A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to Placebo and to Adalimumab in Subjects With Moderately to Severely Active Rheumatoid Arthritis Who Are on a Stable Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX (MTX-IR)
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: AbbVie

Upadacitinib
M14-465 Protocol Amendment 5
EudraCT 2015-003333-95
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1.0
Title Page
Clinical Study Protocol M14-465
A Phase 3, Randomized, Double-Blind Study 
Comparing Upadacitinib (ABT-494) to Placebo and to 
Adalimumab in Subjects with Moderately to Severely 
Active Rheumatoid Arthritis Who are on a Stable 
Background of Methotrexate (MTX) and Who Have 
an Inadequate Response to MTX (MTX-IR)
Incorporating Administrative Change 1, and 
Amendments 0.01, 0.01.01, 1, 2, 2.02, 3, 3.01, 4, 
4.03, and 5
AbbVie Investigational
  Product:
Upadacitinib
Date:
01 December 2017
Development Phase:
3
Study Design:
A 48-week randomized, double-blind, parallel-group, active comparator-
controlled period followed by a long-term extension period
EudraCT Number:
2015-003333-95
Investigators:
Multicenter trial (Investigator information is on file at AbbVie)
Sponsor:
AbbVie*
1 North Waukegan Road
North Chicago, IL  60064
Sponsor/Emergency 
  Contact:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are provided 
within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial Application with the 
Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other applicable regulatory 
requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
NCT02629159

Upadacitinib
M14-465 Protocol Amendment 5
EudraCT 2015-003333-95
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
30 September 2015
Amendment 1
11 December 2015
Administrative Change 1
17 December 2015
Amendment 2
08 January 2016
Amendment 0.01 (Canada Only)
13 January 2016
Amendment 2.02 (Korea Only)
23 March 2016
Amendment 3
01 April 2016
Amendment 3.01 (Korea Only)
21 April 2016
Amendment 0.01.01 (Canada Only)
26 April 2016
Amendment 4
11 January 2017
Amendment 4.03 (Canada Only)
09 March 2017
The purpose of this amendment is to:
●
Apply administrative changes throughout the protocol.
Rationale:  Revised text to improve consistency and readability, and/or 
provide clarity.
●
Changed ABT-494 to Upadacitinib throughout the protocol
Rationale:  Revised to reflect the recently approved International 
Nonproprietary Name.
●
Update Section 1.2, Synopsis
Rationale:  Revised to be consistent with Amendment 5 revisions.
●
Update Section 1.3, List of Abbreviations
Rationale:  Revised to be consistent with Amendment 5 revisions.
●
Update Section 5.1, Overall Study Design and Plan:  Description
Rationale:  
Revised to be consistent with Amendment 5 revisions. 

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Clarified that long term extension period is blinded until last subject completes 
Period 1.
Clarified that additional unblinded analyses may be conducted after the 
Week 26 unblinded analysis for regulatory purposes.
Updated text to clarify TJC/SJC improvement requirements starting at 
Week 48 to remain on study drug. 
Updated Figure 1 to align with protocol text.
Clarified that for subjects that discontinue study drug and continue on study, a 
second premature discontinuation visit is not required if the subject later 
withdraws from study.
Updated safety collection requirements for subjects that are treated with 
commercial adalimumab after end of study treatment.
Clarified the 30 day follow-up visit and 70 day follow-up call are not required 
for subjects who discontinued study drug and continued study participation 
with completion of at least one study visit approximately 30 days after last 
dose of oral or 70 days after last dose of subcutaneous study drug, 
respectively.
●
Update Section 5.2.3.1, Permitted Background RA Therapy
Rationale:  Updated csDMARD language to enable unbiased comparison of 
investigational product to active comparator up to end of Period 1.
●
Update Section 5.2.3.2, Prohibited Therapy
Rationale:  
Updated text to align with permitted background corticosteroid requirements.
Updated Table 1, Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers, to add Rifapentine.
Updated herpes zoster vaccine language for subject safety prior to and after 
study drug.
Updated to further explain the reason oral traditional Chinese medicines are 
not permitted.
●
Update Section 5.2.4, Contraception Recommendations

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M14-465 Protocol Amendment 5
EudraCT 2015-003333-95
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Rationale:  Added clarification on requirements for contraception for females 
if child-bearing potential status changes during the course of the study.
Updated required duration of contraception recommendations for males to 
reflect that upadacitinib is non-genotoxic, and showed no testicular findings in 
chronic animal toxicology studies, and had no impact on male or female 
fertility. 
Added definition of surgical sterility for male subjects.
●
Update Section 5.3.1, Efficacy and Safety Measurements Assessed and Flow 
Chart
Rationale: 
Updated Table 2 Study Activities (Period 1) to reflect Amendment 5 revisions.
Updated Table 2 to clarify the frequency of the Latent TB Risk Assessment 
Form completion.
Updated Table 2 to clarify that an annual ECG is required for all subjects.
Updated foot note "s" to avoid introduction of bias by local CRP testing.
●
Update Section 5.3.1.1, Study Procedures
Rationale:
Revised to include Rifapentine as excluded medication and added clarification 
on indeterminate QuantiFERON TB test results. 
Revised to prevent unnecessary initiation of TB prophylaxis in subject with 
indeterminate QuantiFERON-TB test results by allowing local testing. 
Revised to include Rifapentine as excluded medication for TB prophylaxis. 
Clarified annually is every 48 weeks to align with subject visit schedule.
Updated to allow a pulmonologist to perform an assessment of the chest x-ray.
Updated x-ray time points for subjects that prematurely discontinue from study 
drug but continue in the study to optimize x-ray assessments at Weeks 26, 48, 
and 96.
Updated Figure 3 to align with protocol text.
Updated to be consistent within the protocol that in the event post-baseline 
pregnancy test comes back borderline, a repeat test is required (≥ 3 days later) 
to document continued lack of a positive result.

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Clarified requirements for recording lab abnormalities as AEs.  Updated foot 
notes "i" and "k" to align with protocol text.
●
Update Section 5.3.3, Efficacy Variables
Rationale:
Updated text to clarify efficacy variables. 
Updated text to provide clarity for ranked key secondary endpoints, other key 
secondary endpoints and additional endpoints.
●
Update Section 5.4.1, Discontinuation of Individual Subjects
Rationale:
To clarify that starting at Week 48 at least 20% improvement in both swollen 
joint counts and tender joint counts compared to baseline is required to 
remain on study drug.
To reduce redundancy and reference Section 5.1 where text is originally 
stated.
●
Update Section 5.5.4, Selection and Timing of Dose for Each Subject
Rationale:  Updated study drug interruption time frames to align with 
Section 6.1.7.
●
Update Section 5.5.5.1, Blinding
Rationale:  Clarified who will remain blinded at study time points.
●
Update Section 6.1.1.3, Adverse Events of Special Interest
Rationale:  Updated the adverse events of special interest that will be 
monitored during the study to align in content and presentation with the 
current version of the Product Safety Statistical Analysis Plan.
○
Serious infections, opportunistic infections, herpes zoster, and TB was 
separated into separate bullets for serious infections, opportunistic 
infections, herpes zoster and tuberculosis to indicate that these are 
separate adverse events of interest
○
Malignancy and lymphoproliferative disorders was reduced to Malignancy 
(all types) which encompasses all types of malignancy including 
lymphoproliferative malignancies

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○
Cardiovascular events was amended to adjudicated cardiovascular events 
as all cardiovascular events occurring in the RA Phase 3 development 
program will be adjudicated by an external cardiac adjudication 
committee (CAC)
○
Removed hemoglobin effects as the term Anemia encompasses all 
hemoglobin effects of interest
○
For consistency throughout the program updated terminology from 
Decreased neutrophil counts to the term Neutropenia 
○
For consistency throughout the program updated terminology from 
Decreased lymphocyte counts to the term Lymphopenia
○
For consistency throughout the program updated terminology from 
Increased creatine phosphokinase (CPK) to Elevated creatine 
phosphokinase (CPK)
○
Updated to include embolic and thrombotic events as adverse events of 
special interest, based on data reported for other JAK inhibitors
●
Update Section 6.1.3, Relationship to Study Drug
Rationale:  Updated definition for assessing the relationship of adverse events 
to use of study drug per sponsor guidelines.
●
Update Section 6.1.4, Adverse Event Collection Period
Rationale:  Implement Supplemental eCRF for thrombotic events.
●
Update Section 6.1.7, Toxicity Management and Table 7
Rationale:
Clarified gastrointestinal perforation to align with protocol text.
Clarified that subject should discontinue study drug for an ECG abnormality 
that is considered clinically significant with reasonable possibility that the 
event is related to study drug. 
Clarified all abnormal lab tests that are considered clinically significant by 
the investigator should be followed to a satisfactory resolution.
Updated text within Table 7 to improve readability and provide clarity.  Added 
wording for management of subjects with HBc Ab+ (irrespective of HBs Ab 
status) and negative HBV DNA at screening and laboratory values during 
study which may indicate active hepatitis. 

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Clarified toxicity management for ALT, AST, and INR. 
Clarified toxicity management criteria for serum creatinine levels within 
normal reference range.
Clarified procedures for elevated CPK value (greater than or equal to 4 × 
ULN) but without any clinical signs and symptoms to allow continuation of 
treatment.
●
Update 7.0, Protocol Deviations
Rationale:  Updated AbbVie Clinical Contacts
●
Update Section 8.1, Statistical and Analytical Plans
Rationale:  Clarified that additional unblinded analyses may be conducted 
after the Week 26 unblinded analysis for regulatory purposes.
●
Update Section 8.1.4.1.4, Multiplicity Control for the Primary and Ranked 
Key Secondary Endpoints
Rationale:  Defined key secondary endpoints as ranked.
●
Update Section 8.1.4.1.5, Imputation Methods
Rationale:  Updated text to clarify analysis details.
●
Update Section 8.1.5, Safety Analysis
Rationale:  Updated text to clarify analysis details.
●
Update Appendix B, List of Protocol Signatories
Rationale:  Updated list of Protocol Signatories responsible for Amendment 5.
●
Update Appendix C, Local Requirements
Rationale:  Updated text for local country requirements for Canada to 
incorporate changes with Amendment 4.03 (Canada Only).
●
Update Appendix F, Latent TB Risk Assessment Form Example
Rationale:  Revised to align with previous protocol example.
●
Update Appendix O, Rheumatology Common Toxicity Criteria v.2.0 Example
Rationale:  Clarified that for CPK and serum creatinine NCI CTC grading 
will be used.

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EudraCT 2015-003333-95
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An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix P.

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M14-465 Protocol Amendment 5
EudraCT 2015-003333-95
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M14-465
Name of Study Drug:  Upadacitinib
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  01 December 2017
Protocol Title:  A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to 
Placebo and to Adalimumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Who 
are on a Stable Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX 
(MTX-IR)
Objectives:
Period 1
1.
To compare the efficacy of upadacitinib 15 mg once daily (QD) versus placebo, and versus 
adalimumab (ADA) for the treatment of signs and symptoms of rheumatoid arthritis (RA) in subjects 
with moderately to severely active RA who are on a stable background of methotrexate (MTX) and 
who have an inadequate response to MTX (MTX-IR).
2.
To compare the efficacy of upadacitinib 15 mg QD versus placebo for the prevention of structural 
progression in RA subjects with moderately to severely active RA who are on a stable background of 
MTX and who have an inadequate response to MTX (MTX-IR).
3.
To compare the safety and tolerability of upadacitinib 15 mg QD versus placebo, and versus ADA in 
subjects with moderately to severely active RA subjects who are on a stable background of MTX and 
who have an inadequate response to MTX (MTX-IR).
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg QD in subjects with RA 
who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 400
Study Population:  
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for 
RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints 
(based on 68 joint counts) at Screening and Baseline Visits, and high-sensitivity C-reactive protein 
(hsCRP) ≥ 5 mg/L (central lab, upper limit of normal [ULN] 2.87 mg/L) at Screening.  Subjects must 
have been on oral or parenteral MTX therapy ≥ 3 months and on a stable dose for ≥4 weeks prior to the 
first dose of study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at 
doses ≥12.5 mg/week).
Number of Subjects to be Enrolled:  Approximately 1500

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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 48-week randomized, 
double-blind, parallel-group, placebo-controlled and active comparator-controlled period designed to 
compare the safety and efficacy of upadacitinib 15 mg QD versus placebo and versus ADA for the 
treatment of signs and symptoms of subjects with moderately to severely active RA who are on a stable 
dose of MTX and have an inadequate response to MTX (MTX-IR).  Period 1 is also designed to compare 
the efficacy of upadacitinib 15 mg QD versus placebo for the prevention of structural progression.  
Period 2 is a long-term extension to evaluate the safety, tolerability and efficacy of upadacitinib 15 mg 
QD in subjects with RA who have completed Period 1.
The study duration will include a 35-day screening period; a 48-week randomized, double-blind, 
parallel-group, placebo-controlled and active comparator-controlled treatment period (Period 1); a 
long-term extension period (blinded until the last subject completes the last visit of the double-blind 
treatment period) (up to 5 years) (Period 2); a 30-day follow-up period (call or visit); and a 70-day
follow-up call.
Subjects who meet eligibility criteria will be randomized in a 2:2:1 ratio to one of three treatment groups: 
!
Group 1:  Upadacitinib (ABT-494) 15 mg QD (N = 600)
!
Group 2:  Placebo (N = 600)
!
Group 3:  ADA (40 mg every other week [eow]) (N = 300)
Subjects will receive both oral study drug QD (either upadacitinib 15 mg or matching placebo) and 
subcutaneous study drug eow (either ADA 40 mg or matching placebo) until the study is unblinded.
Subjects must have been on oral or parenteral MTX therapy for ≥ 3 months, on a stable MTX dose for 
≥4 weeks prior to the first dose of study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are 
intolerant of MTX at doses ≥ 12.5 mg/week), and must remain on a stable dose throughout the study; the 
MTX dose may be decreased only for safety reasons.  In addition, all subjects should take a dietary 
supplement of oral folic acid (or equivalent) throughout study participation.  Folic acid dosing and timing 
of regimen should be followed according to the Investigator's instructions.  Starting at the Week 26 visit 
(after Week 26 assessments have been performed), initiation of or change in background RA 
medication(s) including, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, is allowed as per local label.  Starting at Week 48 (after Week 48 
assessments have been performed) and thereafter, initiation of or change in  csDMARDs is allowed as 
per local label (restricted to oral or parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and 
leflunomide, and restricted to concomitant use of up to 2 csDMARDs except the combination of MTX 
and leflunomide).
Subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic drug (bDMARD) 
(except ADA) for RA may be enrolled in the study (up to 20% of total number of subjects) after the 
required washout period is satisfied and if they have a) limited bDMARD exposure (< 3 months), OR 
b) response to a bDMARD but had to discontinue that bDMARD due to intolerability (regardless of 
treatment duration).  These subjects will be equally stratified across all treatment groups.  Subjects who 
are considered bDMARD-inadequate responders (lack of efficacy), as determined by the Investigator, are 
not eligible.
Rescue therapy will be offered to subjects who meet the following criteria:

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Methodology (Continued):
Placebo:
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded upadacitinib treatment.
!
At Week 26, all remaining subjects will be switched to blinded upadacitinib treatment regardless 
of clinical response.
ADA:  
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded upadacitinib treatment.
!
At Week 26, all remaining subjects who do not achieve LDA according to CDAI (LDA defined 
as CDAI ≤10) at Week 26 will be switched to blinded upadacitinib treatment.
Upadacitinib:
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded ADA treatment.
!
At Week 26, all remaining subjects who do not achieve LDA according to CDAI (LDA defined 
as CDAI ≤10) at Week 26 will be switched to blinded ADA treatment.
An unblinded analysis will be conducted after all subjects have completed Week 26 for the purpose of 
regulatory submission.  To maintain integrity of the trial and avoid introduction of bias, study sites and 
subjects will remain blinded for the duration of Period 1.  Additional unblinded analyses may be 
conducted after the Week 26 unblinded analysis for regulatory purposes.
Each subject will undergo a maximum of 5 scheduled visits for x-ray examination of bilateral hands and 
feet during Period 1 (unless unscheduled repeat imaging is needed due to failure to meet the quality 
requirements) at Screening, Week 26, and Week 48/Premature Discontinuation.  Subjects who are non-
responders (defined as those not achieving ≥ 20% improvement in TJC and SJC criterion) at Week 14 
and are switched to rescue therapy will have an x-ray examination at Week 14; in addition, subjects who 
prematurely discontinue from study drug or the study
will have an 
x-ray examination at the premature discontinuation timepoint.
Subjects who complete the Week 48 visit (end of Period 1) will enter the long-term extension portion of 
the study, Period 2 (up to 5 years).  Subjects will continue study treatment as assigned in Period 1.  
Subjects who are assigned to the upadacitinib 15 mg QD treatment group at the end of Period 1 will 
continue to receive upadacitinib 15 mg QD in a blinded manner.  Subjects who are assigned to 
adalimumab 40 mg eow at the end of Period 1 will continue to receive adalimumab 40 mg eow in a 
blinded manner.  When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment in both periods will be unblinded to the Sponsor and sites, and subjects will be dispensed 
study drug in an open-label fashion until the completion of Period 2.
Each subject will undergo an x-ray examination of bilateral hands and feet at Week 96/Premature 
Discontinuation (unless repeat testing is needed due to failure to meet the quality requirements) and every 
96 weeks thereafter.  Subjects who prematurely discontinue from the study will not need an x-ray of 
hands and feet if the previous x-ray was performed within the previous
weeks.

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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who fulfill the 2010 ACR/EULAR classification criteria for RA.
3.
Subjects must have been on oral or parenteral MTX therapy ≥ 3 months and on a stable prescription 
of 15 to 25 mg/week (or ≥ 10 mg/week in subjects intolerant of MTX at doses ≥ 12.5 mg/week) for 
≥4 weeks prior to the first dose of study drug.  In addition, all subjects should take a dietary 
supplement of folic acid or folinic acid throughout the study participation.
4.
Subject meets both of the following disease activity criteria:
a.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at 
Screening and Baseline Visits; and
b.
hsCRP ≥ 5 mg/L (central lab, ULN 2.87 mg/L) at Screening Visit.
5.
Subject has at least one of the following at Screening:  
a.
≥ 3 bone erosions on x-ray; or
b.
≥ 1 bone erosion and a positive rheumatoid factor; or
c.
≥ 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibody.
6.
Subjects with prior exposure to only one bDMARD (except ADA) may be enrolled (up to 20% of 
total study population).  Specifically, prior to enrollment:  
a.
Patients with limited exposure to a bDMARD (< 3 months), OR
b.
Patients who are responding to a bDMARD but had to discontinue due to intolerability
(regardless of treatment duration).
7.
Except for MTX, subject must have discontinued all csDMARDs.  The washout period for 
csDMARDs prior to the first dose of study is specified below or should be at least five times the 
mean terminal elimination half-life of a drug:
o
≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, sulfasalazine, 
hydroxychloroquine, chloroquine, azathioprine, gold formulations, cyclophosphamide, 
tacrolimus, cyclosporine, mycophenolate;
o
≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination procedure was 
followed, or adhere to an elimination procedure (i.e., 11 days with colestyramine, or 30 days 
washout with activated charcoal or as per local label).

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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):
Main Exclusion:
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects who have had any exposure to adalimumab or subjects who have been treated with other 
bDMARD therapy for ≥ 3 months who are considered inadequate responders (lack of efficacy) to 
bDMARD therapy as determined by the Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms], or any arthritis with onset prior to 
age 17 years).  History of secondary Sjogren's Syndrome is permitted.
4.
Laboratory values meeting the following criteria within the Screening period prior to the first dose of 
study drug: serum aspartate transaminase > 2 × ULN; serum alanine transaminase > 2 × ULN; 
estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease 
formula < 40 mL/min/1.73m2; total white blood cell count < 2,500/μL; absolute neutrophil count 
< 1,500/μL; platelet count < 100,000/μL; absolute lymphocyte count < 800/μL; and hemoglobin 
< 10 g/dL.
Investigational Product:
Upadacitinib
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
ADA, matching placebo for ADA, matching placebo for upadacitinib
Dose:
ADA 40 mg eow, matching placebo for upadacitinib QD, and matching 
placebo for ADA eow
Mode of Administration:
ADA and matching placebo for ADA will be administered by 
subcutaneous injection eow and upadacitinib and matching placebo will 
be given orally QD
Duration of Treatment:  Period 1:  48 weeks; Period 2:  up to 5 years

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Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response at Week 12 
(US/FDA regulatory purposes) or the proportion of subjects achieving clinical remission (CR) based on 
Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12 (EU/EMA regulatory purposes).
ACR20 response rate will be determined based on 20% or greater improvement in TJC and SJC and ≥3 
of the 5 measures of Patient's Assessment of Pain (Visual Analog Scale [VAS]), Patient's Global 
Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease Activity (VAS), 
Health Assessment Questionnaire Disability Index (HAQ-DI), or hsCRP.
CR is defined as DAS28 (CRP) < 2.6. 
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) for US/FDA 
regulatory purposes are:
1.
Change from baseline in Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12;
2.
Change from baseline in mTSS at Week 26;
3.
Change from baseline in HAQ-DI at Week 12;
4.
ACR50 response rate at Week 12 (non-inferiority of upadacitinib versus ADA);
5.
Change from baseline in Short Form 36 (SF-36) Physical Component Score (PCS) at Week 12;
6.
Proportion of subjects achieving low disease activity (LDA) based on DAS28 [CRP] ≤ 3.2 at 
Week 12;
7.
Proportion of subjects achieving clinical remission (CR) based on DAS28 (CRP) at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index (CDAI) at Week 12;
9.
Change from baseline in morning stiffness at Week 12;
10. Change from baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) at 
Week 12;
11. ACR50 response rate at Week 12 (superiority of upadacitinib vs. ADA);
12. Change from baseline in Patient's Assessment of Pain at Week 12 (superiority of upadacitinib vs. 
ADA);
13. Change from baseline in HAQ-DI at Week 12 (superiority of upadacitinib vs. ADA).

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Other key secondary endpoints (upadacitinib versus placebo) for US/FDA regulatory purposes are:
!
ACR50 response rate at Week 12
!
ACR70 response rate at Week 12
!
Proportion of subjects with no radiographic progression (defined as change from baseline mTSS 
≤ 0) at Week 26
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) for EU/EMA 
regulatory purposes are:
1.
The change from baseline in modified Total Sharp Score (mTSS) at Week 26;
2.
Proportion of subjects achieving LDA based on DAS28 [CRP] ≤ 3.2 at Week 12;
3.
Change from baseline in DAS28 (CRP) at Week 12;
4.
Change from baseline in HAQ-DI at Week 12;
5.
ACR20 response rate at Week 12;
6.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 (non-inferiority of 
upadacitinib versus ADA);
7.
Change from baseline in SF-36 PCS at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index (CDAI) at Week 12
9.
Change from baseline in morning stiffness at Week 12.
10. Change from baseline in FACIT-F at Week 12
11. Proportion of subjects with no radiographic progression (defined as change from baseline mTSS ≤ 0) 
at Week 26;
Other key secondary endpoints (upadacitinib versus placebo) for EU/EMA regulatory purposes are:
1.
ACR50 response rate at Week 12
2.
ACR70 response rate at Week 12

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Additional endpoints (upadacitinib versus placebo and adalimumab) are:
!
Change from baseline in individual components of ACR response at all visits;
!
ACR20/50/70 response rates at all visits;
!
Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]) at all 
visits;
!
Change from baseline in CDAI and SDAI at all visits;
!
Proportion of subjects achieving LDA or CR based on DAS28 (CRP) and DAS28 (ESR), 
Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) criteria 
at all visits (see below); 
!
Change from baseline in morning stiffness at all visits; 
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22 at all visits;
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3 at all visits; 
!
ACR/EULAR Boolean remission at all visits;
!
Change from baseline in EQ-5D-5L, SF-36, FACIT-F and RA-WIS at Weeks 12, 26, and 48;
!
Change from baseline in modified Total Sharp Score (mTSS) at Weeks 26 and 48;
!
Proportion of subjects with no radiographic progression (defined as change from baseline 
mTSS ≤ 0) at Weeks 26 and 48;
!
Change from baseline in joint space narrowing score and joint erosion score at Weeks 26 and 48

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Criteria for Evaluation (Continued):
Efficacy (Continued):
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 60, 72, 84, 96, and every 12 weeks thereafter until completion of the study:
!
ACR20/50/70 response rates;
!
Change from baseline in individual ACR components;
!
Change from baseline in DAS28 (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness;
!
Proportion of subjects achieving LDA and the proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;
!
Concomitant corticosteroid use (systemic use and intra-articular injections);
!
ACR/EULAR Boolean remission.
Additionally, assessment for the evaluation of radiographic changes in Period 2 will occur at Week 96 
and every 96 weeks thereafter (or Premature Discontinuation visit):
!
Change from baseline in modified Total Sharp Score (mTSS);
!
Proportion of subjects with no radiographic progression (defined as change from baseline in 
mTSS of ≤ 0);
!
Change from baseline in Radiographic joint space narrowing and erosion scores.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other medications in plasma will be collected at 
Weeks 2, 4, 8, 12, 14, 18, 22, 26, 30, 36, 42, and 48/Premature Discontinuation.  
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
Prognostic, predictive, and pharmacodynamics biomarkers signatures may be evaluated. Samples for 
pharmacogenetic, epigenetic, transcriptomic, and proteomic and targeted protein investigations will be 
collected at various time points.  Assessments will include but may not be limited to nucleic acids, 
proteins, metabolites, or lipids.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.

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Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Period 1 Efficacy
Analysis of the Primary and Key Secondary Endpoints:
All statistical comparisons of upadacitinib versus comparators for the primary and key 
secondary endpoints will be conducted using a two-sided alpha = 0.05 level of significance.
In order to preserve Type I error, a step-down approach will be used to test the primary and ranked key 
secondary endpoints where statistical significance can be claimed for a lower ranked endpoint only if the 
previous endpoints in the sequence meets the requirements of significance.
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between upadacitinib and placebo will be conducted using the Cochran-Mantel-Haenszel 
test adjusting for main stratification factors.  For LDA response rates at Week 12, analysis will be 
conducted to test the non-inferiority of upadacitinib versus ADA using the 95% confidence interval of 
treatment difference against a non-inferiority margin of 10%.  For ACR50 response rate at Week 12, 
similar analysis of non-inferiority will be conducted for US/FDA purposes.  Superiority of upadacitinib
vs ADA will also be tested for LDA and ACR50.
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Pairwise comparisons between upadacitinib and placebo will be carried out using the 
analysis of covariance model with treatment group as the fixed factor, and the corresponding baseline 
value and the main stratification factors as the covariates.  For change from baseline in patient's global 
assessment of pain and change from baseline in HAQ-DI at Week 12, superiority of upadacitinib vs 
adalimumab will also be tested.
For mTSS-based endpoints, both linear extrapolation and As Observed (AO) analyses will be conducted.  
For all other endpoints, non-responder imputation approach will serve as the primary analysis approach 
for key binary endpoints and multiple imputation will serve as the primary analysis approach for key 
continuous endpoints.  Sensitivity analyses based on observed cases approach will also be conducted for 
key endpoints.
Long-Term Efficacy for Period 1 and Period 2 Combined
Long-term efficacy by time point will be summarized using descriptive statistics.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values of upadacitinib oral clearance (CL/F) and 
volume of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of 
the data.

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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Analyses will be conducted for both short term and long term.  Safety 
will be assessed by AEs, physical examination, laboratory assessments, ECG, and vital signs.  Frequency 
tables and lists of subjects with treatment-emergent AEs by preferred term as in the Medical Dictionary 
for Regulatory Activities dictionary, by system organ class, by severity, and by relationship to the study 
drug as assessed by the Investigator will be provided.  The changes from baseline in vital signs, physical 
examination results, and clinical laboratory values will be analyzed in a descriptive manner.  Shift of 
laboratory values from baseline to defined time points will be tabulated.

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1.3
List of Abbreviations and Definition of Terms
Abbreviations
ACR
American College of Rheumatology
ADA
adalimumab
AE
adverse event
ALC
absolute lymphocyte count
ALT
alanine transaminase
ANC
absolute neutrophil count
anti-CCP
anti-cyclic citrullinated peptide
AST
aspartate transaminase
AUC
Area under the plasma concentration-time curve
BCG
Bacille Calmette-Guérin
bDMARD
biologic disease-modifying anti-rheumatic drug
BID
twice daily (Latin:  bis in die)
BUN
blood urea nitrogen
CBC
complete blood count
CDAI
clinical disease activity index
CL/F
apparent clearance
Cmax
Maximum Observed Plasma Concentration
Cmin
Minimum Observed Plasma Concentration 
CPK
creatine phosphokinase
CR
clinical remission
CRF
case report form
CRP
C-reactive protein
csDMARD
conventional synthetic disease-modifying anti-rheumatic drug
CSR
clinical study report
CXR
chest x-ray
CYP
cytochrome
DAS
disease activity score
DMARD
disease-modifying anti-rheumatic drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
electrocardiogram

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eCRF
electronic case report form
EDC 
electronic data capture
eow
every other week
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQoL-5D-5L
ESR
erythrocyte sedimentation rate
EU
European Union
EULAR
European League Against Rheumatism
FACIT-F
Functional Assessment of Chronic Illness Therapy – Fatigue
FAS
full analysis set
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBc Ab/anti-HBc
Hepatitis B core antibody
HBs Ab/anti-HBs
Hepatitis B surface antibody
HBs Ag
Hepatitis B surface antigen
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HCV Ab
Hepatitis C virus antibody
HDL-C
high-density lipoprotein cholesterol
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
IAG
Imaging Acquisition Guidelines
ICH
International Conference On Harmonization
IEC
independent ethics committee
IGRA
interferon-gamma release assay
IMP
investigational medicinal product
INR
international normalized ratio
IR
inadequate response
IRB
institutional review board
IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine hormone-releasing system
JAK
Janus kinase

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LDA
low disease activity
LDL-C
low-density lipoprotein cholesterol
MACE
major adverse cardiovascular event
MCID
minimum clinically important differences
MDRD
modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mTSS
modified Total Sharp Score
MTX
methotrexate
MTX-IR
methotrexate inadequate responder
NA
no assessment
NMSC
non-melanoma skin cancer
NONMEM
non-linear mixed-effects modeling
NRI
non-responder imputation
NRS
numerical rating scale
NSAID
non-steroidal anti-inflammatory drug
OC
observed cases
OLE
open-label extension
PCR
polymerase chain reaction
PCS
physical component score
PD
premature discontinuation
PhGA
Physician's Global Assessment of Disease Activity
PK
pharmacokinetic
PPD
purified protein derivative
PRN
as needed (Latin:  pro re nata)
PRO
patient-reported outcome
PT
preferred term
PtGA
Patient's Global Assessment of Disease Activity
QD
once daily (Latin:  quaque die)
RA
rheumatoid arthritis
RA-WIS
Work Instability Scale for Rheumatoid Arthritis
RAVE®
EDC system from Medidata
RBC
red blood cell
RCT
randomized controlled trial
RF
rheumatoid factor

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RNA
Ribonucleic acid
SAE
serious adverse event
SAP
statistical analysis plan
SDAI
simplified disease activity index
SF-36
Short Form-36
SJC
swollen joint count
SmPC
Summary of Product Characteristics
SOC
system organ class
SUSAR
suspected unexpected serious adverse reaction
T2T
treat-to-target
TB
tuberculosis
TEAE
treatment-emergent adverse event
TJC
tender joint count
TNF
tumor necrosis factor
TNF-IR
tumor necrosis factor inadequate responder
Tyk2
Tyrosine kinase 2
ULN
upper limit of normal
V/F
apparent volume of distribution
VAS
visual analog scale
WBC
white blood cell

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2.0
Table of Contents
1.0
Title Page ...............................................................................1
1.1
Protocol Amendment:  Summary of Changes ......................................... 2
1.2
Synopsis................................................................................................. 9
1.3
List of Abbreviations and Definition of Terms...................................... 20
2.0
Table of Contents ................................................................ 24
3.0
Introduction......................................................................... 29
3.1
Differences Statement .......................................................................... 32
3.2
Benefits and Risks................................................................................ 33
4.0
Study Objectives.................................................................. 33
5.0
Investigational Plan.............................................................34
5.1
Overall Study Design and Plan:  Description ........................................ 34
5.2
Selection of Study Population............................................................... 42
5.2.1
Inclusion Criteria.................................................................................. 42
5.2.2
Exclusion Criteria................................................................................. 45
5.2.3
Prior, Concomitant, and Prohibited Therapy......................................... 49
5.2.3.1
Permitted Background RA Therapy...................................................... 50
5.2.3.2
Prohibited Therapy............................................................................... 51
5.2.3.3
Rescue Therapy.................................................................................... 56
5.2.4
Contraception Recommendations ......................................................... 57
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables ......................................................................... 60
5.3.1
Efficacy and Safety Measurements Assessed and Flow Chart ............... 60
5.3.1.1
Study Procedures.................................................................................. 72
5.3.1.2
Collection and Handling of Optional Samples for Exploratory 
Research and Validation Studies........................................................... 93
5.3.2
Drug Concentration and Anti-Drug Antibody Measurements................ 95
5.3.2.1
Collection of Samples for Analysis....................................................... 95
5.3.2.2
Measurement Methods ......................................................................... 96
5.3.3
Efficacy Variables................................................................................ 96
5.3.3.1
Period 1 Variables ................................................................................ 96

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5.3.3.1.1
Primary Variables................................................................................. 96
5.3.3.1.2
Key Secondary Variables ..................................................................... 96
5.3.3.1.3
Additional Variables............................................................................. 98
5.3.3.2
Period 2 Variables ...............................................................................100
5.3.4
Safety Variables ..................................................................................101
5.3.5
Pharmacokinetic Variables ..................................................................101
5.3.6
Exploratory Research Variables and Validation Studies.......................101
5.4
Removal of Subjects from Therapy or Assessment ..............................102
5.4.1
Discontinuation of Individual Subjects ................................................102
5.4.2
Discontinuation of Entire Study...........................................................104
5.5
Treatments ..........................................................................................104
5.5.1
Treatments Administered.....................................................................104
5.5.2
Identity of Investigational Product.......................................................105
5.5.2.1
Packaging and Labeling.......................................................................106
5.5.2.2
Storage and Disposition of Study Drugs ..............................................107
5.5.3
Method of Assigning Subjects to Treatment Groups ............................107
5.5.4
Selection and Timing of Dose for Each Subject ...................................108
5.5.5
Blinding ..............................................................................................109
5.5.5.1
Blinding of Investigational Product .....................................................109
5.5.5.2
Blinding of Data for Data Monitoring Committee................................110
5.5.6
Treatment Compliance ........................................................................111
5.5.7
Drug Accountability ............................................................................111
5.6
Discussion and Justification of Study Design.......................................112
5.6.1
Discussion of Study Design and Choice of Control Groups .................112
5.6.2
Appropriateness of Measurements.......................................................113
5.6.3
Suitability of Subject Population .........................................................113
5.6.4
Selection of Doses in the Study ...........................................................113
6.0
Complaints......................................................................... 114
6.1
Medical Complaints ............................................................................114
6.1.1
Definitions ..........................................................................................115
6.1.1.1
Adverse Event.....................................................................................115
6.1.1.2
Serious Adverse Events.......................................................................116
6.1.1.3
Adverse Events of Special Interest.......................................................117

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6.1.2
Adverse Event Severity .......................................................................117
6.1.3
Relationship to Study Drug..................................................................118
6.1.4
Adverse Event Collection Period.........................................................118
6.1.5
Serious Adverse Event Reporting ........................................................120
6.1.6
Pregnancy............................................................................................122
6.1.7
Toxicity Management..........................................................................123
6.1.8
Data Monitoring Committee................................................................128
6.1.9
Cardiovascular Adjudication Committee .............................................128
6.2
Product Complaint...............................................................................128
6.2.1
Definition............................................................................................128
6.2.2
Reporting ............................................................................................129
7.0
Protocol Deviations ........................................................... 129
8.0
Statistical Methods and Determination of Sample 
Size ..................................................................................... 130
8.1
Statistical and Analytical Plans............................................................130
8.1.1
Analysis Populations ...........................................................................131
8.1.1.1
Full Analysis Set (FAS).......................................................................131
8.1.1.2
Per Protocol Analysis Set ....................................................................131
8.1.1.3
Safety Analysis Set..............................................................................131
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............131
8.1.2.1
Subject Accountability ........................................................................131
8.1.2.2
Subject Disposition..............................................................................132
8.1.2.3
Study Drug Exposure ..........................................................................132
8.1.3
Analysis of Demographic and Baseline Characteristics........................132
8.1.4
Efficacy Analysis ................................................................................133
8.1.4.1
Efficacy Analysis for Period 1.............................................................133
8.1.4.1.1
Primary Efficacy Variables..................................................................133
8.1.4.1.2
Key Secondary Efficacy Variables ......................................................134
8.1.4.1.3
Other Efficacy Variables .....................................................................135
8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key 
Secondary Endpoints...........................................................................135
8.1.4.1.5
Imputation Methods ............................................................................135
8.1.4.2
Long-Term Efficacy for Period 1 and Period 2 Combined ...................136

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8.1.5
Safety Analyses...................................................................................136
8.1.5.1
General Considerations........................................................................136
8.1.5.2
Analysis of Adverse Events.................................................................137
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) .....................................137
8.1.5.2.2
Serious Adverse Events and Death ......................................................138
8.1.5.3
Analysis of Laboratory, Vital Sign, and ECG Data..............................138
8.1.6
Pharmacokinetic and Exposure-Response Analyses.............................139
8.2
Determination of Sample Size .............................................................141
8.3
Randomization Methods......................................................................141
9.0
Ethics.................................................................................. 141
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ........................................................................................141
9.2
Ethical Conduct of the Study...............................................................142
9.3
Subject Information and Consent.........................................................142
10.0
Source Documents and Case Report Form 
Completion ........................................................................ 143
10.1
Source Documents...............................................................................143
10.2
Case Report Forms..............................................................................144
11.0
Data Quality Assurance .................................................... 146
12.0
Use of Information ............................................................ 147
13.0
Completion of the Study ................................................... 148
14.0
Investigator's Agreement.................................................. 149
15.0
Reference List.................................................................... 150
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers................................................................................................ 53
Table 2.
Study Activities (Period 1) ................................................................... 61
Table 3.
Study Activities – Optional Samples for Exploratory Research 
and Validation Studies (Period 1 Only)................................................. 68
Table 4.
Study Activities (Period 2) ................................................................... 69
Table 5.
Clinical Laboratory Tests ..................................................................... 89

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Table 6.
Identity of Investigational Product.......................................................106
Table 7.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values ...............................................................................125
List of Figures
Figure 1.
Period 1 Study Design .......................................................................... 38
Figure 2.
Period 2 Study Design.......................................................................... 39
Figure 3.
Handling of X-Rays of Hands and Feet after Baseline (Period 1).......... 83
Figure 4.
Criteria for HBV DNA PCR Qualitative Testing .................................. 91
Figure 5.
Adverse Event Collection....................................................................119
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator.........................................153
Appendix B.
List of Protocol Signatories .................................................................155
Appendix C.
Local Requirements.............................................................................156
Appendix D.
Physician's Global Assessment of Disease Activity Example...............162
Appendix E.
Joint Evaluation Worksheet Example ..................................................163
Appendix F.
Latent TB Risk Assessment Form Example.........................................165
Appendix G.
Patient's Global Assessment of Disease Activity Example ...................166
Appendix H.
Patient's Assessment of Pain Example .................................................167
Appendix I.
Health Assessment Questionnaire (HAQ-DI) Example ........................168
Appendix J.
Patient's Assessment of Morning Stiffness Example ............................171
Appendix K.
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale Example...................................................................172
Appendix L.
EuroQoL-5D-5L Example ...................................................................173
Appendix M.
Short Form-36 (SF-36™) Health Status Survey Questionnaire 
Example ..............................................................................................176
Appendix N.
RA-WIS Example ...............................................................................182
Appendix O.
Rheumatology Common Toxicity Criteria v.2.0 Example....................183
Appendix P.
Protocol Amendment:  List of Changes ...............................................195

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3.0
Introduction
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown 
etiology.  The hallmark feature of RA is an inflammatory process manifested by persistent 
symmetric polyarthritis of synovial joints which can ultimately lead to bone erosions, 
deformity, and disability.  Left untreated, or inadequately treated, progressive functional 
impairment with increasing disability occurs leading to a reduction in quality of life.  The 
prevalence of RA in the general population is approximately 1%, and increases with age 
in both genders, with women being more prone to developing RA than men.  Early 
therapy with disease-modifying anti-rheumatic drugs (DMARDs) is the standard of care, 
including conventional synthetic DMARDs (csDMARDs) (e.g., methotrexate [MTX], 
sulfasalazine, hydroxychloroquine, and leflunomide), and biologic DMARDs 
(bDMARDs) (e.g., anti-tumor necrosis factor [TNF] and non-anti-TNF biologics).
The European League Against Rheumatism (EULAR) recommends a Treat-to-Target 
(T2T) approach to initiate therapy immediately after diagnosis of RA with a goal of 
achieving clinical remission (CR) or low disease activity (LDA), as these are associated 
with improved long-term outcomes.1-3  Also, in line with recent advances in early 
diagnosis, new classification criteria have been developed.  The 2010 American College 
of Rheumatology (ACR)/EULAR classification criteria redefined the paradigm of RA by 
focusing on features at earlier stages of disease that are associated with persistent and/or 
erosive disease, rather than defining the disease by its late-stage features.4
Despite major progress in the treatment of RA, there still remains a large unmet medical 
need, as only a small percentage of RA patients reach or maintain a status of LDA or CR 
over time or need to discontinue due to safety or tolerability issues.5,6  Novel therapies are 
therefore needed to complement the available interventions to address the unmet need.5-7

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JAK Inhibitor
Evidence suggests that inhibition of Janus kinase (JAK)-mediated pathways is a 
promising approach for the treatment of patients with this chronic disease.8  AbbVie is 
developing a small molecule inhibitor of JAK, upadacitinib (ABT-494), that may address 
the current needs.
The JAK family is composed of 4 family members:  JAK1, 2, 3, and Tyrosine kinase 2 
(Tyk2).  These cytoplasmic tyrosine kinases are associated with membrane cytokine 
receptors such as common gamma-chain receptors and the glycoprotein 130 
transmembrane proteins.9  Activation of JAK pathways initiates expression of survival 
factors, cytokines, chemokines, and other molecules that facilitate leukocyte cellular 
trafficking and cell proliferation which contribute to inflammatory and autoimmune 
disorders.
Hence, the JAK family has evoked considerable interest in the area of inflammatory 
diseases leading to the development of various JAK inhibitors with different selectivity 
profiles against JAK1, JAK2, JAK3, and Tyk2 which have demonstrated efficacy in 
individuals with RA.10-14  Tofacitinib, the first in this class, has been approved in the 
United States and in other countries for treating moderately to severely active RA 
patients.  Although tofacitinib, a non-selective JAK inhibitor, improves the clinical signs 
and symptoms, and inhibits structural progression in RA patients, questions regarding the 
safety profile remain, including serious infections, herpes zoster reactivation, 
malignancies, and hematologic adverse events (AEs).
The second generation of JAK inhibitors, with different selectivity profiles against JAK1, 
JAK2, JAK3, and Tyk2, are in development.8  Upadacitinib is a novel selective JAK1 
inhibitor being developed for the treatment of adult patients with moderately to severely 
active RA.  In an in vitro setting, upadacitinib potently inhibits JAK1 activity, but to a 
lesser degree, inhibits the other isoforms, JAK2 and JAK3.  The enhanced selectivity of 
upadacitinib against JAK1 may offer an improved benefit-risk profile in patients with RA.  
The clinical hypothesis is that upadacitinib should be effective in decreasing joint 

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inflammation and damage associated with RA by interfering with JAK1-mediated 
signaling pathways (i.e., interleukin-6) without causing excessive anemia due to its 
reduced activity against JAK2 (IC50 120 nM), which is essential for erythropoietin 
signaling.  Upadacitinib is also less potent against JAK3 (IC50 2.3 μM), an important 
component of lymphocyte activation and function.  As such, treatment with upadacitinib, 
a selective JAK1 inhibitor with reduced JAK3 inhibition, could result in a decreased risk 
for infection (including viral reactivation) and/or malignancy compared to a pan JAK 
inhibitor or less selective JAK inhibitors.
Phase 2 Studies with Upadacitinib
The Phase 2 program for upadacitinib consisted of 2 randomized controlled trials (RCTs), 
both on stable background MTX therapy, in subjects with moderately to severely active 
RA and one open-label extension (OLE) study (Study M13-538; NCT02049138) for those 
subjects who had completed either one of the RCTs.  Study M13-550 (NCT01960855) 
enrolled subjects who had an inadequate response to anti-TNF therapy and 
Study M13-537 (NCT02066389) enrolled subjects who had shown an inadequate 
response to MTX.  A total of 4 twice daily (BID) and 1 once daily (QD) dose regimens of 
upadacitinib immediate release capsules (3 mg BID, 6 mg BID, 12 mg BID, 18 mg BID, 
and 24 mg QD) were evaluated.
In TNF-inadequate responder (TNF-IR) subjects, who represent the population with the 
greatest unmet need, the primary endpoint of ACR20 response rate at Week 12 was 
significantly greater at all doses of upadacitinib (up to 73%) compared with placebo 
(35%).  In addition, numerically higher proportions of subjects achieved ACR50 and 
ACR70 responses and LDA (based on Disease Activity Score [DAS]28 C-Reactive 
Protein [CRP] and Clinical Disease Activity Index [CDAI]) in the upadacitinib dose 
groups versus placebo.
In MTX-inadequate responder (MTX-IR) subjects, the primary endpoint of ACR20 
response rate at Week 12 was significantly greater (up to 82%) at all but the lowest dose 

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of upadacitinib compared with placebo (50%).  At all doses of upadacitinib compared to 
placebo, significantly higher proportions of subjects achieved LDA and CR at Week 12. 
Safety data from these two studies (N = 575) showed that the types and frequencies of 
AEs during upadacitinib treatment were consistent with subjects with moderately to 
severely active RA receiving immunomodulatory therapy.  The incidences of AEs were 
numerically higher in the upadacitinib dose groups, with a trend toward higher rates with 
higher doses of upadacitinib.  The most frequently reported (≥ 5%) AEs in the 
upadacitinib treated subjects were urinary tract infection, headache, upper respiratory tract 
infection, and nausea.  There were 6 subjects (1.3% of total combined populations) with 
herpes zoster reactivation distributed across the upadacitinib dose groups, and 2 subjects 
(1.9%) in the placebo groups.  In these two 12 week studies, a total of 2 subjects in the 
upadacitinib treatment groups reported malignancies.  One subject reported non-
melanoma skin cancers (NMSC) (basal cell and squamous cell carcinoma) and 1 subject 
was diagnosed with lung cancer after the final scheduled visit, and subsequently died 
14 weeks after study completion.  These events were reported by the Investigators as not 
possibly related to study drug.  Elevations of liver function tests were sporadic with no 
clear dose-response relationship observed.  As observed with other JAK inhibitors, 
treatment with upadacitinib resulted in an increase in lipids (low-density lipoprotein 
cholesterol [LDL-C] and high-density lipoprotein cholesterol [HDL-C]).  Among subjects 
with laboratory evidence of systemic inflammation (as evidenced by high-sensitivity 
C-reactive protein [hsCRP] > upper limit of normal [ULN]), treatment with lower doses 
of upadacitinib (3 mg BID and 6 mg BID) was associated with improvements in mean 
hemoglobin relative to placebo.  At higher doses, there was a reduction in mean 
hemoglobin; however, the mean hemoglobin levels remained within normal range 
throughout the treatment period.
3.1
Differences Statement
Study M14-465 differs from other upadacitinib studies as it is the first study to evaluate 
the safety and efficacy (both clinical and structural) of upadacitinib in the MTX-IR 
population, and to use adalimumab (ADA) as an active comparator.

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3.2
Benefits and Risks
Despite the availability of various RA therapies, including csDMARDs and bDMARDs, 
many patients still do not respond adequately to these treatments, or gradually lose 
response over time.  Upadacitinib is a novel selective JAK1 inhibitor with the ability to 
decrease joint inflammation and damage mediated by JAK1 signaling while having 
minimal inhibitory effects on JAK2 and JAK3.  This could potentially minimize some of 
the reported safety concerns with non-selective JAK inhibition which are thought to be 
mediated by inhibition of JAK2 and JAK3 signaling pathways.  The Phase 2 program 
with upadacitinib demonstrated efficacy for improvement in signs and symptoms of RA 
and the safety results were consistent with those known to be associated with 
JAK inhibition.13-21  Taken together, the safety and efficacy data from the Phase 2 
program support further development of upadacitinib in Phase 3 in subjects with RA.
4.0
Study Objectives
Period 1
1.
To compare the efficacy of upadacitinib 15 mg QD versus placebo, and versus 
ADA for the treatment of signs and symptoms of RA in subjects with moderately 
to severely active RA who are on a stable background of MTX and who have an 
inadequate response to MTX (MTX-IR).
2.
To compare the efficacy of upadacitinib 15 mg QD versus placebo for the 
prevention of structural progression in RA subjects with moderately to severely 
active RA who are on a stable background of MTX and who have an inadequate 
response to MTX (MTX-IR).
3.
To compare the safety and tolerability of upadacitinib 15 mg QD versus placebo, 
and versus ADA in subjects with moderately to severely active RA who are on a 
stable background of MTX and who have an inadequate response to MTX (MTX-
IR).

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Period 2
To evaluate the long-term safety, tolerability and efficacy of upadacitinib 15 mg QD in 
subjects with RA who have completed Period 1.
5.0
Investigational Plan
5.1
Overall Study Design and Plan:  Description
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 48-week 
randomized, double-blind, parallel-group, placebo-controlled and active 
comparator-controlled period designed to compare the safety and efficacy of upadacitinib
15 mg QD versus placebo and versus ADA for the treatment of signs and symptoms of 
subjects with moderately to severely active RA who are on a stable dose of MTX and 
have an inadequate response to MTX (MTX-IR).  Period 1 is also designed to compare 
the efficacy of upadacitinib 15 mg QD versus placebo for the prevention of structural 
progression.  Period 2 is a long-term extension to evaluate the safety, tolerability and 
efficacy of upadacitinib 15 mg QD in subjects with RA who have completed Period 1.
The study is designed to enroll approximately 1500 subjects at approximately 510 study 
centers worldwide to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  Therefore, if the target 
number of subjects has been enrolled, there is a possibility that additional subjects in 
screening will not be enrolled.
The study duration will include a 35-day screening period; a 48-week randomized, 
double-blind, parallel-group, placebo-controlled and active comparator-controlled 
treatment period (Period 1); a long-term extension period (blinded until the last subject 
completes Period 1) (up to 5 years) (Period 2); a 30-day follow-up period (call or visit); 
and a 70-day follow-up call.
Subjects who meet eligibility criteria will be randomized in a 2:2:1 ratio to one of 
three treatment groups:

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●
Group 1:  Upadacitinib (ABT-494) 15 mg QD (N = 600)
●
Group 2:  Placebo (N = 600)
●
Group 3:  ADA (40 mg every other week [eow]) (N = 300)
Subjects will receive both oral study drug QD (either upadacitinib 15 mg or matching 
placebo) and subcutaneous study drug eow (either ADA 40 mg or matching placebo) until 
the study is unblinded.
Subjects must have been on oral or parenteral MTX therapy for ≥ 3 months, on a stable 
MTX dose for ≥ 4 weeks prior to the first dose of study drug (15 to 25 mg/week; or 
≥10 mg/week in subjects who are intolerant of MTX at doses ≥ 12.5 mg/week), and must 
remain on a stable dose throughout the study; the MTX dose may be decreased only for 
safety reasons.  In addition, all subjects should take a dietary supplement of oral folic acid 
(or equivalent) throughout study participation.  Folic acid dosing and timing of regimen 
should be followed according to the Investigator's instructions.  Starting at the Week 26 
visit (after Week 26 assessments have been performed) and thereafter, initiation of or 
change in background RA medication(s) including, corticosteroids, non-steroidal anti-
inflammatory drugs (NSAIDs), acetaminophen/paracetamol is allowed as per local label.  
Starting at Week 48 (after Week 48 assessments have been performed) and thereafter, 
initiation of or change in csDMARDs is allowed as per local label (restricted to oral or 
parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and leflunomide, and 
restricted to concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide). 
Starting at the Week 48 and thereafter, at least 20% improvement in BOTH TJC AND 
SJC compared to baseline is required to remain on study drug.  Anyone who does not 
fulfill this criterion at 2 consecutive visits (starting at Week 48) (see Section 5.4.1) must 
be discontinued from study drug.
Subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic 
drug (bDMARD) (except ADA) for RA may be enrolled in the study (up to 20% of total 
number of subjects) after the required washout period is satisfied and if they have 

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a) limited bDMARD exposure (< 3 months), OR b) response to a bDMARD but had to 
discontinue that bDMARD due to intolerability (regardless of treatment duration) (for 
washout periods, see Inclusion Criterion 8, Section 5.2.1).  These subjects will be equally 
stratified across all treatment groups.  Subjects who are considered bDMARD-inadequate 
responders, as determined by the Investigator, are not eligible.
Rescue therapy will be offered to subjects as described in Section 5.2.3.3 (rescue therapy).
An unblinded analysis will be conducted after all subjects have completed Week 26 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 
Period 1.  Additional unblinded analyses may be conducted after the Week 26 unblinded 
analysis for regulatory purposes.
Each subject will undergo a maximum of 5 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 1 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 26, and 
Week 48/Premature Discontinuation.  Subjects who are non-responders (defined as those 
not achieving ≥ 20% improvement in TJC and SJC criterion) at Week 14 and are switched 
to rescue therapy will have an x-ray examination at Week 14; in addition, subjects who 
prematurely discontinue from study drug or the study
will have an x-ray examination at the premature discontinuation timepoint (refer to 
Section 5.3.1.1 for additional details).
Joint x-rays will be sent to the central imaging vendor designated by the Sponsor.  The x-
rays will only be assessed by the imaging vendor for erosions and joint space narrowing, 
and will not be assessed for any other clinically significant findings that may impact a 
subject's health.
Subjects who complete the Week 48 visit (end of Period 1) will enter the long-term 
extension portion of the study, Period 2 (up to 5 years).  Subjects will continue study 
treatment as assigned in Period 1.  Subjects who are assigned to the upadacitinib 15 mg 

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QD treatment group at the end of Period 1 will continue to receive upadacitinib 15 mg QD 
in a blinded manner.  Subjects who are assigned to adalimumab 40 mg eow at the end of 
Period 1 will continue to receive adalimumab 40 mg eow in a blinded manner.  When the 
last subject completes the last visit of Period 1 (Week 48), study drug assignment in both 
periods will be unblinded to the Sponsor and sites, and subjects will be dispensed study 
drug in an open-label fashion until the completion of Period 2.
Each subject will undergo an x-ray examination of bilateral hands and feet at 
Week 96/Premature Discontinuation (unless repeat testing is needed due to failure to meet 
the quality requirements) and every 96 weeks thereafter.  Subjects who prematurely 
discontinue from the study will not need an x-ray of hands and feet if the previous x-ray 
was performed within the previous
weeks.
Schematics of Period 1 and Period 2 are shown in Figure 1 and Figure 2, respectively.

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Figure 1.
Period 1 Study Design
BL = baseline; EOW = every other week; MTX = methotrexate; QD = once daily; RA = rheumatoid arthritis; 
SJC = swollen joint count; TJC = tender joint count; W = week
#
At W26, all placebo patients will be switched to upadacitinib 15 mg regardless of response.
**
All patients will receive x-rays of hands and feet at Screening, W26, and W48.
*** X-rays at W14 will only be performed for non-responders, see Section 5.3.1.1.
Notes:
The follow-up period is only for subjects who do not enter Period 2.
Early escape for non-responders:  (a) from upadacitinib 15 mg QD to adalimumab at W14, W18, W22, or 
W26; (b) from placebo to upadacitinib 15 mg QD at W14, W18, or W22; (c) from adalimumab to upadacitinib 
15 mg QD at W14, W18, W22, or W26.  Non-response at W14, W18, or W22 is defined as not achieving 
≥20% improvement in TJC and SJC compared to baseline.  Non-response at W26 is defined as not achieving 
LDA according to CDAI (LDA defined as CDAI ≤ 10).  For more details regarding x-rays of hands and feet, 
see Section 5.3.1.1.

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Figure 2.
Period 2 Study Design
csDMARD = conventional synthetic disease modifying anti-rheumatic drug; EOW = every other week; NSAIDs = non-
steroidal anti-inflammatory drugs; QD = once daily; RA = rheumatoid arthritis; W = week
Screening Period
Within 35 days prior to the Baseline Visit, subjects will receive a full explanation of the 
study design and study procedures, provide a written informed consent, and undergo the 
screening procedures outlined in Table 2.  Lab values can be re-tested once during the 
screening period.  If the re-tested lab value(s) remain(s) exclusionary, the subject will be 
considered a screen failure with no additional re-screening possible.  Redrawing samples 
if initial samples were unable to be analyzed would not count as a retest since initial result 
was never obtained.
Subjects that initially screen fail for the study are permitted to re-screen once following 
re-consent.  Lab values can be re-tested once during the re-screening period.  For 
additional re-screening, AbbVie Therapeutic Area Medical Director approval is required.  

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All screening procedures with the possible exceptions noted below will be repeated during 
re-screening.  The subject must meet all the inclusion and none of the exclusion criteria at 
the time of re-screening in order to qualify for the study.  There is no minimum period of 
time a subject must wait to re-screen for the study.  If the subject had a complete initial 
screening evaluation including the assessment of an Interferon-Gamma Release Assay 
(IGRA; QuantiFERON Tuberculosis [TB] Gold In Tube test) and/or a purified protein 
derivative (PPD) test (or equivalent) (or both if required per local guidelines), chest x-ray 
and electrocardiogram (ECG), these tests will not be required to be repeated for re-
screening provided the conditions noted in Section 5.2 are met, there are no changes in the 
subject's medical history that would warrant re-testing, and no more than 90 days have 
passed.
Period 1 (48-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 48 Visit.  At the 
Baseline Visit, subjects who meet all the inclusion criteria and none of the exclusion 
criteria described in Section 5.2.1 and Section 5.2.2 will be enrolled into the study and 
randomized to double-blind treatment.  During this period of the study, subjects will visit 
the study site at Weeks 2, 4, 8, 12, 14, 18, 22, 26, 30, 36, 42, and 48.  A ± 3 day window 
is permitted around scheduled study visits until Week 30 and ± 7 days for the remainder 
of the period.  The last dose of oral study drug in Period 1 is taken the day prior to the 
Week 48 visit.  Subjects who complete Period 1, but decide not to continue in Period 2 
should complete a 30 day follow-up visit after the last dose of study drug.
Period 2 (Long-Term Extension Period [up to 5 years])
Period 2 will begin at the Week 48 visit after all assessments have been completed.  
During Period 2, subjects will have a study visit at Weeks 60, 72, 84, 96, and every 
12 weeks thereafter until completion of the study.  A ± 7 day window is permitted around 
scheduled study visits.  Starting at Week 48 and thereafter, at least 20% improvement in 
BOTH TJC AND SJC compared to baseline is required to remain on study drug.  Anyone 

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who does not fulfill this criterion at 2 consecutive visits (starting at Week 48) (see 
Section 5.4.1) must be discontinued from study drug.
Discontinuation of Study Drug and Continuation of Study Participation (Period 1 
and Period 2)
Subjects may discontinue study drug treatment, but may choose to continue to participate 
in the study (refer to Section 5.4.1 for additional details).  Subjects who prematurely 
discontinue study drug should complete a Premature Discontinuation Visit (PD visit) as 
soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the 
regular visit schedule as outlined in Table 2 and Table 4, and adhere to all study 
procedures except for dispensing study drug, PK sample collection, and blood sample 
collection for optional exploratory research and validation studies.  In addition, all future 
rescue and efficacy-driven discontinuation criteria no longer apply; this includes 20% 
TJC/SJC calculations at Weeks 14 – 22, and Week 48 and thereafter, as well as CDAI 
calculation at Week 26, if applicable.  If at any point a subject no longer wants to provide 
assessments (withdrawal of informed consent) following discontinuation of study drug, a 
second PD visit is not required.
Premature Discontinuation of Study (Withdrawal of Informed Consent) (Period 1 
and Period 2)
Subjects may withdraw from the study completely (withdrawal of informed consent) for 
any reason at any time (refer to Section 5.4.1 for additional details).  If a subject 
prematurely discontinues study drug treatment AND study participation (withdrawal of 
consent) the procedures outlined for the Premature Discontinuation visit (PD visit) should 
be completed as soon as possible, preferably within 2 weeks of study drug 
discontinuation.  In addition, a 30-day follow-up visit (or phone call if a visit is not 
possible) may occur to determine the status of any ongoing AEs/SAEs or the occurrence 
of any new AEs/SAEs.  For subjects on subcutaneous study drug, if the subject is willing, 
a 70-day follow-up phone call may occur to determine the status of any ongoing 
AEs/SAEs or the occurrence of any new AEs/SAEs.  The 70-day follow-up phone call 
will not be required for any subject that initiates commercial adalimumab.

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Follow-Up Period
Subjects who have completed the last visit of Period 1 (Week 48) but decided not to 
participate in the extension Period 2 will have a follow-up visit approximately 30 days 
after the last dose of study drug to obtain information on any new or ongoing AEs and to 
collect vital signs and clinical laboratory tests. 
A 30-day follow-up visit will also occur for subjects who have completed Period 2.
A follow-up phone call will also occur 70 days after the last administration of 
subcutaneous study drug to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs.  The 70-day follow-up phone call will not be required 
for any subject that initiates commercial adalimumab. 
The 30 day follow-up visit and 70 day follow-up call are not required for subjects who 
discontinued study drug and continued study participation with completion of at least 
one study visit approximately 30 days after last dose of oral or 70 days after last dose of 
subcutaneous study drug, respectively.
5.2
Selection of Study Population
It is anticipated that approximately 1500 subjects with moderately to severely active RA 
will be randomized at approximately 510 study centers, globally.
A subject may be enrolled in this study provided that he/she has met all of the inclusion 
criteria specified in Section 5.2.1 and none of the exclusion criteria specified in 
Section 5.2.2 of this protocol.
5.2.1
Inclusion Criteria
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who fulfill the 2010 ACR/EULAR classification 
criteria for RA.

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3.
Subjects must have been on oral or parenteral MTX therapy ≥ 3 months and on a 
stable prescription of 15 to 25 mg/week (or ≥10 mg/week in subjects intolerant of 
MTX at doses ≥ 12.5 mg/week) for ≥ 4 weeks prior to the first dose of study drug.  
In addition, all subjects should take a dietary supplement of folic acid or folinic 
acid throughout the study participation.
●
Additional local requirements may apply.  Refer to Appendix C for local 
requirements (Hong Kong, Korea, Malaysia, Singapore and Taiwan).
4.
Subject meets both of the following disease activity criteria:
a.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 
68 joint counts) at Screening and Baseline Visits; and
b. hsCRP ≥ 5 mg/L (central lab, ULN 2.87 mg/L) at Screening Visit.
5.
Subject has at least one of the following at Screening:  
!
≥ 3 bone erosions on x-ray; or
c.
≥ 1 bone erosion and a positive rheumatoid factor (RF); or
d. ≥ 1 bone erosion and a positive anti-cyclic citrullinated peptide (anti-CCP) 
autoantibody.
6.
Stable dose of non-steroidal anti-inflammatory drugs (NSAIDs) and 
acetaminophen/paracetamol must have been at a stable dose ≥ 1 week prior to the 
first dose of study drug; oral corticosteroids (equivalent to prednisone ≤10 mg/day) 
or inhaled corticosteroids for stable medical conditions are allowed but must have 
been at a stable dose ≥4 weeks prior to the first dose of study drug.
7.
Subjects with prior exposure to at most one bDMARD (except ADA) may be 
enrolled (up to 20% of total study population).  Specifically, prior to enrollment:
a. Patients with limited exposure to a bDMARD (< 3 months), OR
b. Patients who are responding to a bDMARD but had to discontinue due to 
intolerability (regardless of treatment duration).

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8.
Subjects must have discontinued bDMARD therapy prior to the first dose of study 
drug.  The washout period for bDMARDs prior to the first dose of study drug is 
specified below or at least five times the mean terminal elimination half-life of a 
drug:
●
≥ 4 weeks for etanercept;
●
≥ 8 weeks for infliximab, certolizumab, golimumab, abatacept, and 
tocilizumab;
●
≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pre-treatment 
level or normal reference range (central lab) if pre-treatment levels are not 
available.
9.
Except for MTX, subject must have discontinued all csDMARDs.  The washout 
period for csDMARDs prior to the first dose of study is specified below or should 
be at least five times the mean terminal elimination half-life of a drug:
●
≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, 
sulfasalazine, hydroxychloroquine, chloroquine, azathioprine, gold 
formulations, cyclophosphamide, tacrolimus, cyclosporine, mycophenolate;*
●
≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination 
procedure was followed, or adhere to an elimination procedure (i.e., 11 days 
with colestyramine, or 30 days washout with activated charcoal or as per local 
label).
*
Additional local requirements may apply.  Refer to Appendix C for local 
requirements (Korea.)
10.
Subjects must have discontinued all high-potency opiates at least 1 week and oral 
traditional Chinese medicine for at least 4 weeks prior to the first dose of study 
drug (refer to Section 5.2.3.2 for prohibited medications).
11.
Women of childbearing potential (refer to Section 5.2.4), must not have a positive 
serum pregnancy test at the Screening Visit and must have a negative urine 
pregnancy test at the Baseline Visit prior to study drug dosing.  Note:  subjects with 
borderline serum pregnancy test at Screening must have a serum pregnancy test 
≥3 days later to document continued lack of a positive result.

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12.
If female, subject must be postmenopausal, OR permanently surgically sterile, OR 
for women of childbearing potential practicing at least one protocol-specified 
method of birth control (refer to Section 5.2.4), that is effective from Study Day 1 
through at least 150 days after the last dose of subcutaneous study drug and 30 days 
after the last dose of oral study drug.
●
Additional local requirements may apply.  Refer to Appendix C for local 
requirements (Canada and Korea.)
13.
If male, and subject is sexually active with female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
oral study drug, to practice the protocol-specified contraception (refer to 
Section 5.2.4).
●
Additional local requirements may apply.  Refer to Appendix C for local 
requirements (Canada and Korea.)
14.
Subjects must voluntarily sign and date an informed consent, approved by an 
Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to 
the initiation of any screening or study-specific procedures.
Rationale for Inclusion Criteria
1 – 10
To select the appropriate subject population
11 – 13
The effect of upadacitinib on pregnancy and reproduction is unknown
14
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
1.
Prior exposure to any JAK inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects who have had any exposure to adalimumab or subjects who have been 
treated with other bDMARD therapy for ≥ 3 months who are considered inadequate 

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responders (lack of efficacy) to bDMARD therapy as determined by the 
Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of 
inflammatory joint disease other than RA (including but not limited to gout, 
systemic lupus erythematosus, psoriatic arthritis, axial spondyloarthritis including 
ankylosing spondylitis and non-radiographic axial spondyloarthritis, reactive 
arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms], or any arthritis 
with onset prior to age 17 years).  History of secondary Sjogren's Syndrome is 
permitted.
4.
Has been treated with intra-articular, intramuscular, intravenous, trigger point or 
tender point, intra-bursa, or intra-tendon sheath corticosteroids in the preceding 
8 weeks prior to the first dose of study drug.
5.
Has been treated with any investigational drug within 30 days or five half-lives of 
the drug (whichever is longer) prior to the first dose of study drug or is currently 
enrolled in another clinical study.
6.
Female who is pregnant, breastfeeding or considering becoming pregnant during 
the study or for approximately 150 days after the last dose of subcutaneous study 
drug and 30 days after the last dose of oral study drug.
7.
Male subject who is considering fathering a child or donating sperm during the 
study or for approximately 30 days after the last dose of oral study drug.
8.
Any active, chronic or recurrent invasive infection (e.g., listeriosis and 
histoplasmosis) and viral infection that, based on the Investigator's clinical 
assessment, makes the subject an unsuitable candidate for the study, including 
hepatitis B virus (HBV) or hepatitis C virus (HCV), recurrent or disseminated 
(even a single episode) herpes zoster, disseminated (even a single episode) herpes 
simplex, or human immunodeficiency virus (HIV).  Active HBV, HCV and HIV 
infections are defined as:

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●
HBV:  hepatitis B surface antigen (HBs Ag) positive (+) or detected sensitivity 
on the HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR) 
qualitative test for Hepatitis B core antibody (HBc Ab) positive (+) subjects;
●
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-HCV 
antibody (HCV Ab).
●
HIV:  confirmed positive anti-HIV antibody (HIV Ab) test.
9.
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing).
10.
Systemic use of known strong cytochrome P450 (CYP)3A inhibitors or strong 
CYP3A inducers from Screening through the end of the study (refer to Table 1 for 
examples of commonly used strong CYP3A inhibitors and inducers).
11.
Receipt of any live vaccine within 4 weeks prior to the first dose of study drug, or 
expected need of live vaccination during study participation including at least 
4 weeks after the last dose of oral study drug and including at least 70 days after 
the last dose of subcutaneous study drug.
12.
History of any malignancy except for successfully treated NMSC or localized 
carcinoma in situ of the cervix.
13.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months.
14.
History of gastrointestinal perforation (other than appendicitis or penetrating 
injury), diverticulitis or significantly increased risk for GI perforation per 
investigator judgment.
15.
Conditions that could interfere with drug absorption including but not limited to 
short bowel syndrome.
16.
History of demyelinating disease such as Multiple Sclerosis.
17.
Subject has been a previous recipient of an organ transplant.

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18.
History of clinically significant medical conditions or any other reason that in the 
opinion of the Investigator would interfere with the subject's participation in this 
study or would make the subject an unsuitable candidate to receive study drug.
19.
Active infection(s) requiring treatment with parenteral anti-infectives within 
30 days, or oral anti-infectives within 14 days prior to the first dose of study drug.
20.
History of an allergic reaction or significant sensitivity to constituents of the study 
drug(s) (and their excipients) and/or other products in the same class.
21.
Laboratory values meeting the following criteria within the Screening period prior 
to the first dose of study drug:
●
Serum aspartate transaminase (AST) > 2 × ULN;
●
Serum alanine transaminase (ALT) > 2 × ULN;
●
Estimated glomerular filtration rate (GFR) by simplified 4-variable 
Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m2;
●
Total white blood cell count (WBC) < 2,500/μL;
●
Absolute neutrophil count (ANC) < 1,500/μL;
●
Platelet count < 100,000/μL;
●
Absolute lymphocyte count < 800/μL;
●
Hemoglobin < 10 g/dL.
22.
History of any of the following cardiovascular conditions:
●
moderate to severe congestive heart failure (New York Heart Association 
class III or IV); 
●
Recent (within past 6 months) cerebrovascular accident, myocardial infarction, 
coronary stenting;
●
Uncontrolled hypertension as defined by a confirmed systolic blood pressure 
> 160 mmHg or diastolic blood pressure > 100 mmHg; 
●
Any other condition which, in the opinion of the Investigator, would put the 
subject at risk by participating in the protocol.

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23.
Clinically relevant or significant ECG abnormalities, including ECG with QT 
interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) 
> 500 msec.
Rationale for Exclusion Criteria
1 – 3
To select the appropriate subject population
6, 7
The impact of upadacitinib on pregnancies is unknown
4, 5, 8 – 23
To ensure safety of the subjects throughout the study
5.2.3
Prior, Concomitant, and Prohibited Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements including folic acid) that the subject is receiving 
within 28 days prior to Screening, or receives during the study, must be recorded along 
with the reason for use, date(s) of administration including start and end dates, and dosage 
information including dose, route, and frequency on the appropriate electronic case report 
form (eCRF).  Also, medications including but not limited to DMARDs taken for RA 
since date of RA diagnosis (based on subject recollection and available medical records) 
should be entered into the appropriate eCRF.
In addition, for subjects age ≤ 30 with a reported malignancy AE, prior exposure to, or 
current use of, antineoplastics, or other drugs which have a risk of malignancy as stated in 
their label and other relevant dosing information to estimate total exposure will be 
collected in the source documents and appropriate eCRF pages.  At the time of the 
reported malignancy AE, sites will be asked if any of the prior and concomitant 
medications contributed to the event.  Any medications used prior to the study will be 
captured on the appropriate eCRF.  Information on the reason for use, date(s) of 
administration including start and end dates, highest maintained dose, dosage information 
including dose, route and frequency, and reason for stopping the medication will be 
collected in the source documents and appropriate eCRF pages.

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The AbbVie Therapeutic Area Medical Director identified in Section 6.1.5 (Serious 
Adverse event Reporting) should be contacted if there are any questions regarding 
concomitant or prior therapies.
5.2.3.1
Permitted Background RA Therapy
Subjects should continue on their stable (≥ 4 weeks prior to the first dose of study drug) 
background MTX therapy (restricted to oral or parenteral MTX [15 to 25 mg/week; or 
≥10 mg/week in subjects who are intolerant of MTX at doses ≥12.5 mg/week]).  At any 
time, the MTX dose may be decreased only for safety reasons.  In addition, all subjects 
should take a dietary supplement of oral folic acid (or equivalent, such as folinic acid) 
throughout study participation.  Folic acid dosing and timing of regimen should be 
followed according to Investigator's instructions.  AbbVie will not provide the MTX or 
folic acid.
Subjects should also continue on their stable doses of NSAIDs, 
acetaminophen/paracetamol, oral corticosteroids (equivalent to prednisone ≤ 10 mg/day), 
or inhaled corticosteroids.  
●
If taking any of the above on a scheduled basis, they should continue to take 
them as they did at study entry with no change in dose or frequency, including 
on study visit days.
●
If not taking any of the above at baseline, these must not be initiated except 
where permitted by protocol starting at Week 26 (after Week 26 assessments 
have been performed).
●
If taking any of the above, including low potency analgesics, i.e., tramadol, 
codeine, hydrocodone, or propoxyphene at baseline on an as-needed basis 
(PRN), they should continue to use them for the same reason and same dose 
each time but they should not be taken within the 24 hours prior to any study 
visit to avoid bias in outcome measurements.

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In the event of tolerability (or other safety) issues, the doses of these medications may be 
decreased or discontinued with substitution of another permitted medication from that 
class (see Section 5.2.3.2 for prohibited therapies).  
PRN use of inhaled corticosteroids is permitted at any time.
Starting at Week 26 (after Week 26 assessments have been performed) and thereafter, 
two intra-articular, intramuscular, intravenous, trigger point or tender point, intra-bursa, 
and intra-tendon sheath injections of corticosteroids, dosage and frequency per standard of 
care, are allowed.  However, joint injections should be avoided within 21 days prior to the 
next scheduled study visit to avoid confounding effects of systemic absorption of intra-
articular corticosteroids.  For the analysis of the TJC and SJC, injected joints will be 
considered "not assessable" for 3 months from the time of the intra-articular injection.  
Starting at Week 26 (after Week 26 assessments have been performed) and thereafter, 
initiation of or change in corticosteroids, NSAIDs, acetaminophen/paracetamol is allowed 
as per local label.  For RA flare treatment, no more than 3 consecutive days of systemic 
corticosteroids (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent) is 
allowed, after which subject should resume their usual daily oral corticosteroid dose. 
Starting at Week 48 (after Week 48 assessments have been performed) and thereafter 
initiation of or change in csDMARDs is allowed as per local label (restricted to oral or 
parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and leflunomide, and 
restricted to concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide; see Inclusion Criterion 9, Section 5.2.1).
5.2.3.2
Prohibited Therapy
JAK Inhibitor
Prior exposure to JAK inhibitors (including but not limited to tofacitinib [Xeljanz®], 
baricitinib, and filgotinib) is not allowed.

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Corticosteroids
Oral corticosteroids > 10 mg prednisone/day or equivalent are NOT allowed up to 
Week 26.  Intra-articular, intramuscular, intravenous, trigger point or tender point, intra-
bursa, and intra-tendon sheath corticosteroids are NOT allowed up to Week 26.
Biologic Therapies
All biologic therapies are prohibited during the study (i.e., Periods 1 and 2).  
Subjects with prior exposure to at most one bDMARD may be enrolled (up to 20% of 
study population) if they have a) limited exposure (< 3 months), OR b) response to a 
bDMARD but had to discontinue that bDMARD due to intolerability (regardless of 
treatment duration).  Of note:  prior exposure to adalimumab (Humira®) is not permitted.
Subjects must have discontinued the bDMARD prior to the first dose of study drug as 
specified in the washout procedures (Inclusion Criterion 8, Section 5.2.1).  For all other 
bDMARDs, contact the Therapeutic Area Medical Director for the washout period 
required prior to the first dose of study drug.
Examples of biologic therapies include but are not limited to the following:
●
Enbrel® (etanercept)
●
Remicade® (infliximab)
●
Orencia® (abatacept)
●
Kineret® (anakinra)
●
Rituxan® (rituximab)
●
Cimzia® (certolizumab pegol)
●
Simponi® (golimumab)
●
Actemra® (tocilizumab)
●
Raptiva® (efalizumab)
●
Tysabri® (natalizumab)
●
Stelara® (ustekinumab)

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●
Benlysta® (belimumab)
csDMARD Therapies
Except MTX, subjects must have discontinued all csDMARDs prior to the first dose of 
study drug as specified in the washout procedures (Inclusion Criterion 9, Section 5.2.1).  
csDMARD background therapy other than MTX is not allowed during Period 1.
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors or strong CYP3A inducers is excluded 
from the Screening Visit through the end of the study (i.e., Periods 1 and 2).  The most 
common strong CYP3A inhibitors and inducers are listed in Table 1.
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir
Cobicistat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Carbamazepine
Phenytoin
Rifampin
Rifapentine
St. John's Wort

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Opiates
High potency opiates are not permitted during the study (i.e., Periods 1 and 2), and 
subjects must have discontinued high potency opiates at least 1 week prior to the 
first dose of study drug, including (but not limited to):
●
oxycodone
●
oxymorphone
●
fentanyl
●
levorphanol
●
buprenorphine
●
methadone
●
hydromorphone
●
morphine
●
meperidine
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 
five half-lives of the drug (whichever is longer) prior to the first dose of study drug are 
excluded from participation in this study.  Investigational drugs are also prohibited during 
the study.
Vaccines
Vaccines recommended by local guidelines should be considered.  If the investigator 
chooses to administer a vaccine, this should be completed before first dose of study drug 
with appropriate precautions and time interval.  It is recommended that subjects be up to 
date for recommended inactivated, toxoid or biosynthetic vaccines, such as injectable flu 
vaccine, pneumococcal, and pertussis (Tdap).  It is recommended that the live herpes 
zoster vaccine should be considered for administration at least 4 weeks before first dose of 
study drug or administered at least 30 days after last dose of oral study drug, or at least 
70 days after the last dose of subcutaneous study drug.  If the herpes zoster vaccine is to 

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be administered, and there is no known history of primary varicella (chicken pox), pre-
existing immunity to varicella should be confirmed with antibody testing at or prior to 
screening and prior to administration of the herpes zoster vaccine.  If screening varicella 
antibody testing is negative the herpes zoster vaccine should not be administered.  
If the subject and investigator choose to administer live vaccines, these vaccinations must 
be completed (per local label) 4 weeks before first dose of study drug with appropriate 
precautions, or administered at least 30 days after last dose of oral study drug, or at least 
70 days after last dose of subcutaneous study drug.
Examples of live vaccines include, but are not limited to, the following:
●
Monovalent live influenza A (H1N1) (intranasal);
●
Seasonal trivalent live influenza (intranasal);
●
Herpes zoster;
●
Rotavirus;
●
Varicella (chicken pox);
●
Measles-mumps-rubella or measles mumps rubella varicella;
●
Oral polio vaccine;
●
Smallpox;
●
Yellow fever;
●
Bacille Calmette-Guérin (BCG);
●
Typhoid.
Examples of common vaccines that are inactivated, toxoid or biosynthetic, include but are 
not limited to:  injectable influenza vaccine, pneumococcal and pertussis (Tdap) vaccines.
Traditional Chinese Medicine
Traditional oral Chinese medicine is not permitted during the study as these may interfere 
with upadacitinib metabolism and exposure and may impact efficacy and safety of 

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upadacitinib treatment.  Subjects must have discontinued traditional Chinese medicine at 
least 4 weeks prior to the first dose of study drug.
5.2.3.3
Rescue Therapy
Rescue therapy will be offered to subjects who meet the following criteria:
Placebo:
●
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at 
Weeks 14, 18, or 22 compared to baseline will be switched to blinded 
upadacitinib treatment.  
●
At Week 26, all remaining subjects will be switched to blinded upadacitinib 
treatment regardless of clinical response.
ADA:
●
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at 
Weeks 14, 18, or 22 compared to baseline will be switched to blinded 
upadacitinib treatment.
●
At Week 26, all remaining subjects who do not achieve LDA according to 
CDAI (LDA defined as CDAI ≤ 10) at Week 26 will be switched to blinded 
upadacitinib treatment.  
Upadacitinib:
●
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at 
Weeks 14, 18, or 22 compared to baseline will be switched to blinded ADA 
treatment.
●
At Week 26, all remaining subjects who do not achieve LDA according to 
CDAI (LDA defined as CDAI ≤ 10) at Week 26 will be switched to blinded 
ADA treatment.

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5.2.4
Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 mIU/mL.
If the female subject is < 55 years of age and is not permanently surgically sterile, as 
defined above, and has had no menses for ≥ 12 months FSH should be tested at Screening.
●
If FSH is not tested, it is assumed that the subject is of childbearing potential 
and protocol-specified contraception is required.
●
If the FSH is tested and the result is consistent with post-menopausal status, 
contraception is not required.
●
If the FSH is tested and the result is consistent with pre-menopausal status, 
contraception is required, and a serum pregnancy test must be performed (see 
Section 5.3.1.1 pregnancy test).
For a female subject at any age:
●
Female subjects with menses within the past 12 months are of childbearing 
potential and FSH is therefore not required but contraception is required.
●
Female subjects who are surgically sterile (defined above) are not of 
childbearing potential and therefore no FSH testing or contraception is 
required.

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A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 150 days after the last dose of subcutaneous study drug and at 
least 30 days after the last dose of oral study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 30 days prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the women of childbearing potential trial participant.
●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
●
True abstinence:  Refraining from heterosexual intercourse when this is in line 
with the preferred and usual lifestyle of the subject (periodic abstinence 
[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and 
withdrawal are not acceptable).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above (excluding true abstinence).
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational 
therapies.  Duration of contraception after discontinuation of csDMARDs should be based 
on the local label.

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If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation is available, contraception measures as defined above are no
longer required.
Additional local requirements may apply.  Refer to Appendix C for local requirements 
(Canada and Korea).
Contraception Recommendation for Males
Based on data from animal studies (including a fertility study) there is no effect of 
upadacitinib on male reproduction.  
For a male subject who is surgically sterile (vasectomy with medical assessment 
confirming surgical success) OR has a female partner who is postmenopausal or 
permanently sterile, no contraception is required.
●
Condom use and female partner(s) using at least one of the contraceptive 
measures (as defined in the protocol for female study subjects of childbearing 
potential).
●
True abstinence: Refraining from heterosexual intercourse-when this is in line 
with the preferred and usual lifestyle of the subject.  Periodic abstinence (for 
example, using calendar, ovulation, symptothermal, post-ovulation methods 
and withdrawal are not acceptable).
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of oral study drug.
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational 

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therapies.  Duration of contraception after discontinuation of csDMARDs should be based 
on the local label.
Additional local requirements may apply.  Refer to Appendix C for local requirements
(Canada and Korea).
5.3
Efficacy Pharmacokinetic, Pharmacodynamic, Exploratory 
Research and Validation Studies, and Safety 
Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed and Flow 
Chart
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Table 2, Table 3, and Table 4.

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Table 2.
Study Activities (Period 1)
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/
PDa
30-
Day 
F/U 
Visit/
Callc
70-
Day 
F/U 
Callc
Activity
D–35 to 
D–1
D1b
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
Informed consentd
Xd
Inclusion/exclusion 
criteria
X
X
Medical/surgical historye
X
X
Alcohol and nicotine use
X
Adverse event assessmentf
Only 
SAEs and 
protocol-
related 
nonserious 
AEs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Prior/concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Xg
X
Patient questionnairesh
PtGA
Pain (VAS)
HAQ-DI
Morning Stiffness
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 2.
Study Activities (Period 1) (Continued)
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/
PDa
30-
Day 
F/U 
Visit/
Callc
70-
Day 
F/U 
Callc
Activity
D–35 to 
D–1
D1b
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
Patient questionnairesh
FACIT-F
EQ-5D-5L
SF-36
RA-WIS
X
X
X
X
Latent TB risk assessment 
formi
X
Xi
Central lab 
QuantiFERON-TB Gold 
testi (and/or local PPD 
skin test)
X
X
Chest x-rayj
X
X
12-lead ECGk
X
Xl
X-rays (bilateral 
hands/feet)
Xm
Xn
Xn
Xn
Height (screening only) 
and weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signso
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examp
X
X
X
Physician Global 
Assessment (PhGA)
X
X
X
X
X
X
X
X
X
X
X
X
X

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Table 2.
Study Activities (Period 1) (Continued)
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/
PDa
30-
Day 
F/U 
Visit/
Callc
70-
Day 
F/U 
Callc
Activity
D–35 to 
D–1
D1b
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
TJC68/SJC66
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Serum pregnancy test at 
central labq
X
Local urine pregnancy 
testr
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Central lab tests
hsCRPs
Blood chemistryt
Hematology (CBC)
Urinalysisu
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ESR (local lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other central lab tests
Rheumatoid factor
Anti-CCP 
autoantibodies
HBV/HCV screening
ANA/dsDNA
X
HIV central labv
Xv
IgG and IgM (central lab)
X
X
X
X
Blood samples for 
upadacitinib PK assay
Xw
Xw
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx
Xx

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Table 2.
Study Activities (Period 1) (Continued)
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/
PDa
30-
Day 
F/U 
Visit/
Callc
70-
Day 
F/U 
Callc
Activity
D–35 to 
D–1
D1b
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
Blood samples for 
exploratory research and 
validation studies 
(optional – see Table 3)y
X
X
X
X
X
Randomization/Drug 
assignment
X
Calculation for drug 
assignment based on 
TJC/SJC 
Xz
Xz
Xz
Xaa
CDAI IRT calculation
Xab,ac
Dispense study drug and 
subject dosing diary
X
X
X
X
X
X
X
X
X
X
X
Xad
Review and copy subject 
dosing diary and perform 
drug reconciliation
X
X
X
X
X
X
X
X
X
X
X
BL = Baseline Visit; CBC = complete blood count; CCP = cyclic citrullinated peptide; D = Day; ECG = electrocardiogram; EQ-5D-5L = EuroQoL-5D; ESR = erythrocyte 
sedimentation rate; FACIT-F = Functional Assessment of Chronic Illness Therapy – Fatigue; F/U = Follow-Up; HAQ-DI = Health Assessment Questionnaire – Disability Index; 
HBV = hepatitis B virus; HCV = hepatitis C virus; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; NRS = numerical rating scale; 
PD = Premature Discontinuation (completely from study [withdrawal of consent]); PhGA = Physician's Global Disease Activity; PK = pharmacokinetics; PPD = purified protein 
derivative; PtGA = Patient's Global Assessment of Disease Activity; SAE = serious adverse event; SJC = Swollen Joint Count; SF-36 = 36-Item Short Form Health Survey; 
TB = tuberculosis; TJC = Tender Joint Count; VAS = visual analog scale; Wk = Week

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Table 2.
Study Activities (Period 1) (Continued)
a.
If a subject is prematurely discontinued from study drug, the procedures outlined for the Premature Discontinuation visit (PD visit) should be completed as soon as possible, 
preferably within 2 weeks of study drug discontinuation.
b.
The Baseline visit procedures will serve as the reference for all subsequent visits with the exception of the ECG and x-rays of hands and feet, which will be obtained at 
Screening only and used as the baseline reference (see also footnote m regarding x-rays of the hands and feet at Screening).
c.
This visit is 30 days after last dose of study drug for those subjects who complete Period 1 and do NOT enter Period 2.  A 30-day follow-up phone call may be allowed for 
subjects who have completed the PD visit to determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs. The 70-day follow-up call to take place 
70 days after last dose of subcutaneous study drug for those subjects who complete Period 1 and do NOT enter Period 2 and for those who prematurely discontinue the study 
(withdrawal of informed consent).  The 70 day follow-up phone call will not be required for any subject that initiates commercial adalimumab.
d.
Informed consent should be obtained at Screening prior to performing any study related procedures.
e.
Note herpes zoster and hepatitis B vaccination status in medical history.
f.
Collect serious adverse events and protocol-related nonserious AEs that occur after a subject signs the informed consent, prior to the first dose of study drug.
g.
At Week 48 (after Week 48 assessments have been performed), per Investigator judgment, may add or change csDMARDs (concomitant use of up to 2 csDMARDs, except 
the combination of MTX and leflunomide, or increasing csDMARD dose).
h.
Prior to other procedures.
i.
Complete the latent TB risk assessment form annually.  Refer to Section 5.3.1.1.  Study Procedures TB Testing for specific requirements for TB testing and TB Prophylaxis.
j.
The screening chest x-ray will not be required if a subject had a previous normal chest-x-ray within 90 days of Screening, provided that all source documentation is available 
at the site (refer to Section 5.3.1.1 Chest X-Ray for specific requirements).  At Week 48, obtain chest x-ray for subjects with newly identified TB risk factors based on the TB 
risk assessment form, or for subjects living in areas endemic for TB, or for subjects with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
k.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required, provided all source documentation is available.  Refer to 
Section 5.3.1.1 12-Lead ECG for additional details.
l.
All subjects will have an ECG at Week 48 and PD visit as applicable.
m.
Subjects are eligible for the study if  the locally read screening x-rays confirm at least one of the following:  ≥3 bone erosions on x-ray OR ≥ 1 bone erosion combined with a 
positive RF OR ≥ 1 bone erosion combined with positive anti-CCP autoantibodies.  Screening x-rays will serve as baseline x-rays for scoring purposes.  Refer to 
Section 5.3.1.1 Study Procedures X-Rays of Hands and Feet for additional details.
n.
Week 14 x-rays of hands and feet will be performed for all subjects who do not meet ≥ 20% improvement in TJC and SJC compared to baseline.  X-rays of hands and feet 
will be performed for all subjects at Week 26 and Week 48.  Refer to Section 5.3.1.1 Study Procedures X-Rays of Hands and Feet for additional details.
o.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
p.
A full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when necessary.

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Table 2.
Study Activities (Period 1) (Continued)
q.
For all females of childbearing potential, collect serum for pregnancy test at screening.  If serum pregnancy test comes back borderline, a repeat test ≥ 3 days later is necessary 
to document continued lack of positive result (pregnancy is an exclusion criterion).  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
r.
For all females of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits.  If urine pregnancy test (which is performed at the site) is 
negative, begin or continue dosing.  If urine pregnancy test is positive, withhold dosing and perform a serum pregnancy test.  Pregnant subjects must discontinue from the 
study.  Refer to Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
s.
Central lab hsCRP results will remain blinded to the Sponsor, Investigator, study site personnel, and the subject for all visits except Screening.  Results of tests such as hsCRP 
may be blunted in subjects taking a JAK inhibitor, thereby limiting the clinical utility of these tests in the setting of a possible safety assessment or adverse event management. 
Any local hsCRP or local CRP tests should not be reported to the investigator until treatment allocation is unblinded.
t.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-fasting status will be recorded in study source documentation.
u.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A microscopic analysis will be performed in the event the dipstick 
results show leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal.
v.
Anti-HIV Ab will be performed at Screening, unless prohibited by local regulations.  The Investigator must discuss any local reporting requirements to local health agencies 
with the subject.  The site will report confirmed positive results to their health agency per local regulations, if necessary.  If a subject has a confirmed positive result, the 
Investigator must discuss with the subject the potential implications to the subject's health and subject should receive or be referred for clinical care promptly.  A subject will 
not be eligible for study participation if test results indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be made aware of any 
positive result.
w.
At Week 2 and Week 4 visits, PK samples (plasma) should be collected prior to oral drug dosing and the subjects should take the oral study drug dose at the clinic after 
collecting the PK blood sample.  However, if the subject normally takes the study oral drug dose at a time that is after the time of the scheduled study visit, the subject should 
follow the regular dosing schedule and the PK sample should be collected at any time during the visit.
x.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.
y.
Samples only collected if subject provides written consent.
z.
Subjects in the placebo group who do not achieve ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 will be switched to blinded upadacitinib treatment.  At 
Week 26, all placebo subjects will be switched to blinded upadacitinib treatment regardless of response.  Subjects in the ADA group who do not achieve a ≥ 20% 
improvement in TJC and SJC at Weeks 14, 18, or 22 compared to baseline will be switched to blinded upadacitinib treatment.  At Week 26, all remaining subjects in the ADA 
group who do not achieve LDA according to CDAI (LDA defined as CDAI ≤ 10) at Week 26 will be switched to blinded upadacitinib treatment.  Subjects in the upadacitinib 
group who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 compared to baseline will be switched to blinded ADA treatment.  At Week 26, all 
remaining subjects in the upadacitinib group who do not achieve LDA according to CDAI (LDA defined as CDAI ≤ 10) at Week 26 will be switched to blinded ADA 
treatment.

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Table 2.
Study Activities (Period 1) (Continued)
aa.
Starting at Week 48, subjects who failed to show at least 20% improvement in both TJC and SJC compared to baseline at 2 consecutive visits will be discontinued from study 
drug treatment.
ab. Refer to Section 5.2.3.3.
ac.
CDAI calculation requires input of SJC + TJC (based on a 28 joint count) + PtGA + PhGA into IRT system.  
ad. For subjects entering Period 2.
Note:
Visit window is ± 3 days for the first 30 weeks and ± 7 days for the remainder of Period 1.  Any of the procedures may be performed at an unscheduled visit at 
the discretion of the Investigator.  Subjects who choose to discontinue study drug treatment, but continue to participate in the study, should complete a 
Premature Discontinuation Visit (PD Visit) as soon as possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular visit schedule and 
adhere to all study procedures except for dispensing study drug, PK sample collection, and blood sample collection for optional exploratory research and 
validation studies.  In addition, after discontinuing study drug, all rescue and efficacy-driven discontinuation criteria no longer apply; this includes 20% 
TJC/SJC calculations at Weeks 14 – 22, and Week 48 and thereafter, as well as CDAI calculation at Week 26, if applicable.

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Table 3.
Study Activities – Optional Samples for Exploratory Research and Validation Studies (Period 1 Only)
Activity
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/PD
D –35 to 
D –1
D1a
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
Pharmacogenetic samplesa,b
--
X
--
--
--
--
--
--
--
--
--
--
--
--
Epigenetic samplesb
--
X
X
--
X
--
--
--
--
X
--
--
--
X
Transcriptomic and epigenetic 
samplesb
--
X
X
--
X
--
--
--
--
X
--
--
--
X
Plasma samples for proteomic and 
targeted protein investigationsb
--
X
X
--
X
--
--
--
--
X
--
--
--
X
Serum samples for proteomic and 
targeted protein investigationsb
--
X
X
--
X
--
--
--
--
X
--
--
--
X
BL = Baseline Visit; D = Day; F/U = Follow-up; PD = Premature Discontinuation; Wk = Week
a.
The sample is preferred to be collected at BL, but can be drawn at any time during the subject's participation.
b.
Based on the value of the different technologies, samples may also be used to assess other biomarker signatures, including but not limited to metabolomics, lipidomics, and 
other approaches.  Samples may be used for assay of study drugs if needed.
Note:
Collections to be performed only if subject provides separate written consent to collect the exploratory research/validation studies samples; if the separate 
consent is not signed, no samples can be collected.  The separate written consent may be part of the main consent form.

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Table 4.
Study Activities (Period 2)
Activity
Wk 
60
Wk 
72
Wk 
84
Wk 
96
Monthly
Every 
12 Weeks 
Until Study 
Completiona
Every 
24 Weeks 
Until Study 
Completiona
Every 
48 Weeks 
Until Study 
Completiona
Every 
96 Weeks 
Until Study 
Completiona
Final/
PD 
Visit
30-
Day 
F/U 
Visit
/
Callb
70-
Day 
F/U 
Callb
Adverse event assessment
X
X
X
X
X
X
X
X
Concomitant therapy
X
X
X
X
X
X
X
Patient questionnairesc
PtGA
Pain (VAS)
HAQ-DI
Morning stiffness
X
X
X
X
X
X
Latent TB risk assessment form
X
X
Central lab QuantiFERON-TB 
Gold testd (and/or local PPD 
skin test)
Xd
Xd
Chest x-raye
Xe
Xe
12-lead ECGf
Xf
Xf
Xf
X-rays (bilateral hands/feet)g
Xg
Xg
Vital signs and body weighth
X
X
X
X
X
X
X
Physical exami
X
X
Xi
X
Physician Global Assessment 
(PhGA)
X
X
X
X
X
X
TJC68/SJC66
X
X
X
X
X
X

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Table 4.
Study Activities (Period 2) (Continued)
Activity
Wk 
60
Wk 
72
Wk 
84
Wk 
96
Monthly
Every 
12 Weeks 
Until Study 
Completiona
Every 
24 Weeks 
Until Study 
Completiona
Every 
48 Weeks 
Until Study 
Completiona
Every 
96 Weeks
Until Study 
Completiona
Final/
PD 
Visit
30-
Day 
F/U 
Visit
/
Callb
70-
Day 
F/U 
Callb
Local urine pregnancy testj
X
X
X
X
X
X
X
In-home urine pregnancy testk
X
Central lab tests
hsCRPl
Blood chemistrym
Hematology (CBC)
Urinalysisn
X
X
X
X
X
X
X
ESR (local lab)
X
X
X
X
X
X
Calculation for drug 
assignment based on TJC/SJC
Xo
Xo
Xo
Xo
Xo
Dispense study drug and 
subject dosing diary
X
X
X
X
X
Review and copy subject 
dosing diary and perform drug 
reconciliation
X
X
X
X
X
X
CBC = complete blood count; csDMARD = conventional synthetic disease-modifying anti-rheumatic drug; ECG = electrocardiogram; F/U = Follow-Up; HAQ-DI = Health 
Assessment Questionnaire – Disability Index; hsCRP = high-sensitivity C-reactive protein; NRS = numerical rating scale; PD = Premature Discontinuation; PhGA = Physician's 
Global Disease Activity; PPD = purified protein derivative; PtGA = Patient's Global Assessment of Disease Activity; RCT = randomized controlled trial; SAE = serious adverse 
event; SJC = Swollen Joint Count; TB = tuberculosis; TJC = Tender Joint Count; VAS = visual analog scale; Wk = Week
a.
Every 12, 24, 48, or 96 weeks from the Week 96 visit.
b.
This visit is 30 days after last dose of study drug for those subjects who complete Period 2.  A 30-day follow-up phone call and a 70-day follow-up phone call may be allowed 
for subjects who have completed PD visit to determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.

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Table 4.
Study Activities (Period 2) (Continued)
c.
Prior to other procedures.
d.
TB testing should be performed every 48 weeks after Week 96 in subjects with previous negative QuantiFERON-TB Gold and/or PPD tests.  Subjects with new evidence of 
latent TB should initiate prophylactic treatment immediately per local guidelines.  Refer to Section 5.3.1.1, Study Procedures, TB Testing for specific requirements for TB 
testing and TB Prophylaxis.  Study drug(s) should not be withheld at the time of the first positive TB test.
e.
Obtain chest x-ray every 48 weeks after Week 96 for subjects with newly identified TB risk factors based on the TB risk assessment form, or for subjects living in areas 
endemic for TB, or for subjects with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
f.
ECGs will be performed every 48 weeks after Week 48.  An ECG may be performed at any visit if deemed necessary by the Investigator.
g.
X-rays of hands and feet must be performed at Week 96 and every 96 weeks thereafter.  Subjects who prematurely discontinue from the study will not need an x-ray of hands 
and feet if the previous x-ray was performed within the previous
weeks.
h.
Blood pressure, pulse rate, body temperature, and respiratory rate should be performed before blood draws are performed.
i.
A full physical exam is required every 24 weeks after Week 96.  A symptom-directed physical exam may be performed when necessary.
j.
For women of childbearing potential, a urine pregnancy test will be performed at all visits and monthly at home between scheduled study visits.  The results of the monthly at 
home tests will be communicated to the site. If a urine pregnancy test is positive, the subject must stop dosing, come in to the clinic and have blood drawn for a serum 
pregnancy test that will be analyzed at the central laboratory.  Pregnant subjects must discontinue from study drug treatment.  Refer to Section 5.3.1.1 Study Procedures 
Pregnancy Test for additional details.
k.
Starting at Week 48, for women of childbearing potential, in-home urine pregnancy tests will be performed monthly.
l.
hsCRP results will remain blinded to Sponsor, Investigator and study site personnel, and the subject for all visits until the last subject reaches the end of Period 1.
m.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the non-fasting status will be recorded in study source documentation.
n.
Dipstick urinalysis will be completed by the central lab at all required visits.  Specified abnormal macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or 
blood greater than negative, or glucose greater than normal will be followed up with a microscopic analysis at the central laboratory.
o.
Starting at Week 48, subjects who failed to show at least 20% improvement in TJC and SJC compared to baseline at 2 consecutive visits will be discontinued from study drug 
treatment.
Note:
Visit window is ± 7 days for Period 2.  Any of the procedures may be performed at an unscheduled visit at the discretion of the Investigator.  Subjects who 
choose to discontinue study drug treatment, but continue to participate in the study, should complete a Premature Discontinuation Visit (PD Visit) as soon as 
possible, preferably within 2 weeks.  Afterwards, subjects should follow the regular visit schedule and adhere to all study procedures except for dispensing study 
drug, PK sample collection, and blood sample collection for optional exploratory research and validation studies.  In addition, after discontinuing study drug, all 
rescue and efficacy-driven discontinuation criteria no longer apply; this includes 20% TJC/SJC calculations at Week 48 and thereafter.

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5.3.1.1
Study Procedures
The study procedures outlined in Table 2 and Table 4 are discussed in detail in this 
section, with the exception of exploratory research and validation studies (discussed in 
Section 5.3.1.2), drug concentration measurements (discussed in Section 5.3.2), the 
collection of prior and concomitant medication information (discussed in Section 5.2.3), 
and the collection of AE information (discussed in Section 6.0).  All study data will be 
recorded in source documents and on the appropriate eCRFs.
Informed Consent
At the Screening visit, the subject will sign and date a study specific, IEC/IRB approved, 
informed consent form for the study (i.e., includes both Periods 1 and 2) before any study 
procedures are performed or any medications are withheld from the subject in order to 
participate in this study.  Separate written consent will be required for each subject in 
order to participate in the optional exploratory research and validation studies.  Subjects 
can withdraw informed consent at any time.
Details regarding how informed consent will be obtained and documented are provided in 
Section 9.3.
Inclusion/Exclusion Criteria
Subjects will be evaluated to ensure they meet all inclusion criteria and have none of the 
exclusion criteria at both Screening and Baseline Visits.
Medical and Surgical History
A complete non-RA-related medical and surgical history, including history of alcohol and 
nicotine use, will be taken from each subject during the Screening Visit.  Additionally, a 
list of each subject's specific RA-related medical and surgical history will be recorded at 
Screening.  History of herpes zoster, herpes zoster vaccination, and hepatitis B 
vaccination status will be recorded as part of the medical history.  An updated medical 

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history will be obtained prior to study drug administration at Baseline, to ensure the 
subject is still eligible for enrollment.
A detailed medical history with respect to TB risk factors will be documented in the study 
source documentation.  This information will include BCG vaccination, cohabitation with 
individuals who have had TB, and travel to, residence in, or work in TB endemic 
locations.
Patient Questionnaires
Subjects will complete the following questionnaires as specified in Table 2 and Table 4; a 
validated translation will be provided in their local language, as applicable:
Period 1
●
Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) 
(Appendix G)
●
Patient's Assessment of Pain Visual Analog Scale VAS (Appendix H)
●
Health Assessment Questionnaire – Disability Index (HAQ-DI) to assess the 
physical function and health-related quality of life of each subject (Appendix I)
●
Patient's Assessment of Severity and Duration of Morning Stiffness Numerical 
Rating Scale (NRS) (Appendix J)*
●
Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) 
(Appendix K)
●
EuroQoL-5D-5L (EQ-5D-5L) (Appendix L)
●
Short Form-36 (SF-36) (Appendix M)
●
Work Instability Scale for RA (RA-WIS) (Appendix N)
Period 2
●
Patient's Global Assessment of Disease Activity Visual Analog Scale (VAS) 
(Appendix G)
●
Patient's Assessment of Pain Visual Analog Scale VAS (Appendix H)

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●
Health Assessment Questionnaire – Disability Index (HAQ-DI) to assess the 
physical function and health-related quality of life of each subject (Appendix I)
●
Patient's Assessment of Severity and Duration of Morning Stiffness Numerical 
Rating Scale (NRS) (Appendix J)*
*
Paper; all other patient-reported outcomes (PROs) collected electronically.
The subject should complete the questionnaires before site personnel perform any clinical 
assessments and before any interaction with site personnel has occurred to avoid biasing 
the subject's response.
TB Testing/TB Prophylaxis
The TB screening tests provide diagnostic test results to be interpreted in the context of 
the subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB.  Expert 
consultation for the evaluation and/or management of TB may be considered per 
Investigator discretion.
At screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix F) and tested for TB infection by QuantiFERON-TB Gold 
test.  The PPD Skin Test should be utilized only when a QuantiFERON-TB Gold Test is 
not possible for any reason (unless both tests are required per local guidelines).  The site 
staff will complete the TB risk assessment form and enter the data into an appropriate 
eCRF.  The TB risk assessment form will be completed annually for all subjects, 
regardless of TB test results. 
If a subject had a negative PPD test within 90 days prior to Screening and a 
QuantiFERON-TB Gold test cannot be performed by Central Lab at Screening and source 
documentation is available, TB testing by PPD Skin Test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.  
These cases may be discussed with the AbbVie TA MD.  The results of the TB test(s) will 
be retained at the site as the original source documentation. 

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Subjects with a negative TB test and chest x-ray (CXR) not suggestive of active TB or 
prior TB exposure may be enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent 
TB, including signs and symptoms and CXR.  Subjects with no signs or symptoms and a 
CXR not suggestive of active TB may be enrolled after initiation of TB prophylaxis (see 
below).  
Subjects with evidence of active TB must not be enrolled.
For subjects with a negative TB test result at Screening or the most recent evaluation, an 
annual TB follow-up test will be performed.  If an annual TB test is newly positive 
(seroconversion), a chest x-ray (CXR) needs to be performed as soon as possible to aid in 
distinguishing active versus latent TB.  Any positive TB screen after the patient has 
started the study, should be reported as an AE of latent TB or active TB (as applicable). 
If the subject is experiencing signs or symptoms suspicious for TB or something has 
changed in the subject's medical history to warrant a repeat test before the next scheduled 
annual TB re-test, the case (including the TB test results) must be discussed with the 
AbbVie TA MD.
TB test:
●
Subjects with documentation of prior positive result of QuantiFERON-TB 
Gold Test (or equivalent) and/or PPD are not required to repeat either test at 
Screening or during the study and should be considered positive. 
●
For regions that require both PPD and QuantiFERON-TB Gold testing, both 
will be performed.  If either PPD or QuantiFERON-TB Gold are positive, the 
TB test is considered positive.
●
The PPD Skin Test (also known as a TB Skin Test or Mantoux Test) should be 
utilized only when a QuantiFERON-TB Gold Test is not possible for any 
reason (unless both tests are required per local guidelines).  

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●
If only a PPD is placed at screening, then the TB test to be used for the 
remainder of the study for that subject is the PPD.  Similarly, if a subject 
enters the study with a QuantiFERON-TB Gold test (or equivalent) alone, then 
the subject should have their annual TB test performed with a QuantiFERON-
TB Gold test.
●
If the QuantiFERON-TB Gold Test is NOT possible (or if both the 
QuantiFERON-TB Gold Test and the PPD are required per local guidelines) 
the PPD will be performed.  The PPD should be read by a licensed healthcare 
professional between 48 and 72 hours after administration.  A subject who 
does not return within 72 hours will need to be rescheduled for another skin 
test.  The reaction will be measured in millimeters (mm) of induration and 
induration ≥ 5 mm is considered a positive reaction. The absence of induration 
will be recorded as "0 mm" not "negative."  Subjects who have an ulcerating 
reaction to the PPD in the past should not be re-exposed and the PPD should 
be considered positive.
●
If the QuantiFERON-TB Gold test is indeterminate, then the investigator 
should perform a local QuantiFERON-TB Gold test (or through the central 
laboratory if not locally available) to rule out a positive test result.  If testing 
remains indeterminate or is positive, then the subject is considered to be 
positive for the purpose of this study.  If the testing result is negative, then the 
patient is considered to be negative.
For sites participating from the Czech Republic, the following local requirements will also 
be applicable:
●
A pulmonologist will be responsible to obtain a detailed medical history with 
respect to TB exposure.  This information needs to include BCG vaccination, 
cohabitation with individuals who have had TB, and/or who reside or work in 
TB endemic locations.  The information obtained by the pulmonologist must 
be documented in the subject's source note, dated and signed by the 
pulmonologist.
●
A pulmonologist must review the results of the QuantiFERON-TB Gold test 
and/or PPD skin test (or IGRA equivalent such as T-SPOT TB test) and the 
chest x-ray and has to give his/her opinion about the eligibility of each subject 

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to be enrolled to the study.  This opinion must be documented in writing in the 
subject's source documents.
●
All subjects with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) and a chest x-ray not suggestive of 
active TB need to be approved for entry into the trial by both the Czech 
pulmonologist and the AbbVie Therapeutic Area Medical Director and all such 
subjects need to receive prophylaxis for latent TB.  Under no circumstances 
can a subject with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) result and no prior history of 
treatment for active or latent TB be allowed into this trial.
TB prophylaxis:
At screening, if the subject has evidence of a latent TB, prophylactic treatment must be 
initiated at least 2 weeks prior to administration of study drug (or per local guidelines, 
whichever is longer).  At least 6 months of prophylaxis needs to be completed; however, 
the full course of prophylaxis does not need to be completed prior to the first dose of 
study drug.  
Of Note:  Rifampicin or Rifapentine is Not Allowed for TB Prophylaxis
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy within 1 year prior to first study drug administration will be 
allowed to enter the study provided nothing has changed in the subject's medical history to 
warrant repeat treatment.
Subjects with a documented completion of a full course of anti-TB therapy greater than 
1 year prior to first study drug administration may be allowed to enter the study only after 
consultation with the AbbVie Therapeutic Area Medical Director.
During the study, subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines and complete at least 6 months of prophylaxis.  
TB prophylaxis should be initiated and study drug(s) should not be withheld.  Two to 

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four weeks later, the subject should be re-evaluated (unscheduled visit) for signs and 
symptoms as well as laboratory assessment of toxicity to TB prophylaxis.  
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.
Chest X-Ray (CXR)
A CXR (posterior-anterior and lateral views) is required:
●
For all subjects at Screening to rule out the presence of TB or other clinically 
relevant findings.  The CXR will not be required if the subject had a previous 
normal CXR (posterior-anterior and lateral views) within 90 days of 
Screening, provided all source documentation is available at the site as 
outlined below and provided nothing has changed in the subject's medical 
history to warrant a repeat test.
●
Annually (every 48 weeks) for subjects with newly identified TB risk factors 
based on the TB risk assessment form (Appendix F), or for subjects living in 
areas endemic for TB, or for subjects with newly positive PPD and/or 
QuantiFERON-TB Gold test.
Subjects can have a repeat CXR at any time during the study as warranted, based on the 
opinion of the Investigator.
A radiologist or pulmonologist must perform an assessment of the CXR.  The Principal 
Investigator will indicate the clinical significance of any findings and will sign and date 
the report.  In the assessment of the CXR, the Principal Investigator or their delegate must 
indicate the presence or absence of (1) calcified granulomas, (2) pleural 
scarring/thickening, and (3) signs of active TB.  If the CXR demonstrates changes 
suggestive of previous TB (e.g., calcified nodule, fibrotic scar, apical or basilar pleural 
thickening) or other findings that are clinically significant, the Principal Investigator 
should contact the AbbVie Therapeutic Area Medical Director before enrolling the 
subject.

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12-Lead ECG
A resting 12-lead ECG will be performed at the designated study visits as specified in 
Table 2 and Table 4.  A qualified physician will interpret the clinical significance of any 
abnormal finding, sign, and date each ECG.  ECG with QT interval corrected for heart 
rate using Friedericia's correction formula (QTcF) should be reported (or calculated) and 
documented in the source documents and later transcribed on to the appropriate eCRF if 
QTcF prolongation is observed.  In these cases, the baseline QTcF will need to be entered 
into the appropriate eCRF for comparison as well.  In addition, any clinically significant 
findings will be documented in the source documents and later transcribed on to the 
appropriate eCRF.  Each signed original ECG will be monitored by the responsible site 
monitor and kept with subject's source documents onsite.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at 
Screening will not be required, provided source documentation is available and provided 
nothing has changed in the subject's medical history to warrant a repeat test.  If there are 
other findings that are clinically significant, the Investigator must contact the AbbVie 
Therapeutic Area Medical Director before enrolling the subject.
Subjects can have a repeat ECG at any time during the study as warranted, based on the 
opinion of the Investigator.
X-Rays of Hands and Feet
Detailed instructions for performing and transmitting the study related x-rays of hands and 
feet are provided in a separate Imaging Acquisition Guideline (IAG)/Site Operational 
Manual.
Handling of X-Rays of Hands and Feet at Screening
The x-ray inclusion criterion is defined as follows:  ≥ 3 bone erosions on x-ray OR 
≥1 bone erosion and a positive rheumatoid factor OR ≥ 1 bone erosion and a positive 
anti-CCP autoantibody.

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Screening x-rays of bilateral hands (posterior-anterior view) and bilateral feet 
(anteroposterior view) must be performed within the 35-day screening period.
X-rays will be sent to the central imaging laboratory designated by the Sponsor.  
Digitalized images are acceptable, provided that they meet the specifications outlined in 
the IAG/Site Operations Manual.  X-rays not meeting the quality requirements must be 
repeated within the 35-day screening window.  Subjects can receive first dose of study 
drug after the x-rays have been determined to be of sufficient quality by the central 
imaging laboratory.
Screening x-rays of hands and feet will serve as baseline x-rays for scoring purposes.
Handling of X-Rays of Hands and Feet after Baseline
Handling of x-rays of hands and feet after baseline in Period 1 is illustrated in Figure 3.
Week 14 x-rays of hands and feet will be performed for all non-responders (regardless of 
treatment group) (Figure 3, box A).  Non-responders at Week 18 and non-responders at 
Week 22 will not have x-rays.
All subjects (regardless of response) will have Week 26 x-rays (Figure 3, box B) and 
Week 48 x-rays (Figure 3, box C).
If a subject prematurely discontinues the study and/or study drug, depending on the time 
of discontinuation, new x-rays of hands and feet may be needed. 

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X-rays will be sent to the central imaging laboratory designated by the Sponsor.  
Digitalized images are acceptable provided that they meet the specifications outlined the 
IAG/Site Operations Manual.  X-rays not meeting the quality requirements must be 
repeated.
Overall in Period 1, each subject will undergo a maximum of 5 scheduled visits for x-ray 
examination of bilateral hands and feet (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 14 (only for 
non-responders at Week 14), Week 26, and Week 48/PD; in addition, subjects who 
prematurely discontinue from study drug or the study 
will have an x-ray examination at the premature discontinuation timepoint.
In Period 2, a follow-up x-ray of hands and feet is planned at Week 96 and every 
96 weeks thereafter.  Subjects who prematurely discontinue from the study will not need 
an x-ray of hands and feet if the previous x-ray was performed within the previous 
weeks.  Images will be sent to the central imaging laboratory designated by the 
Sponsor.

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Physical Examination
A complete physical examination will be performed at the designated study visits as 
specified in Table 2 and Table 4.  The physical examination at the Baseline Visit will 
serve as the baseline physical examination for the entire study.  Physical examination 
abnormalities noted by the Investigator at Baseline prior to the first dose of study drug 
will be recorded in the subject's medical history; abnormalities noted after the first dose of 
study drug will be evaluated and documented by the Investigator as to whether or not the 
abnormality is an AE (see Section 6.1.1.1 for AE definition).  All findings, whether 
related to an AE or part of each subject's medical history, will be captured on the 
appropriate eCRF page.
At any time, a symptom-directed physical examination can be performed as deemed 
necessary by the Investigator.
Physician Global Assessment of Disease Activity Visual Analog Scale (VAS)
At visits specified in Table 2 and Table 4, the Physician will rate global assessment of 
subject's current disease activity ranging from 0 to 100 independent of the subject's 
self-assessment using the VAS, which consists of a horizontal 100 mm line anchored at 
either end by opposite adjectives reflecting the spectrum/severity of the parameters 
assessed (Appendix D).
TJC and SJC Assessment
TJC Assessment
An assessment of 68 joints (Appendix E) will be done for tenderness by pressure 
manipulation on physical examination at visits specified in Table 2 and Table 4.  Joint 
pain/tenderness will be classified as:  present ("1"), absent ("0"), replaced ("9") or no 
assessment ("NA").

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SJC Assessment
An assessment of 66 joints (Appendix E) will be done by directed physical examination at 
visits specified in Table 2 and Table 4.  The joints to be examined for swelling are the 
same as those examined for tenderness, except the hip joints are excluded.  Joint swelling 
will be classified as present ("1"), absent ("0"), replaced ("9") or no assessment ("NA").
Any injected joints will be considered as "not assessed" ("NA") for 3 months from the 
time of the intra-articular injection.
If possible, the TJC and SJC should be performed by an independent and blinded joint 
assessor who should not perform any other study related procedures.
In order to minimize variability, the same independent joint assessor should evaluate the 
subject at each visit for the duration of the trial as much as possible.  A back-up 
independent joint assessor should be identified.  The independent joint assessors should 
be a qualified medical professional (e.g., nurse, physician's assistant, physician).  Any 
other joint assessor must be trained and competent in performing such assessments.  It is 
the responsibility of the Investigator to ensure that all assessors are qualified and trained 
to perform joint assessments.  If the independent assessor is not available, the pre-
identified back-up assessor should perform such assessments.
CDAI 
The CDAI calculation is required to determine if a subject fails to achieve low disease 
activity at the Week 26 visit.  An Interactive Response Technology (IRT) will calculate 
CDAI with input from site personnel on joint counts and the subject's and physician's 
Global Assessment of RA Disease Activity score.  A worksheet will be provided to 
capture the components required for IRT entry to obtain the CDAI calculation. 
The calculation used to determine CDAI score at Week 26 is as follows:
CDAI = TJC28 + SJC28 + PtGA + PhGA

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Pregnancy Test
A serum pregnancy test will be performed for all women of childbearing potential at the 
Screening Visit.  The serum pregnancy test will be sent to and performed by the central 
laboratory.  If the serum pregnancy test is positive the subject is considered a screen 
failure.  If the serum pregnancy test is borderline, it should be repeated ≥ 3 days later to 
determine eligibility.  If the repeat serum pregnancy test is:
●
Positive, the subject is considered a screen failure;
●
Negative, the subject can be enrolled into the trial;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study in the absence of clinical suspicion of pregnancy and other pathological 
causes of borderline results.
In Period 1, a urine pregnancy test will be performed for all women of childbearing 
potential at the Baseline Visit prior to the first dose of study drug and at all subsequent 
visits.  More frequent pregnancy tests will be performed throughout the study if required 
per local/country requirements.
●
If the baseline urine pregnancy test performed at the site is negative, then 
dosing with study drug may begin.  If the baseline urine pregnancy test 
performed at the site is positive, dosing with study drug must be withheld and 
a serum pregnancy test is required.  The serum pregnancy test will be sent to 
and performed by the central laboratory.  If the serum pregnancy test is 
negative, study drug may be started.  If the serum pregnancy test is positive, 
study drug must be withheld and the subject must be discontinued from the 
study.  In the event a pregnancy test comes back borderline, a repeat test is 
required.
●
If a urine pregnancy test at post-baseline is positive, study drug needs to be 
temporarily discontinued and a serum pregnancy test is required.  The serum 
pregnancy test will be sent to and performed by the central laboratory.  If the 
serum pregnancy test is negative, study drug may be restarted.  If the serum 
pregnancy test is positive, study drug must be permanently discontinued.  In 

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the event a pregnancy test comes back borderline, a repeat test is required 
(≥3 days later) to document continued lack of a positive result.
In Period 2, for women of childbearing potential, a urine pregnancy test will be performed 
at all visits and monthly at home between scheduled study visits.  The results of the 
monthly at home tests will be communicated to the site.  If a urine pregnancy test is 
positive, the subject must stop dosing, come in to the clinic and have blood drawn for a 
serum pregnancy test that will be analyzed at the central laboratory.
At each visit, the study staff should review the pregnancy avoidance recommendations 
with each subject of childbearing potential and male subjects with a partner of 
childbearing potential, and document this discussion in the subject's source records.
A pregnant or breastfeeding female will not be eligible for participation in this study or be 
allowed to continue study drug.
Clinical Laboratory Tests
Samples will be obtained for the clinical laboratory tests listed in Table 5.  Unscheduled 
clinical labs may be obtained at any time during the study if deemed appropriate per 
Investigator's discretion.  A certified central laboratory will be utilized to process and 
provide results for the clinical laboratory tests.  All abnormal laboratory tests that are 
considered clinically significant by the Investigator will be followed to a satisfactory 
resolution.
The central laboratory chosen for this study will provide instructions regarding the 
collection, processing, and shipping of these samples.
Blood samples will be obtained for the laboratory tests at visits specified in Table 2 and 
Table 4.  Blood draws should be performed only after all clinical assessments and 
questionnaires (HAQ DI, Patient's Assessment of Pain, etc.) and vital sign determinations 
are obtained.

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For clinic visits where samples for serum chemistry tests are collected, subjects should be 
fasting (a minimum 8-hour fast) whenever possible.  If a subject is not able to fast when 
necessary, due to unforeseen circumstances, the non-fasting status will be recorded in 
study source documentation.
Urine samples will be obtained for urinalysis testing at visits specified in Table 2 and 
Table 4.  The central laboratory will be responsible for performing a macroscopic 
urinalysis (urine dipstick) on the collected urine specimens.  Specified abnormal 
macroscopic urinalyses defined as leukocytes, nitrite, protein, ketones, or blood greater 
than negative, or glucose greater than normal will be followed up with a microscopic 
analysis at the central laboratory.
For any laboratory test value outside the reference range that the Investigator considers to 
be clinically significant, the Investigator should apply the standard of care for medical 
evaluation and treatment per local guidelines:
●
The Investigator will repeat the test to verify the out-of-range value.
●
The Investigator will follow the out-of-range value to a satisfactory clinical 
resolution.
A laboratory test value that requires a subject to be discontinued from the study or 
requires a subject to receive treatment will be recorded as an AE.  Other laboratory 
abnormalities, including those which meet the toxicity management criteria outlined in 
Section 6.1.7 (Toxicity Management), may be recorded as AEs at the discretion of the 
investigator.

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Table 5.
Clinical Laboratory Tests
Hematology
(Central Lab)
Clinical Chemistrya
(Central Lab)
Urinalysisb
(Central Lab)
Other Laboratory 
Tests
Hematocrit
Hemoglobin
RBC count
WBC count
Neutrophils
Bands
Lymphocytes
Monocytes
Basophils
Eosinophils
Platelet count
BUN
Creatinine
Total bilirubin
INR (reflex only)c
ALT
AST
Alkaline phosphatase
CPK
Sodium
Potassium
Chloride
Bicarbonate
Calcium
Inorganic phosphate
Uric acid
Cholesterol
LDL-C
HDL-C
Total protein
Glucose
Triglycerides
Albumin
Specific gravity
Ketones
pH
Protein
Blood
Glucose
Urobilinogen
Bilirubin
Leukocytes
Nitrites 
Microscopic 
examination, 
if needed
Central Lab Tests:
Serum pregnancy 
(bHCG) testd
HBs Age
HBs Abe
HBc Abe
HBV DNA PCR reflex 
onlye
HCV Abe
HCV RNA reflex onlye
HIVf
QuantiFERON-TB 
Goldg
Rheumatoid Factore
Anti-CCP 
autoantibodiese
ANA and dsDNA 
(reflex) 
autoantibodiese
hs-CRPh
IgG and IgM
FSHi
MRB Panelj
Local Lab Tests
Urine pregnancy testk
ESR
ALT = alanine aminotransferase; AST = aspartate aminotransferase; bHCG = beta human chorionic gonadotropin; 
BUN = blood urea nitrogen; CCP = cyclic citrullinated peptide; CK-MB = creatine kinase-MB  isozymes; 
CPK = creatine phosphokinase; DNA = deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; 
HBc Ab = hepatitis B core antibody; HBs Ab = hepatitis B surface antibody; HBs Ag = hepatitis B surface antigen; 
HBV = hepatitis B virus; HCV Ab = hepatitis C virus antibody; HDL-C = high-density lipoprotein cholesterol; 
HIV = human immunodeficiency virus; hsCRP = high sensitivity C-reactive protein; IgG = immunoglobulin G; 
IgM = immunoglobulin M; INR = international normalized ratio; LDL-C = low-density lipoprotein cholesterol; 
MRB = minimal residual B-cells; PCR = polymerase chain reaction; RBC = red blood cell; RNA = ribonucleic acid; 
TB = tuberculosis; WBC = white blood cell
a.
Minimum 8-hour fast.  If a subject is not able to fast when necessary, due to unforeseen circumstances, the 
non-fasting status will be recorded in study source documentation.
b.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A 
microscopic analysis will be performed in the event the dipstick results show leukocytes, nitrite, protein, ketones, 
or blood greater than negative or glucose greater than normal.

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Table 5.
Clinical Laboratory Tests (Continued)
c.
INR will only be measured if ALT and/or AST > 3 × ULN.
d.
A serum pregnancy test will be performed for all female subjects at the Screening Visit and if postbaseline urine 
pregnancy test turns positive.
e.
At Screening only.
f.
Anti-HIV Ab will be performed at Screening, unless prohibited by local regulations.  The Investigator must discuss 
any local reporting requirements to local health agencies with the subject.  The site will report confirmed positive 
results to their health agency per local regulations, if necessary.  If a subject has a confirmed positive result, the 
Investigator must discuss with the subject the potential implications to the subject's health and subject should 
receive or be referred for clinical care promptly.  A subject will not be eligible for study participation if test results 
indicate a positive HIV infection.  AbbVie will not receive results from the testing and will not be made aware of 
any positive result.
g.
If PPD not performed.
h.
The hsCRP results starting from Baseline (Day 1) will not be reported to the Sponsor, Investigator, study site 
personnel, and the subject.
i.
At screening for female subjects < 55 years old with no menses for ≥ 12 months AND no history of permanent 
surgical sterilization.
j.
If needed to assess B cell counts in subjects who have recently discontinued rituximab, see Inclusion Criterion 8, 
Section 5.2.1.
k.
A urine pregnancy test will be performed for all women of childbearing potential at the Baseline Visit prior to the 
first dose of study drug and at minimum at monthly intervals (either at study visits or at home between scheduled 
study visits).  (for details see Section 5.3.1.1 (Study Procedures).
Hepatitis Screen
All subjects will be tested for the presence of HBV and HCV at Screening.
Hepatitis B:
Subjects will be tested for the presence of HBV at screening using the following tests:
●
HBs Ag (Hepatitis B surface antigen)
●
HBc Ab/anti-HBc (Hepatitis B core antibody)
●
HBs Ab/anti-HBs (Hepatitis B surface antibody)
A positive result for HBs Ag will be exclusionary.
A negative result for HBs Ag will be tested (automatic reflex testing) for core antibodies 
(HBc Ab) and surface antibodies (HBs Ab).

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●
A negative test result for HBc Ab does not require HBV DNA PCR qualitative 
testing and the subject may be enrolled (Figure 4, Scenarios A and B).  For a 
subject who has had a HBV vaccination (should document in the medical 
history), a positive test result for HBs Ab is expected and the subject may be 
enrolled (Figure 4, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 4, Scenarios C and D).
○
A positive result for HBV DNA or a result that exceeds detection 
sensitivity will be exclusionary.
○
A subject with a negative result for HBV DNA may be enrolled.
Figure 4.
Criteria for HBV DNA PCR Qualitative Testing 
*
For subjects who have had a HBV vaccination (should be documented in the medical history), a positive test result 
for HBs Ab is expected and these subjects may be enrolled.
Hepatitis C:
Blood samples for Hepatitis C serology will be obtained at the Screening Visit.  A subject 
will not be eligible for study participation if test results indicate active Hepatitis C 
(HCV RNA detectable in any subject with anti HCV Ab).

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HIV
Subjects with a known history of HIV infection are excluded from study participation.  If 
required by country regulatory authorities to confirm eligibility, subjects should be tested 
for antibodies to HIV at Screening.  This testing is to be done at the central lab.  A subject 
will not be eligible for study participation if test results indicate a positive HIV infection.  
AbbVie will not receive results from the testing and will not be made aware of any 
positive result.
Randomization/Drug Assignment
All Screening laboratory results must be reviewed, signed and dated by the Principal 
Investigator or Sub-investigator prior to the Baseline Visit.  Subjects will not be enrolled 
into the study if laboratory or other Screening result abnormalities are deemed clinically 
significant by the Principal Investigator or Sub investigator.
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.
Subjects will be randomized in a 2:2:1 ratio using interactive response technology (IRT) 
to receive double-blind study drug in one of the following treatment groups:
●
Group 1:  Upadacitinib (ABT-494) 15 mg QD (N = 600)
●
Group 2:  Placebo (N = 600)
●
Group 3:  ADA (40 mg eow) (N = 300)
Randomization will be stratified by prior bDMARD exposure (yes or no) and geographic 
region.
See Section 5.5.3 for details.

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Study Drug Dispensing, Dosing, and Compliance
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in 
Table 2 and Table 4.  The first dose of study drug will be administered after all other 
Baseline (Day 1) procedures are completed.  Subjects will maintain a dosing diary for all 
study drug administered outside of the study visit (i.e., at home) to capture dosing dates 
and times.  At visits specified in Table 2 and Table 4, the site personnel will review and 
retain a copy of the dosing diary, returned study drug kits, and empty study drug 
packaging to verify compliance.
All relevant dosing information will be entered into the eCRF at each visit.
ADA/placebo for ADA study drug can be administered to subjects by study site medical 
staff or designee (subject, friend, family member, or health care professional) during the 
visit at Baseline.  Subjects or a designated family member or friend will be trained to 
administer study drug at this visit.
(Refer to Section 5.5 for additional information).
5.3.1.2
Collection and Handling of Optional Samples for 
Exploratory Research and Validation Studies
In Period 1, subjects will have the option to provide samples for exploratory research and 
validation studies.  Subjects may still participate in the main study even if they decide not 
to participate in this optional exploratory research/validation study.
Exploratory research can help to improve our understanding of how individuals respond 
to drugs and our ability to predict which subjects would benefit from receiving specific 
therapies.  In addition, exploratory research may help to improve our understanding of 
how to diagnose and assess/monitor RA by assessing associations between disease 
characteristics, outcomes data, and biomarkers of interest.

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Validation studies, including those related to the development of potential in vitro 
diagnostic tests, may be carried out retrospectively in order to assess associations between 
events of interest (i.e., efficacy and/or safety events) and candidate biomarkers.
AbbVie (or people or companies working with AbbVie) will store the biomarker 
exploratory research/validation studies samples in a secure storage space with adequate 
measures to protect confidentiality.  The samples will be retained while research on 
upadacitinib (or drugs of this class) or RA and related conditions continues, but for no 
longer than 20 years after study completion.
DNA Samples for Pharmacogenetic or Epigenetic Analyses
Whole blood samples for DNA isolation will be collected at the visits indicated in Table 3
from each subject who consents to provide samples for exploratory/validation research.  
The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
Samples will be shipped frozen to AbbVie or a designated laboratory for DNA extraction 
and/or long-term storage or analyses.  Instructions for the preparation and shipment of the 
pharmacogenetic and/or epigenetic research samples will be provided in a laboratory 
manual.
RNA Samples for Transcriptomic and/or Epigenetic Analyses
Whole blood samples for RNA isolation will be collected at the visits indicated in Table 3
from each subject who consents to provide samples for exploratory/validation research.  
The procedure for obtaining and documenting informed consent is discussed in 
Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for RNA extraction and/or
long-term storage or analyses.  Instructions for the preparation and shipment of the 
samples will be provided in a laboratory manual.

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Serum and Plasma Samples for Systemic Analyses, Including but Not Limited to 
Proteomic and Metabolomic
Serum and plasma samples will be collected at the visits indicated in Table 3 from each 
subject who consents to provide samples for exploratory/validation research.  These 
samples may be used for assay of study drugs if needed.  The procedure for obtaining and 
documenting informed consent is discussed in Section 9.3.
Samples will be shipped to AbbVie or a designated laboratory for long-term storage 
and/or analyses.  Instructions for the preparation and shipment of the samples will be 
provided in a laboratory manual.
5.3.2
Drug Concentration and Anti-Drug Antibody Measurements
5.3.2.1
Collection of Samples for Analysis
Blood Samples for Upadacitinib PK Assay
Blood samples for assay of upadacitinib and possibly other medications will be collected 
as follows:
●
At Weeks 2 and 4 prior to dosing;
●
At Weeks 8, 12, 14, 18, 22, 26, 30, 36, 42 and 48/PD at any time during the 
visit.
On Week 2 and Week 4 visit days, if possible, subjects should take the oral study drug 
dose at the clinic after collecting the pharmacokinetic (PK) blood sample, except if the 
subjects regularly take the study drug dose at night.  Those subjects who regularly take the 
oral study drug dose at night should continue to take oral study drug according to their 
normal schedule.  For all other visits, subjects can take the oral study drug dose on visit 
days at their regular schedule and not necessarily at the clinic.
For all PK samples, the date and accurate time of the PK sample collection will be 
recorded on the lab requisition form.  The date and accurate time of the last two study 
drug doses will be recorded on the eCRF to the nearest minute.

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Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.
5.3.2.2
Measurement Methods
Plasma concentrations of upadacitinib will be determined by the Drug Analysis 
Department at AbbVie using a validated liquid chromatography/mass spectrometry 
method.
5.3.3
Efficacy Variables
5.3.3.1
Period 1 Variables
5.3.3.1.1
Primary Variables
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response 
at Week 12 (US/FDA regulatory purposes) or the proportion of subjects achieving CR 
based on DAS28 (CRP) at Week 12 (EU/EMA regulatory purposes).  Analyses will be 
conducted separately for US/FDA regulatory purposes and EU/EMA regulatory purposes; 
for each set of analysis, only one primary endpoint is specified.
ACR20 response rate will be determined based on 20% or greater improvement in TJC 
and SJC and ≥ 3 of the 5 measures of Patient's Assessment of Pain (VAS), Patient's 
Global Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease 
Activity (VAS), HAQ-DI, or hsCRP.
CR is defined as DAS28 (CRP) < 2.6.
5.3.3.1.2
Key Secondary Variables
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) 
for US/FDA regulatory purposes are:
1.
Change from baseline in DAS28 (CRP) at Week 12;
2.
Change from baseline in mTSS at Week 26;

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3.
Change from baseline in HAQ-DI at Week 12;
4.
ACR50 response rate at Week 12 (non-inferiority of upadacitinib vs ADA);
5.
Change from baseline in SF-36 Physical Component Score (PCS) at Week 12;
6.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
7.
Proportion of subjects achieving CR based on DAS28 (CRP) at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index 
(CDAI) at Week 12;
9.
Change from baseline in morning stiffness at Week 12;
10.
Change from baseline in FACIT-F at Week 12;
11.
ACR50 response rate at Week 12 (superiority of upadacitinib vs. ADA);
12.
Change from baseline in Patient's Assessment of Pain at Week 12 (superiority of 
upadacitinib vs. ADA);
13.
Change from baseline in HAQ-DI at Week 12 (superiority of upadacitinib vs. 
ADA).
Other key secondary endpoints (upadacitinib versus placebo) for US/FDA regulatory 
purposes are:
●
ACR50 response rate at Week 12
●
ACR70 response rate at Week 12
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline mTSS ≤ 0) at Week 26
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) 
for EU/EMA regulatory purposes are:
1.
Change from baseline in modified Total Sharp Score (mTSS) at Week 26;
2.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;

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3.
Change from baseline in DAS28 (CRP) at Week 12;
4.
Change from baseline in HAQ-DI at Week 12;
5.
ACR20 response rate at Week 12;
6.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 
(non-inferiority of upadacitinib versus ADA);
7.
Change from baseline in SF-36 PCS at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index 
(CDAI) at Week 12
9.
Change from baseline in morning stiffness at Week 12; 
10.
Change from baseline in FACIT-F at Week 12.
11.
Proportion of subjects with no radiographic progression (defined as change from 
baseline mTSS ≤ 0) at Week 26;
Other key secondary endpoints (upadacitinib versus placebo) for EU/EMA regulatory 
purposes are:
●
ACR50 response rate at Week 12
●
ACR70 response rate at Week 12
ACR20/50/70 response rates will be determined based on 20%/50%/70% or greater 
improvement in TJC and SJC and ≥ 3 of the 5 measures of Patient's Assessment of Pain 
(VAS), Patient's Global Assessment of Disease Activity (VAS), Physician's Global 
Assessment of Disease Activity (VAS), HAQ-DI, or hsCRP.
5.3.3.1.3
Additional Variables
Additional endpoints (upadacitinib versus placebo and adalimumab) at all visits are:
●
Change from baseline in individual components of ACR response;
●
ACR20/50/70 response rates;

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●
Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation 
rate [ESR]);
●
Change from baseline in CDAI and SDAI;
●
Proportion of subjects achieving LDA or CR based on DAS28 (CRP), DAS28 
(ESR), Simplified Disease Activity Index (SDAI), and CDAI criteria (see 
below);
●
Change from baseline in morning stiffness;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;
●
ACR/EULAR Boolean remission.
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
Additional endpoints at Weeks 12, 26, and 48 are:
●
Change from baseline in SF-36;
●
Change from baseline in FACIT-F. 
●
Change from baseline in RA-WIS.
●
Change from baseline in EQ-5D-5L.
Additional endpoints at Weeks 26 and 48 are:
●
Change from baseline in modified Total Sharp Score (mTSS);
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline in mTSS ≤ 0);
●
Change from baseline in joint space narrowing score and joint erosion score.

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5.3.3.2
Period 2 Variables
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the 
following measures at Weeks 60, 72, 84, 96, and every 12 weeks thereafter until 
completion of the study:
●
ACR20/50/70 response rates;
●
Change from baseline in individual ACR components;
●
Change from baseline in DAS28 (CRP);
●
Change from baseline in DAS28 (ESR);
●
Change from baseline in CDAI and SDAI;
●
Change from baseline in morning stiffness;
●
Proportion of subjects achieving LDA and the proportion of subjects achieving 
CR based on DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as 
defined for Period 1);
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;
●
Concomitant corticosteroid use (systemic use and intra-articular injections);
●
ACR/EULAR Boolean remission.
Additionally, assessment for the evaluation of radiographic changes in Period 2 will occur 
at Week 96 and every 96 weeks thereafter (or Premature Discontinuation visit):
●
Change from baseline in modified Total Sharp Score (mTSS);
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline in mTSS of ≤ 0);
●
Change from baseline in Radiographic joint space narrowing and erosion 
scores.

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5.3.4
Safety Variables
Safety evaluations include AE monitoring, physical examinations, vital sign 
measurements, ECG, and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.
5.3.5
Pharmacokinetic Variables
Plasma upadacitinib concentrations will be obtained at the times indicated in Table 2.  A 
non-linear mixed-effects modeling approach will be used to estimate the population 
central values and the empirical Bayesian estimates of the individual values of 
upadacitinib oral clearance (CL/F) and volume of distribution (V/F).  Additional 
parameters may be estimated if useful in the interpretation of the data.  
5.3.6
Exploratory Research Variables and Validation Studies
Optional samples may be collected to conduct exploratory investigations into known and 
novel biomarkers.  The types of biomarkers to be analyzed may include, but are not 
limited to nucleic acids, proteins, lipids, or metabolites.
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  Theses assessments may be 
explored in the context of RA or related conditions and/or upadacitinib or drugs of similar 
classes.  The results from these analyses are exploratory in nature and may not be 
included with the clinical study report (CSR).
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be stored for future use.  Samples 
may then be used to validate putative biomarker signatures obtained from a prospective 
study, leading to the development of diagnostic tests.

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5.4
Removal of Subjects from Therapy or Assessment
5.4.1
Discontinuation of Individual Subjects
Subjects can request to be discontinued from participating in the study at any time for any 
reason, including but not limited to disease progression or lack of response to treatment.  
The Investigator may discontinue any subject's participation for any reason, including an 
AE, safety concerns, lack of efficacy, or failure to comply with the protocol.  See 
Section 6.1.7 for toxicity management criteria.
Subjects will have study drug treatment discontinued immediately if any of the following 
occur:
●
Clinically significant abnormal laboratory results or AEs, which rule out 
continuation of the study drug, as determined by the Investigator or the 
AbbVie Therapeutic Area Medical Director.
●
Serious infections (e.g., sepsis) which cannot be adequately controlled within 
2 weeks by anti-infective treatment or would put the subject at risk for 
continued participation in the trial as determined by the Investigator.
●
The Investigator believes it is in the best interest of the subject.
●
The subject requests withdrawal from the study.
●
Inclusion or exclusion criteria violation was noted after the subject started 
study drug, when continuation of the study drug would place the subject at risk 
as determined by the AbbVie Therapeutic Area Medical Director.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk, as determined by the AbbVie 
Therapeutic Area Medical Director.
●
Subject is non-compliant with TB prophylaxis (if applicable) or develops 
active TB at any time during the study.
●
The subject becomes pregnant while on study drug.
●
Malignancy, except for localized NMSC or carcinoma in situ of the cervix.
●
Subject is diagnosed with lupus-like syndrome, multiple sclerosis, or 
demyelinating disease.

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●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation as determined by the 
Investigator.
●
Subject develops a gastrointestinal perforation.
●
Subjects with disease progression or not responding to treatment are to be 
withdrawn from the trial based on investigator's discretion.
●
Starting at Week 48, at least 20% improvement in BOTH TJC AND SJC 
compared to baseline is required to remain on study drug. Anyone who does 
not fulfill this criterion at 2 consecutive visits (starting at Week 48) must be 
discontinued from study drug.
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment or study participation should complete a
Premature Discontinuation visit (PD visit) as described in Section 5.1 (Overall Study 
Design and Plan:  Description)
All attempts must be made to determine the date of the last study drug dose and the 
primary reason for discontinuation of study drug or study participation.  The information 
will be recorded on the appropriate eCRF page.  However, these procedures should not 
interfere with the initiation of any new treatments or therapeutic modalities that the 
Investigator feels are necessary to treat the subject's condition.  Following discontinuation 
of study drug, the subject will be treated in accordance with the Investigator's best clinical 
judgment, irrespective of whether the subject decides to continue participation in the 
study.
Lost to Follow-Up
For subjects to be considered lost to follow-up, reasonable attempts must be made to 
obtain information on the final status of the subject.  At a minimum, two phone calls must 
be made and one certified letter must be sent and documented in the subject's source 
documentation.

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5.4.2
Discontinuation of Entire Study
AbbVie may terminate this study prematurely, either in its entirety or at any study site, for 
reasonable cause provided that written notice is submitted in advance of the intended 
termination.  The Investigator may also terminate the study at his/her site for reasonable 
cause, after providing written notice to AbbVie in advance of the intended termination.  
Advance notice is not required by either party if the study is stopped due to safety 
concerns.  If AbbVie terminates the study for safety reasons, AbbVie will immediately 
notify the Investigator by telephone and subsequently provide written instructions for 
study termination.
5.5
Treatments
5.5.1
Treatments Administered
There are two active study drugs in this study.  The first is daily upadacitinib (ABT-494) 
and the second is ADA eow.
Upadacitinib (ABT-494) (or matching placebo) study drug will be taken orally once daily, 
beginning on Day 1 (Baseline), and should be taken at approximately the same time each 
day.  The study drug can be taken with or without food.  Subjects will continue their 
weekly stable background therapy of MTX.  AbbVie will not supply MTX nor folic acid 
(or equivalent, such as folinic acid).
ADA (or matching placebo) will be provided as a subcutaneous injection solution in 1 mL 
pre-filled syringes containing ADA 40 mg/0.8 mL (or matching placebo).  ADA (or 
matching placebo) will be subcutaneously administered eow at approximately the same 
time of day.
Subjects should take a dietary supplement of oral folic acid beginning on Day 1 (Baseline) 
throughout study participation.  Folic acid dosing and timing of regimen should be 
followed according to the Investigator's instructions.

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Subjects will receive both oral study drug QD (either upadacitinib (ABT-494) 15 mg or 
matching placebo) and subcutaneous study drug eow (either ADA 40 mg or matching 
placebo).  When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment in both periods will be unblinded to the Sponsor and sites, and subjects will be 
dispensed study drug in an open-label fashion until the completion of Period 2.
5.5.2
Identity of Investigational Product
The individual study drug information is presented in Table 6.  

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Table 6.
Identity of Investigational Product
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
Upadacitinib 
(ABT-494)
oral
tablet
15 mg
AbbVie
Upadacitinib 
(ABT-494) 
matching placebo 
oral
tablet
NA
AbbVie
Adalimumab
subcutaneous 
injection
Adalimumab/Mannitol, 
Citric acid monohydrate, 
Sodium citrate, Disodium 
phosphate dihydrate, 
Sodium dihydrogen 
phosphate dihydrate, 
Sodium chloride, 
Polysorbate 80, Water for 
injections, Sodium 
hydroxide added as 
necessary to adjust pH
40 mg/
0.8 mL
AbbVie or Vetter
Adalimumab 
matching placebo
subcutaneous 
injection
Mannitol, Citric acid 
monohydrate, Sodium 
citrate, Disodium 
phosphate dihydrate, 
Sodium dihydrogen 
phosphate dihydrate, 
Sodium chloride, 
Polysorbate 80, Water for 
injections, Sodium 
hydroxide added as 
necessary to adjust pH
NA
AbbVie or Vetter
5.5.2.1
Packaging and Labeling
Upadacitinib (ABT-494) and matching placebo will be packaged in bottles with quantities 
sufficient to accommodate study design.  Each kit label will contain a unique kit number.  
This kit number is assigned to a subject via IRT and encodes the appropriate study drug to 
be dispensed at the subject's corresponding study visit.  Each kit will be labeled as 
required per country requirements.  Labels must remain affixed to the kits.  All blank 
spaces on the label will be completed by the site staff prior to dispensing to the subjects.

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ADA will contain 2 pre-filled syringes of ADA 40 mg/0.8 mL or matching placebo per 
carton.  Each kit label will contain a unique kit number.  This kit number is assigned to a 
subject via IRT and encodes the appropriate study drug to be dispensed at the subject's 
corresponding study visit.  Each kit will be labeled as required per country requirements.  
Labels must remain affixed to the kits.  All blank spaces on the label will be completed by 
the site staff prior to dispensing to the subjects.
5.5.2.2
Storage and Disposition of Study Drugs
Upadacitinib (ABT-494) must be stored at controlled room temperature (15° to 25°C/59° 
to 77°F).  ADA must be stored protected from light at 2° – 8°C (36° – 46°F).  Study drug 
must not be frozen at any time.  The investigational products are for investigational use 
only and are to be used only within the context of this study.  The study drug supplied for 
this study must be maintained under adequate security and stored under the conditions 
specified on the label until dispensed for subject use or destroyed on site as appropriate.
5.5.3
Method of Assigning Subjects to Treatment Groups
All subjects will be randomized using IRT.  Before the study is initiated, IRT directions 
will be provided to each site.
All subjects will be assigned a unique identification number by the IRT at the Screening 
Visit.  For subjects that re-screen, the Screening number assigned by the IRT at the initial 
Screening visit should be used; a new Screening number should not be requested.  
Subjects will be eligible for randomization if they continue to meet all of the selection 
criteria (Section 5.2) at Baseline and are willing to continue in the study.
Subjects will be randomized in a 2:2:1 ratio using interactive response technology (IRT) 
to receive double-blind study drug in one of the following treatment groups:
●
Group 1:  Upadacitinib (ABT-494) 15 mg QD (N = 600)
●
Group 2:  Placebo (N = 600)
●
Group 3:  ADA (40 mg eow) (N = 300)

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Subjects will receive both oral study drug QD (either upadacitinib 15 mg or matching 
placebo) and subcutaneous study drug eow (either ADA 40 mg or matching placebo) until 
the study is unblinded.
Randomization will be stratified by prior bDMARD exposure (yes or no) and geographic 
region.
The IRT will assign a randomization number that will encode the subject's treatment 
group assignment according to the randomization schedule generated by the Statistics 
Department at AbbVie.
IRT will provide the appropriate study drug kit number(s) to dispense to each subject.  
Study drug will be administered at the study visits as summarized in Section 5.3.1.1.  
Returned study drug should not be re-dispensed to any subject.
5.5.4
Selection and Timing of Dose for Each Subject
Subjects should take study drug as outlined in Section 5.5.1.
On dosing days that occur on study visit days, subjects should follow the regular dosing 
schedule (refer to Section 5.3.2.1 regarding Week 2 and Week 4 visits).
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's dosing diary.  This will ensure that all subjects enrolled 
into the study maintain their original dosing schedule beginning with the first dose of 
study drug (Baseline/Day 1).
Upadacitinib/Placebo (daily dosing):
●
If a subject should forget to take their upadacitinib (ABT-494) (or matching 
placebo) dose at their regularly scheduled dosing time, they should take the 
forgotten dose as soon as they remember the dose was missed as long as it is at 
least 10 hours before their next scheduled dose.  If a subject only remembers 

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the missed dose within 10 hours before next scheduled dose, the subject should 
skip the missed dose and take the next dose at the scheduled time.
●
If the subject experiences a study drug interruption > 14 consecutive days 
during the first 26 weeks, > 21 days between Week 26 and Week 48 or 
> 30 consecutive days during Period 2 (other than for reasons listed in 
Section 6.1.7), they should notify their study site physician, and the subject 
should be discontinued from study drugs.  If study treatment drug is 
interrupted or withdrawn in Periods 1 or 2, both oral and subcutaneous study 
drug administration must be stopped.
ADA/Placebo (biweekly dosing):
●
Biweekly ADA (or matching placebo) should be injected the same day and 
approximately the same time every other week.  If the subject should forget to 
inject their subcutaneous study drug on their regularly scheduled dosing date, 
they should inject the forgotten dose as soon as they remember the dose was 
missed up to the day before their scheduled dose.  The subject must not 
administer two injections on the same day. 
●
If the subject experiences a study drug interruption of > 2 consecutive missed 
doses during the first 26 weeks or > 3 consecutive missed doses after Week 26 
(other than for reasons listed in Section 6.1.7), they should notify their study 
site physician, and the subject should be discontinued from the study.  If study 
treatment drug is interrupted or withdrawn in Periods 1 or 2, both oral and 
subcutaneous injections must be stopped.
5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personnel with direct oversight, conduct and management of the trial (with 
the exception of AbbVie Drug Supply Management Team), will remain blinded to each 
subject's treatment through Week 26.  The Investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment in Period 1 until the last subject 
completes the last visit of Period 1 (Week 48).

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In order to maintain the blind, the upadacitinib (ABT-494) tablets and placebo tablets, and 
ADA syringes and placebo syringes provided for the study will be identical in appearance.  
The IRT will provide access to unblinded subject treatment information in the case of 
medical emergency.
In the event of a medical situation that requires unblinding of the study drug assignment, 
the Investigator is requested to contact the AbbVie Therapeutic Area Medical Director 
prior to breaking the blind.  However, if an urgent therapeutic intervention is necessary 
which warrants breaking the blind prior to contacting the AbbVie Therapeutic Area 
Medical Director, the Investigator can directly access the IRT system to break the blind 
without AbbVie notification or agreement.  Unblinding is available in the IRT system via 
the Unblind Subject transaction, which is available only to the Investigator.  If the IRT 
system is unavailable, unblinding may occur by contacting EndPoint technical support via 
either phone (preferred) or email (support@endpointclinical.com).  For country-specific 
phone numbers, please see the following website:  http://www.endpointclinical.com/help-
desk/.  In the event that the blind is broken before notification to the AbbVie Therapeutic 
Area Medical Director, AbbVie requests that the AbbVie Therapeutic Area Medical 
Director be notified within 24 hours of the blind being broken.  The date and reason that 
the blind was broken must be conveyed to AbbVie and recorded on the appropriate eCRF.
When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment in both periods will be unblinded to the Sponsor and sites, and subjects will be 
dispensed study drug in an open-label fashion until the completion of Period 2.
5.5.5.2
Blinding of Data for Data Monitoring Committee
An external Data Monitoring Committee (DMC) comprised of persons independent of 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  The primary responsibility of the DMC will be to protect the safety of 
the subjects participating in this study.

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A separate DMC charter will be prepared outside of the protocol and will describe the 
roles and responsibilities of the DMC members, frequency of data reviews, and relevant 
safety data to be assessed.
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
5.5.6
Treatment Compliance
The Investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subject dosing will be recorded on a subject dosing diary.  Subjects will be instructed to 
return all drug containers (even if empty) to the study site personnel at each clinic visit.  
The study site personnel will document compliance in the study source documents.
5.5.7
Drug Accountability
The Investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document and by registering the arrival of drug through the 
IRT.  The original Proof of Receipt Note and the IRT confirmation sheet will be kept in 
the site files as a record of what was received.
In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number, and the identification of the person dispensing the drug.
All empty/used study drug packaging will be inventoried by the site and verified by the 
site monitor.  Empty/used study drug packaging should be returned by the subject at each 
visit for accountability and compliance purposes and new packaging issued as necessary.  
Empty/used packaging will be retained (unless prohibited by local law) until the site 

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monitor is on site to confirm the returned study drug.  Site monitor(s) and site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, and 
by visually inspecting the packaging whenever possible.  After drug accountability has 
been completed, used packaging and unused study drug will be destroyed on site 
according to local procedures or regulations or returned to the destruction depot by the 
site monitor (for those sites that do not meet AbbVie's documentation requirements for 
on-site destruction).  The use of a third party vendor for drug destruction must be 
pre-approved by AbbVie.  For sites performing on-site drug destruction or using a 
third party vendor for drug destruction, a copy of the destruction methodology and date of 
destruction should be maintained at the site's facility.
5.6
Discussion and Justification of Study Design
5.6.1
Discussion of Study Design and Choice of Control Groups
This study includes two periods.  
Period 1 is a 48-week randomized, double-blind, parallel-group, placebo-controlled and 
active-comparator controlled study to compare safety and efficacy of upadacitinib 15 mg 
QD versus placebo and versus ADA 40 mg eow in subjects with moderately to severely 
active RA who are on a on a stable background of MTX and who have an inadequate 
response to MTX.  Period 1 is designed to test superiority of upadacitinib versus placebo 
for achieving the primary endpoint (ACR20 at Week 12 for US/FDA regulatory purposes 
or the proportion of subjects achieving CR based on DAS28 [CRP] at Week 12 for 
EU/EMA regulatory purposes), and other secondary efficacy parameters.
The purpose of Period 2 is to evaluate the long-term safety, tolerability, and efficacy of 
upadacitinib (15 mg QD) in RA subjects who have completed Period 1.  All subjects will 
continue treatment to which they were assigned at the end of Period 1.  This will allow 
assessments of long-term safety of upadacitinib without compromising the study conduct 
or results of ongoing Period 1.  In addition, the study design will allow the assessment of 
the maintenance of treatment response of both study drugs during this extension study.

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When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment will be unblinded to the Sponsor and sites, and subjects will be dispensed 
study drug in an open-label fashion until the completion of Period 2.
Adalimumab was first approved in the United States and European Union for the 
treatment of RA in 2002 and 2003, respectively, and is considered standard of care.  
Additional updates regarding approved indications and safety can be found in the current 
edition of the Package Insert and Summary of Product Characteristics.
5.6.2
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in this study.  All 
efficacy measurements in this study are standard for assessing disease activity in subjects 
with RA.  All clinical and laboratory procedures in this study are standard and generally 
accepted.
5.6.3
Suitability of Subject Population
The intended study population is moderately to severely active RA patients who have had 
an inadequate response to prior MTX treatment.  Key entry criteria are to enroll adult 
female and male subjects who are at least 18 years of age with a diagnosis of RA for 
≥3 months who also fulfill the 2010 ACR/EULAR classification criteria for RA.  Eligible 
study subjects must have ≥6 swollen joints (based on 66 joint counts) and ≥ 6 tender 
joints (based on 68 joint counts) at Screening and Baseline Visits, and hsCRP ≥5 mg/L 
(central lab, ULN 2.87 mg/L) at Screening.  Subjects must have been on oral or parenteral 
MTX therapy for ≥ 3 months and on a stable dose for ≥ 4 weeks prior to the first dose of 
study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at 
doses ≥12.5 mg/week).
5.6.4
Selection of Doses in the Study
One dose of the once-daily formulation of upadacitinib will be evaluated:  upadacitinib 
15 mg QD.  The dose selection in this study is based on extrapolation of pre-clinical 
efficacy models and analyses of PK, pharmacodynamic, safety, and efficacy data from the 

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Phase 1 studies in healthy volunteers (single and multiple ascending dose 
Studies M13-401 and M13-845, respectively) and Phase 2 studies in RA subjects 
(Studies M13-537 and M13-550).  The dose selected for Study M14-465, upadacitinib 
15 mg QD, dosed up to 5 years, is expected to be efficacious with an acceptable safety 
profile.
The 15 mg QD dose using the once-daily formulation provides equivalent daily AUC and 
comparable Cmax and Cmin to 6 mg BID of the immediate-release formulation tested in 
Phase 2 studies in subjects with RA.  In Phase 2 studies, the 6 mg BID dose was shown to 
achieve the near maximum efficacy.
6.0
Complaints
A Complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the physical characteristics, identity, quality, purity, potency, durability, 
reliability, safety, effectiveness, or performance of a product/device after it is released for 
distribution.
The investigational product in this trial contains both a biologic compound and a device 
component (pre-filled syringe, pen).
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For AEs, please refer to Section 6.1.  For product 
complaints, please refer to Section 6.2.
6.1
Medical Complaints
The Investigator will monitor each subject for clinical and laboratory evidence of AEs on 
a routine basis throughout the study.  The Investigator will assess and record any AE in 
detail including the date of onset, event diagnosis (if known) or sign/symptom, severity, 
time course (end date, ongoing, intermittent), relationship of the AE to study drug, and 
any action(s) taken.  For SAEs considered as having "no reasonable possibility" of being 
associated with study drug, the Investigator will provide other cause(s) of the event.  For 

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AEs to be considered intermittent, the events must be of similar nature and severity. AEs, 
whether in response to a query, observed by site personnel, or reported spontaneously by 
the subject will be recorded.
All AEs will be followed to a satisfactory conclusion.
6.1.1
Definitions
6.1.1.1
Adverse Event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or not 
the event is considered causally related to the use of the product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as 
well as from accidental or intentional overdose, drug abuse, or drug withdrawal.  Any 
worsening of a pre-existing condition or illness is considered an AE.  Worsening in 
severity of a reported AE should be reported as a new AE.  Laboratory abnormalities and 
changes in vital signs are considered to be AEs only if they result in discontinuation from 
the study, necessitate therapeutic medical intervention, and/or if the investigator considers 
them to be AEs.
An elective surgery/procedure scheduled to occur during the study will not be considered 
an AE if the surgery/procedure is being performed for a pre-existing condition and the 
surgery/procedure has been pre planned prior to study entry.  However, if the pre-existing 
condition deteriorates unexpectedly during the study (e.g., surgery performed earlier than 
planned), then the deterioration of the condition for which the elective surgery/procedure 
is being done will be considered an AE.

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6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as an SAE 
within 24 hours of the site being made aware of the SAE.
Death of Subject
An event that results in the death of a subject.
Life-Threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical intervention had not 
been taken.  This does not include an event that would have 
been fatal if it had occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any 
length of time or prolongs the subject's hospital stay.  This 
does not include an emergency room visit or admission to an 
outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that 
results in fetal loss.
Persistent or 
Significant 
Disability/Incapacity
An event that results in a condition that substantially 
interferes with the activities of daily living of a study 
subject.  Disability is not intended to include experiences of 
relatively minor medical significance such as headache, 
nausea, vomiting, diarrhea, influenza, and accidental trauma 
(e.g., sprained ankle).
Important Medical 
Event Requiring 
Medical or Surgical 
Intervention to 
Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization, but 
based on medical judgment may jeopardize the subject and 
may require medical or surgical intervention to prevent any 
of the outcomes listed above (i.e., death of subject, 
life-threatening, hospitalization, prolongation of 
hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective 
or spontaneous abortion or stillbirth is considered an 
important medical event.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an 
emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.

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For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
The following AEs of special interest will be monitored during the study (see detailed 
toxicity management in Section 6.1.7):
●
Serious infections
●
Opportunistic infections
●
Herpes Zoster
●
Tuberculosis
●
Malignancy (all types)
●
Gastrointestinal Perforations
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE])
●
Lipid Profile Changes
●
Anemia
●
Neutropenia
●
Lymphopenia
●
Increased serum creatinine and renal dysfunction
●
Hepatic events and increased hepatic transaminases
●
Elevated creatine phosphokinase (CPK)
●
Embolic and thrombotic events (non-cardiac, non-CNS)
6.1.2
Adverse Event Severity
The Investigator will classify adverse events according to the Rheumatology Common 
Toxicity Criteria v.2.0 (Appendix O).22

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6.1.3
Relationship to Study Drug
The Investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is 
given, an Other cause of event must be provided by the investigator for the serious 
adverse event.
6.1.4
Adverse Event Collection Period
All AEs reported from the time of study drug administration until 70 days following 
discontinuation of subcutaneous study drug administration and until 30 days following the 
discontinuation of oral study drug administration have elapsed will be collected, whether 
solicited or spontaneously reported by the subject.  Subjects who discontinue study drug 
treatment but continue to participate in the study will have SAEs and non-serious AEs 
collected for the remainder of the study participation.  In addition, SAEs and protocol-
related nonserious AEs will be collected from the time the subject signed the study-
specific informed consent.

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Adverse event information will be collected as shown in Figure 5.
Figure 5.
Adverse Event Collection
*
30 days after the last dose of oral study drug; 70 days after the last dose of subcutaneous study drug.
Additionally, in order to assist the adjudication process, additional information on any 
potential MACE will be collected, if applicable.
In the case of any of the following reported events, an appropriate supplemental MACE
eCRF should be completed:
●
Cardiac events;
●
Myocardial infarction or unstable angina;
●
Heart failure;
●
Cerebral vascular accident and transient ischemic attack;
In the case of any of the following AEs, the corresponding Supplemental AE eCRF 
should be completed:
●
Hepatic; 
●
Renal;
●
Herpes Zoster Infection;
●
CPK increases considered by the investigator to be an AE;
●
Embolic and thrombotic events (non-cardiac, non-CNS)..

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6.1.5
Serious Adverse Event Reporting
AbbVie is committed to continue to collect safety information including those events that 
may occur in this trial in order to confirm this established safety profile and to identify 
any unknown potential adverse reactions, rare events, and those events with a long 
latency.  AbbVie is participating in an FDA-requested, TNF inhibitor class wide 
exploration of the rare appearance of malignancy in subjects/patients who are 30 years of 
age or younger at the time of diagnosis.  The risk of malignancy in this age group has not 
been established and is difficult to study due to its rarity.  AbbVie appreciates your 
attention to the additional reporting requirements needed in this unlikely event.
In the event of an SAE, and additionally, any nonserious event of malignancy in subjects 
30 years of age and younger, whether related to subcutaneous study drug or not, the 
physician will notify Clinical Pharmacovigilance within 24 hours of the physician 
becoming aware of the event by entering the SAE or nonserious event of malignancy in 
subjects 30 years of age and younger data into the electronic data capture (EDC) system.  
SAEs and nonserious events of malignancy in subjects 30 years of age and younger, that 
occur prior to the site having access to the RAVE® EDC system or if RAVE® is not 
operable, should be documented on the SAE non-case report form (CRF) forms and 
emailed (preferred route) or faxed to the Clinical Pharmacovigilance within 24 hours of 
being made aware of the SAE.
Email: 
FAX to

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For safety concerns, contact the Immunology Safety Team at:
Immunology Safety Team
1 North Waukegan Road
North Chicago, IL  60064
Office:
Email:
For any subject safety concerns, please contact the physician listed below:
Primary Therapeutic Area Medical Director:
In emergency situations involving study subjects when the primary Therapeutic Area 
Medical Director is not available by phone, please contact the 24-hour AbbVie Medical 
Escalation Hotline where your call will be re-directed to a designated backup AbbVie 
Therapeutic Area Medical Director:
Phone:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 

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Global and Local Regulations.  The reference document used for SUSAR reporting in the 
European Union countries will be the most current version of the Investigator's Brochure 
for upadacitinib and/or the Summary of Product Characteristics (SmPC) for ADA, as 
applicable.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 1 working day of the site 
becoming aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued from study drug (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject or the partner of an 
enrolled subject and the outcome of the pregnancy will be collected.  Pregnancies in study 
subjects will be collected from the date of the first dose through 150 days following the 
last dose of subcutaneous study drug.  Pregnancies will be collected from the first dose of 
oral study drug through 30 days following the last dose of oral study drug for female 
subjects and female partners of male subjects.
Pregnancy in a study subject is not considered an AE.  However, the medical outcome of 
an elective or spontaneous abortion, stillbirth, or congenital anomaly is considered an 
SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
Female subjects should avoid pregnancy throughout the course of the study, starting with 
the Screening Visit through 150 days after the last subcutaneous study drug 
administration.  Male and female subjects should avoid pregnancy throughout the course 
of the study, starting with the Screening Visit through 30 days after the last oral study 
drug administration.  Male subjects should refrain from donating sperm for up to 30 days 
post last dose of oral study drug.  Results of a positive pregnancy test or confirmation of a 
pregnancy will be assessed starting with the Screening Visit through the final study visit.  
In the event of pregnancy occurring in the partner of an enrolled subject, written informed 
consent for release of medical information from the partner must be obtained prior to the 

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collection of any pregnancy-specific information and the pregnancy will be followed to 
outcome.
6.1.7
Toxicity Management
The toxicity management of the AEs including AEs of special interest consists of safety 
monitoring (review of AEs on an ongoing basis, and periodical/ad hoc review of safety 
issues by a safety data monitoring committee), interruption of study drug dosing with 
appropriate clinical management if applicable, and discontinuation of the subjects from 
study drug.  The management of specific AEs and laboratory parameters is described 
below.
For subjects who discontinued study drug but continued study participation and are 
instead on standard of care therapies, these toxicity management requirements do not 
apply (including alerts from the central lab) and any intolerability to standard of care 
therapies should be managed by the prescribing physician.
Serious Infections:  Subjects should be closely monitored for the development of signs 
and symptoms of infection during and after treatment with study drug.  Study drug should 
be interrupted if a subject develops a serious infection or an opportunistic infection.  A 
subject who develops a new infection during treatment with study drug should undergo 
prompt diagnostic testing appropriate for an immunocompromised subject.  As 
appropriate, antimicrobial therapy should be initiated, and the subject should be closely 
monitored.  Re-challenge with study drug may occur once the infection has been 
successfully treated.  If study drug has been interrupted for a serious infection for more 
than 14 consecutive days during the first 26 weeks, more than 21 days between Weeks 26 
and 48 or more than 30 consecutive days thereafter, the subject must be discontinued from 
study drug.  Subjects who develop active TB must be permanently discontinued from 
study drug.
Gastrointestinal Perforation:  Subjects presenting with the onset of signs or symptoms 
of a serious gastrointestinal event should be evaluated promptly for early identification of 

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gastrointestinal perforation.  If the diagnosis of gastrointestinal perforation is confirmed, 
the subject must be discontinued from study drug.
Cardiovascular Events: Subjects presenting with potential cardiovascular events should 
be carefully monitored.  These events will be reviewed and adjudicated by an independent 
Cardiovascular Adjudication Committee in a blinded manner.
Malignancy:  Subjects who develop malignancy other than NMSC or carcinoma in-situ 
of the cervix must be discontinued from study drug.  Information including 
histopathological results should be queried for the confirmation of the diagnosis.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant and with reasonable possibility of relationship to study 
drug OR a confirmed absolute QTcF value > 500 msec.
Management of Select Laboratory Abnormalities: For any given laboratory 
abnormality, the Investigator should assess the subject, apply the standard of care for 
medical evaluation and treatment following any local guidelines.  Specific toxicity 
management guidelines for abnormal laboratory values (confirmation by repeat testing is 
required) are described in Table 7 and may require an appropriate supplemental eCRF be 
completed.  All abnormal laboratory tests that are considered clinically significant by the 
Investigator will be followed to a satisfactory resolution.  If a repeat test is required per 
Table 7, the repeat testing must occur as soon as possible.

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Table 7.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Laboratory 
Parameter 
Toxicity Management Guideline
Hemoglobin
!
If hemoglobin < 8 g/dL interrupt study drug dosing and confirm by repeat testing with a 
new sample.
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample. 
!
If hemoglobin decreases ≥ 3.0 g/dL from baseline and an alternative etiology is known, 
the subject may remain on study drug at the investigator's discretion. 
!
If confirmed, continue to withhold study drug until hemoglobin value returns to normal 
reference range or its baseline value.
Absolute 
neutrophil 
count (ANC)
!
If confirmed < 1000/μL by repeat testing with new sample, interrupt study drug dosing 
until ANC value returns to normal reference range or its baseline value.
!
Discontinue study drug if confirmed < 500/μL by repeat testing with new sample.
Absolute 
lymphocyte 
counts (ALC)
!
If confirmed < 500/μL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to normal reference range or its baseline value.
Total white 
blood cell 
count
!
If confirmed < 2000/μL by repeat testing with new sample, interrupt study drug dosing 
until white blood cell count returns to normal reference range or its baseline value.
Platelet count
!
If confirmed < 50,000/μL by repeat testing with new sample, interrupt study drug dosing 
until platelet count returns to normal reference range or its baseline value.

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Table 7.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory 
Parameter 
Toxicity Management Guideline
AST or ALT
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample and either a total bilirubin > 2 × ULN or an international normalized 
ratio > 1.5.
o
A separate blood sample for INR testing will be needed to measure INR at the time 
of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met.
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample along with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
!
Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN by repeat testing 
with new sample for more than 2 weeks. 
!
Interrupt study drug immediately if confirmed ALT or AST > 8 × ULN by repeat testing 
with new sample. 
Subjects who meet any of the above criteria should be evaluated for an alternative etiology of the 
ALT or AST elevation and managed as medically appropriate.  The investigator should contact the 
AbbVie TA MD to discuss the management of a subject when an alternative etiology has been 
determined.  The alternative etiology should be documented appropriately in the eCRF; study drug 
should be discontinued if no alternative etiology can be found.
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental hepatic eCRF.
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at 
screening who develop the following should have HBV DNA by PCR testing performed 
within 1 week:
o
ALT > 5 × ULN OR 
o
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR 
o
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis
A positive result for HBV DNA PCR testing in these subjects will require immediate interruption 
of study drug and a hepatologist consultation should occur within 1 week for recommendation 
regarding subsequent treatment.
Serum 
Creatinine
!
If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for serum 
creatinine (with subject in an euvolemic state) to confirm the results.  If the results of the 
repeat testing still meet this criterion then interrupt study drug and re-start study drug 
once serum creatinine returns to ≤ 1.5 × baseline value and ≤ ULN.
!
If confirmed serum creatinine ≥ 2 mg/dL, interrupt study drug and re-start study drug 
once serum creatinine returns to normal reference range or its baseline value.
For the above serum creatinine elevation scenarios, complete supplemental renal eCRF.
Creatine 
Phosphokinase
!
If confirmed CPK ≥ 4 × ULN and there are no symptoms suggestive of myositis or 
rhabdomyolysis, the subjects may continue study drug at the investigator's discretion.
!
If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD
For the above CPK elevation scenarios, complete supplemental CPK eCRF.

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For allowed study drug interruption, the following rules apply:
Period 1
●
Upadacitinib/Placebo (daily dosing):
○
Allow study drug interruption ≤ 14 consecutive days for AEs and surgery 
during the first 26 weeks;
○
After Week 26, study drug interruption due to AEs/surgery is allowed 
≤21 days.
●
Adalimumab/Placebo (biweekly dosing):
○
Allow study drug interruption ≤ 2 consecutive missed doses for AEs and 
surgery during the first 26 weeks;
○
After Week 26, study drug interruption due to AEs/surgery is allowed 
≤3 consecutive doses.
●
If the subject must undergo emergency surgery, study drug should be 
interrupted at the time of the surgery.
●
Elective surgery during the first 26 weeks is discouraged and needs to be 
discussed with the AbbVie Therapeutic Area Medical Director.
●
If the subject undergoes elective surgery, the subcutaneous study drug should 
be interrupted two weeks prior to the planned surgery and the oral study drug 
should be interrupted 1 week prior to the planned surgery.
●
After surgery, allow reintroduction of study drug once the physician has 
examined the surgical site and determined that it has healed and there is no 
sign of infection.
Period 2
●
Upadacitinib/Placebo (daily dosing):
○
Up to 30 consecutive days of oral study drug interruption is allowed.
●
Adalimumab/Placebo (biweekly dosing):
○
Study drug interruption due to AEs/surgery is allowed ≤3 consecutive 
doses.

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●
If the subject undergoes elective surgery, the subcutaneous study drug should 
be interrupted 2 weeks prior to the planned surgery and the oral study drug 
should be interrupted 1 week prior to the planned surgery.
●
If the subject must undergo emergency surgery, the study drug should be
interrupted at the time of surgery.  
●
After surgery, allow reintroduction of study drug once the physician has 
examined the surgical site and determined that it has healed and there is no 
sign of infection.
6.1.8
Data Monitoring Committee
An external DMC will review unblinded safety data.  See Section 5.5.5.2 for details.
6.1.9
Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess potential cardiovascular AEs in a blinded manner as defined by the 
Cardiovascular Adjudication Committee charter.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.

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6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.  Product Complaints occurring during the study will be followed-up to a 
satisfactory conclusion.  All follow-up information is to be reported to the Sponsor (or an 
authorized representative) and documented in source as required by the Sponsor.  Product 
Complaints associated with adverse events will be reported in the study summary.  All 
other complaints will be monitored on an ongoing basis.
Product Complaints may require return of the product with the alleged complaint 
condition.  In instances where a return is requested, every effort should be made by the 
Investigator to return the product within 30 days.  If returns cannot be accommodated 
within 30 days, the site will need to provide justification and an estimated date of return.
The description of the complaint is important for AbbVie in order to enable AbbVie to 
investigate and determine if any corrective actions are required.
7.0
Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol unless when 
necessary to eliminate an immediate hazard to study subjects.  The Principal Investigator 
is responsible for complying with all protocol requirements, and applicable global and 
local laws regarding protocol deviations.  If a protocol deviation occurs (or is identified) 
after a subject has been enrolled, the Principal Investigator is responsible for notifying 
IEC/IRB regulatory authorities (as applicable), and the following AbbVie Clinical 
Contacts:

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Primary Contact:
Alternate Contact:
Such contact must be made as soon as possible to permit a review by AbbVie to 
determine the impact of the deviation on the subject and/or the study.
Examples of protocol deviations include the following:
●
Subject entered into the study even though she/he did not satisfy entry criteria;
●
Subject who developed withdrawal criteria during the study and was not 
withdrawn;
●
Subject who received wrong treatment or incorrect dose;
●
Subject who received excluded or prohibited concomitant treatment.
8.0
Statistical Methods and Determination of Sample 
Size
8.1
Statistical and Analytical Plans
Unless otherwise specified, statistical tests will be at two-sided significance level of 0.05 
for efficacy analyses and all other analyses.  A test will be deemed significant if the 
P value is less than or equal to 0.05 unless otherwise specified. 
An unblinded analysis will be conducted after all subjects have completed Week 26 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 

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Period 1.  Additional unblinded analyses may be conducted after the Week 26 unblinded 
analysis for regulatory purposes.
Completed and specific details of the statistical analysis will be described and fully 
documented in the Statistical Analysis Plan (SAP).  The SAP will be finalized prior to the 
database lock for the Week 26 analysis.  The statistical analyses will be performed using 
SAS (SAS Institute Inc., Cary, NC, USA).
8.1.1
Analysis Populations
8.1.1.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) includes all randomized subjects who received at least one 
dose of study drug.  The FAS will be used for all efficacy and baseline analyses.
8.1.1.2
Per Protocol Analysis Set
The Per Protocol Analysis Set represents a subset of the FAS and consists of all FAS 
subjects who did not meet any major protocol violations during the study.  Definitions of 
major protocol violations will be detailed in the SAP.  Additional analysis may be 
conducted on the Per Protocol analysis set, in order to evaluate the impact of major 
protocol violations.
8.1.1.3
Safety Analysis Set
The Safety Analysis Set consists of all subjects who received at least one dose of study 
drug.  For the Safety Analysis Set, subjects are assigned to a treatment group based on the 
treatment actually received, regardless of the treatment randomized.
8.1.2
Subject Accountability, Disposition and Study Drug 
Exposure
8.1.2.1
Subject Accountability
The following will be summarized by site and by treatment group as well as overall, 
separately for Period 1 and Period 2:  number of subjects randomized, the number of 

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subjects who received at least one dose of study drug, the number of subjects who 
completed, the number of subjects who prematurely discontinued study drug, and the 
number of subjects who prematurely discontinued study participation.
8.1.2.2
Subject Disposition
Separately for Period 1 and Period 2, the number and percentage of subjects who are 
randomized, received at least one dose of study drug, prematurely discontinued study 
drug, prematurely discontinued study participation, and completed will be summarized by 
treatment group and overall.  Reasons for premature discontinuation of study drug and 
study participation will be summarized separately for all randomized subjects by 
treatment group and overall, with frequencies and percentages by reason for 
discontinuation.
8.1.2.3
Study Drug Exposure
Exposure to study drug will be summarized for the Safety Analysis Set for Period 1 alone 
as well as for Period 1 and Period 2 combined.  The exposure to study drug (days) will be 
summarized with the mean, standard deviation, median, and range for each treatment 
group.  
Study drug compliance will be summarized for each treatment group.  The compliance is 
defined as the number of tablets taken (i.e., the difference between the number of tablets 
dispensed and the number of tablets returned) during the subject's participation in Period 1 
divided by the number of tablets a subject is supposed to take each day times the length of 
time that the subject was in the Treatment Phase.
8.1.3
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group and 
overall for the FAS.  For the purpose of this analysis, baseline data for each subject will 
be the data collected immediately prior to the first dose of study drug in Period 1.

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Summary statistics for continuous variables will include the number of observations, 
mean, standard deviation, median, and range.  For discrete variables, frequencies and 
percentages for each category will be summarized.
Medical history will be presented by counts and percentages of subjects, broken down by 
Body System and Diagnosis. 
Prior therapy and medication will be summarized by treatment group.  Prior therapy and 
medication will include all therapies and medications with a start date prior to the date of 
first dose of study drug.
Concomitant medications will also be summarized with frequencies and percentages for 
each treatment group.  All medications administered during study drug exposure will be 
included.
8.1.4
Efficacy Analysis
All efficacy analyses will be carried out using the FAS population, which includes all 
randomized subjects who receive at least one dose of study drug.
8.1.4.1
Efficacy Analysis for Period 1
8.1.4.1.1
Primary Efficacy Variables
The primary endpoint in Period 1 (at Week 12) for US/FDA regulatory purposes is listed 
in Section 5.3.3.1.1.  The primary endpoint in Period 1 (at Week 12) for EU/EMA 
regulatory purposes is also listed in Section 5.3.3.1.1.  Analyses will be conducted 
separately for US/FDA regulatory purposes and EU/EMA regulatory purposes; for each 
set of analysis, only one primary endpoint is specified.
Analysis of the primary endpoint will be conducted on the FAS based on treatment as 
randomized.  For the ACR20 and CR comparison between the upadacitinib group and the 
placebo group, Cochran-Mantel-Haenszel test adjusting for main stratification factors will 
be used.  For the primary analysis of ACR20 and CR response at Week 12, 

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Non-Responder Imputation (NRI) will be used.  In addition, sensitivity analysis will be 
done using Observed Cases (OC).  Supportive analysis will also be conducted on the Per 
Protocol Analysis Set.
The primary efficacy analyses will be performed in demographic subgroups including 
age, gender, weight, body mass index, race, and geographical region to assess the 
consistency of the treatment effect.  Additional subgroup analyses based on baseline 
disease characteristics and stratification factors will also be conducted.
8.1.4.1.2
Key Secondary Efficacy Variables
Key secondary endpoints in for US/FDA regulatory purposes are listed in 
Section 5.3.3.1.2.  Key secondary endpoints in for EU/EMA regulatory purposes are also 
listed in Section 5.3.3.1.2.
Unless otherwise specified, comparisons are between the upadacitinib group and the 
placebo group.
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  Similar analyses as for the primary endpoint will be conducted.  For EU/EMA 
purposes, analysis will be conducted to test the non-inferiority of upadacitinib versus 
ADA for LDA response rate at Week 12 using the 95% confidence interval of treatment 
difference against a non-inferiority margin of 10%.  For ACR50 response rate at Week 12, 
similar analysis of non-inferiority will be conducted for US/FDA purposes.  Superiority of 
upadacitinib vs ADA will also be tested for LDA and ACR50.
For continuous endpoints, the mean, standard deviation, median, and range will be 
reported for each treatment group.  Between-group comparisons for the upadacitinib 
treatment group and the placebo treatment group will be performed using the ANCOVA 
model with treatment groups as the fixed factor, and the corresponding baseline value and 
the main stratification factors as the covariates.  For change from baseline in patient's 
global assessment of pain and change from baseline in HAQ-DI at Week 12, superiority 
of upadacitinib vs adalimumab will also be tested.

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See Section 8.1.4.1.5 for imputation methods.
8.1.4.1.3
Other Efficacy Variables 
Additional efficacy variables are listed in Section 5.3.3.1.3 and will be summarized for all 
visits, including visits beyond Week 12.  For binary endpoints, frequencies and 
percentages will be reported for each treatment group.  For continuous endpoints, the 
change from baseline mean, standard deviation, median, and range will be reported for 
each treatment group.
8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key 
Secondary Endpoints
In order to preserve Type I error, a step-down approach will be used to test the primary 
and ranked key secondary endpoints where statistical significance can be claimed for a 
lower ranked endpoint only if the previous endpoints in the sequence meet the 
requirements of significance.
8.1.4.1.5
Imputation Methods
The following methods will be used for missing data imputation:
Observed Cases (OC):  The OC analysis will not impute values for missing evaluations, 
and thus a subject who does not have an evaluation on a scheduled visit will be excluded 
from the OC analysis for that visit.
Multiple Imputation (MI):  The MI analysis impute missing data multiple times under 
appropriate random variation and thus generate multiple imputed "pseudo-complete" 
datasets.  Results will be aggregated across the multiple imputed datasets, overcoming 
drawbacks of the single imputation methods.
Non-Responder Imputation (NRI):  NRI applies to binary endpoints only.  In NRI 
analysis, subjects who prematurely discontinue study drug will be considered 
non-responders after discontinuation.

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Linear Extrapolation for Radiographic Data:  For radiographic data (i.e., mTSS-based 
endpoints), if a subject is rescued at Week 14 to a different study drug or prematurely 
discontinued study drug, their Week 26/48 data will be imputed assuming a linear 
relationship between baseline and previous x-ray collected at the time of rescue/PD.
For non-radiographic data, the NRI approach will serve as the primary analysis approach 
for key binary endpoints.  The MI approach will serve as the primary analysis approach 
for key continuous endpoints.  For radiographic data, analysis based on both linear 
extrapolation and an as-observed analysis (where the as-observed Week 26/48 
assessments for all subjects are used) will be conducted.
8.1.4.2
Long-Term Efficacy for Period 1 and Period 2 Combined
The efficacy endpoints of long-term efficacy analysis are listed in Section 5.3.3.2 and will 
be summarized for all visits.
Long-term efficacy by time point will be summarized using descriptive statistics.  For 
binary endpoints, frequencies and percentages will be summarized.  For continuous 
endpoints, the mean and standard deviation will be reported. 
8.1.5
Safety Analyses 
8.1.5.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  Analyses will be 
conducted for both short term and long term.
Safety analyses are based on treatments actually received.  Safety will be assessed by 
AEs, physical examination, laboratory assessments, ECG, and vital signs.  Frequency 
tables and lists of subjects with treatment-emergent AEs by preferred term as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary, by system organ 
class, by severity, and by relationship to the study drug as assessed by the Investigator 
will be provided.  The changes from baseline in vital signs, physical examination results, 

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and clinical laboratory values will be analyzed in a descriptive manner.  Shift of 
laboratory values from baseline to defined time points will be tabulated.
Missing safety data will not be imputed.
8.1.5.2
Analysis of Adverse Events
Unless otherwise specified, the following conventions apply for both short term and long 
term safety analysis.
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE)
AEs will be coded using MedDRA.  A TEAE is defined as AE that began or worsened in 
severity after initiation of study drug.
AEs starting more than 70 days following the last dose of study drug for subjects on ADA 
and AEs starting more than 30 days following the last dose of study drug for subjects on 
upadacitinib or placebo will not be included in summaries of TEAEs.  For subjects who 
continued into Period 2, the AEs that are reported in Period 2 will be summarized in the 
long term safety analysis.
As a general safety summary, the number and percentage of subjects experiencing TEAEs 
will be summarized for each treatment group for the following AE categories:
●
All AEs;
●
All severe AEs;
●
All reasonably possibly related AEs;
●
All SAEs;
●
Frequent AEs (reported in 2% of subjects or more in any treatment group);
●
Frequent reasonably possibly related AEs (reported in 2% of subjects or more 
in any treatment group);
●
Discontinuations due to AEs;
●
Death.

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Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
TEAEs will be summarized and presented by system organ classes (SOCs) and preferred 
terms (PTs) using MedDRA.  The SOCs will be presented in alphabetical order, and the 
PTs will be presented in alphabetical order within each SOC.
TEAE will also be summarized by maximum severity and by maximum relationship.
The AEs of special interest (including but not limited to serious infection, opportunistic 
infection, herpes zoster, TB, gastrointestinal perforations, malignancies, MACE, renal 
dysfunction, anemia, increased CPK, non-cardiac, non-CNS embolic and thrombotic 
events, and drug-related hepatic disorders) will be summarized.  Event rate (per 
100 patient years) for AEs of special interest will also be summarized for the combined 
safety analysis of Period 1 and Period 2.
All AEs leading to discontinuation of study drug will be presented in listing format.  A 
listing by treatment group of TEAEs grouped by SOC and MedDRA preferred term with 
subject identification numbers will be generated.
8.1.5.2.2
Serious Adverse Events and Death
All treatment-emergent SAEs and AEs leading to death will also be presented in listing 
format.  In addition, SAEs will be summarized by SOC and MedDRA PT.
8.1.5.3
Analysis of Laboratory, Vital Sign, and ECG Data
Changes from baseline by visit in continuous laboratory data, and vital signs will be 
summarized by treatment group.  Baseline values are defined as the last non-missing 
measurements recorded on or before the date of the first dose of study drug in Period 1.  
The laboratory data will be categorized as Grade 1, Grade 2, Grade 3, and Grade 4 
according to OMERACT criteria (Rheumatology Common Toxicity Criteria v.2.0).  For 
creatine phosphokinase, and serum creatine, NCI CTC criteria will be used.  The shift 

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tables will tabulate the number and percentage of subjects with baseline and post-baseline 
values by grade levels.  
Listings will be provided for potentially clinically significant laboratory values and vital 
signs.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Individual upadacitinib plasma concentrations at each study visit will be tabulated and 
summarized with appropriate statistical methods.
Data from this study may be combined with data from other studies for the population PK 
and exposure-response analyses.  Population PK and exposure-response analyses of only 
data from this study may not be conducted.  The following general methodology will be 
used for the population PK and exposure-response analyses.
Population PK analyses will be performed for upadacitinib using the actual sampling time 
relative to dosing.  PK models will be built using a non-linear mixed-effects modeling 
approach with NONMEM software (Version 7, or a higher version).  The structure of the 
starting PK model will be based on the PK analysis of data from previous studies.  The 
CL/F and V/F of upadacitinib will be the PK parameters of major interest in the analyses.  
If necessary, other parameters, including the parameters describing absorption 
characteristics, may be fixed if useful in the analysis.
The evaluation criteria described below will be used to examine the performance of 
different models.
1.
The objective function of the best model is significantly smaller than the alternative 
model(s).
2.
The observed and predicted concentrations from the preferred model are more 
randomly distributed across the line of unity (a straight line with zero intercept and 
a slope of one) than the alternative model(s).

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3.
Visual inspection of model fits, standard errors of model parameters and change in
inter-subject and intra-subject error.
Once an appropriate base PK model (including inter- and intra-subject error structure) is 
developed, empirical Bayesian estimates of individual model parameters will be 
calculated by the posterior conditional estimation technique using non-linear 
mixed-effects modeling.  The relationship between these conditional estimates CL/F and 
V/F values with only potentially physiologically relevant or clinically meaningful 
covariates (such as subject age, sex, body weight, concomitant medications, laboratory 
markers of hepatic of renal function, etc.) will be explored using stepwise forward 
selection method, or another suitable regression/smoothing method at a significance level 
of 0.05.  After identification of all relevant covariates, a stepwise backward elimination of 
covariates from the full model will be employed to evaluate the significance (at P < 0.005, 
corresponding to a decrease in objective function > 7.88 for one degree of freedom) of 
each covariate in the full model.
Linear or non-linear relationships of primary PK parameters with various covariates will 
be explored.
Relationships between upadacitinib exposure and clinical observations (primary efficacy 
variable) will be explored.  Exposure-response relationships for secondary efficacy 
variables and/or some safety measures of interest may also be explored.  The relationship 
between exposure (e.g., population PK model predicted average concentrations, area 
under the curve, trough concentrations, the individual model-predicted PK profiles, or 
some other appropriate measure of exposure) and drug effect will be explored.  Several 
classes of models (e.g., linear, log-linear, exponential, Emax, sigmoid Emax, etc.) will be 
evaluated to characterize the exposure-response relationship based on observed data.  
Results of the PK and exposure-response analyses may be summarized in a separate report 
prior to regulatory filing of upadacitinib for the treatment of RA, rather than in the CSR.
Additional analyses may be conducted if useful and appropriate.

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8.2
Determination of Sample Size
The planned total sample size of 1500 for this study (with a 2:2:1 randomization ratio) 
provides at least 90% power for a 22% difference in ACR20 response rate (assuming a 
placebo ACR20 response rate of 37%) at two-sided significance level of 0.05 and 
accounting for a 10% dropout rate.  It will also provide at least 90% power for a 19.3% 
difference in CR response rate (assuming a placebo CR response rate of 6.2%).  With the 
given sample size, there is also approximately 90% power to detect a treatment difference 
of 0.39 in change from baseline in mTSS at Week 26 with a standard deviation of 2, at 
two-sided significance level of 0.05 and accounting for a 10% dropout rate.  This sample 
size will also provide at least 90% power for testing non-inferiority of upadacitinib versus 
ADA in LDA or ACR 50 response rate at Week 12 with a non-inferiority margin being 
10%, assuming 35% and 40% LDA or ACR 50 response rates for ADA and upadacitinib, 
respectively.  It will also provide at least 90% power in testing superiority of upadacitinib 
versus placebo for most of the key secondary endpoints, including change from baseline 
in DAS28 (CRP), change from baseline in HAQ-DI, ACR50 and ACR70 response rate, 
and SF-36 (PCS), at two-sided significance level of 0.05 and accounting for a 10% 
dropout rate.
8.3
Randomization Methods
Subjects will be randomly assigned in a 2:2:1 ratio to one of the three treatment groups 
(Upadacitinib 15 mg QD, placebo and ADA 40 mg eow) stratified by prior bDMARD 
exposure (yes or no) and geographic region.
See Section 5.5.3 for details.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice requires that the clinical protocol, any protocol amendments, the 
Investigator's Brochure, the informed consent, and all other forms of subject information 

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related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB.  The IEC/IRB will review the ethical, scientific 
and medical appropriateness of the study before it is conducted.  IEC/IRB approval of the 
protocol, informed consent, and subject information and/or advertising, as relevant, will 
be obtained prior to the authorization of drug shipment to a study site.
Any amendments to the protocol will require IEC/IRB approval prior to implementation 
of any changes made to the study design.  The investigator will be required to submit, 
maintain and archive study essential documents according to International Conference on 
Harmonization (ICH) GCP.
Any SAEs that meet the reporting criteria, as dictated by local regulations, will be 
reported to both responsible Ethics Committees and Regulatory Agencies, as required by 
local regulations.  During the conduct of the study, the Investigator should promptly 
provide written reports (e.g., ICH Expedited Reports, and any additional reports required 
by local regulations) to the IEC/IRB of any changes that affect the conduct of the study 
and/or increase the risk to subjects.  Written documentation of the submission to the 
IEC/IRB should also be provided to AbbVie.
9.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that 
have their origin in the Declaration of Helsinki.  Responsibilities of the clinical 
investigator are specified in Appendix A.
9.3
Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the 
subject, and answer all questions regarding this study.  Prior to any study-related 
screening procedures being performed on the subject, the informed consent statement will 
be reviewed and signed and dated by the subject, the person who administered the 
informed consent, and any other signatories according to local requirements.  A copy of 

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the informed consent will be given to the subject and the original will be placed in the 
subject's medical record.  An entry must also be made in the subject's dated source 
documents to confirm that informed consent was obtained prior to any study-related 
procedures and that the subject received a signed copy.
Information regarding incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the study can be found in the informed consent.
Samples for exploratory research/validation studies will only be collected if the subject 
has voluntarily signed and dated the separate written consent for exploratory 
research/validation studies, approved by an IRB/IEC, after the nature of the testing has 
been explained and the subject has had an opportunity to ask questions.  The separate 
written consent must be signed before the exploratory research/validation studies samples 
are collected and testing is performed.  The separate written consent may be part of the 
main consent form.  If the subject does not consent to the exploratory research/validation 
studies, it will not impact the subject's participation in the study.
10.0
Source Documents and Case Report Form 
Completion
10.1
Source Documents
Source documents are defined as original documents, data and records.  This may include 
joint evaluation, hospital records, clinical and office charts, laboratory data/information, 
subjects' diaries or evaluation checklists, pharmacy dispensing and other records, recorded 
data from automated instruments, microfiches, photographic negatives, microfilm or 
magnetic media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The Investigator(s)/Institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.

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10.2
Case Report Forms
Case report forms (CRFs) must be completed for each subject screened/enrolled in this 
study.  These forms will be used to transmit information collected during the study to 
AbbVie and regulatory authorities, as applicable.  The CRF data for this study are being 
collected with an EDC system called Rave® provided by the technology vendor Medidata 
Solutions Incorporated, NY, USA.  The EDC system and the study-specific eCRFs will 
comply with Title 21 CFR Part 11.  The documentation related to the validation of the 
EDC system is available through the vendor, Medidata, while the validation of the 
study-specific eCRFs will be conducted by AbbVie and will be maintained in the Trial 
Master File at AbbVie.
The Investigator will document subject data in his/her own subject files.  These subject 
files will serve as source data for the study.  All eCRF data required by this protocol will 
be recorded by investigative site personnel in the EDC system.  All data entered into the 
eCRF will be supported by source documentation.
The Investigator or an authorized member of the investigator's staff will make any 
necessary corrections to the eCRF.  All change information, including the date and person 
performing the corrections, will be available via the audit trail, which is part of the EDC 
system.  For any correction, a reason for the alteration will be provided.  The eCRFs will 
be reviewed periodically for completeness, legibility, and acceptability by AbbVie 
personnel (or their representatives).  AbbVie (or their representatives) will also be allowed 
access to all source documents pertinent to the study in order to verify eCRF entries.  The 
Principal Investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 

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Investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the Investigator to make paper printouts from that media.
Patient and site reported data must be completed for each subject screened/enrolled in this 
study.
●
The following data are being collected with an Electronic Patient-Reported 
Outcome (ePRO) system called Trialmax, provided by the technology vendor 
CRF Health of Plymouth Meeting, PA, USA:
○
Completed by Patient:
●
Patient Global Assessment of Disease Activity VAS
●
Patient's Assessment of Pain VAS
●
HAQ-DI
●
SF-36
●
FACIT-F
●
RA-WIS
●
EQ-5D-5L
○
Completed by Site:
●
Physician Global Assessment of Disease Activity VAS
●
The following data will be completed by the patient on paper and entered into 
the EDC system:
○
Patient's Assessment of Morning Stiffness
The ePRO system is in compliance with Title 21 CFR Part 11.  The documentation related 
to the system validation of the ePRO system is available through the vendor, CRF Health, 
while the user acceptance testing of the study-specific PRO design will be conducted and 
maintained at AbbVie.
The subject will be entering the data on an electronic device; these data will be uploaded 
to a server.  The data on the server will be considered source and will be maintained and 
managed by CRF Health.

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Internet access to the ePRO data will be provided by CRF Health for the duration of the 
trial.  This access will be available for the duration of the trial to the site investigator, as 
well as delegated personnel.  Such access will be removed from investigator sites 
following the receipt of the study archive.  Data from the ePRO system will be archived 
on appropriate data media (CD-ROM, etc.) and provided to the investigator at that time as 
a durable record of the site's ePRO data.  It will be possible for the investigator to make 
paper print-outs from that media.
The ePRO data will be collected by the following method:
Tablet Based
●
The instrument/scale will be collected electronically via a tablet device into 
which the subject will directly enter the required pieces of information.  The 
electronic device will be programmed to allow data entry for only the visits 
specified in the protocol and will not allow for subjects to complete more than 
one of the same assessment at any one visit.  All data entered on the device 
will be immediately stored to the device itself and automatically uploaded to a 
central server administrated by CRF Health.  The Investigator and delegated
staff will be able to access all uploaded subject entered data via a password 
protected website, up until the generation, receipt and confirmation of the 
study archive.
11.0
Data Quality Assurance
Prior to the initiation of the study, a meeting will be held with AbbVie personnel, the 
investigators and appropriate site personnel.  This meeting will include a detailed 
discussion of the protocol, performance of study procedures, CRF, subject dosing diary, 
and specimen collection methods.  
The AbbVie monitor will monitor each site throughout the study.  Source document 
review will be performed against entries on the CRF and a quality assurance check will be 
performed to ensure that the investigator is complying with the protocol and regulations.

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All data hand entered in the database will be verified at AbbVie.  Any discrepancies will 
be reviewed against the CRF and corrected on-line.  After completion of the entry 
process, computer logic and manual checks will be created by AbbVie to identify items 
such as inconsistent study dates.  Any necessary corrections will be made by the site to the 
eCRF.
Routine hematology, serum chemistry and serology, and urinalysis, and other tests such as 
rheumatoid factor, anti-CCP, and HBV/HCV testing, will be conducted using a central 
laboratory (refer to Table 2 and Table 4).  The data from these analyses will be 
electronically transferred from the central laboratory to the study database.
Laboratory tests including, but not limited to, urine pregnancy testing and ESR, will be 
conducted locally by each study site (refer to Table 2 and Table 4).  Sites will provide 
AbbVie with laboratory certifications and normal ranges for each local laboratory used.  
The full name, address, phone number and fax number for each local laboratory will also 
be included.
12.0
Use of Information
Any research that may be done using exploratory research/validation studies samples from 
this study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management.  Hence, the subject will not be informed of 
individual results, should analyses be performed, nor will anyone not directly involved in 
this research.  Correspondingly, researchers will have no access to subject identifiers.  
Individual results will not be reported to anyone not directly involved in this research 
other than for regulatory purposes.  Aggregate data from exploratory research/validation 
studies may be provided to investigators and used in scientific publications or presented at 
medical conventions.  Exploratory research/validation studies information will be 
published or presented only in a way that does not identify any individual subject.

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13.0
Completion of the Study
The Investigator will conduct the study in compliance with the protocol and complete the 
study within the timeframe specified in the contract between the Investigator and AbbVie.  
Continuation of this study beyond this date must be mutually agreed upon in writing by 
both the Investigator and AbbVie.  The investigator will provide a final report to the 
IEC/IRB following conclusion of the study, and will forward a copy of this report to 
AbbVie or their representative.
The Investigator must retain any records related to the study according to local 
requirements.  If the Investigator is not able to retain the records, he/she must notify 
AbbVie to arrange alternative archiving options.
AbbVie will select the signatory Investigator from the Investigators who participate in the 
study.  Selection criteria for this Investigator will include level of participation as well as 
significant knowledge of the clinical research, investigational drug, and study protocol.  
The signatory Investigator for the study will review and sign the final study report in 
accordance with the European Agency for the Evaluation of Medicinal Products Guidance 
on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit.

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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for upadacitinib.
2.
I have read this protocol and agree that the study is ethical.
3.
I agree to conduct the study as outlined and in accordance with all applicable 
regulations and guidelines.
4.
I agree to maintain the confidentiality of all information received or developed in 
connection with this protocol.
5.
I agree that all electronic signatures will be considered the equivalent of a 
handwritten signature and will be legally binding.
Protocol Title: 
A Phase 3, Randomized, Double-Blind Study Comparing 
Upadacitinib (ABT-494) to Placebo and to Adalimumab in Subjects 
with Moderately to Severely Active Rheumatoid Arthritis Who are 
on a Stable Background of Methotrexate (MTX) and Who Have an 
Inadequate Response to MTX (MTX-IR)
Protocol Date:
01 December 2017
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)

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15.0
Reference List
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http://www.glpg.com/files/3514/3016/6234/PR_Darwin2_FINAL.pdf.  
22.
Woodworth T, Furst DE, Alten R, et al.  Standardizing assessment and reporting of 
adverse effects in rheumatology clinical trials II:  the Rheumatology Common 
Toxicity Criteria v.2.0.  J Rheumatol.  2007;34(6):1401-14.

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Appendix A.
Responsibilities of the Clinical Investigator
Clinical research studies sponsored by AbbVie are subject to the Good Clinical Practices 
(GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement in Section 14.0 of this protocol, the investigator is 
agreeing to the following:
1.
Conducting the study in accordance with the relevant, current protocol, making 
changes in a protocol only after notifying AbbVie, except when necessary to 
protect the safety, rights or welfare of subjects.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed 
consent and ethics committees (e.g., independent ethics committee [IEC] or 
institutional review board [IRB]) review and approval of the protocol and 
amendments.
4.
Reporting adverse experiences that occur in the course of the investigation(s) to 
AbbVie and the site director.
5.
Reading the information in the Investigator's Brochure/safety material provided, 
including the instructions for use and the potential risks and side effects of the 
investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the 
study about their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making 
those records available for inspection by representatives of AbbVie and/or the 
appropriate regulatory agency, and retaining all study-related documents until 
notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and 
approved the initial clinical investigation and all amendments.

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9.
Reporting promptly, all changes in the research activity and all unanticipated 
problems involving risks to human subjects or others, to the appropriate individuals 
(e.g., coordinating investigator, institution director) and/or directly to the ethics 
committees and AbbVie.
10.
Following the protocol and not make any changes in the research without ethics 
committee approval, except where necessary to eliminate apparent immediate 
hazards to human subjects.

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Appendix B.
List of Protocol Signatories
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient 
Safety
Statistics
Clinical Pharmacokinetics and 
Pharmacodynamics
Bioanalysis
Clinical Program Development
Clinical Program Development

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Appendix C.
Local Requirements
Canada
Section 5.2.1, Inclusion Criteria
12.
If female of childbearing potential, must be practicing at least two reliable 
methods of contraception (one highly effective method combined with 
one effective method, refer to Section 5.2.4), that are effective from Study Day 1 
through at least 150 days after the last dose of subcutaneous study drug, through at 
least 30 days after the last dose of oral study drug, and through 180 days after the 
last dose of methotrexate.  If more than one of the above intervals apply, the 
longest interval must be adhered to.
13.
If male, and subject is sexually active with the female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
oral study drug and through 90 days after the last dose of methotrexate, to practice 
the protocol-specified contraception (refer to Section 5.2.4).  The same intervals 
apply to abstention from sperm donation.  If more than one of the above intervals 
apply, the longest interval must be adhered to.
Section 5.2.4, Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or

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●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 mIU/mL.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to use two forms of 
contraception.  This includes one form of highly effective contraception and one effective 
method of contraception.  That is effective from Study Day 1 (or earlier) through at least 
150 days after the last dose of subcutaneous study drug, through at least 30 days after the 
last dose of oral study drug, and through 180 days after the last dose of methotrexate.  If 
more than one of the above intervals apply, the longest interval must be adhered to:
●
Highly effective methods:
○
Hormonal contraceptives started at least 2 months prior to randomization 
(e.g., combined [estrogen and progestogen containing] [oral contraceptives, 
patch, vaginal ring, injectables, and implants); 
●
Intrauterine device (IUD) or intrauterine system (IUS);
●
Vasectomy and tubal ligation.
●
Effective methods:
○
Barrier methods of contraception (e.g., male condom, female condom, 
cervical cap, diaphragm, contraceptive sponge)
○
Note: The proper use of diaphragm or cervical cap includes use of 
spermicide and is considered one barrier method. The cervical cap and 
contraceptive sponge are less effective in parous women. The use of 
spermicide alone is not considered a suitable barrier method for 
contraception.  When used consistently and correctly, "double barrier" 
methods of contraception (e.g., male condom with diaphragm, male 
condom with cervical cap) can be used as an effective alternative to the 
highly effective contraception methods described above.  Male and female 
condoms should not be used together as they can tear or become damaged.

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Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug and 
through 90 days after the last dose of methotrexate to practice contraception with:
●
Condom use and female partner(s) using at least one of the highly effective 
contraceptive methods (as defined in the protocol for female study subjects of 
childbearing potential).
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of oral study drug and through 90 days after the last dose of 
methotrexate.
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested 
from the pregnant partner.
Korea
Section 5.2.1, Inclusion Criteria
9.
Except for MTX, subject must have discontinued all csDMARDs.  The washout 
period for csDMARDs prior to the first dose of study is specified below or should 
be at least five times the mean terminal elimination half-life of a drug:
●
≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, 
sulfasalazine, hydroxychloroquine, azathioprine, gold formulations, 
cyclophosphamide, tacrolimus, cyclosporine, mycophenolate;
●
≥ 8 weeks prior to first dose of study drug for leflunomide, if no elimination 
procedure was followed, or adhere to an elimination procedure (i.e., 11 days 

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with colestyramine, or 30 days washout with activated charcoal or as per local 
label).
Section 5.2.4, Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile (bilateral 
oophorectomy, bilateral salpingectomy or hysterectomy) is not considered to be a woman 
of childbearing potential and is not required to follow contraception recommendations.  
Postmenopausal is defined as:
●
Age ≥ 55 years with no menses for 12 or more months without an alternative 
medical cause; or
●
Age < 55 years with no menses for 12 or more months without an alternative 
medical cause AND an FSH level > 40 mIU/mL.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 150 days after the last dose of subcutaneous study drug and 
through at least 30 days after the last dose of oral study drug.
●
Combined (estrogen and progestogen containing) hormonal contraception 
(oral, intravaginal, transdermal) associated with the inhibition of ovulation, 
initiated at least 30 days prior to Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.
●
Vasectomized partner(s), provided the vasectomized partner has received 
medical confirmation of the surgical success and is the sole sexual partner of 
the women of childbearing potential trial participant.

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●
Intrauterine device (IUD).
●
Intrauterine hormone-releasing system (IUS).
If required per local practices, male or female condom with or without spermicide OR 
cap, diaphragm or sponge with spermicide should be used in addition to one of the highly 
effective birth control methods listed above.
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational 
therapies.  Duration of contraception after discontinuation of csDMARDs should be based 
on the local label.
Contraception Recommendation for Males
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug to 
practice contraception with:
●
Condom use and female partner(s) using at least one of the contraceptive 
measures (as defined in the protocol for female study subjects of childbearing 
potential).
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of oral study drug.
Male subjects are responsible for informing his partner(s) of the risk of becoming 
pregnant and for reporting any pregnancy to the study doctor.  If a pregnancy occurs, a 
partner authorization form requesting pregnancy outcome information will be requested
from the pregnant partner.

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It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational 
therapies.  Duration of contraception after discontinuation of csDMARDs should be based 
on the local label.
Hong Kong, Korea, Malaysia, Singapore and Taiwan 
Section 5.2.1, Inclusion Criteria
3.
Subjects must have been on oral or parenteral MTX therapy ≥ 3 months and on a 
stable prescription of 10 to 25 mg/week (or ≥ 7.5 mg/week in subjects intolerant of 
MTX at doses ≥ 10 mg/week) for ≥ 4 weeks prior to the first dose of study drug.  
In addition, all subjects should take a dietary supplement of folic acid or folinic 
acid throughout the study participation.

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Appendix D.
Physician's Global Assessment of Disease Activity Example
Visual Analog Scale (VAS)
VAS will be used to assess the physician's global assessment of disease activity and the 
subject's assessment of pain.  The VAS consists of a horizontal 100 mm line anchored at 
either end by opposite adjectives reflecting the spectrum/severity of the parameters 
assessed:
●
Physician's global assessment of disease activity (current status)
The Physician will rate global assessment of subject's current disease activity 
ranging from 0 to 100 (see example below)
Mark the line below to indicate the subject's rheumatoid arthritis disease activity 
(independent of the subject's self-assessment).
0
100
Very Low
Very High

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Appendix E.
Joint Evaluation Worksheet Example
JOINT EVALUATION
JOINT
(Tick Correct Answer)
Subject Right
Subject Left
0 = Absent
1 = Present
9 = 
Replaced 
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced 
NA = No 
Assessment
Pain/ 
Tenderness
Swelling
Joint
Pain/ 
Tenderness
Swelling
Joint
1.  Temporomandibular
0
1
0
1
9
NA
0
1
0
1
9
NA
2.  Sternoclavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
3.  Acromio-clavicular
0
1
0
1
9
NA
0
1
0
1
9
NA
4.  Shoulder
0
1
0
1
9
NA
0
1
0
1
9
NA
5.  Elbow
0
1
0
1
9
NA
0
1
0
1
9
NA
6.  Wrist
0
1
0
1
9
NA
0
1
0
1
9
NA
7.  Metacarpophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
8.  Metacarpophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
9.  Metacarpophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
10.  Metacarpophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
11.  Metacarpophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
12.  Thumb Interphalangeal
0
1
0
1
9
NA
0
1
0
1
9
NA
13.  Prox. Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
14.  Prox. Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
15.  Prox. Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
16.  Prox. Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
17.  Distal Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
18.  Distal Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
19.  Distal Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
20.  Distal Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
21.  Hip
0
1
--
--
9
NA
0
1
--
--
9
NA
22.  Knee
0
1
0
1
9
NA
0
1
0
1
9
NA
23.  Ankle
0
1
0
1
9
NA
0
1
0
1
9
NA
24.  Tarsus
0
1
0
1
9
NA
0
1
0
1
9
NA
25.  Metatarsophalangeal I
0
1
0
1
9
NA
0
1
0
1
9
NA
26.  Metatarsophalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA

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JOINT EVALUATION
JOINT
(Tick Correct Answer)
Subject Right
Subject Left
0 = Absent
1 = Present
9 = 
Replaced 
NA = No 
Assessment
0 = Absent
1 = Present
9 = 
Replaced 
NA = No 
Assessment
Pain/ 
Tenderness
Swelling
Joint
Pain/ 
Tenderness
Swelling
Joint
27.  Metatarsophalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
28.  Metatarsophalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
29.  Metatarsophalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA
30.  Great Toe/Hallux
0
1
0
1
9
NA
0
1
0
1
9
NA
31.  Interphalangeal II
0
1
0
1
9
NA
0
1
0
1
9
NA
32.  Interphalangeal III
0
1
0
1
9
NA
0
1
0
1
9
NA
33.  Interphalangeal IV
0
1
0
1
9
NA
0
1
0
1
9
NA
34.  Interphalangeal V
0
1
0
1
9
NA
0
1
0
1
9
NA

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Appendix F.
Latent TB Risk Assessment Form Example
1.
Have you or an immediate family member or other close contact ever been 
diagnosed or treated for tuberculosis?
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Sub-Saharan Africa
●
India
●
China
●
Mexico
●
Southeast Asia or Micronesia
●
The former Soviet Union
3.
Have you lived or worked in a prison, homeless shelter, immigration center, or 
nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Production of Sputum
●
Blood-Streaked Sputum
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
From:  http://www mayoclinic.org/diseases-conditions/tuberculosis/symptoms-causes/dxc-20188557
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf

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Appendix G.
Patient's Global Assessment of Disease Activity Example
Visual Analog Scale (VAS)
VAS will be used to assess the subject's global assessment of disease activity.  Each VAS 
consists of a horizontal 100 mm line anchored at either end by opposite adjectives 
reflecting the spectrum/severity of the parameters assessed:
●
Subject's global assessment of disease activity (within last 24 hours)
The subject will rate the severity of the RA symptoms and how he/she is doing 
from 0 to 100.  This assessment will be used for the DAS28 (CRP) calculation 
in this study (see example below):
Please place a vertical mark on the line below to indicate how well your rheumatoid 
arthritis has been doing during THE LAST 24 HOURS:
0
100
Very Well
Very Poorly

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Appendix H.
Patient's Assessment of Pain Example
Visual Analog Scale (VAS)
VAS will be used to assess the subject's assessment of pain.  Each VAS consists of a 
horizontal 100 mm line anchored at either end by opposite adjectives reflecting the 
spectrum/severity of the parameters assessed:
How much pain have you had because of your condition within the previous week?
Place a mark on the line below to indicate how severe your pain has been.
NO 
PAIN
WORST 
POSSIBLE 
PAIN

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Appendix I.
Health Assessment Questionnaire (HAQ-DI) Example
HEALTH ASSESSMENT QUESTIONNAIRE
In this section we are interested in learning how your illness affects your ability to 
function in daily life.
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
WITHOUT ANY
DIFFICULTY
WITH SOME
DIFFICULTY
WITH MUCH
DIFFICULTY
UNABLE
TO DO
DRESSING AND GROOMING
Are you able to:
Dress yourself, including tying 
shoelaces and doing buttons?
Shampoo your hair?
ARISING
Are you able to:
Stand up from a straight chair?
Get in and out of bed?
EATING
Are you able to:
Cut your own meat?
Lift a full cup or glass to your 
mouth?
Open a new milk carton?
WALKING
Are you able to:
Walk outdoors on flat ground?
Climb up five steps?
Please check any AIDS OR DEVICES that you usually use for any of these activities:
  Cane
  Devices used for dressing (button hook, zipper pull, long 
handled shoe horn, etc.)
  Walker
  Built up or special utensils
  Crutches
  Special or built up chair
  Wheelchair
  Other (Specify:  __________________)

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Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
  Dressing and Grooming
  Eating
  Arising
  Walking
Please check the response which best describes your usual abilities OVER THE PAST WEEK:
WITHOUT ANY
DIFFICULTY
WITH SOME
DIFFICULTY
WITH MUCH
DIFFICULTY
UNABLE
TO DO
HYGIENE
Are you able to:
Wash and dry your body?
Take a tub bath?
Get on and off the toilet?
REACH
Are you able to:
Reach and get down a 5-pound 
object (such as a bag of sugar) 
from just above your head?
Bend down to pick up clothing 
from the floor?
GRIP
Are you able to:
Open car doors?
Open jars which have been 
previously opened?
Turn faucets on and off?
ACTIVITIES
Are you able to:
Run errands and shop?
Get in and out of a car?
Do chores such as vacuuming 
or yardwork?
Please check any AIDS OR DEVICES that you usually use for any of these activities:
  Raised toilet seat
  Bathtub bar
  Bathtub seat
  Long-handled appliances for reach
  Jar opener (for jars previously opened)
  Long-handled appliances in bathroom
  Other (Specify: ___________________)

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Please check any categories for which you usually need HELP FROM ANOTHER PERSON:
  Hygiene
  Gripping and opening things
  Reach
  Errands and chores
HAQ – United States/English
HAQ-DI_AU1.0-eng-USori.doc
® Stanford University

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Appendix J.
Patient's Assessment of Morning Stiffness Example
Instructions: 
Please clearly mark an 'x' in the box (☒) that best describes your experience with 
morning stiffness on awakening in the past 7 days.
No morning
stiffness
Worst possible morning 
stiffness
▼
▼
0
1
2
3
4
5
6
7
8
9
10
When you experience morning stiffness, how long does it take to get as limber as 
possible:  ___hours ____ minutes

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Appendix K.
Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-F) Scale Example
Below is a list of statements that other people with your illness have said are important.  
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.

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Appendix L.
EuroQoL-5D-5L Example
Under each heading, please check the ONE box that best describes your health TODAY:
Mobility
I have no problems walking
☐
I have slight problems walking
☐
I have moderate problems walking
☐
I have severe problems walking
☐
I am unable to walk 
☐
Self-Care
I have no problems washing or dressing myself
☐
I have slight problems washing or dressing myself 
☐
I have moderate problems washing or dressing myself
☐
I have severe problems washing or dressing myself
☐
I am unable to wash or dress myself 
☐
Usual Activities (e.g., work, study, housework, family or leisure activities)
I have no problems with doing my usual activities 
☐
I have slight problems with doing my usual activities 
☐
I have moderate problems with doing my usual activities
☐
I have severe problems with doing my usual activities
☐
I am unable to do my usual activities 
☐

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Pain/Discomfort
I have no pain or discomfort 
☐
I have slight pain or discomfort 
☐
I have moderate pain or discomfort
☐
I have severe pain or discomfort
☐
I have extreme pain or discomfort 
☐
Anxiety/Depression
I am not anxious or depressed 
☐
I am slightly anxious or depressed 
☐
I am moderately anxious or depressed
☐
I am severely anxious or depressed
☐
I am extremely anxious or depressed 
☐

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!
We would like to know how good or bad your health is 
TODAY.
!
This scale is numbered from 0 to 100.
!
100 means the best health you can imagine.
0 means the worst health you can imagine.
!
Mark an X on the scale to indicate how your health is 
TODAY.
!
Now, please write the number you marked on the scale in 
the box below. 
YOUR HEALTH TODAY =
10
0
20
30
40
50
60
80
70
90
100
5
15
25
35
45
55
75
65
85
95
The best health    
you can imagine
The worst health  
you can imagine

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Appendix M.
Short Form-36 (SF-36™) Health Status Survey Questionnaire 
Example
Your Health and Well-Being
This survey asks for your views about your health.  This information will help keep 
track of how you feel and how well you are able to do your usual activities.  Thank 
you for completing this survey!
For each of the following questions, please mark an ☒in the box that best describes 
your answer.
5.
In general, would you say your health is:
Excellent
Very good
Good
Fair
Poor
1
2
3
4
5
6.
Compared to 1 year ago, how would you rate your health in general now?
Much better now 
than one year ago
Somewhat better 
now than one year 
ago
About the same as 
one year ago
Somewhat worse 
now than one year 
ago
Much worse now 
than one year ago
1
2
3
4
5

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7.
The following questions are about activities you might do during a typical day.  
Does your health now limit you in these activities?  If so, how much?
Yes,
limited
a lot
Yes,
limited
a little
No, not
limited
at all
a
Vigorous activities, such as running, lifting 
heavy objects, participating in strenuous 
sports
1
2
3
b
Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or playing golf
1
2
3
c
Lifting or carrying groceries
1
2
3
d
Climbing several flights of stairs
1
2
3
e
Climbing one flight of stairs
1
2
3
f
Bending, kneeling, or stooping
1
2
3
g
Walking more than a mile
1
2
3
h
Walking several hundred yards
1
2
3
i
Walking one hundred yards
1
2
3
j
Bathing or dressing yourself
1
2
3

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8.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of your 
physical health?
All of the 
time
Most of 
the time
Some 
of the 
time
A little 
of the 
time
None of the 
time
a   Cut down on the amount of time you 
spent on work or other activities
1
2
3
4
5
b   Accomplished less than you would like
1
2
3
4
5
c   Were limited in the kind of work or 
other activities
1
2
3
4
5
d   Had difficulty performing the work or 
other activities (for example, it took extra
effort) 
1
2
3
4
5

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9.
During the past 4 weeks, how much of the time have you had any of the following 
problems with your work or other regular daily activities as a result of any 
emotional problems (such as feeling depressed or anxious)?
All of 
the 
time
Most of 
the 
time
Some 
of the 
time
A little 
of the 
time
None 
of the 
time
a   Cut down on the amount of time you spent 
on work or other activities
1
2
3
4
5
b   Accomplished less than you would like
1
2
3
4
5
c   Did work or other activities less carefully 
than usual
1
2
3
4
5
10.
During the past 4 weeks, to what extent has your physical health or emotional 
problems interfered with your normal social activities with family, friends, 
neighbors, or groups?
Not at all
Slightly
Moderately
Quite a bit
Extremely
1
2
3
4
5
11.
How much bodily pain have you had during the past 4 weeks?
None
Very mild
Mild
Moderate
Severe
Very Severe
1
2
3
4
5
6

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12.
During the past 4 weeks, how much did pain interfere with your normal work 
(including both work outside the home and housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely
1
2
3
4
5
13.
These questions are about how you feel and how things have been with you during 
the past 4 weeks.  For each question, please give the one answer that comes closest 
to the way you have been feeling.  How much of the time during the past 4 weeks:
All of the 
time
Most of 
the time
Some of 
the time
A little of 
the time
None of 
the time
a   Did you feel full of life?
1
2
3
4
5
b   Have you been very nervous?
1
2
3
4
5
c   Have you felt so down in the dumps 
that nothing could cheer you up?
1
2
3
4
5
d   Have you felt calm and peaceful?
1
2
3
4
5
e   Did you have a lot of energy?
1
2
3
4
5
f   Have you felt downhearted and 
depressed?
1
2
3
4
5
g   Did you feel worn out?
1
2
3
4
5
h   Have you been happy?
1
2
3
4
5
i   Did you feel tired?
1
2
3
4
5

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14.
During the past 4 weeks, how much of the time has your physical health or 
emotional problems interfered with your social activities (like visiting friends, 
relatives, etc.)?
All of the
time
Most of the
time
Some of the
time
A little of the 
time
None of the
time
1
2
3
4
5
15.
How TRUE or FALSE is each of the following statements for you?
Definitely 
true
Mostly 
true
Don't 
know
Mostly 
false
Definitely 
false
a  I seem to get sick a little easier 
than other people
1
2
3
4
5
b  I am as healthy as anybody I know
1
2
3
4
5
c  I expect my health to get worse
1
2
3
4
5
d  My health is excellent
1
2
3
4
5
THANK YOU FOR COMPLETING THESE QUESTIONS
SF-36v2™ Health Survey© 1996, 2000 by QualityMetric Incorporated and Medical Outcomes Trust.  All Rights 
Reserved.
SF-36® is a registered trademark of Medical Outcomes Trust
(SF-36v2 Standard, US Version 2.0)

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Appendix N.
RA-WIS Example

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Appendix O.
Rheumatology Common Toxicity Criteria v.2.0 Example
For designation of adverse event terms not shown in the Rheumatology Common Toxicity 
Criteria v.2.0 table, the approach described in Row 1 should be used.

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Rheumatology Common Toxicity Criteria v.2.0
Based on Woodworth TG, et al.  Standardizing assessment of adverse effects in rheumatology clinical trials II.  Status of OMERACT Drug Safety Working Group 
May 2006:  OMERACT 8.  Standardizing Assessment and Reporting of Adverse Effects in Rheumatology Clinical Trials:  Enabling Description of Comparative 
Safety Profiles for Anti-Rheumatic Therapies
1 – Mild
No medication or OTC
Asymptomatic, or transient
Short duration (< 1 week)
No change in life style
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve.  (may be 
prescription),
Study drug continued
3 – Severe
Prolonged symptoms, reversible, 
major functional impairment
Prescription meds/partial relief
May be hospitalized < 24 hr
Temporary study drug 
discontinuation, or/and dose reduced
4 – Includes Life Threatening
At risk of death
Substantial disability, especially if 
permanent.
Multiple meds
Hospitalised > 24 hr
Study drug discontinued
A.  Allergic/Immunologic
A1.  Allergic 
reaction/ 
hypersensitivity 
(includes drug fever)
Transient rash:  drug fever 
< 38°C:  transient, asymptomatic 
bronchospasm
Generalised urticaria responsive to 
meds; or drug fever > 38°C, or 
reversible bronchospasm
Symptomatic bronchospasm 
requiring meds; symptomatic 
urticaria persisting with meds, 
allergy related oedema/angioedema
Anaphylaxis, laryngeal/pharyngeal 
oedema, requiring resuscitation
A2.  Autoimmune 
reaction
Seriologic or other evidence of 
autoimmune reaction, but patient 
asymptomatic:  all organ function 
normal and no treatment is 
required (e.g., vitiligo)
Evidence of autoimmune reaction 
involving a non-essential organ or 
functions, requiring treatment 
other than immunosuppressive 
drugs (e.g., hypothyroidism)
Reversible autoimmune reaction 
involving function of a major organ 
or toxicity requiring short term 
immunosuppressive treatment 
(e.g., transient colitis or anaemia)
Causes major organ dysfunction, or 
progressive, not reversible, or 
requires long term administration 
of high dose immunosuppressive 
therapy
A3.  Rhinitis 
(includes sneezing, 
nasal stuffiness, post 
nasal discharge)
Transient, non-prescription meds 
relieve
Prescription med. required, slow
Corticosteroids or other prescription 
med. with persistent disabling 
symptoms such as impaired exercise 
tolerance
NA
A4.  Serum sickness
Transient, non-prescription meds 
relieve
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Prolonged; symptoms only partially 
relieved by meds; parenteral 
corticosteroids required
Major organ dysfunction, requires 
long-term high-dose 
immunosuppressive therapy

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A.  Allergic/Immunologic (continued)
A5.  Vasculitis
Localised, not requiring 
treatment; or rapid response to 
meds; cutaneous
Symptomatic, slow response to 
meds (e.g., oral corticosteroids)
Generalised, parenteral 
corticosteroids required or/and short 
duration hospitalisation
Prolonged, hospitalisation, 
ischemic changes, amputation
B.  Cardiac
B1.  Arrhythmia
Transient, asymptomatic
Transient, but symptomatic or 
recurrent, responds to meds
Recurrent/persistent; maintenance 
prescription
Unstable, hospitalisation required, 
parenteral meds
B2.  Cardiac function 
decreased
Asymptomatic decline in resting 
ejection fraction by > 10%, but 
< 20% of baseline value
Asymptomatic decline of resting 
ejection fraction ≥ 20% of baseline 
value
CHF responsive to treatment
Severe or refractory CHF
B3.  Edema
Asymptomatic
(e.g., 1 + feet/calves), self-limited, 
no therapy required
Symptomatic
(e.g., 2 + feet/calves), requires 
therapy
Symptoms limiting function 
(e.g., 3 + feet/calves, 2 + thighs), 
partial relief with treatment 
prolonged
Anasarca; no response to treatment
B4.  Hypertension 
(new onset or 
worsening)
Asymptomatic, transient increase 
by > 20 mmHg (diastolic) or to 
> 150/100 if previously normal, 
no therapy required
Recurrent or persistent increase 
> 150/100 or by > 10 mmHg 
(diastolic), requiring and 
responding readily to treatment
Symptomatic increase > 150/100, 
> 20 mmHg, persistent, requiring 
multi agency therapy, difficult to 
control
Hypertensive crisis
B5.  Hypotension 
(without underlying 
diagnosis)
Transient, intermittent, 
asymptomatic, orthostatic 
decrease in blood pressure 
> 20 mmHg
Symptomatic, without interference 
with function, recurrent or 
persistent > 20 mmHg decrease, 
responds to treatment
Syncope or symptomatic, interferes 
with function, requiring therapy and 
sustained medical attention, dose 
adjustment or drug discontinuation
Shock
B6.  Myocardial 
ischaemia
Transient chest pain/ECG 
changes; rapid relief with nitro
Recurring chest pain, transient 
ECG ST-T changes; treatment 
relieves
Angina with infarction, no or 
minimal functional compromise, 
reduce dose or discontinue study 
drug
Acute myocardial infarction, 
arrthymia or/and CHF

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B.  Cardiac (continued)
B7.  Pericarditis/ 
pericardial effusion
Rub heard, asymptomatic
Detectable effusion by 
echocardiogram, symptomatic 
NSAID required
Detectable on chest x-ray, 
dyspnoea; or pericardiocentesis; 
requires corticosteroids
Pulsus alternates with low cardiac 
output; requires surgery
B8.  
Phlebitis/thrombosis/ 
Embolism (excludes 
injection sites)
Asymptomatic, superficial, 
transient, local, or no treatment 
required
Symptomatic, recurrent, deep vein 
thrombosis, no anticoagulant 
therapy required
Deep vein thrombosis requiring 
anticoagulant therapy
Pulmonary embolism
C.  General (Constitutional)
C1.  Fatigue/malaise 
(asthenia)
Increase over baseline; most usual 
daily functions maintained, short 
term
Limits daily function intermittently 
over time
Interferes with basic ADL, 
persistent
Unable to care for self, bed or 
wheelchair bound > 50% of day 
debilitating, hospitalisation
C2.  Fever (pyrexia) 
(note:  fever due to 
drug allergy should 
be coded as allergy)
Transient, few symptoms
37.7° – 38.5°C
Symptomatic, recurrent
38.6° – 39.9°C.  Relieved by meds.
≥ 40°C; ≤ 24 h, persistent 
symptoms; partial response to meds.
≥ 40°C, debilitating, > 24 h, 
hospitalisation; no relief with meds
C3.  Headache
Transient or intermittent, no meds 
or relieved with OTC
Persistent, recurring, non-narcotic 
analgesics relieve
Prolonged with limited response to 
narcotic medicine
Intractable, debilitating, requires 
parenteral meds.
C4.  Insomnia
Difficulty sleeping, short term, no 
interfering with function
Difficulty sleeping interfering with 
function, use of prescription med.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C5.  Rigors, chills
Asymptomatic, transient, no 
meds, or non-narcotic meds 
relieve
Symptomatic, narcotic meds 
relieve.
Prolonged symptoms, with limited 
response to narcotic meds
Debilitating, hospitalisation; no 
relief with meds
C6.  Sweating 
(diaphoresis)
Episodic, transient
Frequent, short term
Frequent, drenching, disabling
Dehydration, requiring IV 
fluids/hospitalization > 24 hrs
C7.  Weight gain
5% – 9.9%
10% – 19.9%
20% – 30%
NA
C8.  Weight loss
5% – 9.9%
10% – 19.9%
20% – 30%
NA

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D.  Dermatologic
D1.  Alopecia
Subjective, transient
Objective, fully reversible
Patchy, wig used, partly reversible
Complete, or irreversible even if 
patchy
D2.  Bullous eruption
Localised, asymptomatic
Localised, symptomatic, requiring 
treatment
Generalised, responsive to 
treatment; reversible
Prolonged, generalised, or 
requiring hospitalisation for 
treatment
D3.  Dry skin
Asymptomatic, controlled with 
emollients
Symptoms eventually (1 – 2 wks) 
controlled with emollients
Generalised, interfering with ADL 
> 2 wks, persistent pruritis, partially 
responsive to treatment
Disabling for extended period, 
unresponsive to ancillary therapy 
and requiring study drug 
discontinuation for relief
D4.  Injection site 
reaction
Local erythema, pain, pruritis, 
< few days
Erythema, pain, oedema, may 
include superficial phlebitis,
1 – 2 wks
Prolonged induration, superficial 
ulceration; includes thrombosis
Major ulceration necrosis requiring 
surgery
D5.  Petechiae 
(without vasculitis)
Few, transient asymptomatic
Dependent areas, persistent up to 
2 wks
Generalised, responsive to 
treatment; reversible
Prolonged, irreversible, disabling
D6.  Photosensitivity
Transient erythema
Painful erythema and oedema 
requiring topical treatment
Blistering or desquamation, requires 
systematic corticosteroids
Generalised exfoliation or 
hospitalisation
D7.  Pruritis
Localised, asymptomatic, 
transient, local treatment
Intense, or generalised, relieved by 
systematic medication
Intense or generalised; poorly 
controlled despite treatment
Disabling, irreversible
D8.  Rash (not 
bullous)
Erythema, scattered 
macular/popular eruption; pruritis 
transient; TOC or no meds
Diffuse macular/popular eruption 
or erythema with pruritus; dry 
desquamation; treatment required
Generalised, moist desquamation, 
requires systemic corticosteroids; 
responsive to treatment; reversible
Exfoliative or ulcerating; or 
requires hospitalisation; or 
parenteral corticosteroids
D9.  Indurartion/ 
fibrosis/Thickening 
(not sclerodermal)
Localized, high density on 
palpation, reversible, no effect on 
ADL and not disfiguring
Local areas < 50% body surface, 
not disfiguring, transient 
interference with ADL, reversible
Generalized, disfiguring, interferes 
with ADL, reversible
Disabling, irreversible, systemic 
symptoms
E.  Ear/Nose/Throat
E1.  Hearing loss
Transient, intermittent, no 
interference with function
Symptomatic, treatment required, 
reversible
Interferes with function; incomplete 
response to treatment
Irreversible deafness
E2.  Sense of smell
Slightly altered
Markedly altered
Complete loss, reversible
Complete loss, without recovery

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E.  Ear/Nose/Throat (continued)
E3.  Stomatitis
Asymptomatic
Painful, multiple, can eat
Interferes with nutrition, slowly 
reversible
Requires enteral support; residual 
dysfunction
E4.  Taste 
disturbance 
(dysgeusia)
Transiently altered; metallic
Persistently altered; limited effect 
on eating
Disabling, effect on nutrition
NA
E5.  Tinnitus
Intermittent, transient, no 
interference with function
Requires treatment, reversible
Disabling, or associated with 
hearing loss
Irreversible deafness
E6.  Voice changes 
(includes hoarseness, 
loss of voice, 
laryngitis)
Intermittent hoarseness, able to 
vocalise
Persistent hoarseness, able to 
vocalise
Whispered speech, slow return of 
ability to vocalise
Unable to vocalize for extended
E7.  Xerostomia (dry 
mouth)
Transient dryness
Relief with meds
Interferes with nutrition, slowly 
reversible
Extended duration interference 
with nutrition, requires parenteral 
nutrition
F.  Eye/Ophthalmologic
F1.  Cataract
Asymptomatic, no change in 
vision, non-progressive
Symptomatic, partial visual loss, 
progressive
Symptoms impairing function, 
vision loss requiring treatment, 
including surgery
NA
F2.  Conjunctivitis
Asymptomatic, transient, rapid 
response to treatment
Symptomatic, responds to 
treatment, changes not interfering 
with function
Symptoms prolonged, partial 
response to treatment, interferes 
with function
NA
F3.  Lacrimation 
increased (tearing, 
watery eyes)
Symptoms not requiring 
treatment, transient
Symptomatic, treatment required, 
reversible
Unresponsive to treatment with 
major effect on function
NA
F4.  Retinopathy
Asymptomatic, non-progressive, 
no treatment
Reversible change in vision; 
readily responsive to treatment
Disabling change in vision 
ophthalmological findings 
reversible, sight improves over time
Loss of sight

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F.  Eye/Ophthalmologic (continued)
F5.  Vision changes 
(e.g., blurred, 
photophobia, night 
blindness, vitreous 
floaters)
Asymptomatic, transient, no 
treatment required
Symptomatic, vision changes not 
interfering with function, 
reversible
Symptomatic, vision changes 
interfering with function
Loss of sight
F6.  Xerophtalmia 
(dry eyes)
Mild scratchiness
Symptomatic without interfering 
with function, requires artificial 
tears
Interferes with vision/function, 
corneal ulceration
Loss of sight
G.  Gastrointestinal
G1.  Anorexia
Adequate food intake, minimal 
weight loss
Symptoms requiring oral 
nutritional supplementation
Prolonged, requiring iv support
Requires hospitalization for 
nutritional support
G2.  Constipation
Asymptomatic, transient,
responds to stool softener, OTC 
laxatives
Symptomatic, requiring 
prescription laxatives, reversible
Obstipation requiring medical 
intervention
Bowel obstruction.  Surgery 
required.
G3.  Diarrhea
Transient, increase of
2 – 3 stools/day over 
pre-treatment (no blood or 
mucus), OTC agents relieve
Symptomatic, increase
4 – 6 stools/day, nocturnal stools, 
cramping, requires treatment with 
prescription meds.
Increase > 6 stools/day, associated 
with disabling symptoms, 
e.g., incontinence, severe cramping, 
partial response to treatment.
Prolonged, dehydration, 
unresponsive to treatment, requires 
hospitalization.
G4.  Dyspepsia 
(heartburn)
Transient, intermittent, responds 
to OTC antacids, H-2 blockers
Prolonged, recurrent, requires 
prescription meds, relieved by 
meds
Persistent despite treatment, 
interferes with function, associated 
with GI bleeding
NA
G5.  GI bleed 
(gastritis, gastric or 
duodenal ulcer 
diagnosed-define 
aetiology)
Asymptomatic, endoscopic 
finding, haemocult + stools, no 
transfusion, responds rapidly to 
treatment
Symptomatic, transfusion ≤ 2 units 
needed; responds to treatment
Haematemesis, transfusion
3 – 4 units, prolonged interference 
with function
Recurrent, transfusion > 4 units, 
perforation, requiring surgery, 
hospitalisation
G6.  Haematochezia 
(rectal bleeding)
Haemorrhodial, asymptomatic, no 
transfusion
Symptomatic, transfusion
≤ 2 units, reversible
Recurrent, transfusion > 3 – 4 units
> 4 units, hypotension, requiring 
hospitalization

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G7.  Hepatitis
Laboratory abnormalities, 
asymptomatic, reversible
Symptomatic laboratory 
abnormalities, not interfering with 
function, slowly reversible
Laboratory abnormalities persistent 
> 2 wks, symptoms interfere with 
function
Progressive, hepato-renal, anasarca, 
pre-coma or coma
G8.  Nausea, or
nausea/vomiting (use 
diagnostic term)
Transient, intermittent, minimal 
interference with intake, rapid 
response to meds.
Persistent, recurrent, requires 
prescription meds, intake 
maintained
Prolonged, interferes with daily 
function and nutritional intake,
periodic iv fluids
Hypotensive, hospitalization, 
parenteral nutrition, unresponsive 
to out-patient management
G9.  Pancreatitis
Anylase elevation, intermittent 
nausea/vomiting, transient, 
responds rapidly to treatment
Amylase elevation with abdominal 
pain, nausea, occasional vomiting, 
responsive to treatment
Severe, persistent abdominal pain 
with pancreatitic enzyme elevation, 
incomplete or slow response to 
treatment
Complicated by shock, 
haemorrhage (acute circulatory 
failure)
G10.  Proctitis
Perianal pruritus, haemorrhoids 
(new onset), transient, or 
intermittent, relieved by OTC 
meds
Tenesmus or ulcerations, anal 
fissure, responsive to treatment, 
minimal interference with function
Unresponsive to treatment, marked 
interference with function
Mucosal necrosis with 
haemorrhage, infection, surgery 
required.
H.  Musculoskeletal
H1.  Avascular 
necrosis
Asymptomatic MRI changes, 
non-progressive
MRI changes and symptoms 
responsive to rest and analgesia
MRI changes, symptoms requiring 
surgical intervention
Wheelchair bound; surgical repair 
not possible
H2.  Arthralgia
Intermittent transient symptoms, 
no meds or relieved by OTC meds
Persistent or recurrent symptoms, 
resolve with meds, little effect on 
function
Severe symptoms despite meds 
impairs function
Debilitating, hospitalisation 
required for treatment
H3.  Leg cramps
Transient, intermittent, does not 
interfere with function
Recurrent symptoms, minimally 
interferes with function or sleep, 
responds to meds
Persistent, prolonged interference 
with function or sleep, partial or no 
response to meds
NA
H4.  Myalgia
Occasional; does not interfere 
with function
Frequent, requires meds 
(non-narcotic); minor effects on 
function
Major change in function/lifestyle, 
narcotic pain meds
Debilitating, profound weakness, 
requires wheelchair, unresponsive 
to meds

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I.  Neuropsychiatric
I1.  Anxiety or 
Depression (mood 
alteration)
Symptomatic, does not interfere 
with function; no meds
Frequent symptoms, responds to 
meds; interferes with ADL at times
Persistent, prolonged symptoms, 
partial or no response to meds, 
limits daily function
Suicidal ideation or danger to self
I2.  Cerebrovascular 
ischaemia
NA
Single transient ischaemic event, 
responsive to treatment
Recurrent transient ischaemic events
Cerebrovascular vascular accident 
with permanent disability
I3.  Cognitive 
disturbance
Subjective symptoms, transient, 
intermittent, not interfering with 
function
Objective symptoms, persisting, 
interferes with daily function 
occasionally
Persistent, or worsening objective 
symptoms; interferes with routine 
daily routine
Debilitating/disabling and 
permanent; toxic psychosis
I4.  Depressed 
consciousness 
(somnolence)
Observed, transient, intermittent, 
not interfering with function
Somnolence or sedation, 
interfering with function
Persistent, progressive, obundation, 
stupor
Coma
I5.  Inability to 
concentrate
Subjective symptoms, does not 
interfere with function
Objective findings, interferes with 
function
Persistent, prolonged objective 
findings or organic cause
NA
I6.  Insomnia (in 
absence of pain)
Occasional difficulty sleeping, 
transient intermittent, not 
interfering with function
Recurrent difficulty sleeping; 
requires meds for relief; occasional 
interference with function
Persistent or worsening difficulty 
sleeping; severely interferes with 
routine daily function
NA
I7.  Libido decreased
Decrease in interest
Loss of interest; influences 
relationship
Persistent, prolonged interfering 
with relationship
NA
I8.  Peripheral motor 
neuropathy
Subjective or transient loss of 
deep tendon reflexes; function 
maintained
Objective weakness, persistent, no 
significant impairment of daily 
function
Objective weakness with substantial 
impairment of function
Paralysis
I9.  Peripheral 
sensory neuropathy 
(sensory disturbance)
Subjective symptoms without 
objective findings, transient, not 
interfering with function
Objective sensory loss, persistent, 
not interfering with function
Prolonged sensory loss or 
paraethesias interfering with 
function
NA
I10.  Seizure
NA
Recurrence of old seizures, 
controlled with adjustment of 
medication
Recurrence/exacerbation with 
partial response to medication
Recurrence not controlled, 
requiring hospitalization; new 
seizures

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I.  Neuropsychiatric
I11.  Vertigo 
(dizziness)
Subjective symptoms, transient, 
intermittent, no treatment
Objective findings, recurrent, meds 
relieve, occasionally interfering 
with function
Persistent, prolonged, interfering 
with daily function; partial response 
to medication
Debilitating without response to 
medication, hospitalization
J.  Pulmonary
J1.  Asthma
Occasional wheeze, no 
interference with activities
Wheezing, requires oral meds, 
occasional interference with 
function
Debilitating, requires nasal O2
Requires ventilator assistance
J2.  Cough
Transient, intermittent, occasional 
OTC meds relieve
Persistent, requires narcotic or 
other prescription meds for relief
Recurrent, persistent coughing 
spasms without consistent relief by 
meds, interferes with function
Interferes with oxygenation; 
debilitating
J3.  Dyspnea
Subjective, transient, no 
interference with function
Symptomatic, intermittent or 
recurring, interferes with 
exertional activities
Symptomatic during daily routine 
activities, interferes with function, 
treatment with intermittent nasal O2 
relieves
Symptomatic at rest, debilitating, 
requires constant nasal O2
J4.  Pleuritic pain 
(pleurisy)
Transient, intermittent symptoms, 
no treatment or OTC meds relieve
Persistent symptoms, requires 
prescription meds for relief
Prolonged symptoms, interferes 
with function, requires frequent 
narcotic pain relief
Debilitation, requiring 
hospitalisation
J5.  Pneumonitis 
(pulmonary 
infiltrates)
Asymptomatic radiographic 
changes, transient, no treatment 
required
Symptomatic, persistent, requiring 
corticosteroids
Symptomatic, requiring treatment 
including O2
Debilitating, not reversible; or 
requiring assisted ventilation
J6.  Pulmonary 
function decreased 
(FVC or carbon 
monoxide diffusion 
capacity – DLCO)
76% – 90% of pre-treatment value
51% – 75% of pre-treatment value
26% – 50% of pre-treatment value
≤ 25% of pre-treatment value

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Laboratory Data
K.  Haematology
K1.  Hgb (g/dl) 
decrease from 
pre-treatment
1.0 – 1.4
1.5 – 2.0
2.1 – 2.9, or Hgb < 8.0, > 7.0
≥ 3.0; or Hgb < 7.0
K2.  Leukopenia 
(total WBC) × 1000
3.0 – 3.9
2.0 – 2.9
1.0 – 1.9
< 1.0
K3.  Neutropenia 
(× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K4.  Lymphopenia 
(× 1000)
1.5 – 1.9
1.0 – 1.4
0.5 – 0.9
< 0.5
K5.  Platelets 
(× 1000)
75 – LLN
50 – 74.9
20 – 49.9; platelet transfusion 
required
< 20; recurrent platelet transfusions
L.  Chemistry
L1.  Hypercalcaemia 
(mg/dl)
1.1 × ULN – 11.5
11.6 – 12.5
12.6 – 13.5; or symptoms present
> 13.5; or associated coma
L2.  Hyperglycemia 
(mg/dl) Fasting
140 – 160
161 – 250
251 – 500
> 500, or associated with 
ketoacidosis
L3.  Hyperkalaemia 
(mg/dl)
5.5 – 5.9
6.0 – 6.4
6.5 – 7.0 or any ECG change
> 7.0 or any arrhythmia
L5.  Hypocalcaemia 
(mg/dl)
0.9 × LLN – 7.8
7.7 – 7.0
6.9 – 6.5; or associated with 
symptoms
< 6.5 or occurrence of tetany
L6.  Hypoglycemia 
(mg/dl)
55 – 64 (no symptoms)
40 – 54 (or symptoms present)
30 – 39 (symptoms impair function)
< 30 or coma
L7.  Hyponatraemia 
(mg/dl)
--
125 – 129
120 – 124
< 120
L8.  Hypokalaemia 
(mg/dl)
--
3.0 – 3.4
2.5 – 2.9
< 2.5

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L.  Chemistry
L9.  CPK (also if 
polymyositis-
disease)*
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening
L10.  Serum uric acid
1.2 – 1.6 × ULN
1.7 – 2.9 × ULN
3.0 – 5.0 × ULN or gout
NA
L11.  Creatinine 
(mg/dl)*
1.1 – 1.3 × ULN
1.3 – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
L12.  SGOT (AST)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.1 – 8.0 × ULN
> 8.0 × ULN
L13.  SGPT (ALT)
1.2 – 1.5 × ULN
1.6 – 3.0 × ULN
3.0 – 8.0 × ULN
> 8.0 × ULN
L14.  Alkaline 
phosphatase
1.1 – 2.0 × ULN
1.6 – 3.0 × ULN
3.0 – 5.0 × ULN
> 5.0 × ULN
L15.  T. bilirubin
1.1 – 1.4 × ULN
1.5 – 1.9 × ULN
2.0 – 3.0 × ULN
> 3.0 × ULN
L16.  LDH
1.3 – 2.4 × ULN
2.5 – 5.0 × ULN
5.1 – 10 × ULN
> 10 × ULN
M.  Urinalysis
M1.  Haematuria
Micro only
Gross, no clots
Clots, transfusion < 2 units 
Transfusion required
M2.  Proteinuria (per 
24 h)
300 – 500 mg (tr/1+)
501 – 1999 mg (2+)
2 – 5.0 g (3+) nephrotic syndrome
5.0 g (4+) anasarca
M3.  WBC in urine
NA
NA
Indicating acute interstitial nephritis
Associated with acute renal failure
M4.  Uric acid 
crystals
Present without symptoms
NA
With stones or symptoms of stones 
(e.g., renal colic)
Causing renal outflow obstruction 
and hospitalization
OTC = over-the-counter medication; ADL = activities of daily living; IV = intravenous; ECG = electrocardiogram; CHF = congestive heart failure; MRI = magnetic resonance 
imaging; Hb = haemglobin; LLN = lower limit of normal; ULN = upper limit of normal; WBC = white blood cells; SLE = systemic lupus erythematosus; ANA = antinuclear 
antibodies; H-2 blockers = histamine-2 blockers; FVC = forced vital capacity
*
For CPK and Creatinine NCI CTC grading will be used.  For CPK the following gradings apply:  Grade 1:  > ULN – 2.5 × ULN; Grade 2:  > 2.5 – 5.0 × ULN; Grade 3:  
> 5.0 – 10.0 × ULN; Grade 4:  > 10.0 × ULN; For Creatinine the following gradings apply:  Grade 1:  > 1 – 1.5 × Baseline; > ULN – 1.5 × ULN; Grade 2:  > 1.5 –
3.0 × Baseline; > 1.5 – 3.0 × ULN; Grade 3:  > 3.0 baseline; > 3.0 – 6.0 × ULN; Grade 4:  > 6.0 × ULN

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Appendix P.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Global Protocol Change
"ABT-494" has been changed to read "Upadacitinib" or "Upadacitinib (ABT-494)" 
throughout the protocol.
Specific Protocol Changes:
Section 1.0  Title Page
"Sponsor:" previously read:
Sponsor:
AbbVie*
1 North Waukegan Road
North Chicago, IL  60064
Has been changed to read:
Sponsor:
AbbVie*
1 North Waukegan Road
North Chicago, IL  60064
Section 1.0  Title Page
"Sponsor/Emergency Contact:"
Add:  Emergency 24 hour Number:  
Sponsor/Emergency 
  Contact:

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Has been changed to read:
Sponsor/Emergency 
  Contact:
Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M14-465
Name of Study Drug:  ABT-494
Phase of Development:  3
Name of Active Ingredient:  ABT-494
Date of Protocol Synopsis:  11 January 2017
Protocol Title:  A Phase 3, Randomized, Double-Blind Study Comparing ABT-494 to Placebo and to 
Adalimumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Who are on a Stable 
Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX (MTX-IR)
Objectives:
Period 1
1.
To compare the efficacy of ABT-494 15 mg once daily (QD) versus placebo, and versus adalimumab 
(ADA) for the treatment of signs and symptoms of rheumatoid arthritis (RA) in subjects with 
moderately to severely active RA who are on a stable background of methotrexate (MTX) and who 
have an inadequate response to MTX (MTX-IR).
2.
To compare the efficacy of ABT-494 15 mg QD versus placebo for the prevention of structural 
progression in RA subjects with moderately to severely active RA who are on a stable background of 
MTX and who have an inadequate response to MTX (MTX-IR).
3.
To compare the safety and tolerability of ABT-494 15 mg QD versus placebo, and versus ADA in 
subjects with moderately to severely active RA subjects who are on a stable background of MTX and 
who have an inadequate response to MTX (MTX-IR).
Period 2
To evaluate the long-term safety, tolerability, and efficacy of ABT-494 15 mg QD in subjects with RA 
who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 510

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Study Population:  
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for 
RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints 
(based on 68 joint counts) at Screening and Baseline Visits, and high-sensitivity C-reactive protein 
(hsCRP) ≥ 5 mg/L (central lab, upper limit of normal [ULN] 2.87 mg/L) at Screening.  Subjects must 
have been on oral or parenteral MTX therapy ≥ 3 months and on a stable dose for ≥4 weeks prior to the 
first dose of study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at 
doses ≥12.5 mg/week).
Number of Subjects to be Enrolled: Approximately 1500

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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 48-week randomized, 
double-blind, parallel-group, placebo-controlled and active comparator-controlled period designed to 
compare the safety and efficacy of ABT-494 15 mg QD versus placebo and versus ADA for the treatment 
of signs and symptoms of subjects with moderately to severely active RA who are on a stable dose of 
MTX and have an inadequate response to MTX (MTX-IR).  Period 1 is also designed to compare the 
efficacy of ABT-494 15 mg QD versus placebo for the prevention of structural progression.  Period 2 is a 
long-term extension to evaluate the safety, tolerability and efficacy of ABT-494 15 mg QD in subjects 
with RA who have completed Period 1.
The study duration will include a 35-day screening period; a 48-week randomized, double-blind, 
parallel-group, placebo-controlled and active comparator-controlled treatment period (Period 1); a 
long-term extension period (blinded until the last subject completes the last visit of the double-blind 
treatment period) (up to 5 years) (Period 2); a 30-day follow-up period (call or visit); and a 70-day 
follow-up call.
Subjects who meet eligibility criteria will be randomized in a 2:2:1 ratio to one of three treatment groups: 
!
Group 1:  ABT-494 15 mg QD (N = 600)
!
Group 2:  Placebo (N = 600)
!
Group 3:  ADA (40 mg every other week [eow]) (N = 300)
Subjects will receive both oral study drug QD (either ABT-494 15 mg or matching placebo) and 
subcutaneous study drug eow (either ADA 40 mg or matching placebo) until the study is unblinded.
Subjects must have been on oral or parenteral MTX therapy for ≥ 3 months, on a stable MTX dose for 
≥4 weeks prior to the first dose of study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are 
intolerant of MTX at doses ≥ 12.5 mg/week), and must remain on a stable dose throughout the study; the 
MTX dose may be decreased only for safety reasons.  In addition, all subjects should take a dietary 
supplement of oral folic acid (or equivalent) throughout study participation.  Folic acid dosing and timing 
of regimen should be followed according to the Investigator's instructions.  Starting at the Week 26 visit 
(after Week 26 assessments have been performed), initiation of or change in background RA 
medication(s) including, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, and csDMARDs (concomitant use of up to 2 csDMARDs except the 
combination of MTX and leflunomide) is allowed as per local label.
Subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic drug (bDMARD) 
(except ADA) for RA may be enrolled in the study (up to 20% of total number of subjects) after the 
required washout period is satisfied and if they have a) limited bDMARD exposure (< 3 months), OR 
b) response to a bDMARD but had to discontinue that bDMARD due to intolerability (regardless of 
treatment duration).  These subjects will be equally stratified across all treatment groups.  Subjects who 
are considered bDMARD-inadequate responders (lack of efficacy), as determined by the Investigator, are 
not eligible.
Rescue therapy will be offered to subjects who meet the following criteria:
Placebo:
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded ABT-494 treatment.
!
At Week 26, all remaining subjects will be switched to blinded ABT-494 treatment regardless of 
clinical response.

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Methodology (Continued):
ADA:  
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded ABT-494 treatment.
!
At Week 26, all remaining subjects who do not achieve LDA according to CDAI (LDA defined 
as CDAI ≤10) at Week 26 will be switched to blinded ABT-494 treatment.
ABT-494:
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded ADA treatment.
!
At Week 26, all remaining subjects who do not achieve LDA according to CDAI (LDA defined 
as CDAI ≤10) at Week 26 will be switched to blinded ADA treatment.
An unblinded analysis will be conducted after all subjects have completed Week 26 for the purpose of 
regulatory submission.  To maintain integrity of the trial and avoid introduction of bias, study sites and 
subjects will remain blinded for the duration of Period 1.  Another unblinded analysis may be conducted 
for regulatory purposes after all subjects have completed Period 1 (Week 48).
Each subject will undergo a maximum of 4 scheduled visits for x-ray examination of bilateral hands and 
feet during Period 1 (unless unscheduled repeat imaging is needed due to failure to meet the quality 
requirements) at Screening, Week 26, and Week 48/Premature Discontinuation; in addition, all subjects 
who are non-responders (defined as those not achieving ≥ 20% improvement in TJC and SJC criterion) at 
Week 14 and are switched to rescue therapy will have an x-ray examination at Week 14.
Subjects who complete the Week 48 visit (end of Period 1) will enter the long-term extension portion of 
the study, Period 2 (up to 5 years).  Subjects will continue study treatment as assigned in Period 1.  
Subjects who are assigned to the ABT-494 15 mg QD treatment group at the end of Period 1 will 
continue to receive ABT-494 15 mg QD in a blinded manner.  Subjects who are assigned to adalimumab 
40 mg eow at the end of Period 1 will continue to receive adalimumab 40 mg eow in a blinded manner.  
When the last subject completes the last visit of Period 1 (Week 48), study drug assignment in both 
periods will be unblinded to the Sponsor and sites, and subjects will be dispensed study drug in an 
open-label fashion until the completion of Period 2.
Each subject will undergo an x-ray examination of bilateral hands and feet at Week 96/Premature 
Discontinuation (unless repeat testing is needed due to failure to meet the quality requirements) and every 
96 weeks thereafter.  Subjects who prematurely discontinue from the study will not need an x-ray of 
hands and feet if the previous x-ray was performed within the previous
weeks.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who fulfill the 2010 ACR/EULAR classification criteria for RA.
3.
Subjects must have been on oral or parenteral MTX therapy ≥ 3 months and on a stable prescription 
of 15 to 25 mg/week (or ≥ 10 mg/week in subjects intolerant of MTX at doses ≥ 12.5 mg/week) for 
≥4 weeks prior to the first dose of study drug.  In addition, all subjects should take a dietary 
supplement of folic acid or folinic acid throughout the study participation.

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Diagnosis and Main Criteria for Inclusion/Exclusion (Continued):  
Main Inclusion:  
4.
Subject meets both of the following disease activity criteria:
c.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at 
Screening and Baseline Visits; and
d.
hsCRP ≥ 5 mg/L (central lab, ULN 2.87 mg/L) at Screening Visit.
5.
Subject has at least one of the following at Screening:  
d.
≥ 3 bone erosions on x-ray; or
e.
≥ 1 bone erosion and a positive rheumatoid factor; or
f.
≥ 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibody.
6.
Subjects with prior exposure to only one bDMARD (except ADA) may be enrolled (up to 20% of 
total study population).  Specifically, prior to enrollment:  
a.
Patients with limited exposure to a bDMARD (< 3 months), OR
b.
Patients who are responding to a bDMARD but had to discontinue due to intolerability 
(regardless of treatment duration).
7.
Except for MTX, subject must have discontinued all csDMARDs.  The washout period for 
csDMARDs prior to the first dose of study is specified below or should be at least five times the 
mean terminal elimination half-life of a drug:
o
≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, sulfasalazine, 
hydroxychloroquine, chloroquine, azathioprine, gold formulations, cyclophosphamide, 
tacrolimus, cyclosporine, mycophenolate;
o
≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination procedure was 
followed, or adhere to an elimination procedure (i.e., 11 days with colestyramine, or 30 days 
washout with activated charcoal or as per local label).
Main Exclusion:
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects who have had any exposure to adalimumab or subjects who have been treated with other 
bDMARD therapy for ≥ 3 months who are considered inadequate responders (lack of efficacy) to 
bDMARD therapy as determined by the Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms], or any arthritis with onset prior to 
age 17 years).  History of secondary Sjogren's Syndrome is permitted.
4.
Laboratory values meeting the following criteria within the Screening period prior to the first dose of 
study drug: serum aspartate transaminase > 2 × ULN; serum alanine transaminase > 2 × ULN; 
estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease 
formula < 40 mL/min/1.73m2; total white blood cell count < 2,500/μL; absolute neutrophil count 
< 1,500/μL; platelet count < 100,000/μL; absolute lymphocyte count < 800/μL; and hemoglobin 
< 10 g/dL.

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Investigational Product:
ABT-494
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
ADA, matching placebo for ADA, matching placebo for ABT-494
Dose:
ADA 40 mg eow, matching placebo for ABT-494 QD, and matching 
placebo for ADA eow
Mode of Administration:
ADA and matching placebo for ADA will be administered by 
subcutaneous injection eow and ABT-494 and matching placebo will be 
given orally QD
Duration of Treatment:  Period 1:  48 weeks; Period 2:  up to 5 years
Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response at Week 12 
(US/FDA regulatory purposes) or the proportion of subjects achieving clinical remission (CR) based on 
Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12 (EU/EMA regulatory purposes).
ACR20 response rate will be determined based on 20% or greater improvement in TJC and SJC and ≥3 
of the 5 measures of Patient's Assessment of Pain (Visual Analog Scale [VAS]), Patient's Global 
Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease Activity (VAS), 
Health Assessment Questionnaire Disability Index (HAQ-DI), or hsCRP.
CR is defined as DAS28 (CRP) < 2.6. 
Key secondary endpoints (ABT-494 versus placebo if not otherwise specified) for US/FDA regulatory 
purposes are:
1.
Change from baseline in Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12;
2.
Change from baseline in mTSS at Week 26;
3.
Change from baseline in HAQ-DI at Week 12;
4.
ACR50 response rate at Week 12 (non-inferiority of ABT-494 versus ADA);
5.
Change from baseline in Short Form 36 (SF-36) Physical Component Score (PCS) at Week 12;
6.
Proportion of subjects achieving low disease activity (LDA) based on DAS28 [CRP] ≤ 3.2 at 
Week 12;
7.
Proportion of subjects achieving clinical remission (CR) based on DAS28 (CRP) at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index (CDAI) at Week 12;
9.
Change from baseline in morning stiffness at Week 12;
10. Change from baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) at 
Week 12;
11. ACR50 response rate at Week 12 (superiority of ABT-494 vs. ADA);
12. Change from baseline in Patient's Assessment of Pain at Week 12 (superiority of ABT-494 vs. 
ADA);
13. Change from baseline in HAQ-DI at Week 12 (superiority of ABT-494 vs. ADA).

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Key secondary endpoints (ABT-494 versus placebo if not otherwise specified) for EU/EMA regulatory 
purposes are:
1.
The change from baseline in modified Total Sharp Score (mTSS) at Week 26;
2.
Proportion of subjects achieving LDA based on DAS28 [CRP] ≤ 3.2 at Week 12;
3.
Change from baseline in DAS28 (CRP) at Week 12;
4.
Change from baseline in HAQ-DI at Week 12;
5.
ACR20 response rate at Week 12;
6.
ACR50 response rate at Week 12;
7.
ACR70 response rate at Week 12;
8.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 (non-inferiority of 
ABT-494 versus ADA);
9.
Change from baseline in SF-36 PCS at Week 12;
10. Change from baseline in FACIT-F at Week 12;
11. Proportion of subjects with no radiographic progression (defined as change from baseline mTSS ≤ 0) 
at Week 26;
12. Change from baseline in RA-WIS at Week 12;
13. Change from baseline in morning stiffness at Week 12.
Additional endpoints are:
!
Change from baseline in individual components of ACR response at all visits;
!
ACR20/50/70 response rates at all visits;
!
Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]) at all 
visits;
!
Change from baseline in CDAI and SDAI at all visits;
!
Proportions of subjects achieving LDA or CR based on DAS28 (CRP) and DAS28 (ESR), 
Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) criteria 
at all visits (see below); 
!
Change from baseline in EQ-5D-5L, SF-36, FACIT-F and RA-WIS at Weeks 12, 26, and 48;
!
Change from baseline in modified Total Sharp Score (mTSS) at Weeks 26 and 48;
!
Proportion of subjects with no radiographic progression (defined as change from baseline 
mTSS ≤ 0) at Weeks 26 and 48;
!
Change from baseline in joint space narrowing score and joint erosion score at Weeks 26 and 
48;
!
Change from baseline in morning stiffness at all visits;
!
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as change 
from baseline in HAQ-DI ≤ –0.3) at all visits;
!
ACR/EULAR Boolean remission at all visits.

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Criteria for Evaluation (Continued):
Efficacy (Continued):
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 60, 72, 84, 96, and every 12 weeks thereafter until completion of the study:
!
ACR20/50/70 response rates;
!
Change from baseline in individual ACR components;
!
Change from baseline in DAS28 (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in morning stiffness;
!
Proportion of subjects achieving LDA and the proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);
!
Concomitant corticosteroid use (systemic use and intra-articular injections);
!
ACR/EULAR Boolean remission.
Additionally, assessment for the evaluation of radiographic changes in Period 2 will occur at Week 96 
and every 96 weeks thereafter (or Premature Discontinuation visit):
!
Change from baseline in modified Total Sharp Score (mTSS);
!
Proportion of subjects with no radiographic progression (defined as change from baseline in 
mTSS of ≤ 0);
!
Change from baseline in Radiographic joint space narrowing and erosion scores.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of ABT-494 and possibly other medications in plasma will be collected at 
Weeks 2, 4, 8, 12, 14, 18, 22, 26, 30, 36, 42, and 48/Premature Discontinuation.  
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
Prognostic, predictive, and pharmacodynamics biomarkers signatures may be evaluated.  Samples for 
pharmacogenetic, epigenetic, transcriptomic, and proteomic and targeted protein investigations will be 
collected at various time points.  Assessments will include but may not be limited to nucleic acids, 
proteins, metabolites, or lipids.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.

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Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Period 1 Efficacy
Analysis of the Primary and Key Secondary Endpoints:
All statistical comparisons of ABT-494 versus comparators for the primary and key secondary endpoints 
will be conducted using a two-sided alpha = 0.05 level of significance.
In order to preserve Type I error, a step-down approach will be used to test the primary and key 
secondary endpoints where statistical significance can be claimed for a lower ranked endpoint only if the 
previous endpoints in the sequence meets the requirements of significance.
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between ABT-494 and placebo will be conducted using the Cochran-Mantel-Haenszel test 
adjusting for main stratification factors.  For LDA response rates at Week 12, analysis will be conducted 
to test the non-inferiority of ABT-494 versus ADA using the 95% confidence interval of treatment 
difference against a non-inferiority margin of 10%.  For ACR50 response rate at Week 12, similar 
analysis of non-inferiority will be conducted for US/FDA purposes.  Superiority of ABT-494 vs ADA 
will also be tested for LDA and ACR50.
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Pairwise comparisons between ABT-494 and placebo will be carried out using the 
analysis of covariance model with treatment group as the fixed factor, and the corresponding baseline 
value and the main stratification factors as the covariates.  For change from baseline in patient's global 
assessment of pain and change from baseline in HAQ-DI at Week 12, superiority of ABT-494 vs 
adalimumab will also be tested for US/FDA purposes.
For mTSS-based endpoints, both linear extrapolation and As Observed (AO) analyses will be conducted.  
For all other endpoints, non-responder imputation approach will serve as the primary analysis approach 
for binary endpoints and multiple imputation will serve as the primary analysis approach for key 
continuous endpoints.  Sensitivity analyses based on observed cases approach will also be conducted for 
key endpoints.
Long-Term Efficacy for Period 1 and Period 2 Combined
Long-term efficacy by time point will be summarized using descriptive statistics.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values of ABT-494 oral clearance (CL/F) and volume 
of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of the data.

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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Analyses will be conducted for Period 1 alone, as well as for Period 1 
and Period 2 combined.  Safety will be assessed by AEs, physical examination, laboratory assessments, 
ECG, and vital signs.  Frequency tables and lists of subjects with treatment-emergent AEs by preferred 
term as in the Medical Dictionary for Regulatory Activities dictionary, by system organ class, by 
severity, and by relationship to the study drug as assessed by the Investigator will be provided.  The 
changes from baseline in vital signs, physical examination results, and clinical laboratory values will be 
analyzed in a descriptive manner.  Shift of laboratory values from baseline to defined time points will be 
tabulated.
Has been changed to read:
AbbVie Inc.
Protocol Number:  M14-465
Name of Study Drug:  Upadacitinib
Phase of Development:  3
Name of Active Ingredient:  Upadacitinib
Date of Protocol Synopsis:  01 December 2017
Protocol Title:  A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib (ABT-494) to 
Placebo and to Adalimumab in Subjects with Moderately to Severely Active Rheumatoid Arthritis Who 
are on a Stable Background of Methotrexate (MTX) and Who Have an Inadequate Response to MTX 
(MTX-IR)
Objectives:
Period 1
4.
To compare the efficacy of upadacitinib 15 mg once daily (QD) versus placebo, and versus 
adalimumab (ADA) for the treatment of signs and symptoms of rheumatoid arthritis (RA) in subjects 
with moderately to severely active RA who are on a stable background of methotrexate (MTX) and 
who have an inadequate response to MTX (MTX-IR).
5.
To compare the efficacy of upadacitinib 15 mg QD versus placebo for the prevention of structural 
progression in RA subjects with moderately to severely active RA who are on a stable background of 
MTX and who have an inadequate response to MTX (MTX-IR).
6.
To compare the safety and tolerability of upadacitinib 15 mg QD versus placebo, and versus ADA in 
subjects with moderately to severely active RA subjects who are on a stable background of MTX and 
who have an inadequate response to MTX (MTX-IR).
Period 2
To evaluate the long-term safety, tolerability, and efficacy of upadacitinib 15 mg QD in subjects with RA 
who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 400

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Study Population:  
Adult female and male subjects who are at least 18 years of age with a diagnosis of RA for ≥ 3 months 
who fulfill the 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for 
RA.  Eligible study subjects must have ≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints 
(based on 68 joint counts) at Screening and Baseline Visits, and high-sensitivity C-reactive protein 
(hsCRP) ≥ 5 mg/L (central lab, upper limit of normal [ULN] 2.87 mg/L) at Screening.  Subjects must 
have been on oral or parenteral MTX therapy ≥ 3 months and on a stable dose for ≥4 weeks prior to the 
first dose of study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at 
doses ≥12.5 mg/week).
Number of Subjects to be Enrolled:  Approximately 1500

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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is a 48-week randomized, 
double-blind, parallel-group, placebo-controlled and active comparator-controlled period designed to 
compare the safety and efficacy of upadacitinib 15 mg QD versus placebo and versus ADA for the 
treatment of signs and symptoms of subjects with moderately to severely active RA who are on a stable
dose of MTX and have an inadequate response to MTX (MTX-IR).  Period 1 is also designed to compare 
the efficacy of upadacitinib 15 mg QD versus placebo for the prevention of structural progression.  
Period 2 is a long-term extension to evaluate the safety, tolerability and efficacy of upadacitinib 15 mg 
QD in subjects with RA who have completed Period 1.
The study duration will include a 35-day screening period; a 48-week randomized, double-blind, 
parallel-group, placebo-controlled and active comparator-controlled treatment period (Period 1); a 
long-term extension period (blinded until the last subject completes the last visit of the double-blind 
treatment period) (up to 5 years) (Period 2); a 30-day follow-up period (call or visit); and a 70-day 
follow-up call.
Subjects who meet eligibility criteria will be randomized in a 2:2:1 ratio to one of three treatment groups: 
!
Group 1:  Upadacitinib (ABT-494) 15 mg QD (N = 600)
!
Group 2:  Placebo (N = 600)
!
Group 3:  ADA (40 mg every other week [eow]) (N = 300)
Subjects will receive both oral study drug QD (either upadacitinib 15 mg or matching placebo) and 
subcutaneous study drug eow (either ADA 40 mg or matching placebo) until the study is unblinded.
Subjects must have been on oral or parenteral MTX therapy for ≥ 3 months, on a stable MTX dose for 
≥4 weeks prior to the first dose of study drug (15 to 25 mg/week; or ≥ 10 mg/week in subjects who are 
intolerant of MTX at doses ≥ 12.5 mg/week), and must remain on a stable dose throughout the study; the 
MTX dose may be decreased only for safety reasons.  In addition, all subjects should take a dietary 
supplement of oral folic acid (or equivalent) throughout study participation.  Folic acid dosing and timing 
of regimen should be followed according to the Investigator's instructions.  Starting at the Week 26 visit 
(after Week 26 assessments have been performed), initiation of or change in background RA 
medication(s) including, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, is allowed as per local label.  Starting at Week 48 (after Week 48 
assessments have been performed) and thereafter, initiation of or change in  csDMARDs is allowed as 
per local label (restricted to oral or parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and 
leflunomide, and restricted to concomitant use of up to 2 csDMARDs except the combination of MTX 
and leflunomide).
Subjects with prior exposure to at most one biologic disease-modifying anti-rheumatic drug (bDMARD) 
(except ADA) for RA may be enrolled in the study (up to 20% of total number of subjects) after the 
required washout period is satisfied and if they have a) limited bDMARD exposure (< 3 months), OR 
b) response to a bDMARD but had to discontinue that bDMARD due to intolerability (regardless of 
treatment duration).  These subjects will be equally stratified across all treatment groups.  Subjects who 
are considered bDMARD-inadequate responders (lack of efficacy), as determined by the Investigator, are 
not eligible.
Rescue therapy will be offered to subjects who meet the following criteria:

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Methodology (Continued):
Placebo:
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded upadacitinib treatment.
!
At Week 26, all remaining subjects will be switched to blinded upadacitinib treatment regardless 
of clinical response.
ADA:  
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded upadacitinib treatment.
!
At Week 26, all remaining subjects who do not achieve LDA according to CDAI (LDA defined 
as CDAI ≤10) at Week 26 will be switched to blinded upadacitinib treatment.
Upadacitinib:
!
Subjects who do not achieve a ≥ 20% improvement in TJC and SJC at Weeks 14, 18, or 22 
compared to baseline will be switched to blinded ADA treatment.
!
At Week 26, all remaining subjects who do not achieve LDA according to CDAI (LDA defined 
as CDAI ≤10) at Week 26 will be switched to blinded ADA treatment.
An unblinded analysis will be conducted after all subjects have completed Week 26 for the purpose of 
regulatory submission.  To maintain integrity of the trial and avoid introduction of bias, study sites and 
subjects will remain blinded for the duration of Period 1.  Additional unblinded analyses may be 
conducted after the Week 26 unblinded analysis for regulatory purposes.
Each subject will undergo a maximum of 5 scheduled visits for x-ray examination of bilateral hands and 
feet during Period 1 (unless unscheduled repeat imaging is needed due to failure to meet the quality 
requirements) at Screening, Week 26, and Week 48/Premature Discontinuation.  Subjects who are non-
responders (defined as those not achieving ≥ 20% improvement in TJC and SJC criterion) at Week 14 
and are switched to rescue therapy will have an x-ray examination at Week 14; in addition, subjects who 
prematurely discontinue from study drug or the study
will have an 
x-ray examination at the premature discontinuation timepoint.
Subjects who complete the Week 48 visit (end of Period 1) will enter the long-term extension portion of 
the study, Period 2 (up to 5 years).  Subjects will continue study treatment as assigned in Period 1.  
Subjects who are assigned to the upadacitinib 15 mg QD treatment group at the end of Period 1 will 
continue to receive upadacitinib 15 mg QD in a blinded manner.  Subjects who are assigned to 
adalimumab 40 mg eow at the end of Period 1 will continue to receive adalimumab 40 mg eow in a 
blinded manner.  When the last subject completes the last visit of Period 1 (Week 48), study drug 
assignment in both periods will be unblinded to the Sponsor and sites, and subjects will be dispensed 
study drug in an open-label fashion until the completion of Period 2.
Each subject will undergo an x-ray examination of bilateral hands and feet at Week 96/Premature 
Discontinuation (unless repeat testing is needed due to failure to meet the quality requirements) and every 
96 weeks thereafter.  Subjects who prematurely discontinue from the study will not need an x-ray of 
hands and feet if the previous x-ray was performed within the previous
weeks.

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Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
1.
Adult male or female, at least 18 years old.
2.
Diagnosis of RA for ≥ 3 months who fulfill the 2010 ACR/EULAR classification criteria for RA.
3.
Subjects must have been on oral or parenteral MTX therapy ≥ 3 months and on a stable prescription 
of 15 to 25 mg/week (or ≥ 10 mg/week in subjects intolerant of MTX at doses ≥ 12.5 mg/week) for 
≥4 weeks prior to the first dose of study drug.  In addition, all subjects should take a dietary 
supplement of folic acid or folinic acid throughout the study participation.
4.
Subject meets both of the following disease activity criteria:
e.
≥ 6 swollen joints (based on 66 joint counts) and ≥ 6 tender joints (based on 68 joint counts) at 
Screening and Baseline Visits; and
f.
hsCRP ≥ 5 mg/L (central lab, ULN 2.87 mg/L) at Screening Visit.
5.
Subject has at least one of the following at Screening:  
g.
≥ 3 bone erosions on x-ray; or
h.
≥ 1 bone erosion and a positive rheumatoid factor; or
i.
≥ 1 bone erosion and a positive anti-cyclic citrullinated peptide autoantibody.
6.
Subjects with prior exposure to only one bDMARD (except ADA) may be enrolled (up to 20% of 
total study population).  Specifically, prior to enrollment:  
a.
Patients with limited exposure to a bDMARD (< 3 months), OR
b.
Patients who are responding to a bDMARD but had to discontinue due to intolerability
(regardless of treatment duration).
7.
Except for MTX, subject must have discontinued all csDMARDs.  The washout period for 
csDMARDs prior to the first dose of study is specified below or should be at least five times the 
mean terminal elimination half-life of a drug:
o
≥ 4 weeks prior to first dose of study drug for minocycline, penicillamine, sulfasalazine, 
hydroxychloroquine, chloroquine, azathioprine, gold formulations, cyclophosphamide, 
tacrolimus, cyclosporine, mycophenolate;
o
≥ 8 weeks prior to first dose of study drug for leflunomide if no elimination procedure was 
followed, or adhere to an elimination procedure (i.e., 11 days with colestyramine, or 30 days 
washout with activated charcoal or as per local label).

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Main Exclusion:
1.
Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, 
baricitinib, and filgotinib).
2.
Subjects who have had any exposure to adalimumab or subjects who have been treated with other 
bDMARD therapy for ≥ 3 months who are considered inadequate responders (lack of efficacy) to 
bDMARD therapy as determined by the Investigator.
3.
History of any arthritis with onset prior to age 17 years or current diagnosis of inflammatory joint 
disease other than RA (including but not limited to gout, systemic lupus erythematosus, psoriatic 
arthritis, axial spondyloarthritis including ankylosing spondylitis and non-radiographic axial 
spondyloarthritis, reactive arthritis, overlap connective tissue diseases, scleroderma, polymyositis, 
dermatomyositis, fibromyalgia [currently with active symptoms], or any arthritis with onset prior to 
age 17 years).  History of secondary Sjogren's Syndrome is permitted.
4.
Laboratory values meeting the following criteria within the Screening period prior to the first dose of 
study drug: serum aspartate transaminase > 2 × ULN; serum alanine transaminase > 2 × ULN; 
estimated glomerular filtration rate by simplified 4-variable Modification of Diet in Renal Disease 
formula < 40 mL/min/1.73m2; total white blood cell count < 2,500/μL; absolute neutrophil count 
< 1,500/μL; platelet count < 100,000/μL; absolute lymphocyte count < 800/μL; and hemoglobin 
< 10 g/dL.
Investigational Product:
Upadacitinib
Dose:
15 mg QD
Mode of Administration:
Oral
Reference Therapy:
ADA, matching placebo for ADA, matching placebo for upadacitinib
Dose:
ADA 40 mg eow, matching placebo for upadacitinib QD, and matching 
placebo for ADA eow
Mode of Administration:
ADA and matching placebo for ADA will be administered by 
subcutaneous injection eow and upadacitinib and matching placebo will 
be given orally QD
Duration of Treatment:  Period 1:  48 weeks; Period 2:  up to 5 years

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Criteria for Evaluation:
Efficacy:
Period 1
The primary endpoint in Period 1 is the proportion of subjects achieving ACR20 response at Week 12 
(US/FDA regulatory purposes) or the proportion of subjects achieving clinical remission (CR) based on 
Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12 (EU/EMA regulatory purposes).
ACR20 response rate will be determined based on 20% or greater improvement in TJC and SJC and ≥3 
of the 5 measures of Patient's Assessment of Pain (Visual Analog Scale [VAS]), Patient's Global 
Assessment of Disease Activity (VAS), Physician's Global Assessment of Disease Activity (VAS), 
Health Assessment Questionnaire Disability Index (HAQ-DI), or hsCRP.
CR is defined as DAS28 (CRP) < 2.6. 
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) for US/FDA 
regulatory purposes are:
1.
Change from baseline in Disease Activity Score (DAS)28 (C-reactive protein [CRP]) at Week 12;
2.
Change from baseline in mTSS at Week 26;
3.
Change from baseline in HAQ-DI at Week 12;
4.
ACR50 response rate at Week 12 (non-inferiority of upadacitinib versus ADA);
5.
Change from baseline in Short Form 36 (SF-36) Physical Component Score (PCS) at Week 12;
6.
Proportion of subjects achieving low disease activity (LDA) based on DAS28 [CRP] ≤ 3.2 at 
Week 12;
7.
Proportion of subjects achieving clinical remission (CR) based on DAS28 (CRP) at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index (CDAI) at Week 12;
9.
Change from baseline in morning stiffness at Week 12;
10. Change from baseline in Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F) at 
Week 12;
11. ACR50 response rate at Week 12 (superiority of upadacitinib vs. ADA);
12. Change from baseline in Patient's Assessment of Pain at Week 12 (superiority of upadacitinib vs. 
ADA);
13. Change from baseline in HAQ-DI at Week 12 (superiority of upadacitinib vs. ADA).

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Other key secondary endpoints (upadacitinib versus placebo) for US/FDA regulatory purposes are:
!
ACR50 response rate at Week 12
!
ACR70 response rate at Week 12
!
Proportion of subjects with no radiographic progression (defined as change from baseline mTSS 
≤ 0) at Week 26
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) for EU/EMA 
regulatory purposes are:
1.
The change from baseline in modified Total Sharp Score (mTSS) at Week 26;
2.
Proportion of subjects achieving LDA based on DAS28 [CRP] ≤ 3.2 at Week 12;
3.
Change from baseline in DAS28 (CRP) at Week 12;
4.
Change from baseline in HAQ-DI at Week 12;
5.
ACR20 response rate at Week 12;
6.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 (non-inferiority of 
upadacitinib versus ADA);
7.
Change from baseline in SF-36 PCS at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index (CDAI) at Week 12
9.
Change from baseline in morning stiffness at Week 12.
10. Change from baseline in FACIT-F at Week 12
11. Proportion of subjects with no radiographic progression (defined as change from baseline mTSS ≤ 0) 
at Week 26;
Other key secondary endpoints (upadacitinib versus placebo) for EU/EMA regulatory purposes are:
1.
ACR50 response rate at Week 12
2.
ACR70 response rate at Week 12

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Criteria for Evaluation (Continued):
Efficacy (Continued):
Additional endpoints (upadacitinib versus placebo and adalimumab) are:
!
Change from baseline in individual components of ACR response at all visits;
!
ACR20/50/70 response rates at all visits;
!
Change from baseline in DAS28(CRP) and DAS28 (erythrocyte sedimentation rate [ESR]) at all 
visits;
!
Change from baseline in CDAI and SDAI at all visits;
!
Proportion of subjects achieving LDA or CR based on DAS28 (CRP) and DAS28 (ESR), 
Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) criteria 
at all visits (see below); 
!
Change from baseline in morning stiffness at all visits; 
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22 at all visits;
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3 at all visits; 
!
ACR/EULAR Boolean remission at all visits;
!
Change from baseline in EQ-5D-5L, SF-36, FACIT-F and RA-WIS at Weeks 12, 26, and 48;
!
Change from baseline in modified Total Sharp Score (mTSS) at Weeks 26 and 48;
!
Proportion of subjects with no radiographic progression (defined as change from baseline 
mTSS ≤ 0) at Weeks 26 and 48;
!
Change from baseline in joint space narrowing score and joint erosion score at Weeks 26 and 48

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Criteria for Evaluation (Continued):
Efficacy (Continued):
DAS28 (CRP) and DAS28 (ESR)
SDAI
CDAI
LDA
≤ 3.2
≤ 11.0
≤ 10
CR
< 2.6
≤ 3.3
≤ 2.8
Period 2
Assessments to evaluate efficacy of treatment in Period 2 will be analyzed for the following measures at 
Weeks 60, 72, 84, 96, and every 12 weeks thereafter until completion of the study:
!
ACR20/50/70 response rates;
!
Change from baseline in individual ACR components;
!
Change from baseline in DAS28 (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in CDAI and SDAI;
!
Change from baseline in morning stiffness;
!
Proportion of subjects achieving LDA and the proportion of subjects achieving CR based on 
DAS28 (CRP), DAS28 (ESR), SDAI, and CDAI criteria (as defined for Period 1);
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
!
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;
!
Concomitant corticosteroid use (systemic use and intra-articular injections);
!
ACR/EULAR Boolean remission.
Additionally, assessment for the evaluation of radiographic changes in Period 2 will occur at Week 96 
and every 96 weeks thereafter (or Premature Discontinuation visit):
!
Change from baseline in modified Total Sharp Score (mTSS);
!
Proportion of subjects with no radiographic progression (defined as change from baseline in 
mTSS of ≤ 0);
!
Change from baseline in Radiographic joint space narrowing and erosion scores.
Pharmacokinetic (Period 1 Only):
Blood samples for assay of upadacitinib and possibly other medications in plasma will be collected at 
Weeks 2, 4, 8, 12, 14, 18, 22, 26, 30, 36, 42, and 48/Premature Discontinuation.  
Exploratory Research Variables and Validation Studies (Optional) (Period 1 Only):
Prognostic, predictive, and pharmacodynamics biomarkers signatures may be evaluated. Samples for 
pharmacogenetic, epigenetic, transcriptomic, and proteomic and targeted protein investigations will be 
collected at various time points.  Assessments will include but may not be limited to nucleic acids, 
proteins, metabolites, or lipids.
Safety:
Safety evaluations include adverse event (AE) monitoring, physical examinations, vital sign 
measurements, electrocardiogram (ECG), and clinical laboratory testing (hematology, chemistry, and 
urinalysis) as a measure of safety and tolerability for the entire study duration.

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Statistical Methods:
Efficacy:
All efficacy analyses will be carried out using the Full Analysis Set population, which includes all 
randomized subjects who receive at least one dose of study drug.
Period 1 Efficacy
Analysis of the Primary and Key Secondary Endpoints:
All statistical comparisons of upadacitinib versus comparators for the primary and key 
secondary endpoints will be conducted using a two-sided alpha = 0.05 level of significance.
In order to preserve Type I error, a step-down approach will be used to test the primary and ranked key 
secondary endpoints where statistical significance can be claimed for a lower ranked endpoint only if the 
previous endpoints in the sequence meets the requirements of significance.
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between upadacitinib and placebo will be conducted using the Cochran-Mantel-Haenszel 
test adjusting for main stratification factors.  For LDA response rates at Week 12, analysis will be 
conducted to test the non-inferiority of upadacitinib versus ADA using the 95% confidence interval of 
treatment difference against a non-inferiority margin of 10%.  For ACR50 response rate at Week 12, 
similar analysis of non-inferiority will be conducted for US/FDA purposes.  Superiority of upadacitinib
vs ADA will also be tested for LDA and ACR50.
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Pairwise comparisons between upadacitinib and placebo will be carried out using the 
analysis of covariance model with treatment group as the fixed factor, and the corresponding baseline 
value and the main stratification factors as the covariates.  For change from baseline in patient's global 
assessment of pain and change from baseline in HAQ-DI at Week 12, superiority of upadacitinib vs 
adalimumab will also be tested.
For mTSS-based endpoints, both linear extrapolation and As Observed (AO) analyses will be conducted.  
For all other endpoints, non-responder imputation approach will serve as the primary analysis approach 
for key binary endpoints and multiple imputation will serve as the primary analysis approach for key 
continuous endpoints.  Sensitivity analyses based on observed cases approach will also be conducted for 
key endpoints.
Long-Term Efficacy for Period 1 and Period 2 Combined
Long-term efficacy by time point will be summarized using descriptive statistics.
Pharmacokinetic:
A non-linear mixed-effects modeling approach will be used to estimate the population central values and 
the empirical Bayesian estimates of the individual values of upadacitinib oral clearance (CL/F) and 
volume of distribution (V/F).  Additional parameters may be estimated if useful in the interpretation of 
the data.

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Statistical Methods (Continued):
Safety:
Safety analyses will be carried out using the Safety Analysis Set, which includes all subjects who receive 
at least one dose of study drug.  Analyses will be conducted for both short term and long term.  Safety 
will be assessed by AEs, physical examination, laboratory assessments, ECG, and vital signs.  Frequency 
tables and lists of subjects with treatment-emergent AEs by preferred term as in the Medical Dictionary 
for Regulatory Activities dictionary, by system organ class, by severity, and by relationship to the study 
drug as assessed by the Investigator will be provided.  The changes from baseline in vital signs, physical 
examination results, and clinical laboratory values will be analyzed in a descriptive manner.  Shift of 
laboratory values from baseline to defined time points will be tabulated.
Section 1.3  List of Abbreviations and Definition of Terms
Subsection Abbreviations
Add:  MCID
MCID
minimum clinically important differences
Section 5.1  Overall Study Design and Plan:  Description
Third paragraph previously read:
The study duration will include a 35-day screening period; a 48-week randomized, 
double-blind, parallel-group, placebo-controlled and active comparator-controlled 
treatment period (Period 1); a long-term extension period (blinded until the last subject 
completes Week 48 the last visit of the double-blind treatment period) (up to 5 years) 
(Period 2); a 30-day follow-up period (call or visit); and a 70-day follow-up call.
Has been changed to read:
The study duration will include a 35-day screening period; a 48-week randomized, 
double-blind, parallel-group, placebo-controlled and active comparator-controlled 
treatment period (Period 1); a long-term extension period (blinded until the last subject 
completes Period 1) (up to 5 years) (Period 2); a 30-day follow-up period (call or visit); 
and a 70-day follow-up call.

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Section 5.1  Overall Study Design and Plan:  Description
Sixth paragraph, fourth sentence previously read:
Starting at the Week 26 visit (after Week 26 assessments have been performed), initiation 
of or change in background RA medication(s) including, corticosteroids, non-steroidal 
anti-inflammatory drugs (NSAIDs), acetaminophen, and csDMARDs (concomitant use of 
up to 2 csDMARDs except the combination of MTX and leflunomide) is allowed as per 
local label.
Has been changed to read:
Starting at the Week 26 visit (after Week 26 assessments have been performed) and 
thereafter, initiation of or change in background RA medication(s) including, 
corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol is allowed as per local label.  Starting at Week 48 (after 
Week 48 assessments have been performed) and thereafter, initiation of or change in 
csDMARDs is allowed as per local label (restricted to oral or parenteral MTX, 
sulfasalazine, hydroxychloroquine, chloroquine and leflunomide, and restricted to 
concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide).
Section 5.1  Overall Study Design and Plan:  Description
Add:  new seventh paragraph
Starting at the Week 48 and thereafter, at least 20% improvement in BOTH TJC AND 
SJC compared to baseline is required to remain on study drug.  Anyone who does not 
fulfill this criterion at 2 consecutive visits (starting at Week 48) (see Section 5.4.1) must 
be discontinued from study drug.
Section 5.1  Overall Study Design and Plan:  Description
Ninth paragraph previously read:
An unblinded analysis will be conducted after all subjects have completed Week 26 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 

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Period 1.  Another unblinded analysis may be conducted for regulatory purposes after all 
subjects have completed Period 1 (Week 48).
Has been changed to read:
An unblinded analysis will be conducted after all subjects have completed Week 26 for 
the purpose of regulatory submission.  To maintain integrity of the trial and avoid 
introduction of bias, study sites and subjects will remain blinded for the duration of 
Period 1.  Additional unblinded analyses may be conducted after the Week 26 unblinded 
analysis for regulatory purposes.
Overall Study Design and Plan:  Description
Tenth paragraph previously read:
Each subject will undergo a maximum of 4 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 1 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 26, and 
Week 48/Premature Discontinuation; in addition, all subjects who are non-responders 
(defined as those not achieving ≥ 20% improvement in TJC and SJC criterion) at Week 14 
and are switched to rescue therapy will have an x-ray examination at Week 14 (refer to 
Section 5.3.1.1 for additional details).
Has been changed to read:
Each subject will undergo a maximum of 5 scheduled visits for x-ray examination of 
bilateral hands and feet during Period 1 (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 26, and 
Week 48/Premature Discontinuation.  Subjects who are non-responders (defined as those 
not achieving ≥ 20% improvement in TJC and SJC criterion) at Week 14 and are switched 
to rescue therapy will have an x-ray examination at Week 14; in addition, subjects who 
prematurely discontinue from study drug or the study 
will have an x-ray examination at the premature discontinuation timepoint (refer to 
Section 5.3.1.1 for additional details).

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Figure 1.  Period 1 Study Design
Previously read:
BL = baseline; EOW = every other week; MTX = methotrexate; QD = once daily; RA = rheumatoid arthritis; SJC = 
swollen joint count; TJC = tender joint count; W = week
#
At W26, all placebo patients will be switched to ABT-494 15 mg regardless of response.
**
All patients will receive x-rays of hands and feet at Screening, W26, and W48.
*** X-rays at W14 will only be performed for non-responders, see Section 5.3.1.1.
Notes:
The follow-up period is only for subjects who do not enter Period 2.
Early escape for non-responders:  (a) from ABT-494 15 mg QD to adalimumab at W14, W18, W22, or W26; (b) from 
placebo to ABT-494 15 mg QD at W14, W18, or W22; (c) from adalimumab to ABT-494 15 mg QD at W14, W18, 
W22, or W26.  Non-response at W14, W18, or W22 is defined as not achieving ≥ 20% improvement in TJC and 
SJC compared to baseline.  Non-response at W26 is defined as not achieving LDA according to CDAI (LDA 
defined as CDAI ≤ 10).  For more details regarding x-rays of hands and feet, see Section 5.3.1.1.

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Has been changed to read:
BL = baseline; EOW = every other week; MTX = methotrexate; QD = once daily; RA = rheumatoid arthritis; 
SJC = swollen joint count; TJC = tender joint count; W = week
#
At W26, all placebo patients will be switched to upadacitinib 15 mg regardless of response.
**
All patients will receive x-rays of hands and feet at Screening, W26, and W48.
*** X-rays at W14 will only be performed for non-responders, see Section 5.3.1.1.
Notes:
The follow-up period is only for subjects who do not enter Period 2.
Early escape for non-responders:  (a) from upadacitinib 15 mg QD to adalimumab at W14, W18, W22, or 
W26; (b) from placebo to upadacitinib 15 mg QD at W14, W18, or W22; (c) from adalimumab to upadacitinib 
15 mg QD at W14, W18, W22, or W26.  Non-response at W14, W18, or W22 is defined as not achieving 
≥20% improvement in TJC and SJC compared to baseline.  Non-response at W26 is defined as not achieving 
LDA according to CDAI (LDA defined as CDAI ≤ 10).  For more details regarding x-rays of hands and feet, 
see Section 5.3.1.1.

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Section 5.1  Overall Study Design and Plan:  Description
Subsection Period 2 (Long-Term Extension Period [up to 5 years])
Last sentence previously read:
Starting at Week 48, subjects who failed to show at least 20% improvement in TJC and 
SJC compared to baseline at 2 consecutive visits (see Section 5.4.1 will be discontinued 
from study drug treatment.
Has been changed to read:
Starting at Week 48 and thereafter, at least 20% improvement in BOTH TJC AND SJC 
compared to baseline is required to remain on study drug.  Anyone who does not fulfill 
this criterion at 2 consecutive visits (starting at Week 48) (see Section 5.4.1) must be 
discontinued from study drug.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Discontinuation of Study Drug and Continuation of Study Participation 
(Period 1 and Period 2)
Add:  new last sentence
If at any point a subject no longer wants to provide assessments (withdrawal of informed 
consent) following discontinuation of study drug, a second PD visit is not required.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation of Study (Withdrawal of Informed Consent) 
(Period 1 and Period 2)
Third sentence previously read:
In addition, if the subject is willing, a 30-day follow-up visit (or phone call if a visit is not 
possible) may occur to determine the status of any ongoing AEs/SAEs or the occurrence 
of any new AEs/SAEs. 
Has been changed to read:
In addition, a 30-day follow-up visit (or phone call if a visit is not possible) may occur to 
determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.

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Section 5.1  Overall Study Design and Plan:  Description
Subsection Premature Discontinuation of Study (Withdrawal of Informed Consent) 
(Period 1 and Period 2)
Add:  new last sentence
The 70-day follow-up phone call will not be required for any subject that initiates 
commercial adalimumab.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Follow-Up Period
Third paragraph previously read:
A follow-up phone call will also occur 70 days after the last administration of study drug 
to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AEs/SAEs.
Has been changed to read:
A follow-up phone call will also occur 70 days after the last administration of 
subcutaneous study drug to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs.  The 70-day follow-up phone call will not be required 
for any subject that initiates commercial adalimumab. 
The 30 day follow-up visit and 70 day follow-up call are not required for subjects who 
discontinued study drug and continued study participation with completion of at least 
one study visit approximately 30 days after last dose of oral or 70 days after last dose of 
subcutaneous study drug, respectively.
Section 5.2.3  Prior, Concomitant, and Prohibited Therapy
Last paragraph previously read:
The AbbVie Therapeutic Area Medical Director should be contacted if there are any 
questions regarding concomitant or prior therapies.

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Has been changed to read:
The AbbVie Therapeutic Area Medical Director identified in Section 6.1.5 (Serious 
Adverse event Reporting) should be contacted if there are any questions regarding 
concomitant or prior therapies.
Section 5.2.3.1  Permitted Background RA Therapy
Last paragraph previously read:
Starting at Week 26 (after Week 26 assessments have been performed) and thereafter, 
initiation of or change in corticosteroids, NSAIDs, acetaminophen/paracetamol, or adding 
or increasing doses of csDMARDs (concomitant use of up to 2 csDMARDs except the 
combination of MTX and leflunomide; see Inclusion Criterion 9, Section 5.2.1) is allowed 
as per local label.  For RA flare treatment, no more than 3 consecutive days of high-dose 
systemic corticosteroids (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent) 
is allowed, after which subject should resume their usual daily oral corticosteroid dose.
Has been changed to read:
Starting at Week 26 (after Week 26 assessments have been performed) and thereafter, 
initiation of or change in corticosteroids, NSAIDs, acetaminophen/paracetamol is allowed 
as per local label.  For RA flare treatment, no more than 3 consecutive days of systemic 
corticosteroids (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent) is 
allowed, after which subject should resume their usual daily oral corticosteroid dose. 
Starting at Week 48 (after Week 48 assessments have been performed) and thereafter 
initiation of or change in csDMARDs is allowed as per local label (restricted to oral or 
parenteral MTX, sulfasalazine, hydroxychloroquine, chloroquine and leflunomide, and 
restricted to concomitant use of up to 2 csDMARDs except the combination of MTX and 
leflunomide; see Inclusion Criterion 9, Section 5.2.1).

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Section 5.2.3.2  Prohibited Therapy
Subsection Corticosteroids
First sentence previously read:
Oral corticosteroids > 10 mg prednisone/day or equivalent are NOT allowed in Period 1.  
Has been changed to read:
Oral corticosteroids > 10 mg prednisone/day or equivalent are NOT allowed up to 
Week 26.  
Table 1.  Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Column "Strong CYP3A Inducers"
Add:  Rifapentine
Rifapentine
Section 5.2.3.2  Prohibited Therapy
Subsection Vaccines
First paragraph previously read:
Although not mandated by the protocol, vaccines recommended by local guidelines 
should be considered.  If the subject and investigator choose to administer live vaccines, 
these vaccinations must be completed (per local label) 4 weeks before first dose of study 
drug with appropriate precautions or administered at least 30 days after last dose of oral 
study drug, or at least 70 days after last dose of subcutaneous study drug.
Has been changed to read:
Vaccines recommended by local guidelines should be considered.  If the investigator 
chooses to administer a vaccine, this should be completed before first dose of study drug 
with appropriate precautions and time interval.  It is recommended that subjects be up to 
date for recommended inactivated, toxoid or biosynthetic vaccines, such as injectable flu 
vaccine, pneumococcal, and pertussis (Tdap).  It is recommended that the live herpes 
zoster vaccine should be considered for administration at least 4 weeks before first dose of 
study drug or administered at least 30 days after last dose of oral study drug, or at least 

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70 days after the last dose of subcutaneous study drug.  If the herpes zoster vaccine is to 
be administered, and there is no known history of primary varicella (chicken pox), pre-
existing immunity to varicella should be confirmed with antibody testing at or prior to 
screening and prior to administration of the herpes zoster vaccine.  If screening varicella 
antibody testing is negative the herpes zoster vaccine should not be administered.  
If the subject and investigator choose to administer live vaccines, these vaccinations must 
be completed (per local label) 4 weeks before first dose of study drug with appropriate 
precautions or administered at least 30 days after last dose of oral study drug, or at least 
70 days after last dose of subcutaneous study drug.
Section 5.2.3.2  Prohibited Therapy
Subsection Traditional Chinese Medicine
Previously read:
Traditional Chinese medicine (oral) is not permitted during the study, and subjects must 
have discontinued traditional Chinese medicine at least 4 weeks prior to the first dose of 
study drug.
Has been changed to read:
Traditional oral Chinese medicine is not permitted during the study as these may interfere 
with upadacitinib metabolism and exposure and may impact efficacy and safety of 
upadacitinib treatment.  Subjects must have discontinued traditional Chinese medicine at 
least 4 weeks prior to the first dose of study drug.
Section 5.2.4  Contraception Recommendations
Subsection Contraception Recommendation for Females
Third and fourth paragraph previously read:
If the female subject is < 55 years of age:
AND has had no menses for ≥ 12 months AND has no history of permanent surgical 
sterilization (defined above), FSH should be tested at Screening.

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Has been changed to read:
If the female subject is < 55 years of age and is not permanently surgically sterile, as 
defined above, and has had no menses for ≥ 12 months FSH should be tested at Screening.
Section 5.2.4  Contraception Recommendations
Subsection Contraception Recommendation for Females
Add:  new eighth paragraph
If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation is available, contraception measures as defined above are no 
longer required.
Section 5.2.4  Contraception Recommendations
Subsection Contraception Recommendation for Males
Add:  new first paragraph
Based on data from animal studies (including a fertility study) there is no effect of 
upadacitinib on male reproduction.  
Section 5.2.4  Contraception Recommendations
Subsection Contraception Recommendation for Males
First paragraph previously read:
For a male subject who has a female partner who is postmenopausal or permanently 
sterile, no contraception is required.
Has been changed to read:
For a male subject who is surgically sterile (vasectomy with medical assessment 
confirming surgical success) OR has a female partner who is postmenopausal or 
permanently sterile, no contraception is required.

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Section 5.2.4  Contraception Recommendations
Subsection Contraception Recommendation for Males
Second bullet previously read:
True abstinence: Refraining from heterosexual intercourse-when this is in line with the 
preferred and usual lifestyle of the subject.  (Note:  Periodic abstinence (e.g., calendar, 
ovulation, symptothermal, post-ovulation methods and withdrawal are not acceptable).
Has been changed to read:
True abstinence: Refraining from heterosexual intercourse-when this is in line with the 
preferred and usual lifestyle of the subject.  Periodic abstinence (for example, using 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable).

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Table 2.  Study Activities (Period 1)
Activity "Prior/concomitant therapy, "Latent TB risk assessment formi" previously read:
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/
PDa
30-
Day 
F/U 
Visit/
Callc
70-
Day 
F/U 
Callc
Activity
D–35 to 
D–1
D1b
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
Prior/concomitant therapy
X
X
X
X
X
X
X
X
X
Xg
X
X
X
X
X
Latent TB risk assessment 
formi
X
X
Has been changed to read:
Screening
BL
Wk
2
Wk
4
Wk
8
Wk
12
Wk
14
Wk
18
Wk
22
Wk
26
Wk
30
Wk
36
Wk
42
Wk 
48/
PDa
30-
Day 
F/U 
Visit/
Callc
70-
Day 
F/U 
Callc
Activity
D–35 to 
D–1
D1b
D15
D29
D57
D85
D99
D127
D155
D183
D211
D253
D295
D337
Prior/concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
X
Xg
X
Latent TB risk assessment 
formi
X
Xi

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Table 2.  Study Activities (Period 1)
Table note "c."
Add:  new last sentence
The 70 day follow-up phone call will not be required for any subject that initiates 
commercial adalimumab.
Table 2.  Study Activities (Period 1)
Table note "g.," "i.," "j.," "l.," "s.," and "aa." previously read:
g.
At Week 26 (after Week 26 assessments have been performed), per Investigator judgment, may add csDMARDs 
(concomitant use of up to 2 csDMARDs, except the combination of MTX and leflunomide, or increasing 
csDMARD dose).
i.
Refer to Section 5.3.1.1.  Study Procedures TB Testing for specific requirements for TB testing and TB 
Prophylaxis.
j.
The screening chest x-ray will not be required if a subject had a previous normal chest-x-ray within 90 days of 
Screening, provided that all source documentation is available at the site (refer to Section 5.3.1.1 Chest X-Ray for 
specific requirements).  At Week 48, obtain chest x-ray for subjects with TB risk factors as identified by the TB 
risk assessment form for subjects living in areas endemic for TB or for subjects with a newly positive 
QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
l.
For subjects who do not enter Period 2 or prematurely discontinue from the study, an ECG will be performed.
s.
hsCRP results will remain blinded to the Sponsor, Investigator, study site personnel, and the subject for all visits 
except Screening.
aa.
Starting at Week 48, subjects who failed to show at least 20% improvement in TJC and SJC compared to baseline 
at 2 consecutive visits will be discontinued from study drug treatment.
Has been changed to read:
g.
At Week 48 (after Week 48 assessments have been performed), per Investigator judgment, may add or change 
csDMARDs (concomitant use of up to 2 csDMARDs, except the combination of MTX and leflunomide, or 
increasing csDMARD dose).
i.
Complete the latent TB risk assessment form annually.  Refer to Section 5.3.1.1.  Study Procedures TB Testing for 
specific requirements for TB testing and TB Prophylaxis.
j.
The screening chest x-ray will not be required if a subject had a previous normal chest-x-ray within 90 days of 
Screening, provided that all source documentation is available at the site (refer to Section 5.3.1.1 Chest X-Ray for 
specific requirements).  At Week 48, obtain chest x-ray for subjects with newly identified TB risk factors based on 
the TB risk assessment form, or for subjects living in areas endemic for TB, or for subjects with a newly positive 
QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
l.
.All subjects will have an ECG at Week 48 and PD visit as applicable.
s.
Central lab hsCRP results will remain blinded to the Sponsor, Investigator, study site personnel, and the subject for 
all visits except Screening. Results of tests such as hsCRP may be blunted in subjects taking a JAK inhibitor, 
thereby limiting the clinical utility of these tests in the setting of a possible safety assessment or adverse event 
management.  Any local hsCRP or local CRP tests should not be reported to the investigator until treatment 
allocation is unblinded.

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aa.
Starting at Week 48, subjects who failed to show at least 20% improvement in both TJC and SJC compared to 
baseline at 2 consecutive visits will be discontinued from study drug treatment.
Table 4.  Study Activities (Period 2)
Table note "d.," "e.," "f.," and "l." previously read:
d.
TB testing should be performed every 48 weeks after Week 96 in subjects with previous negative Quantiferon 
and/or PPD tests.  Subjects with new evidence of latent TB should initiate prophylactic treatment immediately per 
local guidelines.  Refer to Section 5.3.1.1, Study Procedures, TB Testing for specific requirements for TB testing 
and TB Prophylaxis.  Study drug(s) should not be withheld at the time of the first positive TB test.
e.
Obtain chest x-ray every 48 weeks after Week 96 for subjects with TB risk factors as identified by the TB risk 
assessment form, or for subjects living in areas endemic for TB, or for subjects with a newly positive 
QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
f.
For subjects in the Czech Republic, ECGs will be performed every 48 weeks after Week 96.  An ECG may be 
performed at any visit if deemed necessary by the Investigator.
l.
hsCRP results will remain blinded to Sponsor, Investigator, study site personnel, and the subject for all visits until 
the last subject reaches the end of Period 1.
Has been changed to read:
d.
TB testing should be performed every 48 weeks after Week 96 in subjects with previous negative QuantiFERON-
TB Gold and/or PPD tests.  Subjects with new evidence of latent TB should initiate prophylactic treatment 
immediately per local guidelines.  Refer to Section 5.3.1.1, Study Procedures, TB Testing for specific requirements 
for TB testing and TB Prophylaxis.  Study drug(s) should not be withheld at the time of the first positive TB test.
e.
Obtain chest x-ray every 48 weeks after Week 96 for subjects with newly identified TB risk factors based on the 
TB risk assessment form, or for subjects living in areas endemic for TB, or for subjects with a newly positive 
QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.
f.
ECGs will be performed every 48 weeks after Week 48.  An ECG may be performed at any visit if deemed 
necessary by the Investigator.
l.
hsCRP results will remain blinded to Sponsor, Investigator and study site personnel, and the subject for all visits 
until the last subject reaches the end of Period 1.
Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Previously read:
Period 1
The TB screening tests are diagnostic test results to be interpreted in the context of the 
subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB.

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All subjects will be assessed for evidence of increased risk for TB by a risk assessment 
form (Appendix F) and tested for TB infection by QuantiFERON-TB Gold test.  The PPD 
Skin Test should be utilized only when a QuantiFERON-TB Gold Test is not possible for 
any reason (unless both tests are required per local guidelines).  The site staff will 
complete the TB risk assessment form and enter the data into an appropriate eCRF.
●
Preferred Method:  QuantiFERON-TB Gold Test will be analyzed by the 
central laboratory (QuantiFERON test is preferred over PPD skin test).
●
If QuantiFERON-TB Gold Test is NOT possible (or if both the 
QuantiFERON-TB Gold Test and the PPD Skin Test are required per local 
guidelines):  the PPD Skin Test (also known as a TB Skin Test) will be 
performed according to standard clinical practice. The TB Skin Test should be 
read by a licensed healthcare professional between 48 and 72 hours after 
administration.  A subject who does not return within 72 hours will need to be 
rescheduled for another skin test.  The reaction will be measured in millimeters 
(mm) of induration and induration ≥ 5 mm for RA subjects is considered a 
positive reaction.  The absence of induration will be recorded as "0 mm" not 
"negative."  Subjects who have had an ulcerating reaction to the TB Skin Test 
in the past should not be re-exposed and should not be tested by a PPD skin 
test.
If a subject had a negative QuantiFERON-TB Gold (and/or PPD) test (or IGRA 
equivalent such as T-SPOT TB test) within 90 days prior to Screening and source 
documentation is available, the test does not need to be repeated, provided nothing has 
changed in the subject's medical history to warrant a repeat test.  These cases may be 
discussed with the AbbVie Therapeutic Area Medical Director.  The results of the TB 
test(s) will be retained at the site as the original source documentation.
For sites participating from the Czech Republic, the following local requirements will also 
be applicable:
●
A pulmonologist will be responsible to obtain a detailed medical history with 
respect to TB exposure.  This information needs to include BCG vaccination, 

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cohabitation with individuals who have had TB, and/or who reside or work in 
TB endemic locations.  The information obtained by the pulmonologist must 
be documented in the subject's source note, dated and signed by the 
pulmonologist.
●
A pulmonologist must review the results of the QuantiFERON-TB Gold test 
and/or PPD skin test (or IGRA equivalent such as T-SPOT TB test) and the 
chest x-ray and has to give his/her opinion about the eligibility of each subject 
to be enrolled to the study.  This opinion must be documented in writing in the 
subject's source documents.
●
All subjects with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) and a chest x-ray not suggestive of 
active TB need to be approved for entry into the trial by both the Czech 
pulmonologist and the AbbVie Therapeutic Area Medical Director and all such 
subjects need to receive prophylaxis for latent TB.  Under no circumstances 
can a subject with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) result and no prior history of 
treatment for active or latent TB be allowed into this trial.
In the event both a PPD test and a QuantiFERON-TB Gold test are performed, the result 
of the QuantiFERON-TB Gold test will supersede the result of the PPD test, unless 
otherwise required by local guidelines.  If the QuantiFERON-TB Gold test is 
indeterminate, the site should repeat the test with another blood sample.  If the second 
QuantiFERON-TB Gold test is also indeterminate, the subject is considered to be positive.  
At a site with capacity to perform both tests, if a PPD is placed as the only form of TB test 
at screening, then the TB test to be used for the remainder of the study for that subject is 
the PPD.  Similarly, if a subject enters the study with a Quantiferon TB Gold test alone or 
other IGRA (negative result), then the subject should have their annual TB test performed 
with the Quantiferon-TB Gold Test.
Subjects with a negative QuantiFERON®-TB Gold test (and/or negative PPD TB skin 
test) and chest x-ray (CXR) not suggestive of active TB or prior TB exposure may be 
enrolled.

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If the subject has evidence of a latent TB infection (QuantiFERON®-TB Gold test and/or 
the PPD test positive and the subject has a CXR not suggestive of active TB), 
prophylactic treatment must be initiated at least 2 weeks prior to administration of study 
drug (or per local guidelines, whichever is longer).  The prophylaxis needs to be 
completed; however, the full course of prophylaxis does not need to be completed prior to 
the first dose of study drug.  If the Investigator deems that it is necessary, consultation 
with a TB expert could be considered. 
Of Note:  Rifampicin is Not Allowed for TB Prophylaxis
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy within 1 year prior to first study drug administration will be 
allowed to enter the study provided nothing has changed in the subject's medical history to 
warrant repeat treatment.
Subjects with a documented completion of a full course of anti-TB therapy greater than 
1 year prior to first study drug administration may be allowed to enter the study only after 
consultation with the AbbVie Therapeutic Area Medical Director.
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.
Period 2
For subjects with a negative QuantiFERON-TB Gold (and/or PPD) test at Screening, an 
annual QuantiFERON-TB Gold (and/or PPD) re-test will be performed (or both if 
required by local guidelines).  If one of the annual tests has a positive test result 
(seroconversion), a chest x-ray (CXR) needs to be performed as soon as possible to aid in 
distinguishing active versus latent TB.  Expert consultation can be considered per 
Investigator's discretion.  Any positive TB screen after the patient has started the study, 
should be reported as an adverse event (AE).

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Obtain a CXR annually for subjects with TB risk factors as identified by the TB risk 
assessment form (Appendix F) or for subjects living in areas endemic for TB or for 
subjects with newly positive PPD or QuantiFERON-TB Gold test.
Subjects with new evidence of latent TB during the study should initiate prophylactic 
treatment immediately per local guidelines.  Study drug(s) should not be withheld and 
Isoniazid should be initiated and 2 to 4 weeks later (per local guidelines), subject should 
be re-evaluated (unscheduled visit) for signs and symptoms and isoniazid toxicity.  
If the subject is experiencing signs or symptoms suspicious for TB or something has 
changed in the subject's medical history to warrant a repeat test before the next scheduled 
annual TB re-test, the case (including the TB test results) must be discussed with the 
AbbVie Therapeutic Area Medical Director.
Has been changed to read:
The TB screening tests provide diagnostic test results to be interpreted in the context of 
the subject's epidemiology, history, exam findings, etc., and it is the responsibility of the 
Investigator to determine if a subject has previous, active, or latent TB.  Expert 
consultation for the evaluation and/or management of TB may be considered per 
Investigator discretion.
At screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix F) and tested for TB infection by QuantiFERON-TB Gold 
test.  The PPD Skin Test should be utilized only when a QuantiFERON-TB Gold Test is 
not possible for any reason (unless both tests are required per local guidelines).  The site 
staff will complete the TB risk assessment form and enter the data into an appropriate 
eCRF.  The TB risk assessment form will be completed annually for all subjects, 
regardless of TB test results. 
If a subject had a negative PPD test within 90 days prior to Screening and a 
QuantiFERON-TB Gold test cannot be performed by Central Lab at Screening and source 
documentation is available, TB testing by PPD Skin Test does not need to be repeated, 

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provided nothing has changed in the subject's medical history to warrant a repeat test.  
These cases may be discussed with the AbbVie TA MD.  The results of the TB test(s) will 
be retained at the site as the original source documentation. 
Subjects with a negative TB test and chest x-ray (CXR) not suggestive of active TB or 
prior TB exposure may be enrolled.
Subjects with a positive TB test must be assessed for evidence of active TB versus latent 
TB, including signs and symptoms and CXR.  Subjects with no signs or symptoms and a 
CXR not suggestive of active TB may be enrolled after initiation of TB prophylaxis (see 
below).  
Subjects with evidence of active TB must not be enrolled.
For subjects with a negative TB test result at Screening or the most recent evaluation, an 
annual TB follow-up test will be performed.  If an annual TB test is newly positive 
(seroconversion), a chest x-ray (CXR) needs to be performed as soon as possible to aid in 
distinguishing active versus latent TB.  Any positive TB screen after the patient has 
started the study, should be reported as an AE of latent TB or active TB (as applicable). 
If the subject is experiencing signs or symptoms suspicious for TB or something has 
changed in the subject's medical history to warrant a repeat test before the next scheduled 
annual TB re-test, the case (including the TB test results) must be discussed with the 
AbbVie TA MD.
TB test:
●
Subjects with documentation of prior positive result of QuantiFERON-TB 
Gold Test (or equivalent) and/or PPD are not required to repeat either test at 
Screening or during the study and should be considered positive. 
●
For regions that require both PPD and QuantiFERON-TB Gold testing, both 
will be performed.  If either PPD or QuantiFERON-TB Gold are positive, the 
TB test is considered positive.

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●
The PPD Skin Test (also known as a TB Skin Test or Mantoux Test) should be 
utilized only when a QuantiFERON-TB Gold Test is not possible for any 
reason (unless both tests are required per local guidelines).  
●
If only a PPD is placed at screening, then the TB test to be used for the 
remainder of the study for that subject is the PPD.  Similarly, if a subject 
enters the study with a QuantiFERON-TB Gold test (or equivalent) alone, then 
the subject should have their annual TB test performed with a QuantiFERON-
TB Gold test.
●
If the QuantiFERON-TB Gold Test is NOT possible (or if both the 
QuantiFERON-TB Gold Test and the PPD are required per local guidelines) 
the PPD will be performed.  The PPD should be read by a licensed healthcare 
professional between 48 and 72 hours after administration.  A subject who 
does not return within 72 hours will need to be rescheduled for another skin 
test.  The reaction will be measured in millimeters (mm) of induration and 
induration ≥ 5 mm is considered a positive reaction.  The absence of induration 
will be recorded as "0 mm" not "negative."  Subjects who have an ulcerating 
reaction to the PPD in the past should not be re-exposed and the PPD should 
be considered positive.
●
If the QuantiFERON-TB Gold test is indeterminate, then the investigator 
should perform a local QuantiFERON-TB Gold test (or through the central 
laboratory if not locally available) to rule out a positive test result.  If testing 
remains indeterminate or is positive, then the subject is considered to be 
positive for the purpose of this study.  If the testing result is negative, then the 
patient is considered to be negative.
For sites participating from the Czech Republic, the following local requirements will also 
be applicable:
●
A pulmonologist will be responsible to obtain a detailed medical history with 
respect to TB exposure.  This information needs to include BCG vaccination, 
cohabitation with individuals who have had TB, and/or who reside or work in 
TB endemic locations.  The information obtained by the pulmonologist must 
be documented in the subject's source note, dated and signed by the 
pulmonologist.

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●
A pulmonologist must review the results of the QuantiFERON-TB Gold test 
and/or PPD skin test (or IGRA equivalent such as T-SPOT TB test) and the 
chest x-ray and has to give his/her opinion about the eligibility of each subject 
to be enrolled to the study.  This opinion must be documented in writing in the 
subject's source documents.
●
All subjects with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) and a chest x-ray not suggestive of 
active TB need to be approved for entry into the trial by both the Czech 
pulmonologist and the AbbVie Therapeutic Area Medical Director and all such 
subjects need to receive prophylaxis for latent TB.  Under no circumstances 
can a subject with a positive QuantiFERON-TB Gold test and/or PPD test (or 
IGRA equivalent such as T-SPOT TB test) result and no prior history of 
treatment for active or latent TB be allowed into this trial.
TB prophylaxis:
At screening, if the subject has evidence of a latent TB, prophylactic treatment must be 
initiated at least 2 weeks prior to administration of study drug (or per local guidelines, 
whichever is longer).  At least 6 months of prophylaxis needs to be completed; however, 
the full course of prophylaxis does not need to be completed prior to the first dose of 
study drug.  
Of Note:  Rifampicin or Rifapentine is Not Allowed for TB Prophylaxis
Subjects with a prior history of latent TB that have documented completion of a full 
course of anti-TB therapy within 1 year prior to first study drug administration will be 
allowed to enter the study provided nothing has changed in the subject's medical history to 
warrant repeat treatment.
Subjects with a documented completion of a full course of anti-TB therapy greater than 
1 year prior to first study drug administration may be allowed to enter the study only after 
consultation with the AbbVie Therapeutic Area Medical Director.

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During the study, subjects with new evidence of latent TB should initiate prophylactic 
treatment immediately per local guidelines and complete at least 6 months of prophylaxis.  
TB prophylaxis should be initiated and study drug(s) should not be withheld.  Two to 
four weeks later, the subject should be re-evaluated (unscheduled visit) for signs and 
symptoms as well as laboratory assessment of toxicity to TB prophylaxis.  
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.
Section 5.3.1.1  Study Procedures
Subsection Chest X-Ray (CXR)
Last bullet previously read:
Annually for subjects with TB risk factors as identified by the TB risk assessment form 
(Appendix F) for subjects living in areas endemic for TB or for subjects with newly 
positive PPD and/or QuantiFERON-TB Gold test
Has been changed to read:
Annually (every 48 weeks) for subjects with newly identified TB risk factors based on the 
TB risk assessment form (Appendix F), or for subjects living in areas endemic for TB, or 
for subjects with newly positive PPD and/or QuantiFERON-TB Gold test.
Section 5.3.1.1  Study Procedures
Subsection Chest X-Ray (CXR)
Last paragraph, first sentence previously read:
A radiologist must perform an assessment of the CXR.  
Has been changed to read:
A radiologist or pulmonologist must perform an assessment of the CXR.  

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Section 5.3.1.1  Study Procedures
Subsection X-Rays of Hands and Feet
Bullet list previously read:

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Has been changed to read:

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Section 5.3.1.1  Study Procedures
Subsection X-Rays of Hands and Feet
Thirteenth paragraph previously read:
Overall in Period 1, each subject will undergo a maximum of 4 scheduled visits for x-ray 
examination of bilateral hands and feet (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 14 (only for 
non-responders at Week 14), Week 26, and Week 48/PD.
Has been changed to read:
Overall in Period 1, each subject will undergo a maximum of 5 scheduled visits for x-ray 
examination of bilateral hands and feet (unless unscheduled repeat imaging is needed due 
to failure to meet the quality requirements) at Screening, Week 14 (only for 
non-responders at Week 14), Week 26, and Week 48/PD; in addition, subjects who 

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Table 5.  Clinical Laboratory Tests
Table note "i." and "k." previously read:
i.
At screening for female subjects < 55 years old.
k.
A urine pregnancy test will be performed for all female subjects of childbearing potential at the Baseline Visit prior 
to the first dose of study drug and all subsequent visits.  If the baseline urine pregnancy test performed at the site is 
negative, then dosing with study drug may begin.  If the baseline urine pregnancy test performed at the site is 
positive, dosing with study drug must be withheld and a serum pregnancy test is required.  The serum pregnancy 
test will be sent to and performed by the central laboratory.  If the serum pregnancy test is positive, study drug 
must be withheld and the subject must be discontinued from the study.  In the event a pregnancy test comes back 
borderline, a repeat test is required ≥ 3 days later to document continued lack of a positive result.  If a urine 
pregnancy test postbaseline is positive, study drug needs to be temporarily discontinued and a serum pregnancy test 
is required.  The serum pregnancy test will be sent to and performed by the central laboratory.  If the serum 
pregnancy test is positive, study drug must be permanently discontinued.
Has been changed to read:
i.
At screening for female subjects < 55 years old with no menses for ≥ 12 months AND no history of permanent 
surgical sterilization.
k.
A urine pregnancy test will be performed for all women of childbearing potential at the Baseline Visit prior to the
first dose of study drug and at minimum at monthly intervals (either at study visits or at home between scheduled 
study visits) (for details see Section 5.3.3.1.1 (Study Procedures).
Section 5.3.1.1  Study Procedures
Subsection Hepatitis Screen
Third paragraph, first and second bullet previously read:
●
HBs Ag
●
HBc Ab/anti-HBc
Has been changed to read:
●
HBs Ag (Hepatitis B surface antigen)
●
HBc Ab/anti-HBc (Hepatitis B core antibody)
Section 5.3.3.1.2  Key  Secondary Variables
First paragraph previously read:
Key secondary endpoints (ABT-494 versus placebo if not otherwise specified) for 
US/FDA regulatory purposes are:

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Has been changed to read: 
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) 
for US/FDA regulatory purposes are:
Section 5.3.3.1.2  Key  Secondary Variables
Add:  new second paragraph
Other key secondary endpoints (upadacitinib versus placebo) for US/FDA regulatory 
purposes are:
●
ACR50 response rate at Week 12
●
ACR70 response rate at Week 12
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline mTSS ≤ 0) at Week 26
Section 5.3.3.1.2  Key  Secondary Variables
Second paragraph previously read:
Key secondary endpoints (ABT-494 versus placebo if not otherwise specified) for 
EU/EMA regulatory purposes are:
!
Change from baseline in modified Total Sharp Score (mTSS) at Week 26;
!
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
!
Change from baseline in DAS28 (CRP) at Week 12;
!
Change from baseline in HAQ-DI at Week 12;
!
ACR20 response rate at Week 12;
!
ACR50 response rate at Week 12;
!
ACR70 response rate at Week 12;
!
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 (non-
inferiority of ABT-494 versus ADA);

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!
Change from baseline in SF-36 PCS at Week 12;
!
Change from baseline in FACIT-F at Week 12;
!
Proportion of subjects with no radiographic progression (defined as change from 
baseline mTSS ≤ 0) at Week 26;
!
Change from baseline in RA-WIS at Week 12;
!
Change from baseline in morning stiffness at Week 12.
Has been changed to read:
Ranked key secondary endpoints (upadacitinib versus placebo if not otherwise specified) 
for EU/EMA regulatory purposes are:
1.
Change from baseline in modified Total Sharp Score (mTSS) at Week 26;
2.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12;
3.
Change from baseline in DAS28 (CRP) at Week 12;
4.
Change from baseline in HAQ-DI at Week 12;
5.
ACR20 response rate at Week 12;
6.
Proportion of subjects achieving LDA based on DAS28 (CRP) ≤ 3.2 at Week 12 
(non-inferiority of upadacitinib versus ADA);
7.
Change from baseline in SF-36 PCS at Week 12;
8.
Proportion of subjects achieving LDA based on Clinical Disease Activity Index 
(CDAI) at Week 12
9.
Change from baseline in morning stiffness at Week 12; 
10.
Change from baseline in FACIT-F at Week 12.
11.
Proportion of subjects with no radiographic progression (defined as change from 
baseline mTSS ≤ 0) at Week 26;

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Other key secondary endpoints (upadacitinib versus placebo) for EU/EMA regulatory 
purposes are:
●
ACR50 response rate at Week 12
●
ACR70 response rate at Week 12
Section 5.3.3.1.3  Additional Variables
First paragraph previously read:
Additional endpoints at all visits are:
Has been changed to read:
Additional endpoints (upadacitinib versus placebo and adalimumab) at all visits are:
Section 5.3.3.1.3  Additional Variables
Seventh bullet previously read:
Proportion of subjects achieving MCID in change from baseline in HAQ-DI (defined as 
change from baseline in HAQ-DI ≤ –0.3);
Has been changed to read:
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;
Section 5.3.3.2  Period 2 Variables
First paragraph
Add:  new fifth bullet
Change from baseline in CDAI and SDAI;
Section 5.3.3.2  Period 2 Variables
Add:  new seventh and eighth bullet
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.22;
●
Proportion of subjects with change from baseline in HAQ-DI ≤ –0.3;

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Section 5.4.1  Discontinuation of Individual Subjects
Last bullet previously read:
Starting at Week 48, subjects who failed to show at least 20% improvement in TJC and 
SJC compared to baseline at 2 consecutive visits will be discontinued from study drug 
treatment.
Has been changed to read:
Starting at Week 48, at least 20% improvement in BOTH TJC AND SJC compared to 
baseline is required to remain on study drug. Anyone who does not fulfill this criterion at 
2 consecutive visits (starting at Week 48) must be discontinued from study drug.
Section 5.4.1  Discontinuation of Individual Subjects
Add:  new third paragraph
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment or study participation should complete a 
Premature Discontinuation visit (PD visit) as described in Section 5.1 (Overall Study 
Design and Plan:  Description)
Section 5.4.1  Discontinuation of Individual Subjects
Delete:  third and fourth paragraph
In order to minimize missing data for efficacy and safety assessments, subjects who 
prematurely discontinue study drug treatment should complete a Premature 
Discontinuation Visit (PD visit) as soon as possible, preferably within 2 weeks.  
Afterwards, subjects should continue to be followed for all regularly scheduled visits as 
outlined in Table 2 and Table 4 and adhere to all study procedures except for dispensing 
study drug, PK sample collection, and blood sample collection for optional exploratory 
research and validation studies.  In addition, all future rescue and efficacy-driven 
discontinuation criteria no longer apply; this includes 20% TJC/SJC calculations at 
Weeks 14 – 22, and Week 48 and thereafter, as well as CDAI calculation at Week 26, if 
applicable.  Subjects should be advised on the continued scientific importance of their 
data even if they discontinue treatment with study drug early.

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If a subject prematurely discontinues study participation (withdrawal of informed 
consent), the procedures outlined for the Premature Discontinuation visit (PD visit) should 
be completed as soon as possible, preferably within 2 weeks.  In addition, if subject is 
willing, a 30-day follow-up visit (or phone call if a visit is not possible) may occur to 
determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.  
For subjects on subcutaneous study drug, if the subject is willing, a 70-day phone call 
may occur to determine the status of any ongoing AEs/SAEs or the occurrence of any new 
AEs/SAEs.  Subjects who discontinue the study prematurely after randomization will not 
be replaced.
Section 5.5.4  Selection and Timing of Dose for Each Subject
Fourth paragraph, last bullet, first sentence previously read:
If the subject experiences a study drug interruption > 14 consecutive days during Period 1 
or > 30 consecutive days during Period 2 (other than for reasons listed in Section 6.1.7), 
they should notify their study site physician, and the subject should be discontinued from 
study drugs.
Has been changed to read:
If the subject experiences a study drug interruption > 14 consecutive days during the 
first 26 weeks, > 21 days between Week 26 and Week 48 or > 30 consecutive days during 
Period 2 (other than for reasons listed in Section 6.1.7), they should notify their study site 
physician, and the subject should be discontinued from study drugs.
Section 5.5.4  Selection and Timing of Dose for Each Subject
Fifth paragraph, last bullet, first sentence previously read:
If the subject experiences a study drug interruption of > 3 consecutive missed doses in 
Period 1 or 2 (other than for reasons listed in Section 6.1.7), they should notify their study 
site physician, and the subject should be discontinued from the study. 

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Has been changed to read:
If the subject experiences a study drug interruption of > 2 consecutive missed doses 
during the first 26 weeks or > 3 consecutive missed doses after Week 26 (other than for 
reasons listed in Section 6.1.7), they should notify their study site physician, and the 
subject should be discontinued from the study.  
Section 5.5.5.1  Blinding of Investigational Product
First paragraph previously read:
All AbbVie personnel with direct oversight conduct and management of the trial (with the 
exception of AbbVie Drug Supply Management Team), the Investigator, study site 
personnel, and the subject will remain blinded to each subject's treatment throughout 
Period 1.  
Has been changed to read:
All AbbVie personnel with direct oversight, conduct and management of the trial (with 
the exception of AbbVie Drug Supply Management Team), will remain blinded to each 
subject's treatment through Week 26.  The Investigator, study site personnel, and the 
subject will remain blinded to each subject's treatment in Period 1 until the last subject 
completes the last visit of Period 1 (Week 48).  
Section 6.1.1.3  Adverse Events of Special Interest
Bullet list previously read:
●
Serious infections, opportunistic infections, herpes zoster, and TB;
●
Malignancy and lymphoproliferative disorders;
●
Gastrointestinal perforations;
●
Cardiovascular events (e.g., major adverse cardiovascular event [MACE]);
●
Lipid profile changes;
●
Anemia and hemoglobin effects;
●
Decreased neutrophil counts;
●
Decreased lymphocyte counts;

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●
Increased serum creatinine and renal dysfunction;
●
Hepatic events and increased hepatic transaminases;
●
Increased creatine phosphokinase (CPK).
Has been changed to read: 
●
Serious infections
●
Opportunistic infections
●
Herpes Zoster
●
Tuberculosis
●
Malignancy (all types)
●
Gastrointestinal Perforations
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE])
●
Lipid Profile Changes
●
Anemia
●
Neutropenia
●
Lymphopenia
●
Increased serum creatinine and renal dysfunction
●
Hepatic events and increased hepatic transaminases
●
Elevated creatine phosphokinase (CPK)
●
Embolic and thrombotic events (non-cardiac, non-CNS)
Section 6.1.3  Relationship to Study Drug
"Reasonable Possibility" and "No Reasonable Possibility" previously read:
Reasonable 
Possibility
An adverse event where there is evidence to suggest a causal 
relationship between the study drug and the adverse event.
No Reasonable 
Possibility
An adverse event where there is no evidence to suggest a causal 
relationship between the study drug and the adverse event.

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Has been changed to read:
Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is sufficient evidence (information) to suggest a 
causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, 
biologic plausibility, clinical judgment, and potential alternative 
causes, there is insufficient evidence (information) to suggest a 
causal relationship.
Section 6.1.3  Relationship to Study Drug
Second paragraph, previously read:
For relationship assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a relationship or deemed it not 
assessable, AbbVie will consider the event associated.
Has been changed to read:
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
Section 6.1.4  Adverse Event Collection Period
Fourth paragraph
Delete:  last bullet
Cardiovascular procedures (SAE Supplemental Procedure eCRF).

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Section 6.1.4  Adverse Event Collection Period
Fifth paragraph
Add:  new last bullet
Embolic and thrombotic events (non-cardiac, non-CNS).
Section 6.1.5  Serious Adverse Event Reporting
Last paragraph, first sentence previously read:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.
Has been changed to read:
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Global and Local Regulations.
Section 6.1.7  Toxicity Management
Third paragraph, sixth and seventh sentence previously read:
If study drug has been interrupted for a serious infection for more than 14 consecutive 
days during Period 1 of the study or 30 consecutive days thereafter, the subject must be 
discontinued from study drug.  Subjects who develop active TB must be discontinued 
from study drug.
Has been changed to read:
If study drug has been interrupted for a serious infection for more than 14 consecutive 
days during the first 26 weeks, more than 21 days between Weeks 26 and 48 or more than 
30 consecutive days thereafter, the subject must be discontinued from study drug.  
Subjects who develop active TB must be permanently discontinued from study drug.

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Section 6.1.7  Toxicity Management
Fourth paragraph, first sentence previously read:
Serious Gastrointestinal Events:  Subjects presenting with the onset of signs or 
symptoms of a serious gastrointestinal event should be evaluated promptly for early 
identification of gastrointestinal perforation.
Has been changed to read:
Gastrointestinal Perforation:  Subjects presenting with the onset of signs or symptoms 
of a serious gastrointestinal event should be evaluated promptly for early identification of 
gastrointestinal perforation.
Section 6.1.7  Toxicity Management
Fifth paragraph, first sentence previously read:
Cardiovascular Events (MACE): Subjects presenting with potential cardiovascular 
events should be carefully monitored.
Has been changed to read:
Cardiovascular Events: Subjects presenting with potential cardiovascular events should 
be carefully monitored.
Section 6.1.7  Toxicity Management
Seventh paragraph previously read:
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant OR a confirmed absolute QTcF value > 500 msec.
Has been changed to read:
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant and with reasonable possibility of relationship to study
drug OR a confirmed absolute QTcF value > 500 msec.

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Section 6.1.7  Toxicity Management
Eighth paragraph
Add:  new third and fourth sentence
All abnormal laboratory tests that are considered clinically significant by the Investigator 
will be followed to a satisfactory resolution.  If a repeat test is required per Table 7, the 
repeat testing must occur as soon as possible.
Table 7.  Specific Toxicity Management Guidelines for Abnormal Laboratory Values
"AST or ALT," "Serum Creatinine," and "Creatine Phosphokinase" previously 
read:
Laboratory 
Parameter 
Toxicity Management Guideline
AST or ALT
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample and either a total bilirubin > 2 × ULN or an international normalized ratio > 1.5.
!
INR will only be measured in subjects with ALT or AST > 3 × ULN by the central lab 
by reflex testing and confirmation is not needed for consideration in toxicity 
management criteria.
!
Discontinue study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample along with appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (> 5%). 
!
Discontinue study drug if confirmed ALT or AST > 8 × ULN by repeat testing with new 
sample. 
!
Discontinue study drug if confirmed ALT or AST > 5 × ULN by repeat testing with new 
sample for more than 2 weeks. 
For all of the above ALT or AST elevation scenarios, complete supplemental hepatic 
eCRF.
Serum 
Creatinine
!
If serum creatinine is > 1.5 × the baseline value, repeat the test for serum creatinine 
(with subject in an euvolemic state) to confirm the results.  If the results of the repeat 
testing still meet this criterion then interrupt study drug and re-start study drug once 
serum creatinine returns to ≤ 1.5 × baseline value.
!
If confirmed serum creatinine ≥ 2 mg/dL, interrupt study drug and re-start study drug 
once serum creatinine returns to normal reference range or its baseline value. 
!
For the above serum creatinine elevation scenarios, complete supplemental renal eCRF.
Creatine 
Phosphokinase
!
If any confirmed CPK value ≥ 4 × ULN (if symptomatic or asymptomatic), complete 
supplemental CPK eCRF.
!
If confirmed CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug, complete supplemental CPK eCRF, and contact 
AbbVie TA MD.

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Has been changed to read:
Laboratory 
Parameter 
Toxicity Management Guideline
AST or ALT
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample and either a total bilirubin > 2 × ULN or an international normalized 
ratio > 1.5.
o
A separate blood sample for INR testing will be needed to measure INR at the time 
of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met.
!
Interrupt study drug immediately if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample along with appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%). 
!
Interrupt study drug immediately if confirmed ALT or AST > 5 × ULN by repeat testing 
with new sample for more than 2 weeks. 
!
Interrupt study drug immediately if confirmed ALT or AST > 8 × ULN by repeat testing 
with new sample. 
Subjects who meet any of the above criteria should be evaluated for an alternative etiology of the 
ALT or AST elevation and managed as medically appropriate.  The investigator should contact the 
AbbVie TA MD to discuss the management of a subject when an alternative etiology has been 
determined.  The alternative etiology should be documented appropriately in the eCRF; study drug 
should be discontinued if no alternative etiology can be found.
For any confirmed ALT or AST elevations > 3 ULN, complete supplemental hepatic eCRF.
!
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA at 
screening who develop the following should have HBV DNA by PCR testing performed 
within 1 week:
o
ALT > 5 × ULN OR 
o
ALT or AST > 3 × ULN and either a total bilirubin > 2 × ULN or INR > 1.5 OR 
o
ALT or AST > 3 × ULN along with clinical signs of possible hepatitis
A positive result for HBV DNA PCR testing in these subjects will require immediate interruption 
of study drug and a hepatologist consultation should occur within 1 week for recommendation 
regarding subsequent treatment.
Serum 
Creatinine
!
If serum creatinine is > 1.5 × the baseline value and > ULN, repeat the test for serum 
creatinine (with subject in an euvolemic state) to confirm the results.  If the results of the 
repeat testing still meet this criterion then interrupt study drug and re-start study drug 
once serum creatinine returns to ≤ 1.5 × baseline value and ≤ ULN.
!
If confirmed serum creatinine ≥ 2 mg/dL, interrupt study drug and re-start study drug 
once serum creatinine returns to normal reference range or its baseline value.
For the above serum creatinine elevation scenarios, complete supplemental renal eCRF.
Creatine 
Phosphokinase
!
If confirmed CPK ≥ 4 × ULN and there are no symptoms suggestive of myositis or 
rhabdomyolysis, the subjects may continue study drug at the investigator's discretion.
!
If CPK ≥ 4 × ULN accompanied by symptoms suggestive of myositis or 
rhabdomyolysis, interrupt study drug and contact AbbVie TA MD
For the above CPK elevation scenarios, complete supplemental CPK eCRF.

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Section 6.2.2  Reporting
First paragraph, first sentence previously read:
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 24 hours of the study site's knowledge of the event via the Product 
Complaint form.
Has been changed to read:
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 1 business day of the study site's knowledge of the event via the Product 
Complaint form.
Section 7.0  Protocol Deviations
"Primary Contact:" and "Alternate Contact:' previously read:
Primary Contact:
Alternate Contact:

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Has been changed to read:
Primary Contact:
Alternate Contact:
Section 8.1  Statistical and Analytical Plans
Second paragraph, last sentence previously read:
Another unblinded analysis may be conducted for regulatory purposes after all subjects 
have completed Period 1 (Week 48).
Has been changed to read:
Additional unblinded analyses may be conducted after the Week 26 unblinded analysis for 
regulatory purposes.
Section 8.1.2.3  Study Drug Exposure
Last paragraph previously read:
Study drug compliance will be summarized for each treatment group for Period 1.  The 
compliance is defined as the number of tablets taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 
participation in Period 1 divided by the number of tablets a subject is supposed to take 
each day times the length of time that the subject was in the Treatment Phase of Period 1.

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Has been changed to read:
Study drug compliance will be summarized for each treatment group.  The compliance is 
defined as the number of tablets taken (i.e., the difference between the number of tablets 
dispensed and the number of tablets returned) during the subject's participation in Period 1 
divided by the number of tablets a subject is supposed to take each day times the length of 
time that the subject was in the Treatment Phase.
Section 8.1.4.1.2  Key Secondary Efficacy Variables
Fourth paragraph, last sentence previously read:
For change from baseline in patient's global assessment of pain and change from baseline 
in HAQ-DI at Week 12, superiority of ABT-494 vs adalimumab will also be tested for
US/FDA purposes.
Has been changed to read:
For change from baseline in patient's global assessment of pain and change from baseline 
in HAQ-DI at Week 12, superiority of upadacitinib vs adalimumab will also be tested.
Section 8.1.4.1.4  Multiplicity Control for the Primary and Key Secondary Endpoints
Section title and text previously read:
8.1.4.1.4
Multiplicity Control for the Primary and Key Secondary 
Endpoints
In order to preserve Type I error, a step-down approach will be used to test the primary 
and key secondary endpoints where statistical significance can be claimed for a lower 
ranked endpoint only if the previous endpoints in the sequence meet the requirements of 
significance.

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Has been changed to read:
8.1.4.1.4
Multiplicity Control for the Primary and Ranked Key 
Secondary Endpoints
In order to preserve Type I error, a step-down approach will be used to test the primary 
and ranked key secondary endpoints where statistical significance can be claimed for a 
lower ranked endpoint only if the previous endpoints in the sequence meet the 
requirements of significance.
Section 8.1.4.1.5  Imputation Methods
Fourth paragraph, last sentence previously read:
In NRI analysis, subjects who prematurely discontinue study drug will be considered 
non-responders on or after discontinuation date.
Has been changed to read:
In NRI analysis, subjects who prematurely discontinue study drug will be considered 
non-responders after discontinuation.
Section 8.1.4.1.5  Imputation Methods
Fifth paragraph previously read:
Linear Extrapolation for Radiographic Data:  For radiographic data (i.e., mTSS-based 
endpoints), if a subject escapes at Week 14 or prematurely discontinued before Week 26, 
their Week 26/48 data will be imputed assuming a linear relationship between baseline 
and previous time point when x-ray should be collected.
Has been changed to read:
Linear Extrapolation for Radiographic Data:  For radiographic data (i.e., mTSS-based 
endpoints), if a subject is rescued at Week 14 to a different study drug or prematurely 
discontinued study drug, their Week 26/48 data will be imputed assuming a linear 
relationship between baseline and previous x-ray collected at the time of rescue/PD.

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Section 8.1.5.1  General Considerations
First paragraph, last sentence previously read:
Analyses will be conducted for Period 1 alone, as well as for Period 1 and Period 2 
combined.
Has been changed to read:
Analyses will be conducted for both short term and long term.
Section 8.1.5.2  Analysis of Adverse Events
Previously read:
Unless otherwise specified, the following conventions apply for both the Period 1 safety 
analysis and the combined safety analysis of Period 1 and Period 2.
Has been changed to read:
Unless otherwise specified, the following conventions apply for both short term and long 
term safety analysis.
Section 8.1.5.2.1  Treatment-Emergent Adverse Events (TEAE)
Second paragraph, last sentence previously read:
For subjects who continued into Period 2, the AEs that are reported in Period 2 will be 
summarized in the combined safety analysis of Period 1 and Period 2.
Has been changed to read:
For subjects who continued into Period 2, the AEs that are reported in Period 2 will be 
summarized in the long term safety analysis.
Section 8.1.5.2.1  Treatment-Emergent Adverse Events (TEAE)
Fifth and sixth bullet previously read:
●
Frequent AEs (reported in 5% of subjects or more in any treatment group);
●
Frequent reasonably possibly related AEs (reported in 5% of subjects or more 
in any treatment group);

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Has been changed to read: 
●
Frequent AEs (reported in 2% of subjects or more in any treatment group);
●
Frequent reasonably possibly related AEs (reported in 2% of subjects or more 
in any treatment group);
Section 8.1.5.2.1  Treatment-Emergent Adverse Events (TEAE)
Seventh paragraph, first sentence previously read:
The AEs of special interest (including but not limited to infection, opportunistic infection, 
herpes zoster, TB, gastrointestinal perforations, malignancies, MACE, renal dysfunction, 
anemia, increased CPK, and drug-related hepatic disorders) will be summarized.  
Has been changed to read:
The AEs of special interest (including but not limited to serious infection, opportunistic 
infection, herpes zoster, TB, gastrointestinal perforations, malignancies, MACE, renal 
dysfunction, anemia, increased CPK, non-cardiac, non-CNS embolic and thrombotic 
events, and drug-related hepatic disorders) will be summarized.  
Section 8.1.5.3  Analysis of Laboratory, Vital Sign, and ECG Data
First paragraph, first sentence previously read:
Changes from baseline by visit, and changes from baseline to minimum value, maximum 
value, and final values in continuous laboratory data, and vital signs will be summarized 
by treatment group.
Has been changed to read:
Changes from baseline by visit in continuous laboratory data, and vital signs will be 
summarized by treatment group.

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Section 8.1.5.3  Analysis of Laboratory, Vital Sign, and ECG Data
Second paragraph, second sentence previously read:
For creatinine phosphokinase, serum creatinine, and parameters that are not covered in the 
OMERACT criteria, NCI CTC criteria will be used.
Has been changed to read:
For creatine phosphokinase, and serum creatinine, NCI CTC criteria will be used.
Section 8.2  Determination of Sample Size
Last sentence previously read:
It will also provide at least 90% power in testing superiority of ABT-494 versus placebo 
for most of the ranked secondary endpoints, including change from baseline in DAS28 
(CRP), change from baseline in HAQ-DI, ACR50 and ACR70 response rate, and SF-36 
(PCS), at two sided significance level of 0.05 and accounting for a 10% dropout rate.
Has been changed to read:
It will also provide at least 90% power in testing superiority of upadacitinib versus 
placebo for most of the key secondary endpoints, including change from baseline in 
DAS28 (CRP), change from baseline in HAQ-DI, ACR50 and ACR70 response rate, and 
SF-36 (PCS), at two-sided significance level of 0.05 and accounting for a 10% dropout 
rate.

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Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient 
Safety
Statistics
Clinical Pharmacokinetics and 
Pharmacodynamics
Clinical Program Development
Global Clinical Drug Supply
Clinical Program Development
Has been changed to read:
Name
Title
Functional Area
Therapeutic Area
Therapeutic Area
Pharmacovigilance and Patient 
Safety
Statistics
Clinical Pharmacokinetics and 
Pharmacodynamics
Bioanalysis
Clinical Program Development
Clinical Program Development
Appendix C.  Local Requirements
Criterion 12 and 13 previously read:
12.
If female of childbearing potential, must be practicing at least two reliable methods 
of contraception (one highly effective method combined with one effective method, 
refer to Section 5.2.4), that are effective from Study Day 1 through at least 

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150 days after the last dose of subcutaneous study drug and through at least 30 days 
after the last dose of oral study drug.
13.
If male, and subject is sexually active with the female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
oral study drug, to practice the protocol-specified contraception (refer to 
Section 5.2.4).
Has been changed to read:
12.
If female of childbearing potential, must be practicing at least two reliable methods 
of contraception (one highly effective method combined with one effective method, 
refer to Section 5.2.4), that are effective from Study Day 1 through at least 
150 days after the last dose of subcutaneous study drug, through at least 30 days 
after the last dose of oral study drug, and through 180 days after the last dose of 
methotrexate. If more than one of the above intervals apply, the longest interval 
must be adhered to.
13.
If male, and subject is sexually active with the female partner(s) of childbearing 
potential, he must agree, from Study Day 1 through 30 days after the last dose of 
oral study drug and through 90 days after the last dose of methotrexate, to practice 
the protocol-specified contraception (refer to Section 5.2.4).  The same intervals 
apply to abstention from sperm donation. If more than one of the above intervals 
apply, the longest interval must be adhered to.
Appendix C.  Local Requirements
Subsection Contraception Recommendation for Females
Third paragraph, last sentence previously read:
That is effective from Study Day 1 (or earlier) through at least 150 days after the last dose 
of subcutaneous study drug and through at least 30 days after the last dose of oral study 
drug.

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Has been changed to read:
That is effective from Study Day 1 (or earlier) through at least 150 days after the last dose 
of subcutaneous study drug, through at least 30 days after the last dose of oral study drug, 
and through 180 days after the last dose of methotrexate.  If more than one of the above 
intervals apply, the longest interval must be adhered to:
Appendix C.  Local Requirements
Subsection Contraception Recommendation for Males
Second paragraph previously read:
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug to 
practice contraception with:
Has been changed to read:
A male subject who is sexually active with female partner(s) of childbearing potential 
must agree from Study Day 1 through 30 days after the last dose of oral study drug and 
through 90 days after the last dose of methotrexate to practice contraception with:
Appendix C.  Local Requirements
Subsection Contraception Recommendation for Males
Third paragraph previously read:
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of oral study drug.
Has been changed to read:
Additionally, male subjects must agree not to donate sperm from Study Day 1 through 
30 days after the last dose of oral study drug and through 90 days after the last dose of 
methotrexate.

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Appendix F.  Latent TB Risk Assessment Form Example
Criterion 2, 3, and 4 previously read:
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Africa
●
Eastern Europe
●
Asia
●
Latin America
●
Caribbean Islands 
●
Russia
3.
Have you lived or worked in a prison, homeless shelter/refugee camp, immigration 
center, health care worker in a hospital or nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Chest pain, or pain with breathing or coughing
●
Blood-Streaked Sputum (coughing up blood)
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
Has been changed to read:
2.
Have you lived in or had prolonged travels to countries in the following regions:
●
Sub-Saharan Africa
●
India
●
China
●
Mexico

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●
Southeast Asia or Micronesia
●
The former Soviet Union
3.
Have you lived or worked in a prison, homeless shelter, immigration center, or 
nursing home?
4.
Have you, or an immediate family member, had any of the following problems for 
the past 3 weeks or longer:
●
Chronic Cough
●
Production of Sputum
●
Blood-Streaked Sputum
●
Unexplained Weight Loss
●
Fever
●
Fatigue/Tiredness
●
Night Sweats
●
Shortness of Breath
Appendix O.  Rheumatology Common Toxicity Criteria v.2.0 Example
"2 – Moderate" previously read:
2 – Moderate
No medication or OTC
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve.  (may be prescription),
Study drug continued
Has been changed to read:
2 – Moderate
Symptomatic
Duration (1 – 2 weeks)
Alter lifestyle occasionally
Meds relieve.  (may be prescription),
Study drug continued

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Appendix O.  Rheumatology Common Toxicity Criteria v.2.0 Example
Subsection L. Chemistry
"L9." and "L11." previously read:
L.  Chemistry
L9.  CPK (also if 
polymyositis-disease
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening
L11.  Creatinine 
(mg/dl)
1.1 – 1.3 × ULN
1.3 – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN
Has been changed to read:
L.  Chemistry
L9.  CPK (also if 
polymyositis-
disease)*
1.2 – 1.9 × ULN
2.0 – 4.0 × ULN
4.0 × ULN with weakness but 
without life-threatening signs or 
symptoms
> 4.0 × ULN with signs or 
symptoms of rhabdomyolysis or 
life-threatening
L11.  Creatinine 
(mg/dl)*
1.1 – 1.3 × ULN
1.3 – 1.8 × ULN
1.9 – 3.0 × ULN
> 3.0 × ULN

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Appendix O.  Rheumatology Common Toxicity Criteria v.2.0 Example
Add:  new table note "*."
*
For CPK and Creatinine NCI CTC grading will be used.  For CPK the following gradings apply:  Grade 1:  
> ULN – 2.5 × ULN; Grade 2:  > 2.5 – 5.0 × ULN; Grade 3:  > 5.0 – 10.0 × ULN; Grade 4:  > 10.0 × ULN; For 
Creatinine the following gradings apply:  Grade 1:  > 1 – 1.5 × Baseline; > ULN – 1.5 × ULN; Grade 2:  > 1.5 –
3.0 × Baseline; > 1.5 – 3.0 × ULN; Grade 3:  > 3.0 baseline; > 3.0 – 6.0 × ULN; Grade 4:  > 6.0 × ULN