 2018.
6.
CDER and Center for Evaluation and Research.  Clinical Pharmacology and 
Biopharmaceutics Review(s).  Application 125057/0, page 43. 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/BLA_125057_S000_HUMI
RA_BIOPHARMR.PDF Accessed 18 Oct 2018.
7.
FDA Guidance for Industry, Considerations in Demonstrating Interchangeability With 
A Reference Product.  May 2019.  Available: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gu
idances/UCM537135.pdf.
8.
FDA Guidance for Industry, Scientific considerations in demonstrating biosimilarity to 
a reference product. April 2015. Available:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui
dances/UCM291128.pdf.
9.
FDA Guidance for Industry, Clinical Pharmacology Data to Support a Demonstration of 
Biosimilarity to a Reference Product.  December 2016.  
Available:https://www.fda.gov/media/88622/download.
10.
New York Heart Association Classification of Congestive Heart Failure. 
http://www.heart.org/HEARTORG/Conditions/HeartFailure/AboutHeartFailure/Classes
-of-Heart-Failure_UCM_306328_Article.jsp.


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11.
Hochberg MC, Chang RW, Dwosh I, et al.  The ACR 1991 revised criteria for the 
classification of global functional status in rheumatoid arthritis.  Arthritis Rheum 
1992;35:498-502.

SAP_001.pdf: 
Protocol B5381012 (PF-06410293) Statistical Analysis Plan
PFIZER CONFIDENTIAL 
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Protocol B5381012
A RANDOMIZED COMPARATIVE STUDY ASSESSING THE SWITCHING 
BETWEEN PF-06410293 AND HUMIRA® IN COMBINATION WITH 
METHOTREXATE IN PARTICIPANTS WITH MODERATELY TO SEVERELY 
ACTIVE RHEUMATOID ARTHRITIS
Statistical Analysis Plan 
(SAP)
Version:
2
Date:
13 JUL 2021  


Protocol B5381012 (PF-06410293) Statistical Analysis Plan
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TABLE OF CONTENTS
LIST OF TABLES.....................................................................................................................3
LIST OF FIGURES ...................................................................................................................3
APPENDICES ...........................................................................................................................3
1. VERSION HISTORY............................................................................................................5
2. INTRODUCTION .................................................................................................................6
2.1. Study Objectives, Endpoints, and Estimands............................................................6
2.1.1. Primary Estimand(s).....................................................................................6
2.1.2. Secondary Estimand(s).................................................................................7
2.2. Study Design .............................................................................................................7
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS ..................................................................................................................9
3.1. Primary Endpoint(s) ..................................................................................................9
3.2. Secondary Endpoint(s) ..............................................................................................9
3.3. Other Endpoint(s)....................................................................................................10
3.4. Baseline Value.........................................................................................................10
3.5. Safety Endpoints .....................................................................................................10
3.5.1. Adverse Events...........................................................................................10
3.5.2. Laboratory Data..........................................................................................10
3.5.3. Vital Sign Data ...........................................................................................10
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)...................................................10
5. GENERAL METHODOLOGY AND CONVENTIONS....................................................12
5.1. Hypotheses and Decision Rules ..............................................................................12
5.2. General Methods .....................................................................................................12
5.2.1. Analyses of Variance (ANOVA)................................................................12
5.3. Methods to Manage Missing Data ..........................................................................12
5.3.1. Concentrations below the limit of quantification .......................................12
5.3.2. Deviations, missing concentrations and anomalous values........................12
6. ANALYSES AND SUMMARIES ......................................................................................13
6.1. Primary Endpoint(s) ................................................................................................13
6.1.1. Cmax and AUCτ............................................................................................13
6.2. Secondary Endpoint(s) ............................................................................................13


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6.2.1. Other PK endpoints.....................................................................................13
6.2.2. Anti-drug antibody (ADA) and Neutralizing Anti-Drug Antibody 
(NAb) Results ..................................................................................................13
6.2.3. Safety endpoints..........................................................................................14
6.3. Other Endpoint(s)....................................................................................................14
6.4. Subset Analyses.......................................................................................................14
6.5. Baseline and Other Summaries and Analyses.........................................................14
6.5.1. Participant disposition ................................................................................14
6.5.2. Participant demographics, Baseline characteristics....................................14
6.5.3. Study Treatment Exposure .........................................................................14
6.5.4. Concomitant Medications and Nondrug Treatments..................................14
6.6. Safety Summaries and Analyses. ............................................................................15
6.6.1. Adverse Events...........................................................................................15
6.6.1.1. Adverse Event for TP1..............................................................15
6.6.1.2. Adverse Event for TP2 and Beyond..........................................15
6.6.2. Laboratory Data..........................................................................................16
6.6.3. Vital Signs ..................................................................................................16
6.6.4. COVID-19 Related Summary.....................................................................16
7. INTERIM ANALYSES.......................................................................................................16
7.1. Introduction .............................................................................................................16
7.2. Interim Analyses and Summaries............................................................................17
8. REFERENCES ....................................................................................................................17
9. APPENDICES .....................................................................................................................18
LIST OF TABLES
Table 1.
Summary of Changes..................................................................................5
LIST OF FIGURES
Figure 1.
Study Design...............................................................................................9
APPENDICES
Appendix 1. SMQ MedDRA V24.0 Listings...........................................................................18


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Appendix 2. List of Abbreviations...........................................................................................18


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1. VERSION HISTORY
Table 1.
Summary of Changes
Version/
Date
Associated
Protocol 
Amendment
Rationale
Specific Changes
1
29 Aug 2019
Original 
28 Jun 2019
N/A
N/A
2. draft
Amendment 1
19 May 2020
Update to 
align with 
protocol 
amendent 1 
and 
clarificatio
n/simplifica
tion/comple
tion of 
prior 
version
•
Update the following sections to 
align with protocol amendment 1:

Text update in the protocol title.

Study design for TP4 and follow-
up period (Section 2.2)

The definitions of PK population 
(Section 4)

The definition of treatment-
emergent AEs (Section 3.5.1 and 
Section 6.1.3)

The removal of TP2 to TP3 
cumulative AE summary
•
Update/provide more details on 
AESI definition and immunogenic
AE definition and  medical 
evaluation (Section 3.5.1).
•
Exclude all subjects at site 
 
from all the analysis populations due 
to violation of GCP principles 
(Section 4)
•
More details on Hypothesis and 
Decision rule (Section 5.1)
•
The analyses for Ctrough in TP1 and 
TP2-TP4 are combined as TP1-TP4
analysis using safety-randomized 
population (Section 6.2.1).
•
Update/provide more detailed on 
ADA and NAb analysis (Section 
6.2.2)
•
Clarification/simplificaiton of TP1 
AE summary and provide more 
details on TP2 to TP4 AE summary
including AESI and immunogenic 
AE (Section 6.6.1.1 and Section 
6.6.1.2).
CCI


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
Clarification/simplication of Lab 
data analysis for TP1 and TP2-TP4.

Add COVID-19 related summary 
and analysis for protocol deviation, 
subject discontinuation, AE (Section 
6.6.4)

Removal of the following analyses  
which won’t impact the study 
conclusion: demographic summary 
for Safety-TP1 population and 
Safety-randomized population; 
concomitant medication and non-
drug treatment summary for TP1 
data; vital sign analysis for TP1 
data; physical examination, MTX 
dose and medical history.

Additional typographic errors 
correction and editorial changes as 
necessary throughout the SAP.
2. INTRODUCTION
This statistical analysis plan (SAP) provides the detailed methodology for summary and 
statistical analyses of the data collected in Study B5381012.  This document may modify the 
plans outlined in the protocol; however, any major modifications of the primary endpoint 
definition or its analysis will also be reflected in a protocol amendment.
2.1. Study Objectives, Endpoints, and Estimands
The primary objective of the study is to evaluate interchangeability of PF-06410293 and 
Humira by examining adalimumab steady-state pharmacokinetics (PK) in a switching arm 
(following 3 switches between Humira and PF-06410293) as compared to a non-switching 
arm (receiving only Humira). The secondary objectives are

To evaluate other serum adalimumab PK parameters in the switching arm and the non-
switching arm.

To evaluate the overall safety and tolerability of the switching arm and the non-switching 
arm.

To evaluate immunogenicity of the switching arm and the non-switching arm.
2.1.1. Primary Estimand(s)
The primary estimand of this study is defined according to the primary objective and is in 
alignment with the primary endpoint.  The primary estimands are the geometric mean ratio 
(GMR) and 90% confidence interval (CI) for AUCτ and Cmax to evaluate the PK equivalence 


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between the switching and non-switching arms, after 3 switches, in participants with RA who 
meet the PK population criteria that include criteria for the number and timing of missing 
doses, availability of PK sample data, adherence to background therapy, and major protocol 
deviations related to PK assessment (Section 4).
2.1.2. Secondary Estimand(s)
The secondary estimands are 

Other serum adalimumab PK parameters, including time at which Cmax occurs (Tmax), 
average concentration over the dosing interval (Cav), and apparent clearance (CL/F) 
obtained during the intensive PK sampling interval in participants who meet the PK 
population criteria.  Pre-dose concentrations during multiple dosing (Ctrough) obtained at 
scheduled PK sample timepoints will also be assessed in participants who meet the safety 
population criteria, for the switching arm and non-switching arm.

Safety endpoints for the switching arm and non-switching arm in participants who meet 
the safety population criteria.

Summarize percent of participants with antidrug antibodies (ADA), and neutralizing 
antibodies (NAb) and ADA/NAb titers over time for the switching arm and non-
switching arm in participants who meet the Safety population criteria.
2.2. Study Design
This is an open-label, multi-national, 2-arm, randomized, parallel-group study designed to 
evaluate the interchangeability of the switching arm (PF-06410293 and Humira), compared 
to non-switching arm (Humira), in participants with moderately to severely active RA on 
background methotrexate (MTX). For purposes of this protocol, the treatment arm that 
includes switches between PF-06410293 and Humira will be referred to as the “switching”
arm, while the treatment arm that comprises continuous Humira treatment will be referred to
as the “non-switching” arm.
This study will enroll a maximum of approximately 420 participants so that approximately
314 evaluable participants complete the study.
Study treatment will be provided through 4 treatment periods. For the first 10 weeks, all 
participants will receive Humira [Treatment Period (TP) 1]. Upon completion of TP1, 
participants will be randomized (1:1 ratio) into either the switching or non-switching arm 
prior to dosing on Week 10. Randomization will be stratified by 3 body weight groups (Week 
10 weight) (≥40 kg to <70 kg; ≥70 kg to <100 kg; ≥100 kg to ≤130 kg). Participants 
randomized to the non-switching arm will continue on Humira for the remainder of the study, 
and participants randomized to the switching arm will continue switching in each TP (TP2: 
PF-06410293; TP3: Humira; TP4: PF-06410293).


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
Treatment Period 1 (Lead In Period) will begin with the first dose of investigational
product on Week 0 (Day 1) and conclude with the completion of Week 10 pre-dose 
assessments.

Treatment Period 2 will begin with the 1:1 randomization of the participants to either the 
switching arm or the non-switching arm at Week 10. Investigational product dosing for 
Week 10 will begin after the randomization process in the respective treatment arms and 
will conclude with the completion of Week 16 pre-dose assessments.

Treatment Period 3 will begin with investigational product dosing on Week 16, and
conclude with the completion of Week 22 pre-dose assessments.

Treatment Period 4 will begin with investigational product dosing on Week 22 and 
continue through Week 30, where onsite investigational product dosing is scheduled at 
Weeks 22, 24, 26, 28, and 30, followed by a 2-week PK sampling period from Week 30 
to Week 32. TP4 will conclude with end of treatment (EoT) assessments and final dose
administration at Week 32.

The 2-week PK sampling period within TP4 starts with Week 30 predose PK 
collection and ends with predose PK collection on Week 32.

Safety Follow-Up Period begins after the last investigational product dosing on Week 32, 
and concludes at completion of the Week 36 assessments. All participants (including 
early discontinuations) will be followed for at least 28 calendar days from the date of 
their last dosed investigational product. Week 36 safety follow up may be conducted via
phone.


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Figure 1.
Study Design
3. ENDPOINTS AND BASELINE VARIABLES: DEFINITIONS AND 
CONVENTIONS
3.1. Primary Endpoint(s)
The primary endpoints are Cmax and AUCτ obtained during the intensive PK sampling 
interval.
3.2. Secondary Endpoint(s)
The secondary endpoints are

Other serum adalimumab PK parameters and serum concentration, including Tmax, Cav,
and CL/F obtained during the intensive PK sampling interval and Ctrough obtained at 
scheduled PK sample timepoints.

Safety endpoints including adverse events (AEs), laboratory test and vital signs. More 
detailed information is provided in Section 3.5.

ADA and NAb endpoints including percent of participants with ADA/NAb and 
ADA/NAb titers over time.


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3.3. Other Endpoint(s)
Other endpoints include demographic and baseline characteristics, such as participant age, 
sex, height, weight, race, ethnicity, and medical history, and study drug administration.
3.4. Baseline Value
For the TP1 summary, the baseline value is defined as the most recent measurement prior to 
the first dose of investigational product in TP1. For the TP2 to TP4 summary, the baseline 
value is defined as the most recent measurement prior to the first dose of investigational 
product after randomization in TP2.
3.5. Safety Endpoints
3.5.1. Adverse Events
A treatment-emergent adverse event (TEAE) for TP1 summary is defined as any adverse 
event that occurs after the beginning of the study treatment in TP1 and before the first dose 
of investigational product administrated after randomization in TP2.
A treatment-emergent adverse event (TEAE) for TP2 to TP4 summary is defined as any 
adverse event that occurs after the first dose of investigational product administrated after 
randomization in TP2. Adverse events of special interest (AESI) include Targeted medical 
events (TME) which are defined for Adalimumab biosimilar program and are maintained in a 
list in the product’s Safety Review Plan.
Immunogenic adverse effects include injection-site reactions (ISRs); medically evaluated 
AEs that meet Sampson Criteria1, and medically evaluated AEs identified by broad MedDRA 
SMQ for Hypersensitivity/Anaphylaxis /Angioedema; medically evaluated AEs identified as 
potential Cytokine storm, and medically evaluated AEs tidentified as potential Delayed 
immune responses. 
3.5.2. Laboratory Data
Laboratory data include hematology, chemistry, and urine routine safety laboratory tests 
results at each visit.
3.5.3. Vital Sign Data
Vital signs endpoints include body temperature, pulse rate, respiratory rate, and blood 
pressure.  
4. ANALYSIS SETS (POPULATIONS FOR ANALYSIS)
Data for all participants will be assessed to determine if participants meet the criteria for 
inclusion in each analysis population prior to releasing the database and classifications will 
be documented per standard operating procedures.
All subjects at site 
 will be excluded from all the analysis populations due to violation of 
GCP principles (i.e., suspected falsification of study records).
CCI


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Population
Description
Enrolled Population
All participants who are enrolled in TP1. This population will 
be used for participant accountability in TP1.
Safety Population for TP1 
(Safety-TP1)
All participants who are enrolled in TP1 and receive at least 
one dose of investigational product in TP1. This population will 
be used for the TP1 safety analyses.
Intent-to-Treat Population 
(ITT-Randomized)
All participants who are randomized to a study treatment group 
at Study Week 10. This population will be used for participant 
accountability during TP2 through TP4.
Safety Population (Safety-
Randomized)
All participants who are randomized and receive at least one 
dose of investigational product following the randomization at 
Study Week 10. The Safety Population will be used for the 
safety analyses during TP2 and beyond, ADA and NAb 
analyses and the secondary PK endpoint (Ctrough).
PK population
All randomized participants who are dosed to initiate the
Week 30 steady-state PK profile, remain on background MTX
with no major protocol deviations influencing the PK 
assessment, such as a miss dose (the first dose of the study in 
TP1 cannot be missed, no more than 1 missed dose allowed per 
TP except Week 32 dose, no more than 2 missed doses allowed 
in TP1 through TP4 except Week 32 dose, participants can only 
miss or have an incomplete dose for either the first or second 
dose in TP4 (but not both), and the study doses on Weeks 26, 
28, and 30 cannot be missed or incomplete), and have at least 1 
primary endpoint (AUCτ or Cmax). The last study dose in TP4 
on week 32 after the PK assessments is not included in the 
definition of the population for analyses and can be missed or 
be incomplete. Subjects will be excluded from the PK 
population in case of missed PK sample(s) which significantly 
affect the calculation of PK parameters. The PK population will 
be used for the primary PK analysis and other secondary PK 
endpoint analyses (Tmax, Cav, and CL/F).
The determination of PK population independent of the PK test results will be finalized prior 
to the releasing of the study database.
Protocol deviations independent of PK test results will be determined on an ongoing basis per 
data review. Any participant with major protocol deviations that affect PK assessment as 
determined by the study team will be excluded from the PK population. Major protocol 
deviations may include: Missing or incomplete dosing (the first dose of the study
in TP1 cannot be missed, no more than 1 missed dose allowed per TP except Week 32 dose,
no more than 2 missed doses allowed in TP1 through TP4 except Week 32 dose, participants
can only miss or have an incomplete dose for either the first or second dose in TP4 (but not
both), and the study doses on Weeks 26, 28, and 30 cannot be missed or incomplete). During 
the conduct of the study, it is possible that other deviations will be identified that can impact 
PK assessments, which can result in additional deviations to those noted above.


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5. GENERAL METHODOLOGY AND CONVENTIONS
5.1. Hypotheses and Decision Rules
null hypothesis:  H01      
ஜೞ
ஜ೙ೞ൏0.8                 or  H02       
ஜೞ
ஜ೙ೞ൐1.25
alternative hypothesis: Ha     0.8 ൑
ஜೞ
ஜ೙ೞ൑1.25
μs: geometric mean for the switching arm
μns : geometric mean for the non- switching arm
Interchangeability will be established statistically if the 90% CI for the GMR is within 
80.00% to 125.00% for both Cmax and AUCτ.
5.2. General Methods
The analyses for TP1 (lead-in period) will be performed for Humira group.  The analyses for 
TP2 and beyond will be performed by treatment groups (switching arm vs non-switching 
arm).
5.2.1. Analyses of Variance (ANOVA)
ANOVA will be used for comparing switching arm vs non-switching arm for Cmax and 
AUCτ.  GMR and the associated 90% 2-sided CI are will be obtained using analysis of 
ANOVA applied to log-transformed data, with terms for treatment and randomization 
stratification factor (body weight categories). 
5.3. Methods to Manage Missing Data
In general, no missing data will be imputed.  For PK data, the following rules apply.
5.3.1. Concentrations below the limit of quantification
In all data presentations (except listings), concentrations below the limit of quantification
(BLQ) will be set to zero. In the listings BLQ values will be reported as Ā<LLQā, where
LLQ will be replaced with the value for the lower limit of quantification.
5.3.2. Deviations, missing concentrations and anomalous values
In summary tables and plots of mean profiles of PK, statistics will be calculated having set
concentrations to missing if 1 of the following cases is true:
1. A concentration has been collected as ND (ie, not done) or NS (ie, no sample);
2. A deviation in sampling time is of sufficient concern or a concentration has been flagged
anomalous by the PK analyst.


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6. ANALYSES AND SUMMARIES
6.1. Primary Endpoint(s)
6.1.1. Cmax and AUCτ
The serum concentrations between Week 30 and Week 32 will be analyzed for the PK 
population using standard non-compartmental analysis to estimate the PK parameters (Cmax,
AUCτ, Tmax, Cav, and CL/F) for each individual participant. 
Cmax and AUCτ are the primary endpoints. The primary analysis for Cmax, and AUCτ will be 
ANOVA with terms for treatment and randomization stratification factor (body weight 
categories) to compare switching arm and non-switching arm in log-transformed data in PK 
population.  The mean difference and the confidence intervals (CI) for the differences will be 
obtained using ANOVA model. The mean differences and the CI will be exponentiated to 
provide estimates of geometric mean ratio (GMR) and the 90% confidence intervals for the 
ratio. Interchangeability will be established statistically if the 90% CI for the GMR is within 
80.00% to 125.00% for both endpoints.
Cmax and AUCτ will also be summarized descriptively for switching arm and non-switching 
arm.  In addition, the primary endpoints will be summarized by ADA and NAb status at week 
30.
6.2. Secondary Endpoint(s)
6.2.1. Other PK endpoints 
Secondary PK parameters (Tmax, Cav and CL/F) and serum concentrations collected between 
Week 30 and Week 32 will be summarized descriptively for switching arm and non-
switching arm using PK population.  Ctrough collected in TP1 through TP4 will summarize 
descriptively by each visit using Safety-Randomized population for switching and non-
switching arm.
For serum concentration during week 30 to week 32, mean concentration time plot, median 
concentration time plots and individual concentration time plots on both linear and semi-log 
scales will be provided for PK population by switching and non-switching arms.  For Ctrough, 
box plots will be provided using using  Safety-Randomized population by switching and non-
switching arm for data collected in TP1 through TP4.
In addition, the summarization for secondary PK parameters (Tmax, Cav and CL/F), serum 
concentrations collected between Week 30 and Week 32 will be provided by ADA and NAb 
status at week 30. The plots for serum concentration during week 30 to week 32 will be 
provided by ADA and NAb status at week 30. Ctrough at each visit will also be summarized 
and plotted by ADA and NAb status at the corresponding visit. 
6.2.2. Anti-drug antibody (ADA) and Neutralizing Anti-Drug Antibody (NAb) Results
For the ADA and NAb data, the percentage of participants with positive ADA and NAb will 
be calculated and summarized for the Safety-Randomized population by each visit for TP1
through TP4. The magnitude (titer) and time of first positive sample will also be described.  


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ADA and NAb status at the end of study will be used to characterized the participants 
response as either persistent or transient. For participants with at least one ADA/NAb 
positive sample, persistent response is defined as ADA/NAb positive at the last sample, and
transient response is defined as having had at least one ADA/NAb positive sample, and an 
ADA/NAb negative at last sample. 
In addition, the impact of ADA and NAb on PK over time will be assessed as specified in 
section 6.1.1 and 6.2.1.
6.2.3. Safety endpoints
The analyses and summary for safety endpoints is provided in Section 6.6.
6.3. Other Endpoint(s)
The summary for other endpoints including demographic and baseline characteristic, study 
drug administration is provided in section 6.5.
6.4. Subset Analyses
PK data over time will be assessed by ADA and NAb status. Please see the details in Section 
6.1.1 and 6.2.1.
6.5. Baseline and Other Summaries and Analyses
6.5.1. Participant disposition
Participant disposition will be summarized for enrolled population and ITT-Randomized 
population and will include the number and percentage of participants enrolled, randomized, 
treated, status, reason/description and other relevant data.
6.5.2. Participant demographics, Baseline characteristics 
Demographics and baseline characteristics (age, sex, height, weight, race, ethnicity, etc.) will 
be summarized descriptively using  Enrolled population, , ITT- Randomized population, and 
PK population.
6.5.3. Study Treatment Exposure
Study drug exposure (total number of doses, duration of treatment, total number of 
participants with any missed doses, etc.) will be summarized descriptively using Safety-TP1 
population by Humira arm and Safety-Randomized population by switching arm and non-
switching arm.
6.5.4. Concomitant Medications and Nondrug Treatments
Collected prior and concomitant medications will be coded by WHO medical dictionary; 
participants who received these medications will be summarized using Safety-Randomized 
population from TP2 to TP4 by switching arm and non-switching arm.


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6.6. Safety Summaries and Analyses.
Unless otherwise specified, safety analyses for TP1 will be performed using the Safety-TP1 
population for the Humira arm. Safety analyses for TP2 and beyond will be performed using 
Safety-Randomized populations by switching arm and non-switching arm.
6.6.1. Adverse Events
Adverse events will be classified using the medical dictionary for regulatory activities
(MedDRA) classification system.
Unless otherwise specified, AE analyses for TP1 will be performed using the Safety-TP1 
population for the Humira arm. AE analyses for TP2 and beyond will be performed using 
Safety-Randomized populations by switching arm and non-switching arm. Treatment-
emergent adverse events definitions for TP1 and TP2 and beyond are provided in section 
3.5.1.
6.6.1.1. Adverse Event for TP1
Adverse events (including overall summary of treatment-emergent adverse events; treatment-
related adverse events; adverse events classified as Grade 3 or higher; adverse event leading 
to discontinuation; and SAEs) will be summarized for the Humira arm.  All-causality TEAE 
and SAE will be also summarized by body system and preferred term according to MedDRA 
terminology.
6.6.1.2. Adverse Event for TP2 and Beyond
Adverse events (including overall summary of treatment-emergent adverse events; treatment-
related adverse events; adverse events classified as Grade 3 or higher; adverse event leading 
to discontinuation; and SAEs, etc.) will be summarized by switching arm and non-switching 
arm. All-causality TEAE and SAE will be also summarized by body system and preferred 
term according to MedDRA terminology.
AESI will be summarized by body system and preferred term according to MedDRA 
terminology and also by AESI categories, subcategories and preferred term. 
6.6.1.2.1. Effect of Immunogenicity on Safety
Immunogenic adverse effect during TP2 and beyond will be summarized for 2 subgroups of 
safety-randomized population: ADA positive in TP1 and ADA negative in TP1 subgroups (if 
applicable):

Percentage of participants with ISR AEs (as per the investigators)

Percentage of participants with medically evaluated AEs that meet Sampson’s 
Criteria

Percentage of participants with medically evaluated potential Hypersensitivity,        
Angioedema, Anaphylaxis, Cytokine Storm, and Delayed immune responses


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The identification of participants with AEs that meet Sampson criteria and the statistical 
summary will be provided in a supplemental statistical specification.  
6.6.1.2.2. AESI Summary for Individual Period
The summary of AESI will be provided by switching arm and non-switching arm for
individual switching periods (TP2, TP3, TP4).  
The safety analysis population for each individual period TP2/TP3/TP4 (Safety-
TP2/TP3/TP4) is defined as all participants who are randomized and receive at least one dose 
of investigational product in TP2/TP3/T4.
TEAE for TP2  is defined as any adverse event that occurs after the first dose of 
investigational product administrated in TP2 and before the first dose of investigational 
product administratd in TP3. TEAE for TP3 is defined as any adverse event that occurs after 
the first dose of investigational product administrated in TP3 and before the first dose of 
investigational product administratd in TP4. TEAE for TP4 is defined as any adverse event 
that occurs after the first dose of investigational product administrated in TP4.
6.6.2. Laboratory Data
The incidence of Lab abnormality will be summarized in TP1 for Safety-TP1 population and 
in TP2 through TP4 for Safety-Randomized population. The summary for Lab data by 
Maximum CTC Grade will be provided in TP2 through TP4 for Safety-Randomized 
population. eDISH Analysis will be provided in TP2 through TP4 for Safety-Randomized 
population.
6.6.3. Vital Signs
The vital sign data at each visit will be summarized for TP2 through TP4 data using Safety-
Randomized population.  The mean change from baseline to week 32/EOT/ET will be 
provided for Safety-Randomized populations. Baseline definitions for vital sign data will be 
consistent with Section 3.4. 
6.6.4. COVID-19 Related Summary 
Protocol Deviation, subject discontinuation, AE and SAE related to COVID-19 will be listed 
and/or summarized by Humira group for TP1 data and by switching and non-switching arms 
for TP2-TP4 data. 
7. INTERIM ANALYSES
7.1. Introduction
No formal interim analysis will be conducted for this study. As this is an open-label
study, the sponsor will conduct ongoing reviews of the data during the course of the study for
the purpose of safety.


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7.2. Interim Analyses and Summaries
No interim analyses and summaries will be provided since no formal interim analyses is 
planned for this study. 
8. REFERENCES
(1) Sampson H.A., et al. [2006]. Second Symposium on the Definition and Management of 
Anaphylaxis: Summary Report – Second National Institute of Allergy and 
Infectious Disease/Food Allergy and Anaphylaxis Network Symposium. Annals of 
Emergency Medicine, 47. 373 - 380. 


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9. APPENDICES
Appendix 1. SMQ MedDRA V24.0 Listings
SMQ MedDRA V24.0 listings could be found through the link
https://www.meddra.org/how-to-use/support-documentation/english/welcome
Appendix 2. List of Abbreviations
Abbreviation
Term
ADA
antidrug antibodies
AE
adverse event
AESI
adverse event of special interest
ANOVA
analysis of variance
AUC
area under the curve
AUCτ
area under the concentration - time curve over the dosing interval
Cav
average concentration
CI
confidence interval
CL/F 
apparent clearance
Cmax
maximum observed concentration
Ctrough 
predose concentration during multiple dosing
EoT 
End of Treatment
ET
Early Termination
GMR
geometric mean ratio
MedDRA 
Medical dictionary for regulatory activities
MTX 
methotrexate
NAb 
neutralizing antibodies
ND
not done
NS
no sample
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
statistical analysis plan
SMQ 
standardized MedDRA query
TEAE  
treatment-emergent adverse event
Tmax 
time at which Cmax occurs
TP1 
treatment period 1
TP2 
treatment period 2
TP3 
treatment period 3
TP4 
treatment period 4
WHO
World Health Organization