Conditions: Psoriatic Arthritis
Keywords: Arthritis Psoriasis Anti-inflammatory Joint disease Musculoskeletal disease Anti-Rheumatic
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1705
Healthy volunteers: no

Brief summary:
This study includes two periods. The main objective of Period 1 is to compare the efficacy of upadacitinib 15 mg once daily (QD) and 30 mg QD versus placebo and versus adalimumab (Humira®) in participants with moderately to severely active psoriatic arthritis (PsA) who have had an inadequate response to non-biologic DMARDs (DMARD-IR). Period 1 is also designed to compare the efficacy of upadacitinib 15 mg and 30 mg QD versus placebo for the prevention of structural progression.

The objective of Period 2 is to evaluate the long-term safety, tolerability and efficacy of upadacitinib 15 mg and 30 mg QD in participants who have completed Period 1.

Detailed description:
The study includes a 35-day screening period, a 56-week blinded period (Period 1), a long-term extension period of up to a total treatment duration of approximately 5 years (Period 2), a 30-day follow-up call or visit, and a 70-day follow-up call.

Period 1 includes 24 weeks of randomized, double-blind, placebo-controlled and active comparator-controlled treatment followed by 32 weeks of active comparator-controlled upadacitinib; at Week 24 participants assigned to placebo will be switched to upadacitinib according to their randomization assignment.

Participants who meet eligibility criteria will be randomized in a 2:2:2:1:1 ratio to one of five treatment groups:

* Group 1: Upadacitinib 15 mg QD
* Group 2: Upadacitinib 30 mg QD
* Group 3: Adalimumab 40 mg every other week (EOW)
* Group 4: Placebo followed by upadacitinib 15 mg QD
* Group 5: Placebo followed by upadacitinib 30 mg QD

Randomization will be stratified by extent of psoriasis (≥ 3% body surface area \[BSA\] or \< 3% BSA), current use of at least 1 non-biologic DMARD, presence of dactylitis, and presence of enthesitis, except for participants from China and Japan, where randomization for each country will be stratified by extent of psoriasis (≥ 3% BSA or \< 3% BSA) only.

Participants who complete the Week 56 visit (end of Period 1) will enter the long-term extension portion of the study, Period 2 (total treatment up to approximately 5 years), and continue study treatment as assigned in Period 1 in a blinded manner until the last subject completes the last visit of Period 1 (Week 56), when study drug assignment in both periods will be unblinded and participants will be dispensed study drug in an open-label fashion until the completion of Period 2.

At Week 16, rescue therapy will be offered to participants classified as non-responders (defined as not achieving at least 20% improvement in tender joint count (TJC) and / or swollen joint count (SJC) at both Week 12 and Week 16). Starting at Week 36, participants who fail to demonstrate at least 20% improvement in either or both TJC and SJC compared to Baseline at 2 consecutive visits will be discontinued from study drug treatment. Additionally, in participants continuing on study drug, starting at the Week 36 visit, initiation of or change in background PsA medication(s) is allowed as per local label.

Arms:
arm 1: Period 1: Participants receive upadacitinib 15 mg orally once a day (QD) and matching placebo to adalimumab by subcutaneous injection every other week (EOW) for 56 weeks.

Period 2: Participants will continue to receive upadacitinib 15 mg once daily. arm 2: Period 1: Participants receive upadacitinib 30 mg orally once a day and matching placebo to adalimumab by subcutaneous injection every other week for 56 weeks.

Period 2: Participants will continue to receive upadacitinib 30 mg once daily. arm 3: Period 1: Participants receive adalimumab 40 mg by subcutaneous injection every other week and matching placebo to upadacitinib orally QD for 56 weeks.

Period 2: Participants continue to receive adalimumab 40 mg every other week. arm 4: Period 1: Participants receive matching placebo to upadacitinib orally once a day for 24 weeks then upadacitinib 15 mg once daily for 32 weeks, and matching placebo to adalimumab by subcutaneous injection EOW for the entire 56 weeks.

Period 2: Participants will continue to receive upadacitinib 15 mg once daily. arm 5: Period 1: Participants receive matching placebo to upadacitinib orally once a day for 24 weeks then upadacitinib 30 mg once daily for 32 weeks, and matching placebo to adalimumab by subcutaneous injection EOW for the entire 56 weeks.

Period 2: Participants will continue to receive upadacitinib 30 mg once daily.

Interventions: intervention 1: Adalimumab intervention 2: Upadacitinib intervention 3: Placebo to Upadacitinib intervention 4: Placebo to Adalimumab
Intervention descriptions: intervention 1: Administered by subcutaneous injection intervention 2: Oral tablet intervention 3: Oral tablet intervention 4: Administered by subcutaneous injection

Protocol document:
Prot_000.pdf: 
ABT-494
M15-572 Protocol Amendment 6
EudraCT 2016-004130-24
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1.0
Title Page
Clinical Study Protocol M15-572
A Phase 3, Randomized, Double-Blind, Study 
Comparing Upadacitinib (ABT-494) to Placebo and to 
Adalimumab in Subjects with Active Psoriatic 
Arthritis Who Have a History of Inadequate 
Response to at Least One Non-Biologic Disease 
Modifying Anti-Rheumatic Drug (DMARD) – SELECT –
PsA 1
Incorporating Administrative Changes 1, 2, 3, 4
and 5 and Amendments 1, 1.01 (VHP Countries), 2, 3, 
4, 5 and 6
AbbVie Investigational
  Product:
ABT-494
Date:
15 May 2020
Development Phase:
3
Study Design:
A Phase 3, randomized, double-blind, parallel-group, active and 
placebo-controlled, multicenter study
EudraCT Number:
2016-004130-24
Investigators:
Multicenter trial (Investigator information is on file at AbbVie)
Sponsor:
For Non-EU Countries:
AbbVie Inc.*
1 North Waukegan Road
North Chicago, IL 60064
United States of America
For EU Countries:
AbbVie Deutschland GmbH & Co. KG (AbbVie)  
Knollstrasse 50 
67061 Ludwigshafen  
Germany  
NCT03104400




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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol
Date
Original
10 February 2017
Amendment 1
03 March 2017
Amendment 1.01 (VHP Countries)
20 June 2017
Amendment 2
30 June 2017
Administrative Change 1
27 October 2017
Administrative Change 2
13 December 2017
Amendment 3
22 March 2018
Administrative Change 3
04 April 2018
Administrative Change 4
04 June 2018
Administrative Change 5 
31 October 2018
Administrative Change 6 [Hong Kong (China)]
11 April 2019
Amendment 4
11 October 2019
Amendment 5
11 December 2019
The purpose of this amendment is to:
●
Update Section 1.0 Title Page, Sponsor/Emergency Contact
Rationale:  To reflect changes to personnel contact information.
●
Apply administrative changes throughout protocol.
Rationale:  Revise text to improve consistency and readability, and/or provide 
clarifications.
●
Update Section 1.2 Synopsis to add 2 years to the study duration and add 
1 additional timepoint for hands and feet x-rays.
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Section 5.1 Overall Study Design and Plan: Description to add 2 years 
to the study duration and add 1 additional timepoint for hands and feet x-rays.


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Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Section 5.3.1.1 Study Procedures, X-rays of Hands and Feet to add one 
additional timepoint. 
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Section 5.3.1.1 Study Procedures, TB Testing/TB Prophylaxis, clarify 
how subjects should respond to questions on the TB risk assessment form at 
time of annual evaluation.
Rationale:  To ensure consistent responses throughout the study and prevent 
unnecessary chest x-rays in subjects at low risk for TB.
●
Update Section 5.3.1.1 Study Procedures, Clinical Laboratory Tests, add the 
use of local laboratories during state of emergency/pandemic times to monitor 
safety.
Rationale:  To provide flexibility during state of emergency/pandemic times to 
help study sites manage subject safety.
●
Update Section 5.3.1.1 Study Procedures, Study Drug Dispensing, Dosing, and 
Compliance to add direct to patient (DTP) study drug shipment and remove the 
requirement for dispensing dosing diaries beyond Week 140.
Rationale: To provide flexibility during state of emergency/pandemic times to 
help study sites manage subject continued use of study drug when appropriate.
Rationale:  Subjects will adhere to their dosing schedule for 151 Weeks 
documented in a dosing diary.  It is not value added to continue to collect 
dosing diaries as dosing compliance is captured during the drug 
accountability process for each subject in the IRT system.
●
Update Section 5.3.1.1 Study Procedures, Study Drug Dispensing, Dosing, and 
Compliance, Subject Diary to remove the requirement for dispensing dosing 
diaries beyond Week 140.
Rationale:  Subjects will adhere to their dosing schedule for 151 Weeks 
documented in a dosing diary.  It is not value added to continue to collect 


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dosing diaries as dosing compliance is captured during the drug 
accountability process for each subject in the IRT system. AEs and 
concomitant medications are captured during study visits.
●
Update Section 5.3.1.1 Study Procedures, Patient Questionnaires to add 
telephone interview for PRO collection.
Rationale:  To provide flexibility during state of emergency/pandemic times to 
collect PRO data.
●
Update Section 5.5.4 Selection and Timing of Dose for Each Subject to 
remove the requirement for dispensing dosing diaries beyond Week 140.
Rationale:  Subjects will adhere to their dosing schedule for 151 Weeks 
documented in a dosing diary.  It is not value added to continue to collect 
dosing diaries as dosing compliance is captured during the drug 
accountability process for each subject in the IRT system.
●
Update Section 5.5.6 Treatment Compliance to remove the requirement for 
dispensing dosing diaries beyond Week 140.
Rationale:  Subjects will adhere to their dosing schedule for 151 Weeks 
documented in a dosing diary.  It is not value added to continue to collect 
dosing diaries as dosing compliance is captured during the drug 
accountability process for each subject in the IRT system.
●
Update Section 5.6.4 Selection of Doses in the Study to add 2 years to the 
study duration.
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Section 10.2 Case Report Forms, Electronic Patient Reported Data to 
add telephone interview for PRO collection.
Rationale:  To provide flexibility during state of emergency/pandemic times to 
collect PRO data.
●
Update Appendix C Study Activities to add 2 years to the study duration and 
add 1 additional timepoint for hands and feet x-rays.


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Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Appendix C Study Activities, Footnote "a" to add the additional 
timepoints for every 12 week visits due to the 2 year extension of study 
duration.
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Appendix C Study Activities, Footnote "h" to add the additional 
timepoints for full physical exams due to the 2 year extension of study 
duration.
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Appendix C Study Activities, Footnote "m" to add the additional 
timepoint for x-rays of hands and feet due to the 2 year extension of study 
duration.
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Appendix C Study Activities, Footnote "q" to add the additional 
timepoints for home pregnancy testing due to the 2 year extension of study 
duration.
Rationale:  To accumulate long-term safety and efficacy data to inform 
ongoing benefit-risk assessment of upadacitinib in the treatment of patients 
with PsA.
●
Update Appendix C Study Activities, Footnote "y" to add wording that allows 
HBV DNA PCR testing at unscheduled visits.
Rationale: To clarify that HBV DNA PCR may be tested at unscheduled visits.


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●
Update Appendix C Study Activities, add Footnote "jj" to note that after 
Week 152, EQ-5D-5L and WPAI questionnaires will be administered every 
6 months instead of every 12 weeks.
Rationale:  To continue to collect data on subjects remaining in the study with 
timepoints selected to maintain scientific value and minimize subject burden.
●
Update Appendix C Study Activities, add Footnote "kk" to remove the 
requirement for dispensing dosing diaries beyond Week 140.
Rationale:  Subjects will adhere to their dosing schedule for 151 Weeks 
documented in a dosing diary.  It is not value added to continue to collect 
dosing diaries as dosing compliance is captured during the drug 
accountability process for each subject in the IRT system. AEs and 
concomitant medications are captured during study visits.
●
Update Appendix D Study Activities – Optional Samples for Exploratory 
Research or Validation Studies to add 2 years to the study duration in the 
header of the table to be consistent with the rest of the protocol.
Rationale:  Revised to be consistent with the rest of the protocol.
An itemized list of all changes made to the protocol under this amendment can be found 
in Appendix I.


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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-572
Name of Study Drug:  ABT-494
Phase of Development:  3
Name of Active Ingredient:  ABT-494
Date of Protocol Synopsis:  15 May 2020
Protocol Title:  A Phase 3, Randomized, Double-Blind, Study Comparing Upadacitinib (ABT-494) to 
Placebo and to Adalimumab in Subjects with Active Psoriatic Arthritis Who Have a History of 
Inadequate Response to at Least One Non-Biologic Disease Modifying Anti-Rheumatic Drug (DMARD) 
– SELECT – PsA 1
Objectives:
Period 1
Primary Objective
1.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo and versus 
adalimumab (ADA) for the treatment of signs and symptoms of PsA in subjects with moderately to 
severely active PsA who have an inadequate response or intolerance to 1 or more non-biologic 
DMARD (DMARD-IR).
Secondary Objective
2.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo for the prevention 
of structural progression in subjects with moderately to severely active PsA who have an inadequate 
response or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
3.
To compare the safety and tolerability of ABT-494 15 mg QD and 30 mg QD versus placebo and 
versus adalimumab in subjects with moderately to severely active PsA who have an inadequate 
response or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
Period 2
To evaluate the long-term safety, tolerability and efficacy of ABT-494 15 mg QD and 30 mg QD in 
subjects with PsA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 350 sites
Study Population:  Patients with active psoriatic arthritis despite prior use of at least one non-biologic 
DMARD.
Number of Subjects to be Enrolled:  Approximately 1640


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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is 56 weeks in duration and 
includes a 24-week randomized, double-blind, parallel-group, placebo-controlled and active comparator-
controlled period followed by an additional 32 weeks of blinded, active comparator-controlled treatment 
(Weeks 24 – 56).  Period 1 is designed to compare the safety, tolerability, and efficacy of ABT-494 
15 mg QD and 30 mg QD versus placebo and versus adalimumab 40 mg every other week (eow) in 
subjects with moderately to severely active PsA and have an inadequate response to non-biologic 
DMARDs (DMARD-IR).  Period 1 is also designed to compare the efficacy of ABT-494 15 mg QD and 
30 mg QD versus placebo for the prevention of structural progression.  Period 2 is an open-label (blinded 
until the last subject completes the last visit of Period 1), long-term extension of up to a total treatment 
duration of approximately 5 years to evaluate the safety, tolerability and efficacy of ABT-494 15 mg QD 
and 30 mg QD in subjects with PsA who have completed Period 1.
The study is designed to enroll approximately 1640 subjects at approximately 350 study centers 
worldwide to meet scientific and regulatory objectives without enrolling an undue number of subjects in 
alignment with ethical considerations.  
The study duration will include a 35-day screening period; a 56-week blinded period which includes 
24 weeks of double-blind, placebo-controlled and active comparator controlled treatment followed by 
32 weeks of active comparator controlled treatment (Period 1); a long-term extension period of up to a 
total treatment duration of approximately 5 years ([blinded until the last subject completes the last visit 
of Period 1] Period 2); a 30-day follow-up call or visit; and a 70-day follow-up call.
Subjects who meet eligibility criteria will be stratified by extent of psoriasis (≥ 3% body surface area 
[BSA] or < 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of 
enthesitis, except for subjects from China and Japan, where randomization for each country will be 
stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA) only, and then will be 
randomized in a 2:2:2:1:1 ratio to one of five treatment groups:
Group 1:  ABT-494 15 mg QD (N = 410)
Group 2:  ABT-494 30 mg QD (N = 410)
Group 3:  ADA (40 mg eow) (N = 410) 
Group 4:  Placebo followed by ABT-494 15 mg QD (N = 205)
Group 5:  Placebo followed by ABT-494 30 mg QD (N = 205)
No more than approximately 15% of subjects will be enrolled with concomitant use of 
hydroxychloraquine, sulfasalazine, bucillamine, or iguratimod.
Subjects will receive both oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or matching placebo) 
and subcutaneous study drug eow (either ADA 40 mg or matching placebo) until all subjects have 
completed Period 1 (Week 56) and sites and subjects are unblinded to study treatment.


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Methodology (Continued):
Subjects who were assigned to placebo at Baseline will be preassigned to receiving either ABT-494 
15 mg QD or ABT-494 30 mg QD starting at Week 24 in a 1:1 ratio.  Subjects who complete the 
Week 56 visit (end of Period 1) will enter the long-term extension portion of the study, Period 2 (total 
study duration up to approximately 5 years).  Subjects will continue study treatment as assigned at the 
end of Period 1.  Subjects who are assigned to the ABT-494 15 mg QD, ABT-494 30 mg QD, or 
adalimumab 40 mg eow will continue to receive ABT-494 15 mg QD, ABT-494 30 mg QD, or 
adalimumab 40 mg eow, respectively, in a blinded manner.  When the last subject completes the last 
visit of Period 1 (Week 56), study drug assignment in both periods will be unblinded to the sites, and 
subjects will be dispensed study drug in an open-label fashion until the completion of Period 2.
Subjects must have had inadequate response to ≥ 1 non-biologic DMARD (MTX, SSZ, LEF, 
cyclosporine, apremilast, bucillamine or iguratimod) or an intolerance to or contraindication for 
DMARDs as defined by the investigator prior to the Screening visit.  No background non-biologic 
DMARD therapy is required during participation in this study.  For subjects who are on non-biologic 
DMARD therapy at baseline (MTX, SSZ, LEF, apremilast, hydroxychloroquine (HCQ), bucillamine or 
iguratimod), non-biologic DMARDs should have been started ≥ 12 weeks prior to the baseline visit, 
must be at stable dose for ≥4 weeks prior to the first dose of study drug and remain on a stable dose 
through Week 36 of the study; the non-biologic DMARD dose may be decreased only for safety
reasons.  In addition, all subjects taking MTX 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.  Please refer to Section 5.2.3.1 and Section 5.2.3.2 for 
additional details related to prior and concomitant DMARD therapy, respectively.  Starting at the 
Week 36 visit (after Week 36 assessments have been performed), initiation of or change in background 
PsA medication(s) including, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, low potency opiates, and non-biologic DMARDs (concomitant use of up to 
2 non-biologic DMARDs except the combination of MTX and leflunomide) is allowed as per local label 
with maximum doses as outlined in Section 5.2.3.3.
At Week 16, subjects classified as non-responders (defined as not achieving at least 20% improvement 
in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 and Week 16) 
will add or modify background therapy for PsA.  
After the last subject completes the Week 24 study visit, an unblinded analysis will be conducted for the 
purpose of initial regulatory submission.  To maintain integrity of the trial during the blinded 56-week 
period, study sites and subjects will remain blinded until all subjects have reached Week 56.  A 
second unblinded analysis may be conducted for regulatory purposes after all subjects have completed 
Period 1.  A final analysis will be conducted after all subjects have completed Period 2.  An unblinded 
interim analysis will be conducted by an independent external Data Monitoring Committee (DMC) after 
approximately 600 subjects have completed the Week 12 visit or have prematurely discontinued from 
the study.  The interim analysis is to assess if the study met the pre-defined No-Go boundary for the 
primary endpoint ACR20.  


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Methodology (Continued):
Each subject will undergo a maximum of 6 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 24, Week 56, Week 104, Week 152, and Week 260/Premature discontinuation.  In 
addition, all subjects who fail to attain at least 20% improvement in either or both TJC and SJC at 
Week 12 and Week 16 will have an x-ray examination at Week 16 (refer to Section 5.2.3.4 for additional 
details).  All subjects will receive x-rays of hands and feet if they discontinue from the study or from 
study drug at Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained 
during Period 1 or at least 24 weeks during Period 2.
Starting at Week 36, subjects who fail to demonstrate at least 20% improvement in either or both TJC 
and SJC compared to baseline at 2 consecutive visits will be discontinued from study drug treatment.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, ≥ 18 years old at Screening.
2.
Clinical diagnosis of PsA with symptom onset at least 6 months prior to the Screening Visit and 
fulfillment of the Classification Criteria for PsA (CASPAR) criteria.
3.
Subject has active disease at Baseline defined as ≥ 3 tender joints (based on 68 joint counts) and 
≥3 swollen joints (based on 66 joint counts) at Screening and Baseline Visits.
4.
Presence of either at Screening:
!
≥ 1 erosion on x-ray as determined by central imaging review or;
!
hs-CRP > laboratory defined upper limit of normal (ULN).
5.
Diagnosis of active plaque psoriasis or documented history of plaque psoriasis.
6.
Subject has had an inadequate response (lack of efficacy after a minimum 12 week duration of 
therapy) to previous or current treatment with at least 1 non-biologic DMARD at maximally 
tolerated dose or up to dose defined in Inclusion Criterion 7 [(inadequate response to MTX is 
defined as ≥ 15 to ≤ 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at doses 
≥ 12.5 mg/week after complete titration; for subjects in China, Korea, Malaysia, Singapore, Hong 
Kong (China), Taiwan, and Japan inadequate response to MTX is defined as ≥7.5 mg/week), SSZ, 
LEF, cyclosporine, apremilast, bucillamine or iguratimod)], or subject has an intolerance to or 
contraindication for DMARDs as defined by the investigator.
7.
Subject who is on current treatment with concomitant non-biologic DMARDs at study entry must 
be on ≤ 2 non-biologic DMARDs (except the combination of MTX and leflunomide) at the 
following doses:  MTX (≤ 25 mg/week), SSZ (≤ 3000 mg/day), leflunomide (LEF) (≤ 20 mg/day), 
apremilast (≤ 60 mg/day), HCQ (≤ 400 mg/day), bucillamine (≤ 300 mg/day) or iguratimod 
(≤50 mg/day) for ≥ 12 weeks and at stable dose for ≥ 4 weeks prior to the Baseline Visit.  No other 
DMARDs are permitted during the study.
!
Subjects who need to discontinue DMARDs prior to the Baseline Visit to comply with this 
inclusion criterion must follow the procedure specified below or at least five times the mean 
terminal elimination half-life of a drug:
o
≥ 8 weeks for LEF if no elimination procedure was followed, or adhere to an elimination 
procedure (i.e., 11 days with cholestyramine, or 30 days washout with activated charcoal 
or as per local label);
o
≥ 4 weeks for all others.


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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 ruxolitinib, 
tofacitinib, baricitinib, and filgotinib).
2.
Current treatment with > 2 non-biologic DMARDs or use of DMARDs other than MTX, SSZ, LEF, 
apremilast, HCQ, bucillamine or iguratimod or use of MTX in combination with LEF at Baseline.
3.
History of fibromyalgia, any arthritis with onset prior to age 17 years, or current diagnosis of 
inflammatory joint disease other than PsA (including, but not limited to rheumatoid arthritis, gout, 
overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, systemic lupus 
erythermatosus).  Prior history of reactive arthritis or axial spondyloarthritis including ankylosing 
spondylitis and non-radiographic axial spondyloarthritis is permitted if documentation of change in 
diagnosis to PsA or additional diagnosis of PsA is made.  Prior history of fibromyalgia is permitted 
if documentation of change in diagnosis to PsA or documentation that the diagnosis of fibromyalgia 
was made incorrectly.
Investigational Product:
ABT-494
Doses:
15 mg or 30 mg once daily
Mode of Administration:
Oral
Reference Therapy:
Matching placebo for ABT-494
Dose:
1 tablet once daily
Mode of Administration:
Oral
Reference Therapy:
Adalimumab (ADA)
Dose:
40 mg every other week (eow)
Mode of Administration:
Subcutaneous
Reference Therapy:
Matching Placebo for Adalimumab
Dose:
Subcutaneous
Duration of Treatment:  260 weeks


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Criteria for Evaluation:
Efficacy:
The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
Key secondary endpoints:
The key multiplicity adjusted secondary efficacy endpoints (each dose of ABT-494 versus placebo 
unless noted) are:
1.
Change from baseline in HAQ-DI at Week 12;
2.
Proportion of subjects achieving a static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 
1 and at least a 2-point improvement from baseline at Week 16;
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with ≥ 3% BSA psoriasis 
at baseline);
4.
Change from baseline in SHS at Week 24;
5.
Proportion of subjects achieving MDA at Week 24;
6.
Proportion of subjects with resolution of enthesitis (LEI = 0) at Week 24;
7.
ACR 20 response rate at Week 12 (non-inferiority of ABT-494 vs adalimumab);
8.
Change from baseline in SF-36 PCS at Week 12.
9.
Change from baseline in FACIT-Fatigue Questionnaire at Week 12;
10. ACR 20 response rate at Week 12 (superiority of ABT-494 vs. adalimumab);
11. Proportion of subjects with resolution of dactylitis (LDI = 0) at Week 24;
12. Change from baseline in Patient's Assessment of Pain NRS at Week 12 (superiority of ABT-494 vs. 
adalimumab);
13. Change from baseline in HAQ-DI at Week 12 (superiority of ABT-494 vs. adalimumab); and
14. Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS) Questionnaire at 
Week 16. 
Additional key secondary efficacy endpoints (each dose of ABT-494 versus placebo) are:
!
ACR50/70 response at Week 12;
!
ACR20 response at Week 2;
The following outcome measures will be assessed in subjects treated with ABT-494 as compared to 
placebo and adalimumab at scheduled time points other than those specified for the primary and key 
secondary variables:
!
Proportion of subjects with no radiographic progression (defined as change from baseline in 
SHS ≤ 0); 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
Change from baseline in individual components of ACR response;
o
Change from baseline in Tender Joint Count (TJC) (0 – 68);
o
Change from baseline in Swollen Joint Count (SJC) (0 – 66);
o
Change from baseline in Physician Global Assessment (PGA) – Disease Activity 
Numerical Rating Scale (NRS);
o
Change from baseline in Patient's Global Assessment (PtGA)-Disease Activity NRS;
o
Change from baseline in Patient's Assessment of Pain NRS;
o
Change from baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI);
o
Change from baseline in High-Sensitivity C Reactive Protein (hs-CRP);
!
ACR 20/50/70 response rates;
!
Change from baseline in Leeds Dactylitis Index (LDI);
!
Change from baseline in dactylitis count;
!
Proportion of subjects with resolution of dactylitis;
!
Change from baseline in Leeds Enthesitis Index (LEI);
!
Proportion of subjects with resolution of enthesitis sites included in the LEI;
!
Change from baseline in SPARCC Enthesitis Index;
!
Proportion of subjects with resolution of enthesitis sites included in the SPARCC Enthesitis 
Index;
!
Change from baseline in total enthesitis count; 
!
Proportion of subjects with resolution of enthesitis;
!
PASI 75/90/100 response rates (for subjects with ≥ 3% Body Surface Area (BSA) psoriasis at 
baseline);
!
Proportion of subjects achieving a static Investigator Global Assessment of Psoriasis (sIGA) 
score of 0 or 1 and at least a 2-point improvement from baseline;
!
BSA-Ps;
!
Modified Psoriatic Arthritis Response Criteria (PsARC) response rate;
!
Change from baseline in Disease Activity Score 28 (DAS28) (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in PsA Disease Activity Score (PASDAS);
!
Change from baseline in Disease Activity In Psoriatic Arthritis (DAPSA) score; 
!
Change from baseline in Short Form 36 (SF-36) Health Questionnaire;
!
Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
Questionnaire;
!
Change from baseline in EuroQol-5-Dimensions-5-Levels (EQ-5D-5L) Questionnaire;
!
Change from baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire;
!
Health Resource Utilization (HRU);
!
Change from baseline in SAPS Questionnaire;
!
Change from baseline in BASDAI;


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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
BASDAI 50 response rates:
!
Change from baseline in Morning stiffness (mean of BASDAI Questions 5 and 6);
!
Change from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
!
Proportion of subjects with ASDAS Inactive Disease;
!
Proportion of subjects with ASDAS Major Improvement;
!
Proportion of subjects with ASDAS Clinically Important Improvement;
!
Proportion of subjects achieving a clinically meaningful improvement in HAQ-DI (≥ 0.35);
!
Proportion of subjects achieving MDA.
Pharmacokinetic:
Blood samples for assay of ABT-494 and possibly other medications in plasma will be collected at each 
visit after baseline in Period 1.
Exploratory Research Variables and Validation Studies (Optional)
Prognostic, surrogate, predictive, and pharmacodynamic biomarkers signatures may be evaluated.  
Samples for different applications including, but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, metabolomic, proteomic and targeted 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.
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:
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between each ABT-494 treatment group and the combined placebo groups will be 
conducted using the Cochran-Mantel-Haenszel test adjusting for main stratification factors.
For ACR20 response rate at Week 12, analysis will be conducted to assess the non-inferiority of each 
ABT-494 dose versus ADA on placebo-subtracted treatment difference using Koch's 3-arm test statistic.  
The test aims to show that ABT-494 preserves at least 50% of the placebo-subtracted ADA effect.  
Superiority of ABT-494 versus ADA will also be tested for ACR20.


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Statistical Methods (Continued):
Period 1 Efficacy (Continued):
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Pairwise comparisons for each of the ABT-494 treatment groups and the combined 
placebo groups 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 Assessment of Pain NRS and change from baseline in HAQ-DI at 
Week 12, superiority of ABT-494 vs adalimumab will also be tested.  The overall type I error rate of the 
primary and key secondary endpoints for the two doses will be strongly controlled using a graphical 
multiple testing procedure.
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.
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.  There will be two sets of planned safety analyses:  safety analysis by 
Week 24, and long-term safety analysis.  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
ADL
Activities of Daily Living
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALC
Absolute Lymphocyte Count
ALT
Alanine Transaminase
ANC
Absolute Neutrophil Count
ANA
Antinuclear Antibody
Anti-CCP
Anti-Cyclic Citrullinated Peptide
ASDAS
Ankylosing Spondylitis Disease Activity Score
AST
Aspartate Transaminase
AUC
Area under the plasma concentration-time curve
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BCG
Bacillus Calmette-Guerin
BSA
Body Surface Area
BUN
Blood Urea Nitrogen
CASPAR
Classification Criteria for Psoriatic Arthritis
CBC
Complete Blood Count
CCP
Cyclic Citrullinated Peptide
CDAI
Clinical Disease Activity Index
CL/F
Apparent Clearance
Cmax
Maximum Observed Plasma Concentration
Cmin
Minimum Observed Plasma Concentration
CRF
Case Report Form
CS
Clinically Significant
csDMARD
Conventionally synthetic Disease Modifying Anti-Rheumatic Drug
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CXR
Chest X-Ray
CYP3A
Cytochrome P450 3A


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DAPSA
Disease Activity In Psoriatic Arthritis
DAS
Disease Activity Score
DMARD
Disease Modifying Anti-Rheumatic Drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
dsDNA
Double Strand Deoxyribonucleic Acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EOW
Every Other Week
ePRO
Electronic Patient Reported Outcome
EQ-5D-5L
EuroQoL-5 Dimensions – 5 Levels
ESR
Erythrocyte Sedimentation Rate
EU
European Union
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FAS
Full Analysis Set
FDA
US Food and Drug Administration
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HAQ-DI
Health Assessment Questionnaire – Disability Index
HBcAb
Hepatitis B Core Antibody 
HBsAg
Hepatitis B Surface Antigen
HBV
Hepatitis B Virus
HCQ
Hydroxychloroquine
HCV Ab
Hepatitis C Virus Antibody
HDL-C
High-Density Lipoprotein Cholesterol
HIV
Human Immunodeficiency Virus
HRU
Health Resource Utilization
hs-CRP
High-Sensitivity C Reactive Protein
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma Release Assay
IR
Inadequate Response


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IRB
Institutional Review Board
IRT
Interactive Response Technology
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
JAK
Janus Kinase
LDA
Low Disease Activity
LDI
Leeds Dactylitis Index
LDL-C
Low-Density Lipoprotein Cholesterol
LEF
Leflunomide
LEI
Leeds Enthesitis Indicies
MACE
Major Adverse Cardiovascular Event
MD
Medical Director
MDA
Minimal Disease Activity
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MTX
Methotrexate
N
Number
NCS
Not Clinically Significant
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
OL
Open Label
PASI
Psoriasis Area Severity Index
PBMC
Peripheral Blood Mononuclear Cell
PCR
Polymerase Chain Reaction
PCS
Physical Component Summary
PD
Premature Discontinuation
PGA
Physician's Global Assessment
PK
Pharmacokinetics
PPD
Purified Protein Derivative
PRN
As Needed (Latin:  Pro Re Nata)


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PRO
Patient-Reported Outcome
PsA
Psoriatic Arthritis
PsARC
Psoriatic Arthritis Response Criteria
PsO
Psoriasis
PT
Preferred Term
PtGA
Patient's Global Assessment of Disease Activity
PUVA
Psoralens and Ultraviolet A
QD
Once Daily (Latin:  Quaque Die)
QoL
Quality of Life
QTc
QT interval corrected for heart rate
RA
Rheumatoid Arthritis
RAVE
EDC System from Medidata
RBC
Red Blood Count
RCT
Randomized Controlled Trial
RNA
Ribonucleic acid
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAPS
Self-Assessment of Psoriasis Symptoms
SF-36
36-Item Short Form Health Survey
SHS
Sharp/van der Heijde Score
sIGA
Static Investigator Global Assessment of Psoriasis
SJC
Swollen Joint Count
SOC
System Organ Class
SPARCC
Spondyloarthritis Research Consortium of Canada
SSZ
Sulfasalazine
SUSAR
Suspected Unexpected Serious Adverse Reaction
TA
Therapeutic Area
TA MD
Therapeutic Area Medical Director
TB
Tuberculosis
TBD
To Be Determined
TEAE
Treatment emergent adverse event
TJC
Tender Joint Count
TNF
Tumor Necrosis Factor
Tyk2
Tyrosine kinase 2


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ULN
Upper Limit of Normal
UVA
Ultraviolet A
UVB
Ultraviolet B
V/F
Apparent Volume of Distribution
WBC
White Blood Cell
WPAI
Work Productivity and Activity Impairment


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2.0
Table of Contents
1.0
Title Page..................................................................................1
1.1
Protocol Amendment:  Summary of Changes ...........................................3
1.2
Synopsis .....................................................................................................8
1.3
List of Abbreviations and Definition of Terms........................................17
2.0
Table of Contents...................................................................22
3.0
Introduction ...........................................................................27
3.1
Differences Statement..............................................................................33
3.2
Benefits and Risks....................................................................................33
4.0
Study Objective......................................................................35
5.0
Investigational Plan...............................................................35
5.1
Overall Study Design and Plan:  Description ..........................................35
5.2
Selection of Study Population..................................................................44
5.2.1
Inclusion Criteria .....................................................................................44
5.2.2
Exclusion Criteria ....................................................................................47
5.2.3
Prior and Concomitant Therapy...............................................................51
5.2.3.1
Prior Therapy ...........................................................................................53
5.2.3.2
Permitted Background Therapy ...............................................................53
5.2.3.3
Prohibited Therapy...................................................................................55
5.2.3.4
Rescue Therapy........................................................................................59
5.2.4
Contraception Recommendations ............................................................60
5.3
Efficacy and Safety Assessments/Variables ............................................63
5.3.1
Efficacy and Safety Measurements Assessed ..........................................63
5.3.1.1
Study Procedures .....................................................................................63
5.3.1.2
Optional Samples for Exploratory Research and Validation 
Studies......................................................................................................86
5.3.2
Drug Concentration Measurements .........................................................88
5.3.2.1
Measurement Methods.............................................................................88
5.3.3
Efficacy Variables....................................................................................89
5.3.3.1
Primary Variables ....................................................................................89
5.3.3.2
Key Secondary Variables.........................................................................89
5.3.3.3
Additional Variables ................................................................................90


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5.3.4
Safety Variables.......................................................................................92
5.3.5
Pharmacokinetic Variables ......................................................................93
5.3.6
Exploratory Research Variables and Validation Studies.........................93
5.4
Removal of Subjects from Therapy or Assessment.................................94
5.4.1
Discontinuation of Individual Subjects....................................................94
5.4.2
Discontinuation of Entire Study...............................................................96
5.5
Treatments................................................................................................96
5.5.1
Treatments Administered.........................................................................96
5.5.2
Identity of Investigational Products.........................................................97
5.5.2.1
Packaging and Labeling...........................................................................98
5.5.2.2
Storage and Disposition of Study Drugs..................................................99
5.5.3
Method of Assigning Subjects to Treatment Groups...............................99
5.5.4
Selection and Timing of Dose for Each Subject....................................100
5.5.5
Blinding..................................................................................................102
5.5.5.1
Blinding of Investigational Product.......................................................102
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)....................103
5.5.6
Treatment Compliance...........................................................................103
5.5.7
Drug Accountability...............................................................................104
5.6
Discussion and Justification of Study Design........................................105
5.6.1
Discussion of Study Design and Choice of Control Groups..................105
5.6.2
Appropriateness of Measurements.........................................................106
5.6.3
Suitability of Subject Population ...........................................................106
5.6.4
Selection of Doses in the Study .............................................................106
6.0
Complaints ...........................................................................108
6.1
Medical Complaints...............................................................................108
6.1.1
Definitions..............................................................................................108
6.1.1.1
Adverse Event........................................................................................108
6.1.1.2
Serious Adverse Events .........................................................................109
6.1.1.3
Adverse Events of Special Interest ........................................................111
6.1.2
Adverse Event Severity..........................................................................111
6.1.3
Relationship to Study Drug....................................................................112
6.1.4
Adverse Event Collection Period...........................................................113
6.1.5
Serious Adverse Event and Malignancy Reporting ...............................114


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6.1.6
Pregnancy...............................................................................................116
6.1.7
Toxicity Management ............................................................................117
6.1.8
Data Monitoring Committee..................................................................122
6.1.9
Cardiovascular Adjudication Committee...............................................122
6.2
Product Complaint .................................................................................122
6.2.1
Definition ...............................................................................................122
6.2.2
Reporting................................................................................................123
7.0
Protocol Deviations..............................................................123
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................124
8.1
Statistical and Analytical Plans..............................................................124
8.1.1
Analysis Populations..............................................................................125
8.1.1.1
Full Analysis Set (FAS).........................................................................125
8.1.1.2
Per Protocol Analysis Set.......................................................................125
8.1.1.3
Safety Analysis Set ................................................................................125
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............125
8.1.2.1
Subject Accountability...........................................................................125
8.1.2.2
Subject Disposition ................................................................................126
8.1.2.3
Study Drug Exposure.............................................................................126
8.1.3
Analysis of Demographic and Baseline Characteristics ........................126
8.1.4
Efficacy Analysis ...................................................................................127
8.1.4.1
Primary Efficacy Variable .....................................................................127
8.1.4.2
Key Secondary Efficacy Variables ........................................................128
8.1.4.3
Additional Efficacy Variables................................................................128
8.1.4.4
Multiplicity Control for the Primary and Key Secondary 
Endpoints ...............................................................................................129
8.1.4.5
Imputation Methods...............................................................................129
8.1.4.6
Interim Analysis.....................................................................................130
8.1.4.7
Long-Term Efficacy for Period 1 and Period 2 Combined....................130
8.1.5
Safety Analyses......................................................................................131
8.1.5.1
General Considerations..........................................................................131
8.1.5.2
Analysis of Adverse Events...................................................................131
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) ......................................131


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8.1.5.2.2
Serious Adverse Events and Death ........................................................132
8.1.5.3
Analysis of Laboratory and Vital Sign Data..........................................133
8.1.6
Pharmacokinetic and Exposure-Response Analyses .............................133
8.2
Determination of Sample Size ...............................................................134
8.3
Randomization Methods ........................................................................134
9.0
Ethics.....................................................................................135
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................135
9.2
Ethical Conduct of the Study.................................................................135
9.3
Subject Information and Consent...........................................................136
9.3.1
Informed Consent Form and Explanatory Material ...............................137
9.3.2
Revision of the Consent Form and Explanatory Material .....................137
10.0
Source Documents and Case Report Form 
Completion ...........................................................................137
10.1
Source Documents .................................................................................137
10.2
Case Report Forms.................................................................................138
11.0
Data Quality Assurance ......................................................140
12.0
Use of Information...............................................................140
13.0
Completion of the Study .....................................................141
14.0
Investigator's Agreement....................................................143
15.0
Reference List ......................................................................144
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................57
Table 2.
Clinical Laboratory Tests.........................................................................75
Table 3.
Identity of Investigational Products.........................................................98
Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values..................................................................................119
List of Figures
Figure 1.
Study Design............................................................................................40


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Figure 2.
Interpretation and Management of HBV Serologic Test Results ............78
Figure 3.
Adverse Event Collection ......................................................................113
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................150
Appendix B.
List of Protocol Signatories....................................................................152
Appendix C.
Study Activities......................................................................................153
Appendix D.
Study Activities – Optional Samples for Exploratory Research or 
Validation Studies..................................................................................160
Appendix E.
Latent TB Risk Assessment Form Example ..........................................161
Appendix F.
Injection Instructions – Sample Pre-Filled Syringe ...............................162
Appendix G.
The CASPAR Criteria............................................................................169
Appendix H.
Local Requirements ...............................................................................170
Appendix I.
Protocol Amendment:  List of Changes.................................................174


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3.0
Introduction
Psoriatic Arthritis
Psoriatic Arthritis (PsA) is a chronic systemic inflammatory disease classified as a sub-
type of spondyloarthritis (SpA) and characterized by the association of arthritis and 
psoriasis.  PsA can develop at any time, but for most people it appears between the ages of 
30 and 50, and it affects men and women equally.1  The course of PsA is usually 
characterized by flares and remissions.1  Left untreated, patients with PsA can have 
persistent inflammation, progressive joint damage, disability, and a reduced life 
expectancy.1,2  For most patients, skin manifestations predate the arthritis.1
Patients with PsA experience varying combinations of disease manifestations affecting the 
synovium, tendons, entheses, skin, and bone.  These manifestations of disease range in 
prevalence with peripheral arthritis and variable degrees of psoriasis observed in all 
patients at some point during their disease course, axial disease in 40 – 74% depending on 
the criteria used for diagnosis,3 enthesitis in 25 – 51%, dactylitis in 8 – 59%,4-6 and 
anterior uveitis in 2 – 25%.7  Additionally, PsA patients are more likely to experience the 
co-morbid conditions of cardiovascular disease, metabolic syndrome, obesity, diabetes, 
fatty liver disease, inflammatory bowel disease, kidney disease, osteoporosis, 
fibromyalgia,9 depression, and anxiety than healthy subjects,8 and have decreased quality 
of life and functional impairment.10,11
The prevalence of PsA varies by region and has been reported as 0.13% in North 
America, 0.07% in South America, 0.19% in Europe, and 0.01 – 0.07% in Africa, the 
Middle East, and Asia.12
PsA patients require treatment of the entire spectrum of disease manifestations.  The 
primary goal of treating patients with PsA is to maximize long-term health-related quality 
of life, through control of symptoms, prevention of structural damage, normalization of 
function and social participation and abrogation of inflammation.  Initial treatment of 
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(NSAIDs) and local corticosteroid injections, while topical therapies are used for the 
initial treatment of psoriasis.  For patients who experience lack of efficacy or toxicity with 
these measures, for the treatment of peripheral arthritis, both the European League 
Against Rheumatism (EULAR)13 and Group for Research and Assessment of Psoriasis 
and Psoriatic Arthritis (GRAPPA)14 recommend systemic therapy with conventional 
disease modifying anti-rheumatic drugs (cDMARDs) (methotrexate [MTX], leflunomide 
[LEF], sulfasalazine [SSZ], or ciclosporin A), followed by anti-tumor necrosis factor 
(TNF) therapy in patients who do not respond adequately to cDMARDs.  Other biologic 
therapies (e.g., IL-12 /23 or IL-17 inhibitors) are also recommended as alternatives to 
anti-TNF inhibitors in selected PsA patients.  Additional specific recommendations differ 
slightly between EULAR and GRAPPA, however recommendations for therapeutic 
choice are made based on a patient's clinical presentation as some manifestations of PsA, 
such as enthesitis, dactylitis, and axial disease are either not responsive or poorly 
responsive to cDMARDs.  Additional therapeutic options are also recommended 
specifically for treatment of skin disease.13,14
Despite the beneficial results achieved with currently available biologic agents, 
approximately 40% of patients do not have at least 20% improvement in American 
College of Rheumatology (ACR) scores13,15-21 and only 58%22 to 61%23 of patients with 
PsA who receive them are able to achieve clinical remission after 1 year of treatment, 
with only approximately 43% achieving sustained remission for at least 1 year.24  Thus, 
there remains a clear medical need for additional therapeutic options in PsA for patients 
with inadequate response to or intolerance to currently available therapies.
Targeting the Janus kinase (JAK) signaling pathway for autoimmune diseases, such as 
PsA, rheumatoid arthritis (RA), Crohn's disease, ulcerative colitis (UC), and atopic 
dermatitis, is supported by the involvement of various pro-inflammatory cytokines that 
signal via JAK pathways in the pathogenesis of these immune-related disorders.  The 
activation of JAK signaling 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.25,26


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The JAK family is composed of 4 members:  JAK1, 2, 3, and tyrosine kinase 2 (Tyk2).  
These cytoplasmic tyrosine kinases act in tandem to activate the Signal Transducer and 
Activator of Transcription (STAT) that transduce cytokine-mediated signals, and are 
associated with multiple membrane cytokine receptors such as common gamma-chain 
(CGC) receptors and the glycoprotein 130 trans-membrane proteins.27  JAK3 and JAK1 
are components of the CGC cytokine receptor complexes that are responsible for the 
signaling of the inflammatory cytokines IL-2, -4, -7, -9, -15 and -21; whereas IL-12 and 
IL-23 signal through JAK2 and Tyk2.28  Propagation of these signals is important in the 
amplification of inflammatory responses.  While the exact mechanism of PsA has not 
been fully elucidated, multiple cytokines such as IL-1, -6, -12, -17, -20, and -23 are 
thought to be involved in the activation and proliferation of epidermal keratinocytes in 
psoriatic lesions.29  The IL-17/IL-23 cytokine axis is also thought to be important in PsA 
pathogenesis.30  Thus, blockade of either JAK1 or Tyk2 could inhibit the response of 
central cytokine signals thought to be important in the pathogenesis of PsA.
Tofacitinib is an oral JAK inhibitor that inhibits JAK1, JAK2, and JAK3 with high 
in vitro functional specificity for kinases 1 and 3.  Tofacitinib is currently in Phase 3 
development in PsA.  The Phase 3 studies evaluated the efficacy and safety of tofacitinib 
5 mg and 10 mg twice daily (BID) in adult patients with active PsA who had an 
inadequate response to at least one conventional synthetic DMARD (csDMARD) and 
who were TNF inhibitor-naïve (OPAL Broaden) or who had an inadequate response to at 
least 1 TNF inhibitor (OPAL Beyond).  Both studies achieved the primary endpoints of 
ACR20 and change in Health Assessment Questionnaire Disability Index (HAQ-DI) 
versus placebo for both the 5 mg BID and 10 mg BID doses at Month 3.  Data reported 
from OPAL Broaden indicate ACR20 response at Month 3 for placebo, tofacitinib 5 mg 
BID, tofacitinib 10 mg BID, and adalimumab 40 mg EOW of 33.3%, 50.5%, 60.6%, and 
51.9%, respectively; p-value versus placebo for each active therapy was ≤ 0.05.  At 
Month 3, statistically significant results in favor of tofacitinib over placebo for both dose 
groups were also observed for ACR50/70 responses, and PASI75 response.  Superiority of 
tofactinib versus placebo was seen in the Leeds Enthesitis Index (LEI), and Dactylitis 
Severity Score (DSS) at the 10 mg BID dose only.  Results for the primary and reported 


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secondary efficacy endpoints were maintained to Month 12.  No radiographic data were 
reported at Month 3 (end of double-blind period); however at Month 12 little radiographic 
progression was observed in any dose group.31  OPAL Beyond results for ACR20 
response at Month 3 for placebo, tofacitinib 5 mg BID, and tofacitinib 10 mg BID were 
23.7%, 49.6%, and 47.0%, respectively; p-value versus placebo for each active therapy 
was ≤ 0.0001.  At Month 3 statistically superior results in favor of tofacitinib at both 
doses versus placebo for ACR50, LEI, and DSS were also observed with superiority over 
placebo for PASI75 demonstrated only at the 10 mg BID dose while ACR70 response was 
not significantly different from placebo for either dose group.32  The observed safety 
findings for both studies were consistent with those observed in the RA and psoriasis 
development programs.  In related diseases (RA,33 psoriasis,34 and ankylosing 
spondylitis35), tofacitinib has demonstrated an impact on signs and symptoms, as 
measured by ACR, Psoriasis Area and Severity Index (PASI), and Assessment in 
Ankylosing Spondylitis (ASAS) response criteria.31-35
ABT-494 is a novel JAK1 inhibitor being developed for the treatment of adult patients 
with inflammatory diseases.  Based on in vitro selectivity assays and in vivo animal 
models, ABT-494 has demonstrated inhibition of JAK1 at efficacious drug exposure 
levels that spare an inhibitory effect on JAK2.  The enhanced selectivity of ABT-494 may 
have the potential for an improved benefit/risk profile by mitigating JAK2 inhibitory 
effects on erythropoiesis and myelopoiesis.
ABT-494 Clinical Development
To date, single and multiple doses of ABT-494 have been studied in healthy volunteers in 
10 Phase 1 studies (one of which also employed a substudy in subjects with mild to 
moderate RA), which have completed study conduct.  In addition, ABT-494 has been 
studied in 4 Phase 2 trials in subjects with RA or Crohn's disease.  Two of these Phase 2 
trials have completed study conduct:  2 randomized controlled trials (RCTs) in 
575 subjects with moderately to severely active RA on background MTX 
(Studies M13-550 and M13-537).  One open-label extension to the completed RA studies 
(Study M13-538) and 1 randomized, dose-ranging, placebo-controlled study 


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(Study M13-740) in subjects with moderately to severely active Crohn's disease with a 
history of inadequate response to or intolerance to anti-TNF therapy are ongoing.  The RA 
Phase 3 clinical development program has been initiated and will include 6 randomized, 
controlled studies followed by long-term extension periods.
No Phase 2 studies in subjects with PsA have been performed with ABT-494.  Results 
from the Phase 2 randomized controlled studies in subjects with RA are available.  
Efficacy of treatment with ABT-494 in patients with moderate to severe RA was 
demonstrated in both Phase 2 Studies M13-550 and M13-537.  Results from both studies
demonstrated dose- and exposure-dependent improvement in clinical signs and symptoms 
as measured by the ACR20/50/70 response criteria.
The Phase 2 program for ABT-494 in subjects with moderately to severely active RA 
consisted of 2 randomized controlled trials (RCTs), both on stable background 
methotrexate (MTX) therapy, 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 ABT-494 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 ABT-494 (up to 73%) compared with placebo (35%).
In addition, numerically higher proportions of subjects achieved ACR50 and ACR70 
responses and low disease activity (LDA, based on Disease Activity Score [DAS] 28 
C-reactive protein [CRP] and Clinical Disease Activity Index [CDAI]) in the ABT-494 
dose groups versus placebo.


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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 
of ABT-494 compared with placebo (50%).  At all doses of ABT-494 compared to 
placebo, significantly higher proportions of subjects achieved LDA and clinical remission 
at Week 12.
Safety results across the studies showed that ABT-494 was well tolerated and the types 
and frequencies of adverse events (AEs) were consistent with subjects with moderately to 
severely active RA receiving immunomodulatory therapy.  One subject died from lung 
cancer 14 weeks after completing the 12-week study (Study M13-537); the lung cancer 
was considered by the investigator as not related to study drug.  This subject had a 
40 pack-year history of tobacco use and a positive family history of lung cancer.  The 
rates of serious adverse events (SAEs) and AEs resulting in discontinuation of study drug
were low and not significantly different from placebo.  No trends in the number of 
subjects with potentially clinically significant values or changes per dose group were 
observed for any of the hematology or urine parameters; however, treatment-emergent 
increases in blood creatine phosphokinase (CPK), all of which were asymptomatic, were 
reported with higher doses of ABT-494 (12 to 18 mg BID).  No subject discontinued 
study drug due to elevated CPK.  In all subjects, the CPK values normalized or were 
significantly reduced at the time of last observation.  Among subjects with laboratory 
evidence of systemic inflammation (as evidenced by C-reactive protein [CRP] > upper 
limit of normal [ULN]), treatment with ABT-494 3 mg BID or 6 mg BID was associated 
with improvements in mean hemoglobin (Hgb) relative to placebo.  At higher doses, there 
was a reduction in mean Hgb, however the reduction was not clinically significant, as 
mean Hgb levels remained within normal range throughout the treatment period.  
One subject each in the 18 mg BID group in both Study M13-550 and Study M13-537 had 
an AE of anemia.  Overall, the AEs observed during the Phase 2 development, as well as 
changes in physical examination findings, vital signs and clinical laboratory results, do 
not indicate any safety concerns for further development of ABT-494.


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Phase 3 Studies with ABT-494
Six multi-country randomized controlled trials (RCTs) inclusive of approximately 
4,425 subjects are planned or ongoing for ABT-494 in subjects with moderately to 
severely active RA.  Study M13-542 (NCT02706847) will enroll subjects who had an 
inadequate response to biologic DMARDs.  Study M15-925 (NCT03086343) will 
compare ABT-494 vs. abatacept in subjects who had an inadequate response to biologic 
DMARDs.  Study M13-549 (NCT02675426) will enroll subjects who are on a stable dose 
of conventional synthetic DMARD (csDMARD) and have an inadequate response to 
csDMARDs.  Study M14-465 (NCT02629159) will enroll subjects who are on a stable 
dose of MTX and have an inadequate response to MTX.  Study M13-545 (NCT02706873) 
will enroll subjects who are MTX naïve.  Study M15-555 (NCT02706951) will enroll 
subjects who had an inadequate response to MTX and will investigate the use of ABT-494 
as monotherapy.  A total of 3 dose regimens of ABT-494 once-daily tablets [30 mg QD, 
15 mg QD, and 7.5 mg QD (Japan only)] will be evaluated.  There are no data available 
from these studies at this time.
3.1
Differences Statement
This study is the first to evaluate safety, tolerability, and efficacy of ABT-494 in subjects 
with PsA and a previous inadequate response to at least one non-biologic DMARD.
3.2
Benefits and Risks
Despite the availability of various PsA therapies, including conventional synthetic 
(cs)DMARDs, 1 targeted synthetic (ts)DMARD and biologic (b)DMARDs, many patients 
still do not respond adequately to these treatments, or gradually lose response over time.  
There is evidence for clinical benefit of JAK inhibition in PsA based on 2 Phase 3 studies 
of tofacitinib, a non-selective JAK inhibitor.31,32  Many AEs (serious infections, herpes 
zoster reactivation, malignancies, and hematologic adverse events) observed for 
tofacitinib are thought to be a consequence of non-selectivity against the members of the 
JAK family of proteins.  ABT-494 is a novel selective JAK1 inhibitor with the ability to 
decrease joint inflammation and damage mediated by JAK1 signaling while having 


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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 safety profile specific to ABT-494 is evolving with safety results to date consistent 
with those known to be associated with JAK inhibition.  Adverse events in the categories 
of infection such as urinary tract infection, upper respiratory tract infection and herpes 
zoster reactivation have been reported as well as adverse events in the categories of 
malignancies, and gastrointestinal disorders such as gastrointestinal perforation.  Events 
of deep vein thrombosis (DVT) and pulmonary embolism (PE) have been reported in 
patients receiving JAK inhibitors including upadacitinib.
In addition, laboratory changes including elevations of liver function tests, increase in 
lipids, elevation in serum creatinine, creatine phosphokinase, reduced hemoglobin 
depending on baseline inflammatory burden, lower white blood cell counts, and 
reductions in Natural Killer (NK) cells have been observed with ABT-494 therapy. 
The results of all genetic toxicology testing indicate that ABT-494 is not genotoxic, 
however ABT-494 is teratogenic based on animal studies, which necessitates avoidance of 
pregnancy in women of childbearing potential. Based on an embryofetal development 
study in rats, there is judged to be no risk associated with administration of upadacitinib to 
male partners of females of childbearing potential.
A detailed discussion of the pre-clinical and clinical toxicology, metabolism, 
pharmacology and safety experience with ABT-494 can be found in the current 
Investigator's Brochure.
A Phase 2 program with ABT-494 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.36-44,50,51  Together, the safety and efficacy data from the Phase 2 RA 
program and establishment of proof of concept for efficacy of JAK inhibition in PsA 
support further development of ABT-494 in Phase 3 in subjects with PsA.


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4.0
Study Objective
Period 1
Primary Objective
1.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo and 
versus adalimumab (ADA) for the treatment of signs and symptoms of PsA in 
subjects with moderately to severely active PsA who have an inadequate response 
or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
Secondary Objective
2.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo for 
the prevention of structural progression in subjects with moderately to severely 
active PsA who have an inadequate response or intolerance to 1 or more non-
biologic DMARD (DMARD-IR).
3.
To compare the safety and tolerability of ABT-494 15 mg QD and 30 mg QD 
versus placebo and versus adalimumab in subjects with moderately to severely 
active PsA who and have an inadequate response or intolerance to 1 or more non-
biologic DMARD (DMARD-IR).
Period 2
To evaluate the long-term safety, tolerability and efficacy of ABT-494 15 mg QD and 
30 mg QD in subjects with PsA 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 56 weeks in 
duration and includes a 24-week randomized, double-blind, parallel-group, placebo-
controlled and active comparator-controlled period followed by an additional 32 weeks of 


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blinded, active comparator-controlled treatment (Weeks 24 – 56).  Period 1 is designed to 
compare the safety, tolerability, and efficacy of ABT-494 15 mg QD and 30 mg QD 
versus placebo and versus adalimumab 40 mg eow for the treatment of signs and 
symptoms of subjects with moderately to severely active PsA and have an inadequate 
response or intolerance to non-biologic DMARDs (DMARD-IR).  Period 1 is also 
designed to compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo 
for the prevention of structural progression.  Period 2 is an open-label (blinded until the 
last subject completes the last visit of Period 1), long-term extension of up to a total 
treatment duration of approximately 5 years to evaluate the safety, tolerability and 
efficacy of ABT-494 15 mg QD and 30 mg QD in subjects with PsA who have completed 
Period 1.
The study is designed to enroll approximately 1640 subjects at approximately 350 study 
centers worldwide to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  
The study duration will include a 35-day screening period; a 56-week blinded period 
which includes 24 weeks of double-blind, placebo-controlled and active comparator-
controlled treatment followed by 32 weeks of active comparator controlled treatment 
(Period 1); a long-term extension period of up to a total treatment duration of 
approximately 5 years ([blinded until the last subject completes the last visit of Period 1] 
Period 2); a 30-day follow-up call or visit; and a 70-day follow-up call.
Subjects who meet eligibility criteria will be stratified by extent of psoriasis (≥ 3% body 
surface area [BSA] or < 3% BSA), current use of at least 1 DMARD, presence of 
dactylitis, and presence of enthesitis, except for subjects from China and Japan, where 
randomization for each country will be stratified by extent of psoriasis (≥ 3% body 
surface area [BSA] or < 3% BSA) only, and then randomized in a 2:2:2:1:1 ratio to one of 
five treatment groups:
Group 1:  ABT-494 15 mg QD (N = 410)


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Group 2:  ABT-494 30 mg QD (N = 410)
Group 3:  ADA (40 mg every other week [eow]) (N = 410) 
Group 4:  Placebo followed by ABT-494 15 mg QD (N = 205)
Group 5:  Placebo followed by ABT-494 30 mg QD (N = 205)
No more than approximately 15% of subjects will be enrolled with concomitant use of 
HCQ, sulfasalazine, bucillamine, or iguratimod.
Subjects will receive both oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or 
matching placebo) and subcutaneous study drug eow (either ADA 40 mg or matching 
placebo) until all subjects have completed Period 1 (Week 56) and sites and subjects are 
unblinded to study treatment.
Subjects who were assigned to placebo at Baseline will be preassigned to receive either 
ABT-494 15 mg QD or ABT-494 30 mg QD starting at Week 24 in a 1:1 ratio.  Subjects 
who complete the Week 56 visit (end of Period 1) will enter the long-term extension 
portion of the study, Period 2 (total treatment up to approximately 5 years).  Subjects will 
continue study treatment as assigned in Period 1.  Subjects who are assigned to the 
ABT-494 15 mg QD, ABT-494 30 mg QD, or adalimumab 40 mg eow will continue to 
receive ABT-494 15 mg QD, ABT-494 30 mg QD, or adalimumab 40 mg eow, 
respectively, in a blinded manner.  When the last subject completes the last visit of 
Period 1 (Week 56), study drug assignment in both periods will be unblinded to the sites, 
and subjects will be dispensed study drug in an open-label fashion until the completion of 
Period 2.
Subjects must have had inadequate response to ≥ 1 non-biologic DMARD (MTX, SSZ, 
LEF, cyclosporine, apremilast, bucillamine or iguratimod) or an intolerance to or 
contraindication for DMARDs as defined by the investigator prior to the Screening visit.  
No background non-biologic DMARD therapy is required during participation in this 
study.  For subjects who are on non-biologic DMARD therapy at baseline (MTX, SSZ, 


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LEF, apremilast, hydroxychloroquine (HCQ), bucillamine or iguratimod), non-biologic 
DMARDs should have been started ≥ 12 weeks prior to the baseline visit, must be at 
stable dose for ≥4 weeks prior to the first dose of study drug and remain at stable dose 
through Week 36 of the study; the non-biologic DMARD dose may be decreased only for 
safety reasons.  In addition, all subjects taking MTX 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.  Please 
refer to Section 5.2.3.2 for additional details related to prior and concomitant DMARD 
therapy.
At Week 16, rescue therapy will be offered to subjects classified as non-responders 
(defined as not achieving at least 20% improvement in either or both tender joint count 
(TJC) and swollen joint count (SJC) at both Week 12 and Week 16) as follows:  1) add or 
modify doses of non-biologic DMARDs, NSAIDs, acetaminophen/paracetamol, low 
potency opioid medications (tramadol or combination of acetaminophen and codeine or 
hydrocodone), oral corticosteroids and/or 2) receive 1 intra-articular, trigger point or 
tender point, intra-bursa, or intra-tendon sheath corticosteroid injection for 1 peripheral 
joint, 1 trigger point, 1 tender point, 1 bursa, or 1 enthesis as described in Section 5.2.3.4
(Rescue Therapy).  
After the last subject completes the Week 24 study visit, an unblinded analysis will be 
conducted for the purpose of initial regulatory submission.  To maintain integrity of the 
trial during the blinded 56-week period study sites and subjects will remain blinded until 
all subjects have reached Week 56.  A second unblinded analysis may be conducted for 
regulatory purposes after all subjects have completed Period 1.  A final analysis will be 
conducted after all subjects have completed Period 2.
Starting at Week 36, subjects who fail to demonstrate at least 20% improvement in either 
or both TJC and SJC compared to baseline at 2 consecutive visits will be discontinued 
from study drug treatment.  Additionally, in subjects continuing on study drug, starting at 
the Week 36 visit (after Week 36 assessments have been performed), initiation of or 
change in background PsA medication(s) including, corticosteroids, non-steroidal anti-


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inflammatory drugs (NSAIDs), acetaminophen/paracetamol, low potency opiates, and 
non-biologic DMARDs (concomitant use of up to 2 non-biologic DMARDs except the 
combination of MTX and leflunomide) is allowed as per local label with maximum doses 
as outlined in Section 5.2.3.3.
Each subject will undergo a maximum of 6 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 24, Week 56, Week 104, Week 152, 
and Week 260/Premature discontinuation.
All subjects who fail to attain at least a 20% improvement in either or both TJC and SJC 
at Week 12 and Week 16 will have an x-ray examination at Week 16.  All subjects will 
receive x-rays of hands and feet if they discontinue from the study or from study drug at 
Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained 
during Period 1 or at least 24 weeks during Period 2.  
X-rays of the hands and feet will be sent to the central imaging vendor designated by the 
Sponsor.  Images should be reviewed by the investigator to assess for clinically significant 
findings.  The x-rays will not be assessed by the central imaging vendor for any clinically 
significant findings that may impact a subject's health.
A schematic of the overall study design is shown in Figure 1 below.


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Figure 1.
Study Design
a.
All subjects will receive x-rays of hands and feet at Screening, Wk 24, Wk 56, Wk 104, 152, and Wk 260/PD.
b.
At Week 16 rescue therapy will be offered to, subjects classified as non-responders (defined as not achieving at 
least 20% improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 
and Week 16) as described in Section 5.2.3.4.  
c.
At Week 24, all placebo subjects will switch to ABT-494 15 mg QD or 30 mg QD (1:1 ratio) regardless of 
response.
Additionally, an unblinded interim analysis will be conducted by an independent external 
Data Monitoring Committee (DMC) after approximately 600 subjects have completed the 
Week 12 visit or have prematurely discontinued from the study.  The interim analysis is to 
assess if the study met the pre-defined No-Go boundary for the primary endpoint ACR20.  
Details of the interim analysis and decision criteria will be specified in a separate DMC 
charter.


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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 Appendix C.  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.  If the subject does not have either an elevated hs-CRP or an 
erosion on x-ray examination of bilateral hands and feet (inclusion criterion 4), hs-CRP 
may be re-tested once during the screening period.  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 without prior AbbVie approval.  For additional re-screening, AbbVie 
Therapeutic Area Medical Director (TA MD) approval is required.  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 HBV, HCV and HIV 
serology, the assessment of an Interferon-Gamma Release Assay (IGRA; QuantiFERON 
Tuberculosis [TB] Gold test) and/or a purified protein derivative (PPD) test (or 
equivalent) (or both if required per local guidelines), ANA, chest x-ray, and 
electrocardiogram (ECG), these tests will not be required to be repeated for re-screening 
provided the conditions noted in Section 5.3.1.1 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.  Provided the conditions noted in the central imaging manual are met, if the 
subject had x-rays of hands and feet performed within 12 weeks of re-screening these tests 
will not be required for re-screening.


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Period 1 (56-Week Randomized, Double-Blind Treatment Period)
Period 1 will begin at the Baseline Visit (Day 1) and will end at the Week 56 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 Baseline (Day 1), Weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 44 and 56.  A 
± 3 day window is permitted around scheduled study visits up to Week 36.  Following 
Week 36, a ± 7 day window is permitted.  The last dose of oral study drug in Period 1 is 
taken the day prior to the Week 56 visit.
Period 2 (Long-Term Extension Period [Up to a Total Treatment Duration of 
Approximately 5 Years])
Period 2 will begin at the Week 56 visit after all assessments have been completed.  When 
the last subject completes the last visit of Period 1 (Week 56), study drug assignment in 
both periods will be unblinded to the sites, and subjects will be dispensed study drug in an 
open-label fashion until the completion of Period 2.  During Period 2, subjects will have a 
study visit at Week 56 and every 12 weeks thereafter until completion of the study.  A 
± 7 day window is permitted around scheduled study visits.  The last dose of oral study 
drug is taken the day prior to the Week 260 visit.
Discontinuation of Study Drug and Continuation of Study Participation (Period 1 
and Period 2)
Starting at Week 36, subjects who failed to show at least 20% improvement in either or 
both TJC and SJC compared to baseline at 2 consecutive visits will be discontinued from 
study drug treatment.  Subjects who discontinue study drug treatment 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 Appendix C and adhere to all study 
procedures except for dispensing study drug, annual TB testing, PK sample collection, 


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blood sample collection for optional exploratory research and validation studies, and
calculation for drug assignment based on TJC/SJC.  If 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 5.4.2 for additional details).  If a subject 
prematurely discontinues study drug treatment and 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 of study drug 
discontinuation.  In addition, a 30-day follow-up visit (or phone call if a visit is not 
possible) should occur to determine the status of any ongoing AEs/SAEs or the 
occurrence of any new AEs/SAEs.  For subjects on subcutaneous study drug, a 70-day 
follow-up phone call should 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.  Subjects who discontinue 
from the study will not be replaced.
Follow-Up Period
Subjects who complete the last visit of Period 2 (Week 260) will have a follow-up visit 
approximately 30 days after the last dose of oral study drug to obtain information on any 
new or ongoing AEs and to collect vital signs and clinical laboratory tests.  A follow-up 
phone call will also occur 70 days after the last administration of injectable study drug to 
determine the status of any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.  
Subjects completing the study on open label (OL) therapy will only be required to have 
the 30-day follow-up visit if on oral study drug or the 70-day follow-up phone call if on 
injectable study drug.  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 


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study participation with completion of at least one study visit approximately 30 days or 
70 days after last dose of study drug, respectively.
5.2
Selection of Study Population
It is anticipated that approximately 1640 subjects with active PsA with inadequate 
response to at least one non-biologic DMARD will be randomized at approximately 
350 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 at Screening.
2.
Clinical diagnosis of PsA with symptom onset at least 6 months prior to the 
Screening Visit and fulfillment of the Classification Criteria for PsA (CASPAR) 
criteria.
3.
Subject has active disease at Baseline defined as ≥ 3 tender joints (based on 
68 joint counts) and ≥ 3 swollen joints (based on 66 joint counts) at Screening and 
Baseline Visits.
4.
Presence of either at Screening:
●
≥ 1 erosion on x-ray as determined by central imaging review or;
●
hs-CRP > laboratory defined upper limit of normal (ULN).
5.
Diagnosis of active plaque psoriasis or documented history of plaque psoriasis.
6.
Subject has had an inadequate response (lack of efficacy after a minimum 12 week 
duration of therapy) to previous or current treatment with at least 1 non-biologic 
DMARD at maximally tolerated dose or up to dose defined in Inclusion Criterion 7 
[(inadequate response to MTX is defined as ≥ 15 to ≤25 mg/week; or 
≥10 mg/week in subjects who are intolerant of MTX at doses ≥12.5 mg/week after 


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complete titration; for subjects in China, Korea, Malaysia, Singapore, Hong Kong
(China), Taiwan, and Japan inadequate response to MTX is defined as 
≥7.5 mg/week), SSZ, LEF, cyclosporine, apremilast, bucillamine or iguratimod], 
or subject has an intolerance to or contraindication for DMARDs as defined by the 
investigator.
7.
Subject who is on current treatment with concomitant non-biologic DMARDs at 
study entry must be on ≤ 2 non-biologic DMARDs (except the combination of 
MTX and leflunomide) at the following doses:  MTX (≤ 25 mg/week), SSZ 
(≤3000 mg/day), leflunomide (LEF) (≤ 20 mg/day), apremilast (≤ 60 mg/day), 
HCQ (≤ 400 mg/day), bucillamine (≤ 300 mg/day) and iguratimod (≤ 50 mg/day) 
for ≥ 12 weeks and at stable dose for ≥ 4 weeks prior to the Baseline Visit.  No 
other DMARDs are permitted during the study.  Use of MTX in combination with 
LEF is prohibited.  Subjects who need to discontinue DMARDs prior to the 
Baseline Visit to comply with this inclusion criterion must follow the procedure 
specified below or at least five times the mean terminal elimination half-life of a 
drug:
●
≥ 8 weeks for LEF if no elimination procedure was followed, or adhere to 
an elimination procedure (i.e., 11 days with cholestyramine, or 30 days 
washout with activated charcoal or as per local label);
●
≥ 4 weeks for all others. 
8.
Stable doses of non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, low-potency opiates (tramadol or combination of 
acetaminophen and codeine or hydrocodone), 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 for ≥ 1 week prior to the Baseline 
Visit.
9.
Subjects must have discontinued all opiates (except for tramadol, or combination of 
acetaminophen and codeine or hydrocodone) at least 1 week and oral traditional 


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Chinese medicine for at least 4 weeks prior to the first dose of study drug (refer to 
Section 5.2.3.3 for prohibited medications).
10.
Where mandated by local requirements only, treatment with at least one of the 
following background medications is required:  non-biologic DMARDs, NSAIDs, 
acetaminophen, low potency opiates (tramadol or combination of acetaminophen 
codeine or hydrocodone), or oral corticosteroids at doses described in Inclusion 
Criteria 7 and 8.
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.  Where mandated 
by local requirements a negative serum pregnancy test will be required.
Note:  Subjects with a borderline serum pregnancy test at Screening must have a 
serum pregnancy test ≥3 days later to document continued lack of a positive result.
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 (Section 5.2.4) that is effective from the Baseline visit 
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 H.  
13.
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.  For subjects in Japan 
only:  if a subject is under 20 years of age, then the subject and their parent or legal 
guardian must voluntarily sign and date an informed consent.
Rationale for Inclusion Criteria
1 – 10
To select the appropriate subject population
11 – 12
The effect of ABT-494 on pregnancy and reproduction is unknown


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13
In accordance with harmonized Good Clinical Practice (GCP)
5.2.2
Exclusion Criteria
A subject will not be eligible for study participation if he/she meets any of the following 
criteria:
1.
Prior exposure to any biologic immunomodulation agents.
2.
Prior exposure to any Janus Kinase (JAK) inhibitor (including but not limited to 
ruxolitinib, tofacitinib, baricitinib, and filgotinib).
3.
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 interventional clinical study.
4.
Current treatment with > 2 non-biologic DMARDs or use of DMARDs other than 
MTX, SSZ, LEF, apremilast, HCQ, bucillamine or iguratimod or use of MTX in 
combination with LEF at Baseline.
5.
Current or past history of infection including:
●
History of recurrent or disseminated (even a single episode) herpes zoster;
●
History of disseminated (even a single episode) herpes simplex;
●
History of known invasive infection (e.g., listeriosis and histoplasmosis); 
●
Active human immunodeficiency virus (HIV) or immunodeficiency syndrome.  
Active HIV is defined as confirmed positive anti-HIV antibody (HIV Ab) test;
●
Subject has active TB or meets TB exclusionary parameters (refer to 
Section 5.3.1.1 for specific requirements for TB testing);
●
For subjects in Japan only:  Positive result of beta-D-glucan or 
two consecutive indeterminate results of beta-D-glucan (screening for 
pneumocystis jiroveci infection).
●
Active infection(s) requiring treatment with parenteral anti-infectives within 
30 days, or oral anti-infectives within 14 days prior to the Baseline Visit.


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●
Chronic recurring infection and/or active viral infection that based on the 
investigator's clinical assessment makes the subject an unsuitable candidate for 
the study;
●
Active HBV or HCV defined as:
○
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 (and for Hepatitis B surface antibody positive [+] 
subjects in China and Japan, or where mandated by local requirements);
○
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with anti-
HCV antibody (HCV Ab).
6.
Underlying medical diseases or problems including but not limited to the 
following:
●
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;
●
Subject has been a previous recipient of an organ transplant which requires 
continued immunosuppression;
●
History of gastrointestinal perforation (other than appendicitis or penetrating 
injury), diverticulitis, or significantly increased risk for GI perforation per 
investigator judgment;
●
Conditions that could interfere with drug absorption including but not limited 
to short bowel syndrome;
●
History of any malignancy except for successfully treated non-melanoma skin 
cancer (NMSC) or localized carcinoma in situ of the cervix;
●
History of demyelinating disease such as Multiple Sclerosis or neurologic 
symptoms suggestive of demyelinating disease (including myelitis);


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●
History of clinically significant medical conditions or any other reason which 
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 or would put the subject at risk by participating in the 
protocol; or permanently wheelchair-bound or bedridden or very poor 
functional status which prevents the ability to perform self-care.
7.
Use of the following concomitant psoriasis treatments within the specified 
timeframe:
●
Oral retinoids within 4 weeks of the Baseline visit;
●
Fumarates within 1 week of the Baseline Visit:
●
Psoralens and Ultraviolet A (PUVA) within 4 weeks of the Baseline visit;
●
Ultraviolet A (UVA) or Ultraviolet B (UVB); or Laser therapy within 2 weeks 
of the Baseline visit; 
●
All topical psoriasis treatments, including medicated shampoos, within 
2 weeks of the Baseline visit. The following exceptions are allowed:
○
Bland (without beta or alpha hydroxy acids, urea or salicylic acids) 
emollients
○
Low potency (Class VI or VII) topical corticosteroids on the palms, soles, 
face, inframammary area and groin only.
○
Topical anti-itch treatment with no expected effect on psoriatic skin 
lesions.
8.
Systemic use of known strong cytochrome P450 (CYP) 3A inhibitors or strong 
CYP3A inducers from Screening through the last dose of the study drug (refer to 
Table 1 for examples of commonly used strong CYP3A inhibitors and inducers).
9.
Receipt of any live vaccine within 4 weeks (8 weeks in Japan) prior to the Baseline 
Visit, or expected need of live vaccination during study participation including at 
least 4 weeks (8 weeks in Japan) after the last dose of oral study drug, and 
including at least 70 days after the last dose of subcutaneous study drug.
10.
Subject has received oral or parenteral Traditional Chinese Medicines within 
4 weeks prior to Baseline, has received opioid analgesics (except for tramadol or 


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combination of acetaminophen and codeine or hydrocodone which are allowed) 
within 1 week prior to Baseline, or use of inhaled marijuana within 2 weeks prior 
to Baseline.
11.
History of an allergic reaction or significant sensitivity to constituents of the study 
drugs (including adalimumab or its excipients) and/or other products in the same 
class.
12.
History of fibromyalgia, any arthritis with onset prior to age 17 years or current 
diagnosis of inflammatory joint disease other than PsA (including, but not limited 
to rheumatoid arthritis, gout, overlap connective tissue diseases, scleroderma, 
polymyositis, dermatomyositis, systemic lupus erythematosus.)  Prior history of 
reactive arthritis or axial spondyloarthritis including ankylosing spondylitis and 
non-radiographic axial spondyloarthritis is permitted if documentation of change in 
diagnosis to PsA or additional diagnosis of PsA is made.  Prior history of 
fibromyalgia is permitted if documentation of change in diagnosis to PsA or 
documentation that the diagnosis of fibromyalgia was made incorrectly.
13.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months preceding the Baseline Visit.
14.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study within 150 days after the last dose of subcutaneous study drug, 
and within 30 days after the last dose of oral study drug.
15.
Laboratory values meeting the following criteria within the Screening period:
●
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/1.73 m2;
●
Total white blood cell count (WBC) < 2,500/μL;
●
Absolute neutrophil count (ANC) < 1,500/μL;
●
Platelet count < 100,000/μL;


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●
Absolute lymphocyte count < 800/μL;
●
Hemoglobin < 10 g/dL. 
16.
Active skin disease other than psoriasis that would interfere with the assessment of 
psoriasis.
17.
Subject with extra-articular manifestations of PsA (e.g., PsO, uveitis, or IBD) that 
are not clinically stable for at least 30 days prior to study entry.
18.
Subject has had joint surgery at joints to be assessed within this study or 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 Baseline visit.
19.
Consideration by the Investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-494 or adalimumab or subject has any contraindication 
to adalimumab, according to the local label.
Rationale for Exclusion Criteria
1 – 4
To select the appropriate subject population
14
The impact of ABT-494 on pregnancies is unknown
5 – 13, 15 – 19
To ensure safety of the subjects throughout the study
5.2.3
Prior and Concomitant 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 and/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 must be recorded in the eCRF.
In addition, for subject's ≤ 30 years old with a reported malignancy AE, prior exposure to, 
or current use of antineoplastics, or other drugs which have a risk of malignancy as stated 


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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 below prior and concomitant 
medication categories contributed to the event.  Any medications in these categories 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.
Medication Categories:
●
corticosteroids
●
immunosuppressants
●
biologic agents
●
antineoplastics
●
other
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 (8 weeks in Japan) 
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 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.  See Section 5.2.3.3 for a list of commonly used live vaccines. 


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The AbbVie Therapeutic Area Medical Director (TA MD) should be contacted if there are 
any questions regarding concomitant or prior therapy(ies).
5.2.3.1
Prior Therapy
All prior drug therapies for PsA (arthritis and psoriasis), since initial diagnosis, must be 
recorded in the eCRF along with the dates of first and last dose, maximum dosage taken, 
route of administration and reason for discontinuation, if known.  Additionally, the 
investigator will record response to DMARDs (e.g., no response, inadequate response, 
loss of response), intolerance to DMARD and/or contraindication for DMARDs.
5.2.3.2
Permitted Background Therapy
In Period 1, if subjects are on background DMARDs they should continue on stable 
treatment of up to 2 non-biologic DMARDs (DMARDs should have been started 
≥12 weeks prior to the Baseline visit and without dosing or administration changes 
≥4 weeks prior to the Baseline visit).  The following non-biologic DMARDs are allowed 
as background therapy during the study:  MTX (≤ 25 mg/week), SSZ (≤ 3000 mg/day), 
leflunomide (LEF) (≤ 20 mg/day), apremilast (≤ 60 mg/day), HCQ (≤ 400 mg/day), 
bucillamine (≤ 300 mg/day) and iguratimod (≤ 50 mg/day).  In addition, for all subjects 
taking MTX, 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.  No other DMARDs 
are permitted during the first 36 weeks of study participation in Period 1.  At any time, the 
background DMARD dose may be decreased for safety reasons.  AbbVie will not provide 
background DMARDs or folic acid.
In the first 36 weeks of study participation in Period 1, subjects should also continue on 
their stable doses of NSAIDs, acetaminophen/paracetamol, low-potency opiates (tramadol 
or combination of acetaminophen with codeine or hydrocodone), oral corticosteroids 
(equivalent to prednisone ≤ 10 mg/day).  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 


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should not be initiated except where permitted by protocol (specific time period or 
protocol-defined rescue).  If taking any of the above 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.  In the event of tolerability (or other safety) issues, these 
medications may be decreased, or discontinued with substitution of another permitted 
medication from that class.  PRN use of inhaled corticosteroids is permitted at any time.
In Periods 1 and 2, starting at Week 36 (after Week 36 assessments have been performed) 
and thereafter, 1 intra-articular, trigger point or tender point, intra-bursa, or intra-tendon 
sheath injections of corticosteroids, dosage and frequency per standard of care, is allowed 
every 12 weeks.  However, corticosteroid injections should be avoided within 21 days 
prior to the next scheduled study visit to avoid confounding effects of systemic absorption 
of intra-articular, trigger point or tender point, intra-bursa, and intra-tendon sheath 
corticosteroids.
In addition, at Week 36 (after Week 36 assessments have been performed) and thereafter, 
initiation of or change in corticosteroids, NSAIDs, acetaminophen/paracetamol, low-
potency opiates (tramadol or combination of acetaminophen with codeine or 
hydrocodone) or adding or changing doses of non-biologic DMARDs (MTX, LEF, SSZ, 
apremilast, HCQ, bucillamine or iguratimod) is allowed as per local label.  Concomitant 
use of up to 2 non-biologic DMARDs (MTX, LEF, SSZ, apremilast, HCQ, bucillamine or 
iguratimod) except the combination of MTX and LEF is permitted.  Doses of non-biologic 
DMARDs and oral corticosteroids may not exceed maximums defined above and in 
inclusion criteria (Section 5.2.1).
After the Week 16 visit has been completed, a subject who qualifies for rescue therapy 
will be permitted to add or modify doses of non-biologic DMARDs, NSAIDs, 
acetaminophen/paracetamol, low potency opioid medications (tramadol or combination of 
acetaminophen and codeine or, hydrocodone), oral corticosteroids, and/or receive 1 intra-
articular, trigger point or tender point, intra-bursa, or intra-tendon sheath corticosteroid 
injection for 1 peripheral joint, 1 trigger point, 1 tender point, 1 bursa, or 1 enthesis as 


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described in Section 5.2.3.4 (Rescue Therapy).  Corticosteroid injections should be 
avoided within 21 days prior to the next scheduled study visit to avoid confounding 
effects of systemic absorption of corticosteroids.
In Period 1 and Period 2 permitted topical treatments for Psoriasis (PsO) include:
●
Non-medicated shampoos 
●
Bland (without beta or alpha hydroxy acids, urea or salicylic acid) emollients
●
Low potency (Class VI or VII) topical corticosteroids on the palms, soles, face, 
inframammary area and groin only.
Starting at Week 16 (after Week 16 assessments have been performed) and thereafter, 
subjects may use any therapy for PsO per investigator judgment, with the exception of 
non-biologic DMARDs which may not be initiated or modified at Week 16 unless non-
responder criteria are met as detailed in Section 5.2.3.4 Rescue Therapy. At Week 36 and 
thereafter, initiation of or change in dose of non-biologic DMARDs is permitted, as 
described above.
5.2.3.3
Prohibited Therapy
Non-Biologic DMARDs
Prior exposure to or concomitant use of JAK inhibitors (including but not limited to 
ruxolitinib [Jakafi®], tofacitinib [Xeljanz®], baricitinib, and filgotinib) is not allowed.
Use of MTX in combination with LEF is NOT allowed.
Concomitant therapy with > 2 non-biologic DMARDs or therapy with DMARDs other 
than MTX (≤ 25 mg/week), SSZ (≤ 3000 mg/day), leflunomide (LEF) (≤ 20 mg/day), 
apremilast (≤ 60 mg/day), HCQ (≤ 400 mg/day), bucillamine (≤ 300 mg/day) and 
iguratimod (≤ 50 mg/day).  Subjects must have discontinued all other non-biologic 
DMARDs prior to Baseline Visit as specified in Inclusion Criterion 7, Section 5.2.1.


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Corticosteroids
Intravenous (IV), intramuscular (IM) and epidural corticosteroids are NOT allowed.  
Biologic Therapies
All prior and concomitant biologic therapies, and biosimilar versions of biologic drugs for 
treatment of PsA are prohibited during the study (Period 1 and Period 2).  Examples of 
biologic therapies include but are not limited to the following:
●
Humira® (adalimumab)
●
Enbrel® (etanercept)
●
Remicade® (infliximab)
●
Orencia® (abatacept)
●
Kineret® (anakinra)
●
Rituxan® (rituximab)
●
Cimzia® (certolizumab pegol)
●
Simponi® (golimumab)
●
Actemra® (tocilizumab)
●
Raptiva® (efalizumab)
●
Tysabri® (natalizumab)
●
Stelara® (ustekinumab)
●
Benlysta® (belimumab)
●
Taltz® (ixekizumab)
●
Cosentyx® (secukinumab)
●
Prolia® (denosumab)
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.  The most commonly strong 
CYP3A inhibitors and inducers are listed in Table 1.


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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers
Strong CYP3A Inhibitors 
Strong CYP3A Inducers
Boceprevir
Cobicstat
Clarithromycin
Conivaptan
Grapefruit (fruit or juice)
Indinavir
Itraconazole
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
Carbamazepine
Phenytoin
Rifampin (Rifampicin)
Rifapentine
St. John's Wort
Cannabis
Use of inhaled medicinal and recreational marijuana is prohibited during the study and 
subjects must have discontinued use at least 2 weeks prior to Baseline.
Opiates
Opiates, with the exception of tramadol or combination of acetaminophen and codeine or 
hydrocodone, are not permitted during the study, and subjects must have discontinued 
prohibited opiates at least 1 week prior to the first dose of study drug, including (but not 
limited to):
●
buprenorphine
●
codeine 


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●
fentanyl
●
hydrocodone
●
hydromorphone
●
levorphanol
●
meperidine
●
methadone
●
morphine
●
oxycodone
●
oxymorphone
●
propoxyphene
Low potency opioid medications limited to tramadol or combination of acetaminophen 
and codeine or hydrocodone are permitted during the study.
Traditional Chinese Medications
Oral or parenteral Traditional Chinese Medicine is not permitted during the study, and 
subjects must have discontinued Traditional Chinese Medicines at least 4 weeks prior to 
the first dose of study drug.  Subjects may not use oral or parenteral Traditional Chinese 
Medicines during the study including for treatment of AEs.
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
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 at least 4 weeks (8 weeks in Japan) before first dose 


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of study drug.  Live vaccinations are prohibited during the study participation including at
least 30 days after the last dose of study drug.
Examples of live vaccines include, but are not limited to, the following:
●
Monovalent live attenuated influenza A (H1N1) (intranasal);
●
Seasonal trivalent live attenuated 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.
5.2.3.4
Rescue Therapy
At Week 16, subjects classified as non-responders (defined as not achieving at least 20% 
improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at 
both Week 12 and Week 16) will add or modify doses of non-biologic DMARDs, 
NSAIDs, acetaminophen/paracetamol, low potency opioid medications (tramadol or 
combination of acetaminophen and codeine or hydrocodone), oral corticosteroids, and/or 
receive 1 intra-articular, trigger point or tender point, intra-bursa, or intra-tendon sheath 
corticosteroid injection for 1 peripheral joint, 1 trigger point, 1 tender point, 1 bursa, or 
1 enthesis.  Doses of non-biologic DMARDs and oral corticosteroids may not exceed 
maximums defined in inclusion criteria (Section 5.2.1).  


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Corticosteroid injections should be avoided within 21 days prior to the next scheduled 
study visit to avoid confounding effects of systemic absorption of intra-articular, trigger 
point or tender point, intra-bursa, and intra-tendon sheath corticosteroids.  For the analysis 
of the TJC, SJC, and enthesitis sites, injected joints or enthesitis sites will be considered 
"not assessable" for 90 days from the time of the injection.
5.2.4
Contraception Recommendations
Contraception Recommendation for Females
A woman who is postmenopausal or permanently surgically sterile is not considered to be 
a woman of childbearing potential and is not required to follow contraception 
recommendations.
Surgically sterile is defined as:
●
bilateral oophorectomy (surgical removal of both ovaries); or  
●
bilateral salpingectomy (surgical removal of both fallopian tubes); or  
●
hysterectomy (surgical removal of uterus)
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 a follicle-stimulating hormone (FSH) level > 40 mIU/mL.
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:
●
If FSH is not tested, it is assumed that the subject is of childbearing potential 
and protocol-specified contraception is required.


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●
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 pregnancy testing requirements for women of 
childbearing potential must be followed (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.
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, injectable, intravaginal, transdermal) associated with the inhibition of 
ovulation, initiated at least 30 days prior to Baseline Visit.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to 
Baseline Visit.
●
Bilateral tubal occlusion/ligation (Japan only:  bilateral tubal ligation only).
●
Vasectomized partner(s) provided the vasectomized partner verbally confirms 
receipt of medical assessment 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).


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●
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.
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 birth 
control methods listed above (excluding true abstinence).
If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation is available, contraceptive measures as defined above are no 
longer required.
It is important to note that contraception recommendations described above are 
specifically intended to prevent pregnancy during exposure to the investigational therapy.  
Contraception recommendations related to use of concomitant therapies prescribed per 
standard of care should be based on the local label.
Additional local requirements may apply.  Refer to Appendix H for local requirements. 
Contraception Recommendation for Males
Based on data from animal studies (including a fertility study) there is no effect of 
upadacitinib on male reproduction. 
No contraception is required for male subjects. 
If a pregnancy occurs, a partner authorization form requesting pregnancy outcome 
information may be requested from the pregnant partner.
Contraception recommendations related to use of concomitant therapies prescribed per 
standard of care should be based on the local label.


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5.3
Efficacy and Safety Assessments/Variables
5.3.1
Efficacy and Safety Measurements Assessed
Subjects will be allowed a visit window of ± 3 days for all study visits (with the exception 
of the Baseline Visit, as the screening window is a maximum of 35 days) up to the 
Week 36 visit.  Visits after the Week 36 visit will have a visit window of ± 7 days.
If a subject has an out of window visit, the next visit should occur as originally scheduled 
based on the first date of study drug administration (Baseline Visit).
Study procedures described are listed in the following section of this protocol and are 
summarized in tabular format in Appendix C.
5.3.1.1
Study Procedures
The study procedures outlined in Appendix C are discussed in detail in this section, with 
the exception of in vivo pharmacodynamic biomarkers (discussed in Section 5.3.1.2), 
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 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.  The separate written consent may be part of the main 
consent form.  Subjects can withdraw informed consent at any time.  Details regarding 
how informed consent will be obtained and documented are provided in Section 9.3.


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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/Surgical History
A complete non-PsA medical and surgical history, including history of alcohol use and 
nicotine use will be taken from each subject during the Screening Visit.  Additionally, a 
list of each subjects' PsA and PsO 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 
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.
Vital Signs, Weight and Height
Vital sign determinations of systolic and diastolic blood pressure, pulse rate (counted for 
at least 30 seconds after 5 minutes in sitting position), respiratory rate, body weight, and 
body temperature will be obtained at the designated study visits in Appendix C.  Vital 
signs should be performed before blood draws and prior to receipt of study drug.  Height 
will be measured at the Screening Visit only (with shoes off).  All measurements will be 
recorded in metric units where applicable.
Physical Exam
A complete physical examination will be performed at the designated study visits as 
specified in Appendix C.  The physical examination at the Baseline Visit will serve as the 
baseline physical examination for the entire study.  Physical examination abnormalities 


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noted by the Investigator at the Baseline Visit prior to the first dose of study drug should 
be recorded in the subject's medical history.  Abnormalities noted after the Baseline Visit 
and first dose of study drug should be evaluated and documented by the Investigator as to 
whether or not these are AEs.  All findings whether related to an AE or part of each 
subject's medical history should be captured on the appropriate eCRF page.
A symptom-directed physical examination will be performed when necessary.
12-Lead Electrocardiogram (ECG)
A resting 12-lead ECG will be performed at the Screening and Week 56 Visit.  A 
qualified physician will interpret the clinical significance of any abnormal finding, sign, 
and date each ECG.  ECGs 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.  A valid QTcF cannot be calculated in subjects who have a 
pacemaker or supraventricular or ventricular conduction abnormalities.  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 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 all protocol required documentation is available 
and nothing has changed in the subject's health status since the time of the test that 
warrants a repeat test.  If there are clinically significant findings, the Investigator must 
contact the AbbVie TA MD 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.


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X-Rays of the Hands and Feet
Each subject will undergo a maximum of 6 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 24, Week 56, Week 104, Week 152, 
and Week 260/Premature discontinuation.
All subjects who fail to attain at least 20% improvement in either or both TJC and SJC at 
Week 12 and Week 16 will have an x-ray examination at Week 16.  All subjects will 
receive x-rays of hands and feet if they discontinue from the study or from study drug at 
Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained 
during Period 1 or at least 24 weeks during Period 2.  In such subjects, x-rays should be 
obtained as close as possible to the date of study drug discontinuation.
For subjects who re-screen:  Provided the conditions outlined in the imaging manual are 
met, if the subject had x-rays of hands and feet performed within 12 weeks of re-screening 
these tests will not be required for re-screening.
Radiographs will be sent to the designated central imaging vendor and will be interpreted 
by an experienced reader selected for the study, who will make the final determination as 
to whether a subject has at least 1 erosion.  The imaging vendor will return an eligibility 
notification report to the site as outlined in the central imaging documents.  
Further details regarding the specific imaging techniques to be used will be provided in an 
imaging manual from AbbVie or designee.
The Investigator or their qualified delegate should read the Screening visit x-rays of the 
hands and feet to determine if the subject fulfills item 5 of the CASPAR criteria 
(Appendix G).  It is the responsibility of the Investigator to ensure that all delegates are 
qualified and that all training is documented.
Chest X-Ray (CXR)
A CXR (posterior-anterior and lateral views) is required:


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●
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 
previously 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 for subjects with one or more TB risk factors as identified by the TB 
risk assessment form (Appendix E), subjects living in areas endemic for TB, 
and subjects with newly positive PPD and/or QuantiFERON-TB Gold test or 
equivalents after baseline.
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 (review of images required), a radiologist, the 
Principal Investigator or their physician 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 TA MD before enrolling the subject.
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 study;


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●
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.  Where mandated by local requirements a negative 
serum pregnancy test will be required.
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 study drug treatment.  In the event a serum 
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 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 
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 


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positive, the subject must stop dosing, return to the study site 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 document this discussion in the subject's 
source records.
If during the course of the study a woman becomes surgically sterile or post-menopausal 
and complete documentation as described in Section 5.2.4 is available, pregnancy testing 
is no longer required.
A pregnant or breastfeeding female will not be eligible for participation in this study or be 
allowed to continue study drug.
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.
At screening, all subjects will be assessed for evidence of increased risk for TB by a risk 
assessment form (Appendix E) 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.  One or more "yes" response on the TB risk assessment form 
indicates increased risk of TB.  At annual evaluations, questions on the TB risk 
assessment form should be answered considering the previous year when the timeframe is 
not indicated in the question.
If a QuantiFERON-TB Gold Test cannot be performed by the Central Lab at Screening 
and a subject had a negative PPD within 90 days prior to Screening and source 


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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 Therapeutic Area Medical Director.  The 
results of the TB test(s) will be retained at the site as the original source documentation.
In cases where the annual QuantiFERON-TB Gold test by the central laboratory is 
positive and the investigator considers the subject at low risk for TB (i.e., no risk factors 
identified on the TB risk questionnaire) and has no clinical suspicion of TB, the 
investigator may perform a local QuantiFERON-TB Gold test (or repeat testing through 
the central laboratory if not locally available) to confirm the positive test result.  If repeat 
testing result is negative, the investigator may consider the test to be negative based on 
his/her clinical judgment; if the repeat testing result is positive, the test is considered 
positive.  
For subjects with a negative TB test result at Screening or most recent evaluation, an 
annual TB re-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.  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 AE of latent TB or active TB (as applicable).
Subjects with documentation of a prior positive result of QuantiFERON-TB Gold Test (or 
equivalent) or PPD are not required to repeat either test at Screening or during the study 
and should be considered positive.
TB test:
●
For regions that require both PPD and QuantiFERON-TB Gold testing, both 
will be performed.  If either PPD or QuantiFERON-TB Gold is positive, the 
TB test is considered positive.
●
If a site has the capacity to perform both PPD and QuantiFERON-TB Gold 
tests, and local guidelines require only one test to be performed, then the 
QuantiFERON-TB Gold is the preferred test.  At a site with capacity to 


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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 QuantiFERON-TB Gold test.
●
If the 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 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 the TB Skin Test 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.
●
An equivalent Interferon Gamma Release Assay (IGRA) (such as T-SPOT TB 
test) may be substituted for the QuantiFERON-TB Gold.
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.


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TB prophylaxis:
At screening, if the subject has evidence of latent TB infection (positive TB test 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); 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.  If the 
Investigator deems that it is necessary, consultation with a TB expert could be considered.
Of note:  Rifampin (Rifampicin) or Rifapentine are 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 will be allowed to enter the study provided nothing has changed 
in the subject's medical history to warrant repeat treatment.
For subjects with completion of a full course of anti-TB therapy, but insufficient 
documentation, the investigator should consult with the AbbVie TA MD.
Newly initiated prophylactic treatment should be captured in the eCRF and in the source 
documents.  Prior therapy should be captured in the eCRF.
During the study, subjects with new evidence of latent TB must initiate prophylactic 
treatment immediately per local guidelines and complete at least 6 months of prophylaxis.  
Study drug(s) should not be withheld. Two to 4 weeks later the subject should be re-
evaluated (unscheduled visit) for signs and symptoms of toxicity to TB prophylaxis.
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.


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Clinical Laboratory Tests
Blood and urine samples will be obtained for clinical laboratory tests listed in Table 2.  
Samples will be obtained at the designated study visits in Appendix C.
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 test 
results 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 draws should be performed after all clinical assessments and questionnaires and 
vital sign determinations have been completed but before any study drug administration 
during a visit.
In cases of state-of emergency or pandemic situations, local laboratories may be used to 
collect laboratory samples per instructions from AbbVie, as local regulations allow.
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 the specified time points as noted 
in Appendix C.  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.


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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 study drug 
treatment or requires a subject to receive treatment will be recorded as an AE.  The central 
laboratory chosen for this study will provide instructions regarding the collection, 
processing and shipping of these samples.  The baseline laboratory test results for clinical 
assessment for a particular test will be defined as the last measurement prior to the initial 
dose of study drug.


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Table 2.
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 
Blood Urea Nitrogen 
(BUN)
Creatinine
Total bilirubin
INR (reflex only)c
Albumin
AST
ALT
Alkaline phosphatase
CPK
Sodium
Potassium
Bicarbonate/CO2
Chloride 
Calcium
Inorganic phosphate
Uric acid
Total protein
Glucose 
Cholesterol
LDL-C
HDL-C
Triglycerides
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Microscopic 
examination, if 
needed
Central Lab Tests:
Serum Pregnancy (bHCG) testd
ANA/reflex anti-dsDNAe
HBsAge
HBsAbe
HBcAbe
HBV DNA PCR reflex onlye
HCV Abe
HCV RNA reflex onlye
Rheumatoid Factore
Anti-CCP antibodiese
QuantiFERON-TB Goldf
hs-CRPg
FSHih
beta-D-glucani
HIV Ab j
Local Lab Tests:
Urine pregnancy testk
ESR
Varicella antibody, if indicated
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.
c.
INR will only be measured if ALT and/or AST > 3 × ULN.  A separate blood sample for INR testing will be 
needed to measure INR at the time of repeat testing for ALT or AST.
d.
A serum pregnancy test will be performed for all female subjects of childbearing potential at the Screening Visit 
and if any post-baseline urine pregnancy is positive.
e.
At Screening only.  For subjects in China and Japan, or where mandated by local requirements:  for subjects with 
HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening, the HBV-DNA PCR test should be performed 
again every 12 weeks.  Retesting every 12 weeks is not necessary with subjects that have a history of HBV vaccine 
and is HBs Ab+ and HBc Ab–.  
f.
All subjects will be assessed for evidence of increased risk for TB by a risk assessment form (Appendix E) and 
tested for TB infection by QuantiFERON-TB Gold test analyzed by the central laboratory.  The PPD Skin Test 
should be utilized only when an IGRA is not possible for any reason (unless both tests are required per local 
guidelines).


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Table 2.
Clinical Laboratory Tests (Continued)
g.
Starting from Baseline (Day 1) the hs-CRP results will not be reported to the Sponsor, Investigator, study site 
personnel, or the subject.  For safety evaluations of signs and symptoms of infection and management of adverse 
events, the investigator may locally test procalcitonin.  Results of tests such as hs-CRP, and procalcitonin 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 hs-CRP, CRP, or serial procalcitonin tests 
reported to the investigator until a subject is known to receive upadacitinib or until treatment allocation is 
unblinded will be recorded as protocol deviations.
h.
At screening for female subjects < 55 years of age AND has had no menses for ≥ 12 months AND has no history of 
permanent surgical sterilization.
i.
Japan only.  If the result from the central lab is indeterminate or otherwise not interpretable, a local lab may be 
used.
j.
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.
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 study drug treatment.  In the event a serum 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 post-baseline is positive, study drug must 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.
HIV Test
Subjects with HIV infection are excluded from study participation.  HIV antibody (Ab) 
testing will be performed at Screening.  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 HIV Ab 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 


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indicate a positive HIV infection (HIV Ab positive).  AbbVie will not receive results from 
the testing and will not be made aware of any positive result.
Hepatitis Screening
All subjects will be tested for the presence of the Hepatitis B Virus (HBV) 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).
●
A negative test result for HBc Ab does not require HBV DNA PCR qualitative 
testing and the subject may be enrolled (Figure 2, Scenarios A and B).  For a 
subject who has had a HBV vaccination (should document in the medical 
history), the HBV DNA PCR qualitative testing is not required and the subject 
may be enrolled.  For subjects without a history of HBV vaccination (and 
where mandated by local requirements) a positive result for HBs Ab requires 
HBV DNA PCR testing (automatic reflex testing).  (Figure 2, Scenario B).*
●
A positive test result for HBc Ab requires HBV DNA PCR testing (automatic 
reflex testing) (Figure 2, Scenarios C and D). 
○
A positive result for HBV DNA or a result that exceeds detection 
sensitivity will be considered positive and will be exclusionary.  A subject 
with a negative result for HBV DNA may be enrolled.
○
For China and Japan, or where mandated by local requirements:  for 
subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at 
Screening, the HBV-DNA PCR test should be performed again every 


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12 weeks.  Retesting every 12 weeks is not necessary for subjects that have 
a history of HBV vaccine and are HBs Ab+ and HBc Ab–.  
Figure 2.
Interpretation and Management of HBV Serologic Test Results
*
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.  For subjects without a history of HBV vaccination 
(and where mandated by local requirements.  a positive result for HBs Ab requires HBV DNA PCR testing.
**
For China and Japan, or where mandated by local requirements; subjects with HBs Ab+ and/or HBc Ab+ and 
negative HBV DNA at screening should have HBV DNA PCR testing performed every 12 weeks.  HBV DNA 
PCR testing every 12 weeks is not necessary when the subject has a history of HBV vaccine and is HBs Ab+ and 
HBc Ab–.
Hepatitis C:
All subjects will be tested for the presence of Hepatitis C Virus antibodies (HCV Ab) at 
Screening.  Samples positive for HCV Ab require PCR qualitative testing for HCV RNA.  
Any HCV RNA PCR result that meets or exceeds detection sensitivity will be 
exclusionary.  Subjects with a history of treated HCV infection may be allowed to enroll 
if documentation of effective treatment is available and no evidence of HCV is detected 
by HCV RNA PCR.


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Randomization and 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 the Baseline Visit and are willing to continue in the study.  
Subjects will be randomized in a 2:2:2:1:1 ratio using an Interactive Response 
Technology (IRT) to receive double-blind study drug in one of the following treatment 
groups:
●
Group 1:  ABT-494 15 mg QD (N = 410)
●
Group 2:  ABT-494 30 mg QD (N = 410)
●
Group 3:  ADA (40 mg every other week [eow]) (N = 410) 
●
Group 4:  Placebo followed by ABT-494 15 mg QD (N = 205)
●
Group 5:  Placebo followed by ABT-494 30 mg QD (N = 205)
No more than approximately 15% subjects will be enrolled with concomitant use of HCQ, 
sulfasalazine, bucillamine, or iguratimod.
Randomization will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or 
< 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of 
enthesitis, except for subjects from China and Japan, where randomization for each 
country will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% 
BSA) only.  See Section 5.5.3 for details.
Study Drug Dispensing, Dosing, and Compliance
Study drug will be dispensed to subjects beginning at Baseline (Day 1) and as specified in 
Appendix C.  The first dose of study drug will be administered after all other Baseline 
(Day 1) procedures are completed.  Subjects will maintain a diary through Week 151 for 


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all study drug administered (i.e., at home) to capture dosing dates and times.  At visits 
specified in Appendix C, the site personnel will review and retain a copy of the diary, 
returned study drug kits, and empty study drug packaging to verify compliance. Diaries 
will not be dispensed beyond Week 140; dosing compliance will be captured during the 
drug accountability process for each subject in the IRT system.
In cases of state-of emergency or pandemic situations, study drug may be shipped directly 
to subjects per instructions from AbbVie, as local regulations allow.
All relevant dosing information will be entered into the eCRF at each visit.  ADA/placebo 
for ADA study drug can be self-administered, or 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.
Subject Diary
During the Baseline Visit, subjects will be dispensed a paper subject diary and will be 
trained on how to complete the diary by site staff.  Subjects will be asked to notate their 
concomitant medication use, AEs, and document date and times of doses of study drug 
taken between study visits.  The subject diary will be reviewed by site personnel with the 
subject at each visit and a review and description of the subject diary notations will be 
documented in the subject's source documentation and recorded on the applicable eCRF.  
Replacement diaries will be dispensed as needed should a subject misplace a subject 
diary.  The completed diaries will be collected at the subject's Week 152 visit and 
maintained at the site as source documentation.  Diaries will not be dispensed beyond 
Week 140; concomitant medication use and AEs will be documented in the subject's 
source documentation during study visits and recorded on the applicable eCRF.


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Patient Questionnaires
Subjects will complete the following questionnaires as specified in Appendix C.  A 
validated translation will be provided in their local language, as applicable:
●
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
●
EuroQol-5D-5L (EQ-5D-5L) Health Questionnaire
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
●
Disability Index of the Health Assessment Questionnaire (HAQ-DI) 
●
Patient's Assessment of Pain NRS
●
Patient's Global Assessment (PtGA) of Disease Activity Numeric Rating Scale
●
Self-Assessment of Psoriasis Symptoms (SAPS)
●
SF-36 Health Questionnaire
●
Work Productivity and Activity Impairment (WPAI)
All patient-reported outcomes (PROs) are 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.
In cases of state-of emergency or pandemic situations, PROs may be administered on 
paper or over the telephone directly to subjects by site personnel within the study visit 
window per instructions from AbbVie, as local regulations allow.
Investigator Assessments
The investigator assessments will be recorded on paper worksheets and entered into the 
eCRF and conducted at the study visits specified in Appendix C.  For the following 
assessment, if possible, the investigator assessments should be performed by an 
independent and blinded assessor who should not perform any other study related 
procedures.  
●
Psoriasis Area Severity Index (PASI)


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●
Body Surface Area (BSA)
●
Static Investigator Global Assessment (sIGA)
●
TJC and SJC Assessment
●
Dactylitis
●
Enthesitis
In order to minimize variability, the same assessor should evaluate the subject at each visit 
for the duration of the trial.  A back-up assessor should be identified.  The assessor should 
be a qualified medical professional (e.g., nurse, physician's assistant, or physician) or be 
pre-approved by the TA MD as an assessor after review of assessor training and 
experience.  Any 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 assessments and that all training is documented.  If the assessor is not 
available, the pre-identified back-up assessor should perform such assessments.
Physician's Global Assessment of Disease Activity Numerical Rating Scale (PGA-Disease 
Activity)
The PGA-Disease Activity will be conducted to assess the subject's current disease 
activity, taking into consideration both arthritis and psoriasis activity, independent of the 
subject's self-assessment, using a 0 – 10 NRS, anchored at either end by opposite 
adjectives.
The assessor is not required to be independent but should be a qualified medical 
professional, preferably a physician.
Health Resource Utilization (HRU) Questionnaire
Sites will complete a HRU questionnaire at the study visits specified in Appendix C.  The 
questionnaire will be interview administered by the site.  The assessor is not required to 
be independent and may be a qualified medical professional or a study coordinator.  The 
answers will be completed on the source worksheet provided by the sponsor and entered 
in the eCRF.


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Psoriasis Assessments
Psoriasis Area Severity Index (PASI)45
The PASI is a measure of psoriasis severity.  Four anatomic sites – head, upper 
extremities, trunk, and lower extremities – are assessed for erythema, induration and 
desquamation using a 5-point scale.  Based on the extent of lesions in a given anatomic 
site, the area affected is assigned a numerical value.
Since the head, upper extremities, trunk and lower extremities correspond to 
approximately 10, 20, 30 and 40% of body surface area, respectively; the PASI score is 
calculated using the formula:
PASI = 0.1(Eh + Ih + Dh)Ah + 0.2(Eu + Iu + Du)Au + 0.3(Et + It + Dt)At + 0.4(El + Il
+ Dl)Al
Where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, 
and h, u, t, and l denote head, upper extremities, trunk, and lower extremities, 
respectively.  PASI scores range from 0.0 to 72.0 with the highest score representing 
complete erythroderma of the severest possible degree.
Typically scores of 3 or less represent mild disease, scores over 3 and up and including 
15 represent moderate disease and scores over 15 are considered to be associated with 
severe disease.
The assessor should be an independent qualified medical professional.
Body Surface Area (BSA) – Psoriasis
The subject's right or left hand should be selected as the measuring device.  For purposes 
of clinical estimation, the total surface of the palm plus five digits will be assumed to be 
approximately equivalent to 1%.  Measurement of the total area of involvement is aided 
by imagining if scattered plaques were moved so that they were next to each other and 
then estimating the total area involved.


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The assessor should be an independent qualified medical professional.
Static Investigator Global Assessment (sIGA)
The sIGA is a 5-point score ranging from 0 to 4, based on the investigator's assessment of 
the average elevation, erythema, and scaling of all psoriatic lesions.
The assessment is considered "static" which refers to the patient's disease state at the time 
of the assessments, without comparison to any of the patient's previous disease states, 
whether at Baseline or at a previous visit.
A lower score indicates less body coverage, with 0 being clear and 1 being almost clear.
The assessor should be an independent qualified medical professional.
TJC and SJC Assessment
TJC Assessment
An assessment of 68 joints will be done for tenderness by pressure manipulation on 
physical examination.  Joint pain/tenderness will be classified as:  present, absent, 
replaced or no assessment.  Joints injected with corticosteroid will be considered non-
evaluable for 90 days from the time of the injection.
The assessor should be an independent qualified medical professional.
SJC Assessment
An assessment of 66 joints will be done by directed physical examination.  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, absent, replaced or no 
assessment.  Joints injected with corticosteroid will be considered non-evaluable for 
90 days from the time of the injection.
The assessor should be an independent qualified medical professional.


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Dactylitis
Leeds Dactylitis Index (LDI46)
This evaluation will be conducted to assess the presence or absence of dactylitis in all 
20 of the subject's digits.  The assessment should begin with visual inspection of the hands 
and feet.  For each pair of digits in which one or both digits appear dactylitic, the 
circumference of the affected digits (both right and left side) will be assessed using a 
dactylometer.  Additionally, the affected digit pairs will be assessed for tenderness by 
squeezing the digital shaft mid-way between the metacarpophalangeal and proximal 
interphalangeal joints and will be recorded as tenderness, yes or no. Tenderness should 
not be assessed by squeezing the joint lines.  Digits injected with corticosteroid will be 
considered non-evaluable for 90 days from the time of the injection.  If a digit is missing 
and its contralateral digit is dactylitic, "digit absent" will be recorded for the missing digit.  
For any digit without an available dacylometer measurement the standard reference value 
will be utilized in calculation of the LDI.  The standard reference values will not be 
entered into the eCRF.  A dactylometer will be provided to sites for use.
The assessor should be an independent qualified medical professional.
Enthesitis
Leeds Enthesitis Index (LEI)
This evaluation will be conducted to assess the presence or absence of enthesitis at 
3 bilateral sites.  Tenderness on examination is recorded as either present, absent, or not 
assessed for each of the 6 sites, for an overall score range of 0 – 6.  Enthesitis sites 
injected with corticosteroid will be considered non-evaluable for 90 days from the time of 
the injection.
The assessor should be an independent qualified medical professional.


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Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index
This evaluation will be conducted to assess the presence or absence of enthesitis at 
9 bilateral sites. Tenderness on examination is recorded as either present, absent, or not 
assessed for each of the 18 sites.  For scoring purposes, the inferior patella and tibial 
tuberosity are considered to be one site due to their anatomical proximity.  The overall 
score range is 0 – 16.  Enthesitis sites injected with corticosteroid will be considered non-
evaluable for 90 days from the time of the injection.
The Lateral epicondyle and Achilles tendon insertion will only need to be assessed once 
since the 2 bilateral sites overlap between the LEI and SPARCC Enthesitis Index.
The assessor should be an independent qualified medical professional.
Psoriatic Spondylitis
This evaluation will be conducted at Baseline only as a single question asking the 
investigator to take into consideration all that is known about the subject to assess whether 
or not the subject has psoriatic spondylitis.  Responses will be recorded as yes or no.  This 
evaluation should be assessed by the rheumatologist investigator.
5.3.1.2
Optional Samples for Exploratory Research and Validation 
Studies
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 the optional collection of samples for exploratory research/validation 
studies.
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 PsA by assessing associations between disease 
characteristics, outcomes data and biomarkers of interests.


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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.
For Japan only:  The research on DNA and RNA exploratory research samples will be 
restricted to the subject's response to the treatment in terms of pharmacokinetics, efficacy, 
tolerability, and safety.
AbbVie (or people or companies working with AbbVie) will store the exploratory 
research/validation studies samples in a secure storage space with adequate measures to 
protect confidentiality.  The samples will be retained while research on ABT-494 (or 
drugs of this class) or PsA and related conditions continues, but for no longer than 
20 years after study completion.
All subjects are preferred to have been fasting for a minimum of 8 hours prior to sample 
collection.  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.  
The following samples will be collected according to Appendix D for each subject who 
consents to provide samples for exploratory research/validation studies:
●
DNA samples for pharmacogenetic or epigenetic analyses;
●
RNA samples for transcriptomic and/or epigenetic analyses;
●
Serum and plasma samples for systemic analyses, including but not limited to 
proteomic and metabolomics;
●
Urine samples, including but not limited to targeted protein and metabolomic 
analyses.
The procedures for obtaining and documenting informed consent are discussed in 
Section 9.3.


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Samples will be shipped to AbbVie or a designated laboratory for RNA/DNA extraction, 
if applicable, and/or analyses or long-term storage.  Instructions for the preparation and 
shipment of the samples will be provided in the laboratory manual.
5.3.2
Drug Concentration Measurements
Blood Samples for ABT-494 PK Assay (Period 1 Only)
Blood samples (plasma) for assay of ABT-494 and possibly other medications will be 
collected as follows (Appendix C):
●
Weeks 2 and 4 prior to oral study drug dosing;
●
Weeks 8 and beyond at any time during the visit.  For subjects who 
prematurely discontinue from study drug treatment prior to Week 56, at any 
time during the PD 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 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 study drug according to their normal schedule.  For 
all other visits, subjects can take the 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.
Refer to the study specific laboratory manual for detailed instructions on sample 
collection, processing, and shipment.
5.3.2.1
Measurement Methods
Plasma concentrations of ABT-494 will be determined by the Drug Analysis Department 
at AbbVie using a validated liquid chromatography/mass spectrometry method.


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5.3.3
Efficacy Variables
5.3.3.1
Primary Variables
The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at 
Week 12.
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 NRS, PtGA-Disease 
Activity NRS, PGA-Disease Activity NRS, HAQ-DI, or hs-CRP.
5.3.3.2
Key Secondary Variables
The key multiplicity adjusted secondary efficacy endpoints (each dose of ABT-494 versus 
placebo unless noted) are:
1.
Change from baseline in HAQ-DI at Week 12;
2.
Proportion of subjects achieving a static Investigator Global Assessment (sIGA) of 
Psoriasis of 0 or 1 and at least a 2-point improvement from baseline at Week 16;
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with 
≥3% BSA psoriasis at baseline);
4.
Change from baseline in modified PsA Sharp/van der Heijde Score (SHS) at 
Week 24;
5.
Proportion of subjects achieving Minimal Disease Activity (MDA) at Week 24;
6.
Proportion of subjects with resolution of Enthesitis (LEI = 0) at Week 24;
7.
ACR 20 response rate at Week 12 (non-inferiority of ABT-494 vs adalimumab);
8.
Change from baseline in SF-36 PCS at Week 12;
9.
Change from baseline in FACIT-Fatigue Questionnaire at Week 12;
10.
ACR 20 response rate at Week 12 (superiority of ABT-494 vs. adalimumab);
11.
Proportion of subjects with resolution of dactylitis (LDI = 0) at Week 24;


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12.
Change from baseline in Patient's Assessment of Pain NRS at Week 12 (superiority 
of ABT-494 vs. adalimumab);
13.
Change from baseline in HAQ-DI at Week 12 (superiority of ABT-494 vs. 
adalimumab); and
14.
Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS) 
Questionnaire at Week 16.
Additional key secondary efficacy endpoints (each dose of ABT-494 versus placebo) are:
●
ACR50/70 response at Week 12;
●
ACR20 response at Week 2;
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 
NRS, PtGA-Disease Activity NRS, PGA-Disease Activity NRS, HAQ-DI, or hs-CRP.
The proportion of subjects achieving MDA14 will be determined based on subjects 
fulfilling 5 of 7 outcome measures:  TJC ≤ 1; SJC ≤ 1; PASI ≤ 1 or BSA-Ps ≤ 3%; 
Patient's Assessment of Pain NRS ≤ 1.5; PtGA-Disease Activity NRS ≤ 2.0; HAQ-DI 
score ≤ 0.5; and tender entheseal points ≤ 1.
5.3.3.3
Additional Variables
The following outcome measures will be assessed in subjects treated with ABT-494 as 
compared to placebo and adalimumab when obtained at the scheduled time points in 
Appendix C other than those specified for the primary and key secondary variables:
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline in SHS ≤ 0); 
●
Change from baseline in joint space narrowing score and joint erosion score.
●
Change from baseline in individual components of ACR response; 
○
Change from baseline in Tender Joint Count (TJC) (0 – 68);


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○
Change from baseline in Swollen Joint Count (SJC) (0 – 66);
○
Change from baseline in Physician Global Assessment (PGA) – Disease 
Activity (NRS);
○
Change from baseline in Patient's Global Assessment (PtGA) – Disease 
Activity (NRS);
○
Change from baseline in Patient's Assessment of Pain Numerical Rating 
Scale (NRS);
○
Change from baseline in Health Assessment Questionnaire – Disability 
Index (HAQ-DI);
○
Change from baseline in High-Sensitivity C Reactive Protein (hs-CRP);
●
ACR 20/50/70 response rates;
●
Change from baseline in Leeds Dactylitis Index (LDI);
●
Change from baseline in dactylitis count;
●
Proportion of subjects with resolution of dactylitis;
●
Change from baseline in Leeds Enthesitis Index (LEI);
●
Proportion of subjects with resolution of enthesitis sites included in the LEI;
●
Change from baseline in SPARCC Enthesitis Index;
●
Proportion of subjects with resolution of enthesitis sites included in the 
SPARCC Enthesitis Index;
●
Change from baseline in total enthesitis count; 
●
Proportion of subjects with resolution of enthesitis;
●
PASI 75/90/100 response rates (for subjects with ≥ 3% Body Surface Area 
(BSA) psoriasis at baseline);
●
Proportion of subjects achieving a static Investigator Global Assessment of 
Psoriasis (sIGA) score of 0 or 1 and at least a 2-point improvement from 
baseline;
●
BSA-Ps;
●
Modified Psoriatic Arthritis Response Criteria (PsARC) response rate;
●
Change from baseline in Disease Activity Score 28 (DAS28) (CRP);
●
Change from baseline in DAS28 (ESR);


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●
Change from baseline in PsA Disease Activity Score (PASDAS);
●
Change from baseline in Disease Activity in Psoriatic Arthritis (DAPSA) 
score;
●
Change from baseline in Short Form 36 (SF-36) Health Questionnaire;
●
Change from baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)- Fatigue Questionnaire;
●
Change from baseline in EuroQol-5D-5L (EQ-5D-5L) Questionnaire;
●
Change from baseline in Work Productivity and Activity Impairment (WPAI) 
Questionnaire;
●
Health Resource Utilization (HRU);
●
Proportion of subjects achieving MDA
●
Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS) 
Questionnaire;
●
Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI);
●
BASDAI 50 response rates:
●
Change from baseline in morning stiffness (mean of BASDAI Questions 5 and 
6); Change from baseline in Ankylosing Spondylitis Disease Activity Score 
(ASDAS);
●
Proportion of subjects with ASDAS Inactive Disease;
●
Proportion of subjects with ASDAS Major Improvement;
●
Proportion of subjects with ASDAS Clinically Important Improvement;
●
Proportion of subjects achieving a clinically meaningful improvement in 
HAQ-DI (≥ 0.35);
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.


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5.3.5
Pharmacokinetic Variables
Plasma ABT-494 concentrations will be obtained at the times indicated in Appendix C.  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 for 
ABT-494 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.
For Japan only:  The research on DNA and RNA exploratory research samples will be 
restricted to the subject's response to the treatment in terms of pharmacokinetics, efficacy, 
tolerability, and safety.
Biomarker assessments may be used to assess and generate prognostic, predictive, 
pharmacodynamic, or surrogate biomarker signatures.  These assessments may be 
explored in the context of PsA or related conditions and/or ABT-494 or drugs of similar 
classes.  The results from these analyses are exploratory in nature and may not be 
included with the study report.
The samples may also be used to develop new therapies, research methods or 
technologies.  In addition, samples from this study may be banked 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
A subject may withdraw from the study at any time and for any reason.  The Investigator 
may discontinue any subject's participation for any reason, including an AE, safety 
concerns or failure to comply with the protocol.  See Section 6.1.7 for toxicity 
management criteria.  Subjects will be withdrawn from study drug treatment immediately 
if any one of the following occurs:
●
Clinically significant abnormal laboratory result(s) or AE(s), which rule out 
continuation of the study drug, as determined by the Investigator or the 
AbbVie TA MD.
●
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 study drug or the study.
●
Inclusion and 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 TA MD.
●
Introduction of prohibited medications or dosages when continuation of the 
study drug would place the subject at risk as determined by the AbbVie TA 
MD.
●
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.
●
Subject is significantly non-compliant with study procedures which would put 
the subject at risk for continued participation in the trial as determined by the 
Investigator or AbbVie TA MD.


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●
Subject develops a gastrointestinal perforation.
●
Subjects with disease progression or not responding to treatment are to be
withdrawn from study drug treatment based on investigator's discretion.
●
Starting at Week 36, subjects who fail to show at least 20% improvement in 
either or both TJC and SJC compared to baseline at 2 consecutive visits will be 
discontinued from study drug treatment.
●
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or non-
cardiac, non-neurologic arterial thrombosis
In order to minimize missing data for safety and efficacy assessments, subjects who 
prematurely discontinue study drug treatment should continue to be followed for all 
regularly scheduled visits as outlined in Appendix C, and adhere to all study procedures 
except for dispensing study drug, annual TB testing, PK sample collection, and blood 
sample collection for optional exploratory research and validation studies unless they have 
decided to discontinue the study participation entirely (withdrawal of informed consent).  
In addition, all future rescue and efficacy driven discontinuation criteria no longer apply.  
Subjects should be advised on the continued scientific importance of their data even if 
they discontinue treatment with study drug early.
If a subject is discontinued from study drug, the procedures outlined for the PD Visit 
should be completed as soon as possible, preferably within 2 weeks of the last dose of 
study drug, and preferably prior to the initiation of another therapy.  In addition, if subject 
is willing, 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 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, the occurrence of any 
new AEs/SAEs, and medications used to treat AEs/SAEs.  Subjects who discontinue the 
study prematurely after randomization will not be replaced.
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 


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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 the study drug, the subject will be treated in accordance with the Investigator's best 
clinical judgment.
Lost to Follow-Up
For subjects that are 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 
documents.
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 ABT-494 and the second 
is ADA eow.
ABT-494 (or matching placebo) 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 stable background non-
biologic DMARD therapy.  AbbVie will not supply background DMARDs.


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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 taking MTX as background therapy 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.  AbbVie will not supply folic acid (or equivalent, such as folinic acid).
Subjects will receive both oral study drug QD (either ABT-494 15 mg, ABT-494 30 mg, 
or matching placebo) and subcutaneous study drug eow (either ADA 40 mg or matching 
placebo).  When the last subject completes the Week 56 visit, study drug assignment in 
both periods will be unblinded to the 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 Products
The individual study drug information is presented in Table 3.


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Table 3.
Identity of Investigational Products
Investigational 
Product
Mode of 
Administration
Formulation
Strength
Manufacturer
ABT-494
Oral
Tablet
15 mg
30 mg
AbbVie
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
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.
Adalimumab will contain 2 pre-filled syringes of 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.


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5.5.2.2
Storage and Disposition of Study Drugs
ABT-494 must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  
Adalimumab and placebo for adalimumab pre-filled syringes are to be stored protected 
from light at 2°C to 8°C/36°F to 46°F.  Adalimumab and placebo for ADA must not be 
frozen at any time.  A storage temperature log is to be maintained to document proper 
storage conditions.  The refrigerator temperature must be recorded on a temperature log to 
record proper function.  Malfunctions or any temperature excursions must be reported to 
the Sponsor immediately.  Study medication should be quarantined until AbbVie deems 
the medication as acceptable.  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 meeting eligibility criteria will be centrally randomized using an IRT system.  
Before the study is initiated, IRT directions will be provided to each site.
At the Screening Visit, subjects will be assigned a unique subject number by the IRT.  
The unique subject number will be used for each subject throughout the study.  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 who meet the inclusion and exclusion criteria defined in Section 5.2.1 and 
Section 5.2.2 will be centrally randomized in a 2:2:2:1:1 ratio to one of five treatment 
groups at Baseline (Day 1) as follows:
●
Group 1:  ABT-494 15 mg QD (N = 410)
●
Group 2:  ABT-494 30 mg QD (N = 410)
●
Group 3:  ADA (40 mg every other week [eow]) (N = 410)
●
Group 4:  Placebo followed by ABT-494 15 mg QD (N = 205)
●
Group 5:  Placebo followed by ABT-494 30 mg QD (N = 205)


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No more than approximately 15% of subjects will be enrolled with concomitant use of 
HCQ, sulfasalazine, bucillamine, or iguratimod.
Subjects will receive both oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or 
matching placebo) and subcutaneous study drug eow (either ADA 40 mg or matching 
placebo) until all subjects have completed Period 1 (Week 56) and sites and subjects are 
unblinded to study treatment.
Randomization will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or 
< 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of 
enthesitis, except for subjects from China and Japan, where randomization for each 
country will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% 
BSA) only.
The IRT will assign a randomization number that will encode the subject's treatment 
group assignment according to the randomization schedule generated by the Data 
Sciences and Statistics Departments 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 drugs 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 regarding Week 2 and Week 4 visits).
Each subject's dosing schedule should be closely monitored by the site at each study visit 
through Week 151 by careful review of the subject's 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). Diaries will not be dispensed beyond 


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Week 140; dosing compliance will be captured during the drug accountability process for 
each subject in the IRT system.
ABT-494/Placebo (daily dosing):
●
If a subject should forget to take their 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 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 24 weeks or > 21 consecutive days after Week 24, they should 
notify their study site physician, and the subject should be discontinued from 
study drug treatment.  If study drug treatment 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 24 weeks or > 3 consecutive missed doses after Week 24, 
they should notify their study site physician, and the subject should be 
discontinued from study drug.  If study drug treatment is interrupted or 
withdrawn in Periods 1 or 2, both oral and subcutaneous study drug 
administration must be stopped.
Refer to Appendix F for injection instructions.


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5.5.5
Blinding
5.5.5.1
Blinding of Investigational Product
All AbbVie personnel with direct oversight of the 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 
the study.  In order to maintain the blind, the ABT-494/placebo tablets and 
adalimumab/matching 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 TA MD prior to breaking the blind.  
However, if an urgent therapeutic intervention is necessary which warrants breaking the 
blind prior to contacting the AbbVie TA MD, 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/helpdesk/.
In the event that the blind is broken before notification to the AbbVie TA MD, AbbVie 
requests that the AbbVie TA MD 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.
After the last subject completes the Week 24 visit the Sponsor will be unblinded to study 
drug assignment to facilitate regulatory filings.  When the last subject completes the last 
visit of Period 1 (Week 56), study drug assignment will be unblinded to the sites, and 
subjects will be dispensed study drug in an open-label fashion until the completion of 
Period 2.


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5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)
An independent Data Monitoring Committee (DMC) comprised of persons external to 
AbbVie and with relevant expertise in their field will review unblinded safety data from 
the ongoing study.  If necessary to ensure subject safety, the DMC will also be given 
access to selected efficacy data which will be specified in the DMC charter.  The primary 
responsibility of the DMC will be to protect the safety of the subjects participating in this 
study.
Additionally, the external DMC will review efficacy data after at least 600 subjects have 
completed the Week 12 Visit or have prematurely discontinued from the study.  The 
interim analysis is to assess if the study met the pre-defined No-Go boundary for the 
primary endpoint ACR20.
A DMC charter will be prepared for the safety and efficacy data review outside of the 
protocol and will describe the roles and responsibilities of the DMC members, frequency 
of data reviews, and relevant safety and efficacy data to be assessed.
Communications from the DMC to the Study Team 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 diary through Week 151.  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.  Dosing compliance will be captured during the drug accountability process 
for each subject in the IRT system.


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5.5.7
Drug Accountability
The Investigator or his/her representative will verify that study drug supplies are received 
intact, at the appropriate temperature (US/Puerto Rico is cool to touch and outside the US 
temperature recording devices, i.e., Temptales provided in shipments) 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 including pre-filled syringes will be inventoried by 
the site.  Each subject will be given their own Sharps container to dispose of used 
syringes.  Empty/used study drug packaging and Sharps containers should be returned by 
the subject at each visit for accountability and compliance purposes.  Site staff will 
complete study drug accountability via IRT, source documents, subject dosing diaries, 
empty IP boxes and by visually inspecting the packaging whenever possible.  
After drug accountability has been completed by the site, empty used packaging may be 
discarded with any subject identifiers removed or returned to AbbVie-designated 
destruction depot.  
Unused study drug and used packaging with remaining study drug will be destroyed on 
site according to local procedures or regulations or returned to the AbbVie-designated 
destruction depot (for those sites that do not meet AbbVie's documentation requirements 
for on-site destruction).  
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/date prepared 
for destruction should be maintained at the site's facility.  Monitors will reconcile the site's 


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process, source documents, subject's dosing diaries, IRT or site accountability records, 
and destruction records to assure site compliance.
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 56-weeks in duration and includes a 24 week randomized, double-blind, 
parallel-group, placebo-controlled and active-comparator controlled period followed by an 
additional 32 weeks of blinded, active comparator-controlled treatment (Weeks 24 – 56).  
Period 1 is designed to compare the safety, tolerability, and efficacy of ABT-494 15 mg 
QD and ABT-494 30 mg versus placebo and versus ADA 40 mg eow in subjects with
moderately to severely active PsA who have an inadequate response to non-biologic 
DMARD therapy.  Period 1 is designed to test the superiority of ABT-494 versus placebo 
for achieving the primary endpoint (ACR20 at Week 12) and other efficacy parameters at
Weeks 12 – 24, and to test non-inferiority of ABT-494 versus adalimumab (ACR20 at 
Week 12).  At Week 24 all subjects will be given ABT-494 and will continue on blinded 
treatment until all subjects have completed the last visit of Period 1 (Week 56).  This will 
allow unbiased assessments of long-term safety of ABT-494 without compromising the 
study conduct or results of the ongoing study.  In addition, the blinded study design will 
allow the assessment of the maintenance of treatment response of both doses in an 
unbiased manner during the first year of the study.
The purpose of Period 2 is to further evaluate the long-term safety, tolerability, and 
efficacy of ABT-494 (15 mg QD and 30 mg QD) in PsA subjects who have completed 
Period 1.  All subjects will continue treatment to which they were assigned at the end of 
Period 1 in a blinded manner.
When the last subject completes the last visit of Period 1 (Week 56), study drug 
assignment will be unblinded to the sites, and subjects will be dispensed study drug in an 
open-label fashion until the completion of Period 2.


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Adalimumab was first approved in the United States and European Union for the 
treatment of PsA in 2005 and 2006, 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.  
Efficacy measurements in this study have been selected or designed to assess disease 
activity in subjects with PsA.  Other than the biomarker analyses which are exploratory, 
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 PsA patients who have had 
an inadequate response to prior non-biologic DMARD treatment.  Key entry criteria are to 
enroll adult female and male subjects who are at least 18 years of age with a clinical 
diagnosis of PsA and who fulfill the CASPAR criteria with symptoms for at least 
6 months.  Eligible study subjects must have ≥ 3 swollen joints (based on 66 joint counts) 
and ≥ 3 tender joints (based on 68 joint counts) at Screening and Baseline Visits, and 
either ≥ 1 erosion on x-ray of the hands or feet as determined by the central imaging 
reader or an elevated hs-CRP > laboratory defined ULN) at Screening.
5.6.4
Selection of Doses in the Study
The doses of ABT-494 selected for this study, 15 mg QD and 30 mg QD, dosed up to 
approximately 5 years, are expected to be efficacious with an acceptable safety profile.  
Two doses of ABT-494 have been selected for this study in order to perform limited dose 
ranging in subjects with PsA.  The ABT-494 15 mg QD and 30 mg QD doses were 
selected as they are expected to demonstrate efficacy in the treatment of patients with PsA 
while limiting potential drug-related effects on laboratory parameters (e.g., hemoglobin).  
Doses of 15 mg QD and 30 mg QD are the doses that are currently being evaluated in 
Phase 3 trials in rheumatoid arthritis (RA).  The doses being evaluated in the RA Phase 3 


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trials are considered appropriate for investigation in PsA as (1) effects of ABT-494 on 
tender and swollen joints, markers of inflammation, and ACR responses are expected to 
be similar in RA and PsA; and (2) proof of concept has been demonstrated with another 
JAK inhibitor (tofacitanib) at the doses that are efficacious in RA.  In addition, in RA the 
plateau for efficacy was achieved by exposures equivalent to 30 mg QD, indicating that 
higher doses may not provide greater therapeutic benefit.
Results from two Phase 2b trials in subjects with RA with the ABT-494 immediate release 
capsule formulation indicate that all evaluated doses (3 mg BID, 6 mg BID, 12 mg BID, 
18 mg BID, and 24 mg QD) were generally well tolerated and without unexpected safety 
concerns.  The Phase 2 dose-response and exposure-response results in RA show that the 
6 mg BID dose approaches the plateau of efficacy, and increasing the dose to 12 mg BID 
appears to result in some incremental efficacy benefit, particularly in the more refractory 
subjects with inadequate response or intolerance to anti-TNF biologic therapy.  Therefore, 
ABT-494 exposures associated with 6 mg BID and 12 mg BID were selected as the target 
exposures to evaluate in Phase 3 trials in RA.
In order to enhance patients' compliance and to provide a more convenient dosing 
regimen than BID administration, AbbVie developed a once-daily tablet formulation 
which will be used in the current study.
A bioavailability study has demonstrated that 15 mg QD and 30 mg QD regimens of the 
once-daily tablet formulation provide equivalent daily AUC and comparable Cmax, and 
Cmin to 6 mg BID and 12 mg BID, respectively, of the immediate-release capsule 
formulation used in Phase 2 studies in RA.
The mean exposures (AUC and Cmax) for the highest dose that will be evaluated in this 
study (30 mg QD) are predicted to be lower than the exposures associated with the no-
observed-adverse-effect level in the 9-month GLP preclinical toxicology study in dogs 
(1.5 mg/kg/day) and lower than the highest mean ABT-494 exposures evaluated in 
healthy subjects or in patients in previous clinical studies.


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The adalimumab dose selected for this study, 40 mg SQ EOW, is the dose marketed for 
treatment of patients with PsA.
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.
Complaints associated with any component of this investigational product must be 
reported to the Sponsor (Section 6.2.2).  For adverse events (AE), 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 serious adverse events (SAE) considered as having "no 
reasonable possibility" of being associated with study drug, the investigator will provide 
an Other cause of the event.  For 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 


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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.
Expected manifestations of PsA (i.e., psoriasis, joint pain and swelling, dactylitis, 
enthesitis, etc.) are not to be recorded as AEs unless the manifestation is considered to be 
a disease flare (worsening) of the underlying condition. 
An elective surgery/procedure scheduled to occur during a 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.
6.1.1.2
Serious Adverse Events
If an AE meets any of the following criteria, it is to be reported to AbbVie as a 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.


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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.
For SAEs with the outcome of death, the date and cause of death will be recorded on the 
appropriate case report form.


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6.1.1.3
Adverse Events of Special Interest
The following adverse events of special interest (AESI) will be monitored during the 
study (see detailed toxicity management in Section 6.1.7):
●
Serious infections; 
●
Opportunistic infections; 
●
Malignancy (all types);
●
Hepatic disorder;
●
Gastrointestinal Perforations;
●
Anemia;
●
Neutropenia;
●
Lymphopenia;
●
Herpes Zoster;
●
Creatine Phosphokinase (CPK elevation);
●
Renal dysfunction;
●
Tuberculosis; 
●
Adjudicated cardiovascular events (e.g., major adverse cardiovascular event 
[MACE]);
●
Embolic and thrombotic events (non-cardiac, non-CNS).
6.1.2
Adverse Event Severity
When criteria are available, events should be graded as described in the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE, version 5.0), which 
can be accessed at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.  If 
guidance for specific events is not available grading should be as follows:  
Mild (Grade 1):  asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 


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Moderate (Grade 2):  minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (ADL).  (Instrumental ADL refer to 
preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc.).
Severe (Grade 3 – 5): 
●
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.  (Self-care ADL refers to bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden.)
●
Grade 4: Life-threatening consequences; urgent intervention indicated
●
Grade 5: Death related to AE.
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.


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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 (AEs due to study procedures) will be collected from the time the 
subject signed the study-specific informed consent.
Adverse event information will be collected as shown in Figure 3.
Figure 3.
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.


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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 a reported AE of herpes zoster infection or a non-cardiac, non-CNS embolic 
or thrombotic event, a Supplemental AE eCRF should be completed.
6.1.5
Serious Adverse Event and Malignancy 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 a 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 that occur prior to the site having access to the RAVE® system, or if RAVE is not 
operable, should be documented on the SAE Non-CRF forms and emailed (preferred 
route) or faxed to Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the SAE.




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Directive 2001/20/EC.  The reference document used for SUSAR reporting in the EU 
countries will be the most current version of the Investigator's Brochure for ABT-494 
and/or the Summary of Product Characteristics (SmPC) for adalimumab, as applicable.
In Japan, the principal investigator will provide documentation of all SAEs to the Director 
of the investigative site and the Sponsor.
6.1.6
Pregnancy
Pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  Subjects who become pregnant during the study must 
be discontinued from study drug treatment (Section 5.4.1).
Information regarding a pregnancy occurrence in a study subject and the outcome of the 
pregnancy will be collected.  Pregnancies in study subjects and female partners of male 
subjects will be collected from the date of the first dose through 30 days of the last dose of 
oral study drug and 150 days following the last dose of subcutaneous study drug.
Pregnancy in a study subject is not considered an AE.  The medical outcome for either 
mother or infant, meeting any serious criteria including an elective or spontaneous 
abortion is considered a 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 
for female subjects and through 30 days after the last oral study drug administration.  
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 collection of any 
pregnancy-specific information and the pregnancy will be followed to outcome.


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6.1.7
Toxicity Management
The toxicity management of the AEs including AESIs consists of safety monitoring 
(review of AEs on an ongoing basis, and periodic/ad hoc review of safety issues by an 
independent external 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 have had study drug discontinued 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.  Subjects who develop active TB must be permanently discontinued 
from study drug.  See Section 5.5.4 Selection and Timing of Dose for Each Subject for 
study drug interruption guidelines.
Herpes zoster:  If a subject develops herpes zoster, consider temporarily interrupting 
study drug until the episode resolves.
Gastrointestinal Perforation:  Subjects presenting with the onset of signs or symptoms 
of a gastrointestinal perforation should be evaluated promptly for early diagnosis and 
treatment.  If the diagnosis of gastrointestinal perforation is confirmed, the subject must 
be discontinued from study drug.


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Cardiovascular Events (MACE):  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.  Periodic 
skin examination is recommended for subjects who are at increased risk for skin cancer.
Muscle-related symptoms:  If a subject experiences symptoms suggestive of myositis or 
rhabdomyolysis, consider checking CPK and aldolase with clinical management and/or 
study drug interruption as deemed appropriate by the treating physician.
Thrombosis Events:  Subjects who develop symptoms of thrombosis should be promptly 
evaluated and treated appropriately.  If the diagnosis of deep vein thrombosis, pulmonary 
embolus, or non-cardiac, non-neurologic arterial thrombosis is confirmed, the subject 
must be discontinued from study drug.
ECG Abnormality:  Subjects must be discontinued from study drug for an ECG change 
considered clinically significant and with a 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 are described in Table 4 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 4, the repeat testing must 
occur as soon as possible.


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Table 4.
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 4.
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 (INR) > 1.5
o
A separate blood sample for INR testing will be needed to measure INR 
at 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 if confirmed ALT or AST > 3 × ULN by repeat testing 
with new sample along with new appearance of fatigue, nausea, vomiting, 
right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% 
increase from Baseline).
!
Interrupt study drug if confirmed ALT or AST > 8 × ULN by repeat testing 
with new sample.
!
Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing 
with new sample for more than 2 weeks.  
Subjects with HBc Ab+ (irrespective of HBs Ab status) and negative HBV DNA 
PCR testing at Screening who develop the following laboratory findings should 
have HBV DNA PCR testing performed within 1 week (based on initial elevated 
value): 
!
ALT > 5 × ULN OR 
!
ALT or AST > 3 × ULN if an alternative cause is not readily identified.
o
A separate blood sample for HBV DNA PCR testing will be needed at the 
time of repeat testing for ALT or AST.  
A positive result for HBV DNA PCR testing will require immediate interruption 
of study drug (unless not acceptable by local practices) and a hepatologist 
consultation should occur within 1 week for recommendation regarding 
subsequent treatment.  
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.  If 
applicable, the alternative etiology should be documented appropriately in the 
eCRF.  If ALT or AST values return to the normal reference range or its Baseline 
value, study drug may be restarted.  If restarting study drug, documentation should 
include reason that rechallenge is expected to be safe.  If after clinically 
appropriate evaluation, no alternative etiology for ALT or AST elevation is found 
or the ALT or AST elevation has not resolved or is not trending down toward 
normal, the subject should be discontinued from study drug.  For any confirmed 
ALT or AST elevation > 3 ULN, complete the appropriate supplemental hepatic 
eCRF(s).


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory 
Parameter
Toxicity Management Guideline
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 the appropriate 
supplemental renal eCRF(s).
Creatine 
Phosphokinase
!
If confirmed CPK value ≥ 4 × ULN and there are no symptoms suggestive of 
myositis or rhabdomyolysis, the subjects may continue study drug at the 
investigator's discretion.
!
If confirmed 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.
For study drug interruption, the following rules apply:
●
For ABT-494/placebo (daily dosing):
○
During first 24 weeks, study drug interruption of ≤ 14 consecutive days is 
allowed. 
○
After Week 24, study drug interruption of ≤ 21 consecutive days is 
allowed.
●
For adalimumab/placebo (biweekly dosing):
○
During first 24 weeks, study drug interruption is allowed ≤ 2 consecutive 
missed doses. 
○
After Week 24, study drug interruption is allowed ≤ 3 consecutive missed 
doses. 
●
If the subject must undergo emergency surgery, the study drugs should be 
interrupted at the time of the surgery.


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●
Elective surgery during the first 24 weeks is not allowed.
●
Elective surgery between Weeks 24 and 56 is discouraged and should be 
discussed with the AbbVie TA MD. 
●
If the subject undergoes elective surgery, oral study drug should be interrupted 
1 week prior to the planned surgery and injectable study drug should be 
interrupted 2 weeks prior to the planned surgery.
●
After surgery, allow reintroduction of study drugs once a 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 independent external DMC will review unblinded safety data.  See Section 5.5.5.2 for 
details. 
The independent external DMC will also review unblinded efficacy data at a single time 
point to perform a Go analysis.  See Section 8.1.4.6 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 


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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.
6.2.2
Reporting
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.  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 AEs 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 
Independent Ethics Committee (IEC)/Independent Review Board (IRB) regulatory 
authorities (as applicable), and the following AbbVie Clinical Monitor(s):




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for regulatory purposes after all subjects have completed Week 56.  A final analysis will 
be conducted after all subjects have completed the last visit of the study.
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 
first unblinded analysis (Week 24 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 have major protocol violations which are expected to impact the 
primary endpoint.  Additional analysis may be conducted on the Per Protocol analysis set, 
in order to evaluate the impact of major protocol violations.  The Per Protocol Analysis 
Set will be determined prior to the Week 24 analysis.
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 as appropriate:  the number of subjects randomized, 


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the number of subjects who received at least one dose of study drug, the number of 
subjects who completed, 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.  The exposure to study drug is defined as the difference between the dates of the 
first and last doses of the study drug plus 1 day for oral study drug and plus 14 days for 
injectable study drug.
Study drug compliance will be summarized for each treatment group for Period 1.  The 
compliance for oral study drug is defined as the total number of tablets taken divided by 
the total number of tablets a subject is supposed to take during Period 1.  The compliance 
for injectable study drug is defined as the total number of injections received divided by 
the total number of injections a subject is supposed to receive during Period 1.
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 prior to the first dose of study drug.


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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
Primary Efficacy Variable
Analysis of the primary endpoint will be conducted on the FAS based on treatment as 
randomized.  Comparison of the primary endpoint will be made between each ABT-494 
dose group and the combined placebo groups using the Cochran-Mantel-Haenszel test 
adjusting for main stratification factors.  For the primary analysis, Non-Responder 
Imputation (NRI) will be used.  The analysis will be repeated using Observed Cases (OC).  
Supportive analysis will also be conducted on the Per Protocol Analysis Set.
The primary efficacy analyses will also be performed in demographic subgroups including 
age, gender, race, body mass index, 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.


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8.1.4.2
Key Secondary Efficacy Variables
Unless otherwise specified, comparisons are between each dose group of ABT-494 and 
the combined 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 ACR20 response rate at Week 12, analysis will be conducted to assess the non-
inferiority of each ABT-494 dose versus ADA on placebo-subtracted treatment difference 
using Koch's 3-arm test statistic.  Non-inferiority will be claimed if ABT-494 preserves at 
least 50% of the placebo-subtracted ADA effect, i.e., the multiplicity adjusted lower 
confidence limit for the ratio of placebo-subtracted ABT-494 ACR20 rate versus the 
placebo-subtracted ADA ACR20 rate is at least 50%.  Superiority of ABT-494 versus 
ADA will also be tested for ACR20 at Week 12.
For continuous endpoints, the mean, standard deviation, median, and range will be 
reported for each treatment group.  Pairwise comparisons between each ABT-494 dose 
group and the combined placebo groups will be carried out using the Mixed-Effects 
Model Repeated Measures (MMRM) with treatment group, visit, treatment-by-visit 
interaction as the fixed factor, and the corresponding baseline value and the main 
stratification factors as the covariates.  For change from baseline in Patient's Assessment 
of Pain NRS and change from baseline in HAQ-DI at Week 12, superiority of ABT-494 
vs ADA will also be tested.
8.1.4.3
Additional Efficacy Variables
Additional efficacy variables as listed in Section 5.3.3.3 will be summarized for all visits.  
For binary endpoints, frequencies and percentages will be reported by treatment group by 
visit.  For continuous endpoints, the mean, standard deviation, median, and range will be 
reported by treatment group by visit.


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8.1.4.4
Multiplicity Control for the Primary and Key Secondary 
Endpoints
The overall type I error rate of the primary and key secondary endpoints for the two doses 
will be strongly controlled using a graphical multiple testing procedure.47,48  Specifically, 
the testing will utilize the endpoint sequence of primary endpoint followed by key 
secondary endpoints in the order as specified in Section 5.3.3.2, and will begin with 
testing the primary endpoint using α of 0.025 for each dose.  Continued testing will follow 
a pre-specified α transfer path which includes downstream transfer along the endpoint 
sequence within each dose as well as cross-dose transfer.  More details of the graphical 
procedure will be specified in the SAP.
8.1.4.5
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 imputes missing data multiple times under 
appropriate random variation and thus generates 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 for visits after the discontinuation.
Linear Extrapolation for Radiographic Data:  For radiographic data (i.e., SHS-based 
endpoints), if a subject prematurely discontinued before Week 24/56, their Week 24/56 
data will be imputed assuming a linear relationship between baseline and the time point 
when x-ray should be collected.


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Mixed Model Repeated Measures (MMRM):  The MMRM includes treatment, visit, 
and treatment-by-visit interaction as fixed effects, and baseline as covariate.
For non-radiographic data, the NRI approach will serve as the primary analysis approach 
for binary endpoints.  Analysis for key binary endpoints will also be repeated using OC.  
The mixed model repeated measures (MMRM) will serve as the primary analysis for key 
continuous endpoints at Week 12 which are prior to potential modification of background 
therapy.  The Multiple Imputation (MI) approach will serve as the primary analysis for 
key continuous endpoints at Week 24.  A Missing Not At Random (MNAR) model that 
varies assumptions for the missing data in active treatment groups and placebo groups 
may be used as a sensitivity analysis for important continuous endpoints to account for 
potential deviation from the missing at random assumption.  For radiographic data, both 
linear extrapolation and as-observed analysis will be conducted.
8.1.4.6
Interim Analysis
An unblinded interim efficacy analysis will be conducted by an independent external 
DMC after at least 600 subjects have completed the Week 12 Visit or have prematurely 
discontinued from the study.  The interim analysis is to assess if the study met the pre-
defined No-Go boundary for the primary endpoint ACR20.  A futility recommendation 
will be made only when both the ABT-494 15 mg and 30 mg QD doses meet the futility 
criteria.  Details of the decision making rules will be specified in a separate DMC charter.
8.1.4.7
Long-Term Efficacy for Period 1 and Period 2 Combined
The efficacy variables are listed in Section 5.3.3.3 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.


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8.1.5
Safety Analyses
8.1.5.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set.  There will be two sets 
of planned safety analysis: safety analysis by Week 24, and long-term safety analysis.
Safety analyses are based on treatments actually received.  Safety will be assessed by 
AEs, physical examination, laboratory assessments, 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 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.
Missing safety data will not be imputed.
8.1.5.2
Analysis of Adverse Events
Unless otherwise specified, the following conventions apply for both sets of 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 
ABT-494 or PBO will not be included in summaries of TEAEs.  
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:


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●
All AEs;
●
All severe AEs;
●
All reasonably possibly related AEs;
●
All SAEs;
●
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);
●
Discontinuations due to AEs;
●
Death.
Additional AEs may be considered for tabulation/summary based on recommendations 
from the TA MD and Pharmacovigilance and Patient 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 AESIs listed in Section 6.1.1.3 will be summarized.  Event rate (per 100 patient 
years) for AESIs will also be summarized for the long-term safety analysis.
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.


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8.1.5.3
Analysis of Laboratory and Vital Sign Data
Summary statistics 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.
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 0, Grade 1, Grade 2, Grade 3, and 
Grade 4 based on National Cancer Institute (NCI) Common Toxicity Criteria for Adverse 
Events (CTCAE).  The shift tables will tabulate the number and percentage of subjects 
with baseline and post-baseline values by the above categories.  
Descriptive summary and listings will be provided for potentially clinically significant 
laboratory values and vital signs.
8.1.6
Pharmacokinetic and Exposure-Response Analyses
Individual ABT-494 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 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 CL/F and V/F of ABT-494 
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 relationship between the conditional estimates of CL/F and
V/F values with only potentially physiologically relevant or clinically meaningful 


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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 backward elimination approach.  Relationships between ABT-494 exposure and 
clinical observations will be explored.  The effect of meaningful covariates (e.g., body 
weight) on the exposure-response relationships for efficacy measures (e.g., ACR and
PASI) in PsA patients will be evaluated.
Results of the PK and exposure-response analyses may be summarized in a separate 
report, rather than in the CSR.  Additional analyses will be performed if useful and 
appropriate.
8.2
Determination of Sample Size
The planned sample size of approximately 1640 for this study (with 
2:2:2:1:1 randomization ratio for ABT-494 15 mg, ABT-494 30 mg, adalimumab and 
placebo subjects) provides at least 90% power for a 20% difference in ACR20 response 
rate (assuming a placebo ACR20 response rate of 30%).  It will also provide at least 90% 
power for the majority of the key secondary endpoints.  With the given sample size, there 
is approximately 90% power to detect a standardized effect size of 0.26 in change from 
baseline in SHS for each ABT-494 dose group versus the combined placebo group at 
Week 24.49  This sample size will also provide at least 85% power for evaluating non-
inferiority for each ABT-494 dose group vs. ADA in ACR20 response rate at Week 12 
assuming 50% ACR20 response rates for ADA and ABT-494 and 30% ACR20 response 
rates for placebo.  All power and sample size calculations are performed at two-sided 
significance level of 0.025 and accounting for a 10% dropout rate.
8.3
Randomization Methods
Subjects will be randomly assigned in a 2:2:2:1:1 ratio to one of the five treatment 
sequences per study design diagram Figure 1.
Randomization will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or 
< 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of 


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enthesitis, except for subjects from China and Japan, where randomization for each 
country will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% 
BSA) only.  See Section 5.5.3 for details.
9.0
Ethics
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol 
amendments, the Investigator's Brochure, the informed consent and all other forms of 
subject information 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 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, International Conference on 
Harmonization (ICH) guidelines, applicable regulations and guidelines governing clinical 


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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 the 
informed consent form 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 form.
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 IEC/IRB, 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.  If the subject does not consent to the exploratory 
research/validation studies, it will not impact the subject's participation in the study.
In the event a subject withdraws from the main study, optional exploratory 
research/validation samples will continue to be stored and analyzed unless the subject 
specifically withdraws consent for the optional samples.  If consent is withdrawn for the 
optional sampling, the subject must inform their study doctor, and once AbbVie is 
informed, the optional samples will be destroyed.  However, if the subject withdraws 


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his/her consent and the samples have already been tested, those results will still remain as 
part of the overall research data.
In cases of state-of emergency or pandemic situations, verbal consent may be obtained 
prior to adaptations to substantial changes in study conduct, according to local 
regulations.
9.3.1
Informed Consent Form and Explanatory Material
In Japan, the principal investigator will prepare the consent form and explanatory material 
required to obtain subject's consent to participate in the study with the cooperation of the 
sponsor and will revise these documents as required.  The prepared or revised consent 
forms and explanatory material will be submitted to the sponsor.  Approval of the IRB 
will be obtained prior to use in the study.
9.3.2
Revision of the Consent Form and Explanatory Material
In Japan, when important new information related to the subject's consent becomes 
available, the principal investigator will revise the consent form and explanatory material 
based on the information without delay and will obtain the approval of the IRB prior to 
use in the study.  The investigator will provide the information, without delay, to each 
subject already participating in the study, and will confirm the intention of each subject to 
continue the study or not.  The investigator shall also provide a further explanation using 
the revised form and explanatory material and shall obtain written consent from each 
subject of their own free will to continue participating 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 
hospital records, clinical and office charts, laboratory data/information, subjects' diaries or 
evaluation checklists, pharmacy dispensing and other records, recorded data from 


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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.
10.2
Case Report Forms
Case report forms (CRF) 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 electronic data capture (EDC) system called Rave® provided by the 
technology vendor Medidata Solutions Incorporated, NY, USA.  The EDC system and the 
study-specific electronic case report forms (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 


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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 
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.
Electronic Patient Reported Data:
Patient reported data must be completed for each subject screened/enrolled in this study.  
Some of these data are being collected with an Electronic Patient Reported Outcome 
(ePRO) system called Trialmanager, provided by the technology vendor CRF Health of 
Plymouth Meeting, PA, USA.  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 maintained and 
managed by CRF Health.
The ePRO data will be collected electronically via a Tablet device into which the patient 
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 patients to complete more than one of the same assessments 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 patient entered data via a password 
protected website, up until the generation, receipt and confirmation of the study archive.


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In cases of state-of emergency or pandemic situations, PROs may be administered within 
the study visit window on paper or over the telephone by site personnel directly to 
subjects per instructions from AbbVie, as local regulations allow.
Internet access to the ePRO data will be provided by CRF Health for the duration of the 
study.  This access will be available for the duration of the study 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 assessments completed by the subject will be considered source documentation.
11.0
Data Quality Assurance
Computer logic and manual checks will be created to identify items such as inconsistent 
study dates.  Any necessary corrections will be made to the eCRF.
12.0
Use of Information
All information concerning ABT-494, adalimumab and AbbVie operations, such as 
AbbVie patent applications, formulas, manufacturing processes, basic scientific data, or 
formulation information, supplied by AbbVie and not previously published is considered 
confidential information.
The information developed during the conduct of this clinical study is also considered 
confidential and will be used by AbbVie in connection with the development of ABT-494.  
This information may be disclosed as deemed necessary by AbbVie to other clinical 
investigators, other pharmaceutical companies, and to governmental agencies.  To allow 
for the use of the information derived from this clinical study and to ensure complete and 
thorough analysis, the investigator is obligated to provide AbbVie with complete test 
results and all data developed in this study and to provide direct access to source 


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data/documents for study-related monitoring, audits, IEC/IRB review, and regulatory 
inspection.
This confidential information shall remain the sole property of AbbVie, shall not be 
disclosed to others without the written consent of AbbVie, and shall not be used except in 
the performance of this study.
The investigator will maintain a confidential subject identification code list of all subjects 
enrolled in the study, including each subject's name, subject number, address, phone 
number and emergency contact information.  This list will be maintained at the study site 
with other study records under adequate security and restricted access, and will not be 
retrieved by AbbVie.
Any exploratory research/validation studies that may be done using the samples from this 
study will be experimental in nature and the results will not be suitable for clinical 
decision making or patient management, hence, neither the investigator, the subject, nor 
the subject's physician (if different from the investigator) will be informed of individual 
subject 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 exploratory research/validation studies 
from this study may be used in scientific publications or presented at medical 
conventions.  The data from exploratory research/validation studies will be published or 
presented only in a way that does not identify any individual subject.
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 (Director of 
the Site in Japan) and AbbVie.  Continuation of this study beyond this date must be 
mutually agreed upon in writing by both the investigator (Director of the Site in Japan) 
and AbbVie.  The investigator will provide a final report to the IEC/IRB following 


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conclusion of the study and will forward a copy of this report to AbbVie or their 
representative.
The Investigator (Director of the Site in Japan) must retain any records related to the study 
according to local requirements.  If the investigator (Director of the Site in Japan) 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 (EMEA) 
Guidance on Investigator's Signature for Study Reports.
The end-of-study is defined as the date of the last subject's last visit or the actual date of 
follow-up contact, whichever is later.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-494 and product 
labeling for Humira® (adalimumab).
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 Active Psoriatic Arthritis Who Have a History of Inadequate 
Response to at Least One Non-Biologic Disease Modifying Anti-
Rheumatic Drug (DMARD) – SELECT – PsA 1
Protocol Date:
15 May 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
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34.
Menter M, Papp KA, Cather J, et al.  Efficacy of tofacitinib for the treatment of 
moderate-to-severe chronic plaque psoriasis in patient subgroups from 
two randomised phase 3 trials.  J Drugs Dermatol.  2016;15(5):568-80.
35.
van der Heijde D, Deodhar AA, Wei JC, et al.  Tofacitinib in patients with 
ankylosing spondylitis:  a phase 2, 16-week, randomized, placebo-controlled, dose-
ranging study.  In:  Proceedings of the 2015 ACR/ARHP annual meeting; 
November 6-11, 2015; San Francisco, CA.
36.
Westhovens R, Alten R, Pavlova D, et al.  Filgotinib (GLPG0634), an oral JAK1 
selective inhibitor, is effective in combination with MTX in patients with active 
RA:  results from a Phase 2B dose ranging study.  Available from:  
http://www.glpg.com/docs/view/5772570d7c158-en.  In a presentation from 
EULAR 2016.
37.
Kavanaugh A, Ponce L, Cseuz R, et al.  Filgotinib (GLPG0634, GS-6034), an oral 
JAK1 selective inhibitor is effective as monotherapy in patients with active 
rheumatoid arthritis:  results from a 24-week phase 2B dose randing study, in 
[posted from EULAR 2016r].
38.
Lawendy N, Krishnaswami S, Wang R, et al.  Effect of CP-690,550, an orally 
active janus kinase inhibitor, on renal function in healthy adult volunteers.  J Clin 
Pharmacol.  2009;49(9):423-9.
39.
Greenwald MW, Fidelus-Gort R, Levy R, et al.  A randomized dose-ranging, 
placebo-controlled study of INCB028050, a selective JAK1 and JAK2 inhibitor in 
subjects with active rheumatoid arthritis [abstract].  Arthritis Rheum.  
2010;62 (Suppl 10):2172.


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40.
Vaddi K, Luchi M.  JAK inhibition for the treatment of rheumatoid arthritis:  a new 
era in oral DMARD therapy.  Expert Opin Investig Drugs.  2012;21(7):961-73.
41.
Dougados M, van der Heijde D, Chen YC, et al.  Baricitinib, an oral janus kinase 
(JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an 
inadequate response to CDMARD therapy:  results of the phase 3 RA-build study.  
Ann Rheum Dis.  2015;74 (Suppl 2):79.
42.
Genovese MC, Kremer J, Zamani O, et al.  Baricitinib, an oral janus kinase 
(JAK)1/JAK2 inhibitor, in patients with active rheumatoid arthritis (RA) and an 
inadequate response to TNF inhibitors:  results of the phase 3 RA-beacon study.  
Ann Rheum Dis.  2015;74 (Suppl 2):75.
43.
Fleischmann R, Kremer J, Cush J, et al.  Placebo-controlled trial of tofacitinib 
monotherapy in rheumatoid arthritis.  N Engl J. Med.  2012;367(6):495-507.
44.
van Vollenhoven RF, Fleischmann R, Cohen S.  Tofacitinib or adalimumab versus 
placebo in rheumatoid arthritis.  N Engl J Med.  2012;367(6):508-19.
45.
Feldman SR, Fleischer AB Jr, Reboussin DM, et al.  The self-administered 
psoriasis area and severity index is valid and reliable.  J Invest Dermatol.  
1996;106(1):183-6.
46.
Helliwell PS, Firth J, Ibrahim GH, et al.  Development of an assessment tool for 
dactylitis in patients with psoriatic arthritis.  J Rheumatol.  2005;32(9):1745-50.
47.
Bretz F, Maurer W, Brannath W.  A graphical approach to sequentially rejective 
multiple test procedures.  Stat Med.  2009;28(4):586-604.
48.
Hochberg Y.  A sharper bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75(4):800-2.
49.
van der Heijde D, Sharp J, Wassenberg S.  Psoriatic arthritis imagining:  a review 
of scoring methods.  Ann Rheum Dis.  2005;64 (Suppl 2):ii:61-4.
50.
Burmester GR, Blanco R, Charles-Schoeman C.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors:  a randomized phase 3 
trial.  Lancet. 2013;381(9865):451-60.


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51.
Kremer J, Li ZG, Hall S, et al.  Tofacitinib in combination with nonbiologic 
disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: 
a randomized trial.  Ann Intern Med.  2013;159(4):253-61.


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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
Immunology Therapeutic Area
Immunology Therapeutic Area
Pharmacovigilance and Patient Safety
Statistics
Statistics
Clinical Pharmacology and Pharmacometrics
Clinical Program Development


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Appendix C.
Study Activities
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Informed Consentc
X
Inclusion/Exclusion Criteria
X
X
CASPAR Criteria
X
Medical/Surgical Historyd
X
X
Vital Signse/Weight/Heightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol/Nicotine Use
X
Prior/Concomitant Therapyg
X
X
X
X
X
X
X
X
X
X
X
Xg
X
X
X
X
X
Physical Examh
X
X
X
X
Xh
X
12-Lead ECG
Xi
X
Xi
Chest X-Rayk,l
Xk
Xl
Xl
Xl
Bilateral X-Rays of Hands and Feetm,n
Xm, n
Xm
Xm
Xm
Xm
Xm
Serum Pregnancy Test at Central Labo
X
Local Urine Pregnancy Testp,q
X
X
X
X
X
X
X
X
X
X
Xq
Xq
Xq
Xq
X
X
Latent TB Risk Factor Questionnairer
X
X
Xr
X
Central Lab QuantiFeron TB Gold Test 
(and Local PPD Skin Test if Required)s
X
X
Xs
Xs


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Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Central Lab Testst
hs-CRPu
Clinical Chemistryv
Hematology (CBC)v
Urinalysisw
FSHx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xhh
Central Lab Testt
Total Cholesterol
HDL-C
LDL-C
Triglycerides
X
X
X
X
ESR (Local Lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Central Lab Tests
HIV Screeningj
Hepatitis B and C
Screening
Rheumatoid Factor 
Anti-CCP Antibodies
ANA/Reflex Anti-dsDNA
X
Xy
Xy
Blood Samples for ABT-494 PK 
Assayz,aa
Xz
Xz
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Subject Questionnairesbb
HAQ-DI
Patient-Pain
PtGA-Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Subject Questionnairesbb
SF-36
EQ-5D-5Ljj
FACIT-F
WPAIjj
BASDAI 
X
X
X
X
X
X
X
Subject Questionnairebb,cc
SAPS
X
X
X
X
X
Xcc
X
Tender and Swollen Joint Counts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Psoriatic Spondylitis Question
X
PGA-Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRU
X
X
X
X
X
X
X
BSA Psoriasiscc
X
X
X
X
X
X
Xcc
X
PASIcc
X
X
X
X
X
X
Xcc
X
sIGAcc
X
X
X
X
X
X
Xcc
X
Leeds Dactylitis Index (LDI)
X
X
X
X
X
X
X
X
Leeds/SPARCC Enthesitis Indicies 
(LEI)
X
X
X
X
X
X
X
X
Adverse Event Assessmentdd
Xdd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X


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Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Dispense Study Drug and Subject 
Diaryee
X
X
X
X
X
X
X
X
X
X
X
X
Xkk
Calculation of TJC/SJC Responsesff,gg
Xff
Xff
Xgg
Xgg
Xgg
Xgg
Xgg
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
Xkk
a.
These visits every 12 weeks are at:  Wk 68, Wk 80, Wk 92, Wk 104, Wk 116, Wk 128, Wk 140, Wk 152, Wk 164, Wk 176, Wk 188, Wk 200, Wk 212, Wk 224, Wk 236, 
Wk 248.
b.
This on-site visit is 30 days after the last dose of study drug.  For those subjects who prematurely discontinue from the study (withdrawal of informed consent) a 30-day 
follow-up phone call (and not an on-site visit) 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 phone call is to take place 70 days after the last dose of study drug.  The 70-day follow-up phone call is also for 
those subjects who prematurely discontinue from the study (withdrawal of informed consent).  Subjects completing the study on OL therapy will only be required to have the 
30-day follow-up visit if on oral study drug and the 70-day follow-up call if on injectable study drug.  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 or 70 days after last dose of 
study drug, respectively.  
c.
Obtain informed consent prior to performing any study related procedures.
d.
Note herpes zoster, herpes zoster vaccination, and hepatitis B vaccination status in medical history.
e.
Blood pressure, pulse rate, body temperature, body weight, and respiratory rate should be performed before blood draws are performed.
f.
Height will be measured at Screening visit only (with shoes off).
g.
For concomitant medications, at Week 36 (after Week 36 assessments have been performed), per Investigator judgment, may add non-biologic DMARDs (concomitant use of 
up to 2 non-biologic DMARDs, except the combination of MTX and leflunomide), or increase DMARD dose.
h.
For Period 1 (up to and including Week 56 visit), a full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when 
necessary.  For Period 2 (after Week 56), a full physical exam is required approximately every 24 weeks (Wk 80, Wk 104, Wk 128, Wk 152, Wk 176, Wk 200, Wk 224 visits) 
and at the Wk 260/PD visit.  A symptom-directed physical exam may be performed when necessary.


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i.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required; provided all protocol-required documentation is available 
and nothing has changed in the subject's health status since the time of the test that warrants a repeat test.  If required by country regulatory authorities, an annual ECG will be 
performed.
j.
HIV testing will be performed at Screening.  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.
k.
The screening chest x-ray will not be required if a subject had a previously normal chest-x-ray (posterior-anterior and lateral views) within 90 days of Screening, provided that 
all protocol-required documentation is available at the site and nothing has changed in the subject's health status since the time of the test that warrants a repeat test (refer to 
Section 5.3.1.1 for specific requirements).
l.
Obtain a chest x-ray annually for subjects with one or more TB risk factors as identified by the TB risk assessment form, subjects living in areas endemic for TB, and subjects 
with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.  In the case a subject prematurely discontinues from the study drug a chest x-ray 
should not be performed if it has been less than 48 weeks since the last examination.
m.
X-rays of hands and feet will be performed for all subjects at Screening, Wk 24, Wk 56, Wk 104, Wk 152 and Wk 260/PD visits.  All subjects who fail to attain at least 20% 
improvement in either or both TJC and SJC at Week 12 and Week 16 will have an x-ray examination at Week 16.  An x-ray examination at Week 16 is not required for 
subjects with at least a 20% improvement in either or both TJC and SJC at Week 12 and Week 16.  All subjects will receive x-rays of hands and feet if they discontinue from 
the study or from study drug at Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained during Period 1 or at least 24 weeks during Period 2.
n.
Randomization is permitted prior to results of the central reading of hand and foot x-rays for eligibility if a subject has an elevated hs-CRP available from the central 
laboratory and all other criteria are met.
o.
For all women of childbearing potential, collect serum for pregnancy test at Screening and if any urine pregnancy test is positive at any time during the study.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If serum pregnancy test comes back borderline, a repeat test is necessary (pregnancy is an exclusion 
criterion).  If 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.  Refer to 
Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
p.
For all female subjects of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits.  More frequent pregnancy tests will be performed 
throughout the study if required per local/country requirements.  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 study drug treatment.  Refer to Section 5.3.1.1
Study Procedures Pregnancy Test for additional details.


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q.
If time between visits is longer than one month, then collect the results of the monthly at home urine pregnancy test between scheduled visits.  If a urine pregnancy test is 
positive, the subject must stop dosing, come into the clinic and have blood drawn for a serum pregnancy test that will be analyzed at the central laboratory.  A pregnant or 
breastfeeding female will not be eligible for participation or continuation in this study.  The monthly at home tests between scheduled on-site visits are to occur at Weeks 40, 
48, 52, 60, 64, 72, 76, 84, 88, 96, 100, 108, 112, 120, 124, 132, 136, 144, 148, 156, 160, 168, 172, 180, 184, 192, 196, 204, 208, 216, 220, 228, 232, 240, 244, 252, and 256.
r.
Latent TB risk factor questionnaire will be obtained at Screening and annually thereafter through study participation.  Refer to Section 5.3.1.1 for specific requirements for TB 
testing and TB Prophylaxis.
s.
TB testing will be performed at Screening and annually thereafter through study participation.  In the case a subject prematurely discontinues from the study drug TB testing 
should not be performed if it has been less than 48 weeks since the last test was obtained.  Refer to Section 5.3.1.1 for specific requirements for TB testing and TB 
Prophylaxis.
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.
Starting from Baseline (Day 1) the hs-CRP results will not be reported to the Sponsor, Investigator, study site personnel, or the subject.  For safety evaluations of signs and 
symptoms of infection and management of adverse events, the investigator may locally test procalcitonin.  Results of tests such as hs-CRP, and procalcitonin 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 hs-
CRP, CRP, or serial procalcitonin tests reported to the investigator until a subject is known to receive upadacitinib or until treatment allocation is unblinded will be recorded 
as protocol deviations.
v.
If required by country regulatory authorities, subjects who initiate or increase dose of MTX during the study should undergo ALT, AST, creatinine and CBC testing every 
4 weeks for a 12-week period.
w.
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.
x.
FSH should be tested at Screening 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 in Section 5.2.4).
y.
For China and Japan, or where mandated by local requirements:  for subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening, the HBV-DNA PCR test 
should be performed again every 12 weeks.  Retesting every 12 weeks is not necessary for subjects that have a history of HBV vaccine and HBs Ab+ and HBc Ab–. If 
necessary, HBV DNA PCR may be tested at unscheduled visits.
z.
At Week 2 and Week 4 visits, PK samples should be collected prior to oral study drug dosing and the subjects should take the study drug dose at the clinic after collecting the 
PK blood sample.  However, if the subject normally takes the study 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.
aa.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.  Collect PK samples at Week 8, Week 12, Week 16, Week 20, 
Week 24, Week 32, Week 56, and at PD visit only for subjects who prematurely discontinue from study drug treatment prior to Week 56.  No PK sample collection is 
required at Week 260.
bb. Prior to other study visit procedures.  


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cc.
PASI, BSA-Ps, sIGA, and SAPS are to be done at Week 80, Week 104, and Week 128 (every 24 weeks after the Week 56 visit).
dd. Collect serious adverse events and protocol-related non-serious AEs that occur after a subject signs the informed consent; prior to the first dose of study drug.
ee.
At Week 24, all placebo subjects will be switched to blinded ABT-494 regardless of clinical response.
ff.
At Week 16, subjects who do not achieve ≥ 20% improvement in either or both TJC and SJC compared to baseline at both Weeks 12 and 16 will be offered rescue therapy 
(see Section 5.2.3.4).
gg. Starting at Week 36, subjects who failed to show at least 20% improvement in either or both TJC and SJC compared to baseline at 2 consecutive visits will be discontinued 
from study drug treatment.
hh. Only blood chemistry and hematology.
jj.
After Week 152, administer these questionnaires every 6 months: EQ-5D-5L, WPAI.
kk. After the Week 140 visit, Dosing Diaries will no longer be dispensed.
Note:
Visit window is ± 3 days for the first 36 weeks and ± 7 days for the remainder of the study.  Any of the procedures may be performed at an unscheduled visit at 
the discretion of the Investigator.


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Appendix D.
Study Activities – Optional Samples for Exploratory Research or Validation Studies
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68 to 
Wk 248
(Every 
12 Wks)
Wk 260
or PD
D – 35 
to D – 1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D
1821
Pharmacogenetic Samplea,b
X
Epigenetic Samplea,b,c
X
X
X
Transcriptomic and Epigenetic 
Samplea,b,c
X
X
X
Proteomic and Targeted Protein 
Investigations Sample (Serum)a,b,c,d
X
X
X
Proteomic and Targeted Protein 
Investigations Sample (Plasma)a,b,c,d
X
X
X
Proteomic and Targeted Protein 
Investigations Sample (Urine)a,b,c,d
X
X
X
BL = Baseline Visit; D = Day; F/U = Follow-up; PD = Premature Discontinuation; SCR = Screening Visit; Wk = Week
a.
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.
b.
Optional with signed ICF:  if the ICF is not signed, samples for exploratory research or validation studies will not be collected.
c
Subjects are preferred to have been fasting approximately 8 hours prior to collection.
d.
An effort should be made to collect prior to dosing.
e.
Samples will be collected at selected sites from approximately 30 subjects at the time of the clinical skin assessments.


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Appendix E.
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:
●
Africa
●
Eastern Europe
●
Asia
●
Russia
●
Latin America
●
Caribbean Islands
3.
Have you lived or worked in a prison, refugee camp, 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/home/ovc-20188556
http://www.in.gov/fssa/files/Tuberculosis_Questionnaire.pdf


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Appendix F.
Injection Instructions – Sample Pre-Filled Syringe
Injection Instructions – Sample Pre-Filled Syringe
Subject Instructions
0.8 mL dose
(Administered as a single dose-pre-filled syringe)
Protocol M15-572
Tables of Contents
Dosing Schedule
General Information & Supplies
Injection Procedures


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Study Drug Dosing Schedule
Subject Number:  _____________________________________
You will require subcutaneous (SC) injections during the study.  You will receive a kit 
each visit containing 2 syringes.
You will receive the following number of injections during this study:
●
Baseline visit (the first visit to receive study medication for this study) you 
will receive 1 injection at the clinic (self-administer or receive help from site 
staff).
●
You will receive either active study medication or placebo every other week 
throughout the blinded study period.  You or a trained designee will inject your 
study drug.
●
After all subjects have completed the blinded period you will only receive SQ 
injections if you continue on open-label adalimumab.   
You should complete your injections the same day and approximately the same time every 
other week.  If you forget to inject your study drug on your regularly scheduled dosing 
date, you should inject the forgotten dose as soon as you remember the dose was missed 
up to the day before the next scheduled dose.  Two injections should not be administered 
on the same day.  
If you experience a study drug interruption of > 2 consecutive missed doses during the 
first 24 weeks or > 3 consecutive missed doses after Week 24, you should notify your 
study site physician, and you should be discontinued from study drug.  If study drug 
treatment is interrupted or withdrawn in Periods 1 or 2, study drug administration must be 
stopped.
Study drug kits containing 2 syringes will be provided for at home dosing, as needed. 


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Please return all used and unused syringes, the sharps container and empty boxes to the 
clinic on your next visit.  Used syringes should be placed in the special Sharps container 
provided.  All unused syringes should be returned in the original box.
If an injection is missed or something occurs where the full dose cannot be injected, 
contact your study center immediately for further instructions.  Please record any missed 
doses on your subject dosing sheet.
Remember to complete your dosing sheet after each injection and to call the doctor's 
office if you are having problems administering your study medication.
General Information
●
Pre-filled syringes with study medication will be labeled "Adalimumab or 
Placebo" during the blinded period and "Adalimumab" during the open label 
period.
●
Store all pre-filled syringes in your refrigerator at 36°F to 46°F (2°C to 8°C) in 
the original container until it is used.  NOT in the freezer.  Should the syringes 
accidentally become frozen, call your study doctor's office.
●
Protect the study medication from light.
●
When traveling, study medication should be stored in a cool carrier with an ice 
pack.
●
Do not use a prefilled syringe if the liquid is cloudy, discolored, or has flakes 
or particles in it.
●
Do not drop or crush the study medication.  The prefilled syringe is glass.
●
Study medication should be taken at about the same time of day, on the same 
day of the week as directed by your study doctor.
●
USE A NEW SYRINGE EVERY INJECTION DAY.  There may be 
medication left in the syringe.  DO NOT RE-USE.
●
Save all study medications.  Pre-filled syringes (used and unused) & empty
boxes must be returned to the study center at each visit.  Used syringes will 
be disposed of in a sharps container provided to you.


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●
Call your doctor IMMEDIATELY if you experience any itching, hives, 
shortness of breath, or any symptom that has you concerned.  If you are unable 
to reach your doctor or if you experience life-threatening symptoms call, 
______________________ or proceed to your nearest emergency room.
●
Keep study medication, injection supplies, and all other medicines out of the 
reach of children.
Injection Procedures (PFS)
1.
Setting up for an injection
●
Find a clean flat surface.
●
Do not use if the seals on the carton are broken or missing.  Contact your study 
doctor's office if the seals are broken.
●
Take one kit with the prefilled syringe(s) of study drug from the refrigerator.  
Do not use a prefilled syringe that has been frozen or if it has been left in direct 
sunlight.
●
Return any unused syringe(s) to the refrigerator.
●
You will need the following items for each dose:
●
study medication in pre-filled syringe(s)
●
alcohol prep(s) 
●
cotton ball(s) or gauze pad(s)
If you do not have all of the items you need to give yourself an injection, call your study 
physician.  Use only the items provided in the box your study drug comes in.


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●
Make sure the liquid in the prefilled syringe is clear and colorless.  Do not use 
a prefilled syringe if the liquid is cloudy or discolored or has flakes or particles 
in it. 
●
Have a special sharps (puncture proof) container nearby for disposing of used 
needles and syringes. 
For your protection, it is important that you follow these instructions. 
2.
Choosing and preparing an injection site
●
Wash and dry your hands well 
●
Choose a site on the front of your thighs or your stomach area (abdomen).  If 
you choose your abdomen, you should avoid the area 2 inches around your 
belly button (navel).
●
Choose a different site each time you give yourself an injection.  Each new 
injection should be given at least one inch from a site you used before.  
○
Never inject into areas where the skin is tender, bruised, red or hard or 
where you have scars or stretch marks.
●
If you have psoriasis, you should try not to inject directly into any raised, 
thick, red or scaly skin patches or lesions.
●
You may find it helpful to keep notes on the location of your injection sites. 
●
Wipe the injection site with an alcohol prep (swab) using a circular motion.
●
Do not touch this area again until you are ready to inject.


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3.
How to prepare your study drug dose for injection with a Prefilled Syringe
●
Hold the syringe upright with the needle facing down.
●
Check to make sure that there is liquid in the pre-filled
●
The top of the liquid may be curved. 
●
If the syringe does not have liquid, do not use that syringe and call your study 
doctor.
If the syringe does not have the correct amount of liquid, do not use that syringe.  Call 
your study doctor.
●
Remove the needle cover taking care not to touch the needle with your fingers 
or allow it to touch any surface.
●
Turn the syringe so the needle is facing up and slowly push the plunger in to 
push the air in the syringe out through the needle.  If a small drop of liquid 
comes out of the needle that is okay.
●
Do not shake the syringe.
4.
Injecting your study drug dose
●
With your other hand, gently squeeze an area of the cleaned area of skin and 
hold it firmly. 
●
You will inject into this raised area of skin.  Hold the syringe like a pencil at 
about a 45° angle (see picture) to the skin. 
●
With a quick, short, "dart-like" motion, push the needle into the skin. 


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●
After the needle is in, let go of the skin.  Pull back slightly on the plunger.  If 
blood appears in the syringe it means that you have entered a blood vessel.  Do 
not inject the study drug.  Pull the needle out of the skin and repeat the steps to 
choose and clean a new injection site.  Do not use the same syringe.  Dispose 
of it in your special sharps container.  If no blood appears, slowly push the 
plunger all the way in until all of the study drug is injected. 
●
When the syringe is empty, remove the needle from the skin keeping it at the 
same angle it was when it was pushed into the skin. 
●
Press a cotton ball or gauze pad over the injection site and hold it for 
10 seconds.  Do not rub the injection site.  You may have slight bleeding.  This 
is normal. 
●
Dispose of the syringe right away into your special sharps container.


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Appendix G.
The CASPAR Criteria
To meet the CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria,* a patient 
must have inflammatory articular disease (joint, spine, or entheseal) with ≥ 3 points from 
the following 5 categories:
1.
Evidence of current psoriasis, a personal history of psoriasis, or a family history of 
psoriasis (one of a, b, c).
a.
Current psoriasis is defined as psoriatic skin or scalp disease present today as 
judged by a rheumatologist or dermatologist.†
b. A personal history of psoriasis is defined as a history of psoriasis that may be 
obtained from a patient, family physician, dermatologist, rheumatologist, or 
other qualified health care provider.
c.
A family history of psoriasis is defined as a history of psoriasis in a first- or 
second-degree relative according to a patient report.
2.
Typical psoriatic nail dystrophy including onycholysis, pitting, and hyperkeratosis 
observed on current physical examination.
3.
A negative test result for the presence of rheumatoid factor by any method except 
latex but preferably by enzyme-linked immunosorbent assay or nephelometry, 
according to the local laboratory reference range.
4.
Either current dactylitis, defined as swelling of an entire digit, or a history of 
dactylitis recorded by a rheumatologist.
5.
Radiographic evidence of juxtaarticular new bone formation, appearing as ill 
defined ossification near joint margins (but excluding osteophyte formation) on 
plain radiographs of the hand or foot.
*
The CASPAR criteria have specificity of 98.7% and sensitivity of 91.4%.
†
Current psoriasis is assigned a score of 2; all other features are assigned a score of 1.


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Appendix H.
Local Requirements
Canada
Section 5.2.1, Inclusion Criteria
11.
If female of childbearing potential, must be practicing at least two reliable methods 
of contraception (one highly effective method combined with one effective method 
or two highly effective methods, 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 and through at least 30 days after the last dose of oral study drug.
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 a FSH level > 40 mIU/mL.
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.
●
If FSH is not tested, it is assumed that the subject is of childbearing potential 
and protocol-specified contraception is required.


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●
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.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice 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 and through at least 30 days after 
the last dose of oral study drug.
●
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 


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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.
South Korea
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 a 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.


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●
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).
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.  Contraception recommendations related to use of concomitant therapies 
prescribed per standard of care should be based on the local label.




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Section 1.2  Synopsis
Previously read:
AbbVie Inc.
Protocol Number:  M15-572
Name of Study Drug:  ABT-494
Phase of Development:  3
Name of Active Ingredient:  ABT-494
Date of Protocol Synopsis:  11 December 2019
Protocol Title:  A Phase 3, Randomized, Double-Blind, Study Comparing Upadacitinib (ABT-494) to 
Placebo and to Adalimumab in Subjects with Active Psoriatic Arthritis Who Have a History of 
Inadequate Response to at Least One Non-Biologic Disease Modifying Anti-Rheumatic Drug (DMARD) 
– SELECT – PsA 1
Objectives:
Period 1
Primary Objective
1.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo and versus 
adalimumab (ADA) for the treatment of signs and symptoms of PsA in subjects with moderately to 
severely active PsA who have an inadequate response or intolerance to 1 or more non-biologic 
DMARD (DMARD-IR).
Secondary Objective
2.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo for the prevention 
of structural progression in subjects with moderately to severely active PsA who have an inadequate 
response or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
3.
To compare the safety and tolerability of ABT-494 15 mg QD and 30 mg QD versus placebo and 
versus adalimumab in subjects with moderately to severely active PsA who have an inadequate 
response or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
Period 2
To evaluate the long-term safety, tolerability and efficacy of ABT-494 15 mg QD and 30 mg QD in 
subjects with PsA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 350 sites
Study Population:  Patients with active psoriatic arthritis despite prior use of at least one non-biologic 
DMARD.
Number of Subjects to be Enrolled:  Approximately 1640


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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is 56 weeks in duration and 
includes a 24-week randomized, double-blind, parallel-group, placebo-controlled and active comparator-
controlled period followed by an additional 32 weeks of blinded, active comparator-controlled treatment 
(Weeks 24 – 56).  Period 1 is designed to compare the safety, tolerability, and efficacy of ABT-494 
15 mg QD and 30 mg QD versus placebo and versus adalimumab 40 mg every other week (eow) in 
subjects with moderately to severely active PsA and have an inadequate response to non-biologic 
DMARDs (DMARD-IR).  Period 1 is also designed to compare the efficacy of ABT-494 15 mg QD and 
30 mg QD versus placebo for the prevention of structural progression.  Period 2 is an open-label (blinded 
until the last subject completes the last visit of Period 1), long-term extension of up to a total treatment 
duration of approximately 3 years to evaluate the safety, tolerability and efficacy of ABT-494 15 mg QD 
and 30 mg QD in subjects with PsA who have completed Period 1.
The study is designed to enroll approximately 1640 subjects at approximately 350 study centers 
worldwide to meet scientific and regulatory objectives without enrolling an undue number of subjects in 
alignment with ethical considerations.  
The study duration will include a 35-day screening period; a 56-week blinded period which includes 
24 weeks of double-blind, placebo-controlled and active comparator controlled treatment followed by 
32 weeks of active comparator controlled treatment (Period 1); a long-term extension period of up to a 
total treatment duration of approximately 3 years ([blinded until the last subject completes the last visit 
of Period 1] Period 2); a 30-day follow-up call or visit; and a 70-day follow-up call.
Subjects who meet eligibility criteria will be stratified by extent of psoriasis (≥ 3% body surface area 
[BSA] or < 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of 
enthesitis, except for subjects from China and Japan, where randomization for each country will be 
stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA) only, and then will be 
randomized in a 2:2:2:1:1 ratio to one of five treatment groups:
Group 1:  ABT-494 15 mg QD (N = 410)
Group 2:  ABT-494 30 mg QD (N = 410)
Group 3:  ADA (40 mg eow) (N = 410) 
Group 4:  Placebo followed by ABT-494 15 mg QD (N = 205)
Group 5:  Placebo followed by ABT-494 30 mg QD (N = 205)
No more than approximately 15% of subjects will be enrolled with concomitant use of 
hydroxychloraquine, sulfasalazine, bucillamine, or iguratimod.
Subjects will receive both oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or matching placebo) 
and subcutaneous study drug eow (either ADA 40 mg or matching placebo) until all subjects have 
completed Period 1 (Week 56) and sites and subjects are unblinded to study treatment.


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Methodology (Continued):
Subjects who were assigned to placebo at Baseline will be preassigned to receiving either ABT-494 
15 mg QD or ABT-494 30 mg QD starting at Week 24 in a 1:1 ratio.  Subjects who complete the 
Week 56 visit (end of Period 1) will enter the long-term extension portion of the study, Period 2 (total 
study duration up to approximately 3 years).  Subjects will continue study treatment as assigned in 
Period 1.  Subjects who are assigned to the ABT-494 15 mg QD, ABT-494 30 mg QD, or adalimumab 
40 mg eow will continue to receive ABT-494 15 mg QD, ABT-494 30 mg QD, or adalimumab 40 mg 
eow, respectively, in a blinded manner.  When the last subject completes the last visit of Period 1 
(Week 56), study drug assignment in both periods will be unblinded to the sites, and subjects will be 
dispensed study drug in an open-label fashion until the completion of Period 2.
Subjects must have had inadequate response to ≥ 1 non-biologic DMARD (MTX, SSZ, LEF, 
cyclosporine, apremilast, bucillamine or iguratimod) or an intolerance to or contraindication for 
DMARDs as defined by the investigator prior to the Screening visit.  No background non-biologic 
DMARD therapy is required during participation in this study.  For subjects who are on non-biologic 
DMARD therapy at baseline (MTX, SSZ, LEF, apremilast, hydroxychloroquine (HCQ), bucillamine or 
iguratimod), non-biologic DMARDs should have been started ≥ 12 weeks prior to the baseline visit, 
must be at stable dose for ≥4 weeks prior to the first dose of study drug and remain on a stable dose 
through Week 36 of the study; the non-biologic DMARD dose may be decreased only for safety 
reasons.  In addition, all subjects taking MTX 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.  Please refer to Section 5.2.3.1 and Section 5.2.3.2 for 
additional details related to prior and concomitant DMARD therapy, respectively.  Starting at the 
Week 36 visit (after Week 36 assessments have been performed), initiation of or change in background 
PsA medication(s) including, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, low potency opiates, and non-biologic DMARDs (concomitant use of up to 
2 non-biologic DMARDs except the combination of MTX and leflunomide) is allowed as per local label 
with maximum doses as outlined in Section 5.2.3.3.
At Week 16, subjects classified as non-responders (defined as not achieving at least 20% improvement 
in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 and Week 16) 
will add or modify background therapy for PsA.  
After the last subject completes the Week 24 study visit, an unblinded analysis will be conducted for the 
purpose of initial regulatory submission.  To maintain integrity of the trial during the blinded 56-week 
period, study sites and subjects will remain blinded until all subjects have reached Week 56.  A 
second unblinded analysis may be conducted for regulatory purposes after all subjects have completed 
Period 1.  A final analysis will be conducted after all subjects have completed Period 2.  An unblinded 
interim analysis will be conducted by an independent external Data Monitoring Committee (DMC) after 
approximately 600 subjects have completed the Week 12 visit or have prematurely discontinued from 
the study.  The interim analysis is to assess if the study met the pre-defined No-Go boundary for the 
primary endpoint ACR20.  


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Methodology (Continued):
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 24, Week 56, Week 104, and Week 152/Premature discontinuation.  In addition, all 
subjects who fail to attain at least 20% improvement in either or both TJC and SJC at Week 12 and 
Week 16 will have an x-ray examination at Week 16 (refer to Section 5.2.3.4 for additional details).  All 
subjects will receive x-rays of hands and feet if they discontinue from the study or from study drug at 
Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained during Period 1 
or at least 24 weeks during Period 2.
Starting at Week 36, subjects who fail to demonstrate at least 20% improvement in either or both TJC 
and SJC compared to baseline at 2 consecutive visits will be discontinued from study drug treatment.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, ≥ 18 years old at Screening.
2.
Clinical diagnosis of PsA with symptom onset at least 6 months prior to the Screening Visit and 
fulfillment of the Classification Criteria for PsA (CASPAR) criteria.
3.
Subject has active disease at Baseline defined as ≥ 3 tender joints (based on 68 joint counts) and 
≥3 swollen joints (based on 66 joint counts) at Screening and Baseline Visits.
4.
Presence of either at Screening:
!
≥ 1 erosion on x-ray as determined by central imaging review or;
!
hs-CRP > laboratory defined upper limit of normal (ULN).
5.
Diagnosis of active plaque psoriasis or documented history of plaque psoriasis.
6.
Subject has had an inadequate response (lack of efficacy after a minimum 12 week duration of 
therapy) to previous or current treatment with at least 1 non-biologic DMARD at maximally 
tolerated dose or up to dose defined in Inclusion Criterion 7 [(inadequate response to MTX is 
defined as ≥ 15 to ≤ 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at doses 
≥ 12.5 mg/week after complete titration; for subjects in China, Korea, Malaysia, Singapore, Hong 
Kong (China), Taiwan, and Japan inadequate response to MTX is defined as ≥7.5 mg/week), SSZ, 
LEF, cyclosporine, apremilast, bucillamine or iguratimod)], or subject has an intolerance to or 
contraindication for DMARDs as defined by the investigator.
7.
Subject who is on current treatment with concomitant non-biologic DMARDs at study entry must 
be on ≤ 2 non-biologic DMARDs (except the combination of MTX and leflunomide) at the 
following doses:  MTX (≤ 25 mg/week), SSZ (≤ 3000 mg/day), leflunomide (LEF) (≤ 20 mg/day), 
apremilast (≤ 60 mg/day), HCQ (≤ 400 mg/day), bucillamine (≤ 300 mg/day) or iguratimod 
(≤50 mg/day) for ≥ 12 weeks and at stable dose for ≥ 4 weeks prior to the Baseline Visit.  No other 
DMARDs are permitted during the study.
!
Subjects who need to discontinue DMARDs prior to the Baseline Visit to comply with this 
inclusion criterion must follow the procedure specified below or at least five times the mean 
terminal elimination half-life of a drug:
o
≥ 8 weeks for LEF if no elimination procedure was followed, or adhere to an elimination 
procedure (i.e., 11 days with cholestyramine, or 30 days washout with activated charcoal 
or as per local label);
o
≥ 4 weeks for all others.


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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 ruxolitinib, 
tofacitinib, baricitinib, and filgotinib).
2.
Current treatment with > 2 non-biologic DMARDs or use of DMARDs other than MTX, SSZ, LEF, 
apremilast, HCQ, bucillamine or iguratimod or use of MTX in combination with LEF at Baseline.
3.
History of fibromyalgia, any arthritis with onset prior to age 17 years, or current diagnosis of 
inflammatory joint disease other than PsA (including, but not limited to rheumatoid arthritis, gout, 
overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, systemic lupus 
erythermatosus).  Prior history of reactive arthritis or axial spondyloarthritis including ankylosing 
spondylitis and non-radiographic axial spondyloarthritis is permitted if documentation of change in 
diagnosis to PsA or additional diagnosis of PsA is made.  Prior history of fibromyalgia is permitted 
if documentation of change in diagnosis to PsA or documentation that the diagnosis of fibromyalgia 
was made incorrectly.
Investigational Product:
ABT-494
Doses:
15 mg or 30 mg once daily
Mode of Administration:
Oral
Reference Therapy:
Matching placebo for ABT-494
Dose:
1 tablet once daily
Mode of Administration:
Oral
Reference Therapy:
Adalimumab (ADA)
Dose:
40 mg every other week (eow)
Mode of Administration:
Subcutaneous
Reference Therapy:
Matching Placebo for Adalimumab
Dose:
Subcutaneous
Duration of Treatment:  152 weeks


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Criteria for Evaluation:
Efficacy:
The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
Key secondary endpoints:
The key multiplicity adjusted secondary efficacy endpoints (each dose of ABT-494 versus placebo 
unless noted) are:
1.
Change from baseline in HAQ-DI at Week 12;
2.
Proportion of subjects achieving a static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 
1 and at least a 2-point improvement from baseline at Week 16;
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with ≥ 3% BSA psoriasis 
at baseline);
4.
Change from baseline in SHS at Week 24;
5.
Proportion of subjects achieving MDA at Week 24;
6.
Proportion of subjects with resolution of enthesitis (LEI = 0) at Week 24;
7.
ACR 20 response rate at Week 12 (non-inferiority of ABT-494 vs adalimumab);
8.
Change from baseline in SF-36 PCS at Week 12.
9.
Change from baseline in FACIT-Fatigue Questionnaire at Week 12;
10. ACR 20 response rate at Week 12 (superiority of ABT-494 vs. adalimumab);
11. Proportion of subjects with resolution of dactylitis (LDI = 0) at Week 24;
12. Change from baseline in Patient's Assessment of Pain NRS at Week 12 (superiority of ABT-494 vs. 
adalimumab);
13. Change from baseline in HAQ-DI at Week 12 (superiority of ABT-494 vs. adalimumab); and
14. Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS) Questionnaire at 
Week 16. 
Additional key secondary efficacy endpoints (each dose of ABT-494 versus placebo) are:
!
ACR50/70 response at Week 12;
!
ACR20 response at Week 2;
The following outcome measures will be assessed in subjects treated with ABT-494 as compared to 
placebo and adalimumab at scheduled time points other than those specified for the primary and key 
secondary variables:
!
Proportion of subjects with no radiographic progression (defined as change from baseline in 
SHS ≤ 0); 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
Change from baseline in individual components of ACR response;
o
Change from baseline in Tender Joint Count (TJC) (0 – 68);
o
Change from baseline in Swollen Joint Count (SJC) (0 – 66);
o
Change from baseline in Physician Global Assessment (PGA) – Disease Activity 
Numerical Rating Scale (NRS);
o
Change from baseline in Patient's Global Assessment (PtGA)-Disease Activity NRS;
o
Change from baseline in Patient's Assessment of Pain NRS;
o
Change from baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI);
o
Change from baseline in High-Sensitivity C Reactive Protein (hs-CRP);
!
ACR 20/50/70 response rates;
!
Change from baseline in Leeds Dactylitis Index (LDI);
!
Change from baseline in dactylitis count;
!
Proportion of subjects with resolution of dactylitis;
!
Change from baseline in Leeds Enthesitis Index (LEI);
!
Proportion of subjects with resolution of enthesitis sites included in the LEI;
!
Change from baseline in SPARCC Enthesitis Index;
!
Proportion of subjects with resolution of enthesitis sites included in the SPARCC Enthesitis 
Index;
!
Change from baseline in total enthesitis count; 
!
Proportion of subjects with resolution of enthesitis;
!
PASI 75/90/100 response rates (for subjects with ≥ 3% Body Surface Area (BSA) psoriasis at 
baseline);
!
Proportion of subjects achieving a static Investigator Global Assessment of Psoriasis (sIGA) 
score of 0 or 1 and at least a 2-point improvement from baseline;
!
BSA-Ps;
!
Modified Psoriatic Arthritis Response Criteria (PsARC) response rate;
!
Change from baseline in Disease Activity Score 28 (DAS28) (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in PsA Disease Activity Score (PASDAS);
!
Change from baseline in Disease Activity In Psoriatic Arthritis (DAPSA) score; 
!
Change from baseline in Short Form 36 (SF-36) Health Questionnaire;
!
Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
Questionnaire;
!
Change from baseline in EuroQol-5-Dimensions-5-Levels (EQ-5D-5L) Questionnaire;
!
Change from baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire;
!
Health Resource Utilization (HRU);
!
Change from baseline in SAPS Questionnaire;
!
Change from baseline in BASDAI;


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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
BASDAI 50 response rates:
!
Change from baseline in Morning stiffness (mean of BASDAI Questions 5 and 6);
!
Change from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
!
Proportion of subjects with ASDAS Inactive Disease;
!
Proportion of subjects with ASDAS Major Improvement;
!
Proportion of subjects with ASDAS Clinically Important Improvement;
!
Proportion of subjects achieving a clinically meaningful improvement in HAQ-DI (≥ 0.35);
!
Proportion of subjects achieving MDA.
Pharmacokinetic:
Blood samples for assay of ABT-494 and possibly other medications in plasma will be collected at each 
visit after baseline in Period 1.
Exploratory Research Variables and Validation Studies (Optional)
Prognostic, surrogate, predictive, and pharmacodynamic biomarkers signatures may be evaluated.  
Samples for different applications including, but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, metabolomic, proteomic and targeted 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.
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:
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between each ABT-494 treatment group and the combined placebo groups will be 
conducted using the Cochran-Mantel-Haenszel test adjusting for main stratification factors.
For ACR20 response rate at Week 12, analysis will be conducted to assess the non-inferiority of each 
ABT-494 dose versus ADA on placebo-subtracted treatment difference using Koch's 3-arm test statistic.  
The test aims to show that ABT-494 preserves at least 50% of the placebo-subtracted ADA effect.  
Superiority of ABT-494 versus ADA will also be tested for ACR20.


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Statistical Methods (Continued):
Period 1 Efficacy (Continued):
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Pairwise comparisons for each of the ABT-494 treatment groups and the combined 
placebo groups 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 Assessment of Pain NRS and change from baseline in HAQ-DI at 
Week 12, superiority of ABT-494 vs adalimumab will also be tested.  The overall type I error rate of the 
primary and key secondary endpoints for the two doses will be strongly controlled using a graphical 
multiple testing procedure.
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.
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.  There will be two sets of planned safety analyses:  safety analysis by 
Week 24, and long-term safety analysis.  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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Has been changed to read:
AbbVie Inc.
Protocol Number:  M15-572
Name of Study Drug:  ABT-494
Phase of Development:  3
Name of Active Ingredient:  ABT-494
Date of Protocol Synopsis:  15 May 2020
Protocol Title:  A Phase 3, Randomized, Double-Blind, Study Comparing Upadacitinib (ABT-494) to 
Placebo and to Adalimumab in Subjects with Active Psoriatic Arthritis Who Have a History of 
Inadequate Response to at Least One Non-Biologic Disease Modifying Anti-Rheumatic Drug (DMARD) 
– SELECT – PsA 1
Objectives:
Period 1
Primary Objective
1.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo and versus 
adalimumab (ADA) for the treatment of signs and symptoms of PsA in subjects with moderately to 
severely active PsA who have an inadequate response or intolerance to 1 or more non-biologic 
DMARD (DMARD-IR).
Secondary Objective
2.
To compare the efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo for the prevention 
of structural progression in subjects with moderately to severely active PsA who have an inadequate 
response or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
3.
To compare the safety and tolerability of ABT-494 15 mg QD and 30 mg QD versus placebo and 
versus adalimumab in subjects with moderately to severely active PsA who have an inadequate 
response or intolerance to 1 or more non-biologic DMARD (DMARD-IR).
Period 2
To evaluate the long-term safety, tolerability and efficacy of ABT-494 15 mg QD and 30 mg QD in 
subjects with PsA who have completed Period 1.
Investigators:  Multicenter
Study Sites:  Approximately 350 sites
Study Population:  Patients with active psoriatic arthritis despite prior use of at least one non-biologic 
DMARD.
Number of Subjects to be Enrolled:  Approximately 1640


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Methodology:
This is a Phase 3 multicenter study that includes two periods.  Period 1 is 56 weeks in duration and 
includes a 24-week randomized, double-blind, parallel-group, placebo-controlled and active comparator-
controlled period followed by an additional 32 weeks of blinded, active comparator-controlled treatment 
(Weeks 24 – 56).  Period 1 is designed to compare the safety, tolerability, and efficacy of ABT-494 
15 mg QD and 30 mg QD versus placebo and versus adalimumab 40 mg every other week (eow) in 
subjects with moderately to severely active PsA and have an inadequate response to non-biologic 
DMARDs (DMARD-IR).  Period 1 is also designed to compare the efficacy of ABT-494 15 mg QD and 
30 mg QD versus placebo for the prevention of structural progression.  Period 2 is an open-label (blinded 
until the last subject completes the last visit of Period 1), long-term extension of up to a total treatment 
duration of approximately 5 years to evaluate the safety, tolerability and efficacy of ABT-494 15 mg QD 
and 30 mg QD in subjects with PsA who have completed Period 1.
The study is designed to enroll approximately 1640 subjects at approximately 350 study centers 
worldwide to meet scientific and regulatory objectives without enrolling an undue number of subjects in 
alignment with ethical considerations.  
The study duration will include a 35-day screening period; a 56-week blinded period which includes 
24 weeks of double-blind, placebo-controlled and active comparator controlled treatment followed by 
32 weeks of active comparator controlled treatment (Period 1); a long-term extension period of up to a 
total treatment duration of approximately 5 years ([blinded until the last subject completes the last visit 
of Period 1] Period 2); a 30-day follow-up call or visit; and a 70-day follow-up call.
Subjects who meet eligibility criteria will be stratified by extent of psoriasis (≥ 3% body surface area 
[BSA] or < 3% BSA), current use of at least 1 DMARD, presence of dactylitis, and presence of 
enthesitis, except for subjects from China and Japan, where randomization for each country will be 
stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA) only, and then will be 
randomized in a 2:2:2:1:1 ratio to one of five treatment groups:
Group 1:  ABT-494 15 mg QD (N = 410)
Group 2:  ABT-494 30 mg QD (N = 410)
Group 3:  ADA (40 mg eow) (N = 410) 
Group 4:  Placebo followed by ABT-494 15 mg QD (N = 205)
Group 5:  Placebo followed by ABT-494 30 mg QD (N = 205)
No more than approximately 15% of subjects will be enrolled with concomitant use of 
hydroxychloraquine, sulfasalazine, bucillamine, or iguratimod.
Subjects will receive both oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or matching placebo) 
and subcutaneous study drug eow (either ADA 40 mg or matching placebo) until all subjects have 
completed Period 1 (Week 56) and sites and subjects are unblinded to study treatment.


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Methodology (Continued):
Subjects who were assigned to placebo at Baseline will be preassigned to receiving either ABT-494 
15 mg QD or ABT-494 30 mg QD starting at Week 24 in a 1:1 ratio.  Subjects who complete the 
Week 56 visit (end of Period 1) will enter the long-term extension portion of the study, Period 2 (total 
study duration up to approximately 5 years).  Subjects will continue study treatment as assigned at the 
end of Period 1.  Subjects who are assigned to the ABT-494 15 mg QD, ABT-494 30 mg QD, or 
adalimumab 40 mg eow will continue to receive ABT-494 15 mg QD, ABT-494 30 mg QD, or 
adalimumab 40 mg eow, respectively, in a blinded manner.  When the last subject completes the last 
visit of Period 1 (Week 56), study drug assignment in both periods will be unblinded to the sites, and 
subjects will be dispensed study drug in an open-label fashion until the completion of Period 2.
Subjects must have had inadequate response to ≥ 1 non-biologic DMARD (MTX, SSZ, LEF, 
cyclosporine, apremilast, bucillamine or iguratimod) or an intolerance to or contraindication for 
DMARDs as defined by the investigator prior to the Screening visit.  No background non-biologic 
DMARD therapy is required during participation in this study.  For subjects who are on non-biologic 
DMARD therapy at baseline (MTX, SSZ, LEF, apremilast, hydroxychloroquine (HCQ), bucillamine or 
iguratimod), non-biologic DMARDs should have been started ≥ 12 weeks prior to the baseline visit, 
must be at stable dose for ≥4 weeks prior to the first dose of study drug and remain on a stable dose 
through Week 36 of the study; the non-biologic DMARD dose may be decreased only for safety 
reasons.  In addition, all subjects taking MTX 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.  Please refer to Section 5.2.3.1 and Section 5.2.3.2 for 
additional details related to prior and concomitant DMARD therapy, respectively.  Starting at the 
Week 36 visit (after Week 36 assessments have been performed), initiation of or change in background 
PsA medication(s) including, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), 
acetaminophen/paracetamol, low potency opiates, and non-biologic DMARDs (concomitant use of up to 
2 non-biologic DMARDs except the combination of MTX and leflunomide) is allowed as per local label 
with maximum doses as outlined in Section 5.2.3.3.
At Week 16, subjects classified as non-responders (defined as not achieving at least 20% improvement 
in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 and Week 16) 
will add or modify background therapy for PsA.  
After the last subject completes the Week 24 study visit, an unblinded analysis will be conducted for the 
purpose of initial regulatory submission.  To maintain integrity of the trial during the blinded 56-week 
period, study sites and subjects will remain blinded until all subjects have reached Week 56.  A 
second unblinded analysis may be conducted for regulatory purposes after all subjects have completed 
Period 1.  A final analysis will be conducted after all subjects have completed Period 2.  An unblinded 
interim analysis will be conducted by an independent external Data Monitoring Committee (DMC) after 
approximately 600 subjects have completed the Week 12 visit or have prematurely discontinued from 
the study.  The interim analysis is to assess if the study met the pre-defined No-Go boundary for the 
primary endpoint ACR20.  


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Methodology (Continued):
Each subject will undergo a maximum of 6 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 24, Week 56, Week 104, Week 152, and Week 260/Premature discontinuation.  In 
addition, all subjects who fail to attain at least 20% improvement in either or both TJC and SJC at 
Week 12 and Week 16 will have an x-ray examination at Week 16 (refer to Section 5.2.3.4 for additional 
details).  All subjects will receive x-rays of hands and feet if they discontinue from the study or from 
study drug at Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained 
during Period 1 or at least 24 weeks during Period 2.
Starting at Week 36, subjects who fail to demonstrate at least 20% improvement in either or both TJC 
and SJC compared to baseline at 2 consecutive visits will be discontinued from study drug treatment.
Diagnosis and Main Criteria for Inclusion/Exclusion:
Main Inclusion:
1.
Adult male or female, ≥ 18 years old at Screening.
2.
Clinical diagnosis of PsA with symptom onset at least 6 months prior to the Screening Visit and 
fulfillment of the Classification Criteria for PsA (CASPAR) criteria.
3.
Subject has active disease at Baseline defined as ≥ 3 tender joints (based on 68 joint counts) and 
≥3 swollen joints (based on 66 joint counts) at Screening and Baseline Visits.
4.
Presence of either at Screening:
!
≥ 1 erosion on x-ray as determined by central imaging review or;
!
hs-CRP > laboratory defined upper limit of normal (ULN).
5.
Diagnosis of active plaque psoriasis or documented history of plaque psoriasis.
6.
Subject has had an inadequate response (lack of efficacy after a minimum 12 week duration of 
therapy) to previous or current treatment with at least 1 non-biologic DMARD at maximally 
tolerated dose or up to dose defined in Inclusion Criterion 7 [(inadequate response to MTX is 
defined as ≥ 15 to ≤ 25 mg/week; or ≥ 10 mg/week in subjects who are intolerant of MTX at doses 
≥ 12.5 mg/week after complete titration; for subjects in China, Korea, Malaysia, Singapore, Hong 
Kong (China), Taiwan, and Japan inadequate response to MTX is defined as ≥7.5 mg/week), SSZ, 
LEF, cyclosporine, apremilast, bucillamine or iguratimod)], or subject has an intolerance to or 
contraindication for DMARDs as defined by the investigator.
7.
Subject who is on current treatment with concomitant non-biologic DMARDs at study entry must 
be on ≤ 2 non-biologic DMARDs (except the combination of MTX and leflunomide) at the 
following doses:  MTX (≤ 25 mg/week), SSZ (≤ 3000 mg/day), leflunomide (LEF) (≤ 20 mg/day), 
apremilast (≤ 60 mg/day), HCQ (≤ 400 mg/day), bucillamine (≤ 300 mg/day) or iguratimod 
(≤50 mg/day) for ≥ 12 weeks and at stable dose for ≥ 4 weeks prior to the Baseline Visit.  No other 
DMARDs are permitted during the study.
!
Subjects who need to discontinue DMARDs prior to the Baseline Visit to comply with this 
inclusion criterion must follow the procedure specified below or at least five times the mean 
terminal elimination half-life of a drug:
o
≥ 8 weeks for LEF if no elimination procedure was followed, or adhere to an elimination 
procedure (i.e., 11 days with cholestyramine, or 30 days washout with activated charcoal 
or as per local label);
o
≥ 4 weeks for all others.


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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 ruxolitinib, 
tofacitinib, baricitinib, and filgotinib).
2.
Current treatment with > 2 non-biologic DMARDs or use of DMARDs other than MTX, SSZ, LEF, 
apremilast, HCQ, bucillamine or iguratimod or use of MTX in combination with LEF at Baseline.
3.
History of fibromyalgia, any arthritis with onset prior to age 17 years, or current diagnosis of 
inflammatory joint disease other than PsA (including, but not limited to rheumatoid arthritis, gout, 
overlap connective tissue diseases, scleroderma, polymyositis, dermatomyositis, systemic lupus 
erythermatosus).  Prior history of reactive arthritis or axial spondyloarthritis including ankylosing 
spondylitis and non-radiographic axial spondyloarthritis is permitted if documentation of change in 
diagnosis to PsA or additional diagnosis of PsA is made.  Prior history of fibromyalgia is permitted 
if documentation of change in diagnosis to PsA or documentation that the diagnosis of fibromyalgia 
was made incorrectly.
Investigational Product:
ABT-494
Doses:
15 mg or 30 mg once daily
Mode of Administration:
Oral
Reference Therapy:
Matching placebo for ABT-494
Dose:
1 tablet once daily
Mode of Administration:
Oral
Reference Therapy:
Adalimumab (ADA)
Dose:
40 mg every other week (eow)
Mode of Administration:
Subcutaneous
Reference Therapy:
Matching Placebo for Adalimumab
Dose:
Subcutaneous
Duration of Treatment:  260 weeks


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Criteria for Evaluation:
Efficacy:
The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
Key secondary endpoints:
The key multiplicity adjusted secondary efficacy endpoints (each dose of ABT-494 versus placebo 
unless noted) are:
1.
Change from baseline in HAQ-DI at Week 12;
2.
Proportion of subjects achieving a static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 
1 and at least a 2-point improvement from baseline at Week 16;
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with ≥ 3% BSA psoriasis 
at baseline);
4.
Change from baseline in SHS at Week 24;
5.
Proportion of subjects achieving MDA at Week 24;
6.
Proportion of subjects with resolution of enthesitis (LEI = 0) at Week 24;
7.
ACR 20 response rate at Week 12 (non-inferiority of ABT-494 vs adalimumab);
8.
Change from baseline in SF-36 PCS at Week 12.
9.
Change from baseline in FACIT-Fatigue Questionnaire at Week 12;
10. ACR 20 response rate at Week 12 (superiority of ABT-494 vs. adalimumab);
11. Proportion of subjects with resolution of dactylitis (LDI = 0) at Week 24;
12. Change from baseline in Patient's Assessment of Pain NRS at Week 12 (superiority of ABT-494 vs. 
adalimumab);
13. Change from baseline in HAQ-DI at Week 12 (superiority of ABT-494 vs. adalimumab); and
14. Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS) Questionnaire at 
Week 16. 
Additional key secondary efficacy endpoints (each dose of ABT-494 versus placebo) are:
!
ACR50/70 response at Week 12;
!
ACR20 response at Week 2;
The following outcome measures will be assessed in subjects treated with ABT-494 as compared to 
placebo and adalimumab at scheduled time points other than those specified for the primary and key 
secondary variables:
!
Proportion of subjects with no radiographic progression (defined as change from baseline in 
SHS ≤ 0); 


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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
Change from baseline in individual components of ACR response;
o
Change from baseline in Tender Joint Count (TJC) (0 – 68);
o
Change from baseline in Swollen Joint Count (SJC) (0 – 66);
o
Change from baseline in Physician Global Assessment (PGA) – Disease Activity 
Numerical Rating Scale (NRS);
o
Change from baseline in Patient's Global Assessment (PtGA)-Disease Activity NRS;
o
Change from baseline in Patient's Assessment of Pain NRS;
o
Change from baseline in Health Assessment Questionnaire – Disability Index (HAQ-DI);
o
Change from baseline in High-Sensitivity C Reactive Protein (hs-CRP);
!
ACR 20/50/70 response rates;
!
Change from baseline in Leeds Dactylitis Index (LDI);
!
Change from baseline in dactylitis count;
!
Proportion of subjects with resolution of dactylitis;
!
Change from baseline in Leeds Enthesitis Index (LEI);
!
Proportion of subjects with resolution of enthesitis sites included in the LEI;
!
Change from baseline in SPARCC Enthesitis Index;
!
Proportion of subjects with resolution of enthesitis sites included in the SPARCC Enthesitis 
Index;
!
Change from baseline in total enthesitis count; 
!
Proportion of subjects with resolution of enthesitis;
!
PASI 75/90/100 response rates (for subjects with ≥ 3% Body Surface Area (BSA) psoriasis at 
baseline);
!
Proportion of subjects achieving a static Investigator Global Assessment of Psoriasis (sIGA) 
score of 0 or 1 and at least a 2-point improvement from baseline;
!
BSA-Ps;
!
Modified Psoriatic Arthritis Response Criteria (PsARC) response rate;
!
Change from baseline in Disease Activity Score 28 (DAS28) (CRP);
!
Change from baseline in DAS28 (ESR);
!
Change from baseline in PsA Disease Activity Score (PASDAS);
!
Change from baseline in Disease Activity In Psoriatic Arthritis (DAPSA) score; 
!
Change from baseline in Short Form 36 (SF-36) Health Questionnaire;
!
Change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
Questionnaire;
!
Change from baseline in EuroQol-5-Dimensions-5-Levels (EQ-5D-5L) Questionnaire;
!
Change from baseline in Work Productivity and Activity Impairment (WPAI) Questionnaire;
!
Health Resource Utilization (HRU);
!
Change from baseline in SAPS Questionnaire;
!
Change from baseline in BASDAI;


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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
BASDAI 50 response rates:
!
Change from baseline in Morning stiffness (mean of BASDAI Questions 5 and 6);
!
Change from baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
!
Proportion of subjects with ASDAS Inactive Disease;
!
Proportion of subjects with ASDAS Major Improvement;
!
Proportion of subjects with ASDAS Clinically Important Improvement;
!
Proportion of subjects achieving a clinically meaningful improvement in HAQ-DI (≥ 0.35);
!
Proportion of subjects achieving MDA.
Pharmacokinetic:
Blood samples for assay of ABT-494 and possibly other medications in plasma will be collected at each 
visit after baseline in Period 1.
Exploratory Research Variables and Validation Studies (Optional)
Prognostic, surrogate, predictive, and pharmacodynamic biomarkers signatures may be evaluated.  
Samples for different applications including, but not limited to, pharmacogenetic, epigenetic, 
transcriptomic, metabolomic, proteomic and targeted 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.
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:
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons between each ABT-494 treatment group and the combined placebo groups will be 
conducted using the Cochran-Mantel-Haenszel test adjusting for main stratification factors.
For ACR20 response rate at Week 12, analysis will be conducted to assess the non-inferiority of each 
ABT-494 dose versus ADA on placebo-subtracted treatment difference using Koch's 3-arm test statistic.  
The test aims to show that ABT-494 preserves at least 50% of the placebo-subtracted ADA effect.  
Superiority of ABT-494 versus ADA will also be tested for ACR20.


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Statistical Methods (Continued):
Period 1 Efficacy (Continued):
For continuous endpoints, the mean, standard deviation, median, and range will be reported for each 
treatment group.  Pairwise comparisons for each of the ABT-494 treatment groups and the combined 
placebo groups 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 Assessment of Pain NRS and change from baseline in HAQ-DI at 
Week 12, superiority of ABT-494 vs adalimumab will also be tested.  The overall type I error rate of the 
primary and key secondary endpoints for the two doses will be strongly controlled using a graphical 
multiple testing procedure.
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.
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.  There will be two sets of planned safety analyses:  safety analysis by 
Week 24, and long-term safety analysis.  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 5.1  Overall Study Design and Plan:  Description
First paragraph, last sentence previously read:
Period 2 is an open-label (blinded until the last subject completes the last visit of 
Period 1), long-term extension of up to a total treatment duration of approximately 3 years 
to evaluate the safety, tolerability and efficacy of ABT-494 15 mg QD and 30 mg QD in 
subjects with PsA who have completed Period 1.
Has been changed to read:
Period 2 is an open-label (blinded until the last subject completes the last visit of 
Period 1), long-term extension of up to a total treatment duration of approximately 5 years 


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to evaluate the safety, tolerability and efficacy of ABT-494 15 mg QD and 30 mg QD in 
subjects with PsA who have completed Period 1.
Section 5.1  Overall Study Design and Plan:  Description
Third paragraph previously read:
The study duration will include a 35-day screening period; a 56-week blinded period 
which includes 24 weeks of double-blind, placebo-controlled and active comparator-
controlled treatment followed by 32 weeks of active comparator controlled treatment 
(Period 1); a long-term extension period of up to a total treatment duration of 
approximately 3 years ([blinded until the last subject completes the last visit of Period 1] 
Period 2); a 30-day follow-up 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 56-week blinded period 
which includes 24 weeks of double-blind, placebo-controlled and active comparator-
controlled treatment followed by 32 weeks of active comparator controlled treatment 
(Period 1); a long-term extension period of up to a total treatment duration of 
approximately 5 years ([blinded until the last subject completes the last visit of Period 1] 
Period 2); a 30-day follow-up call or visit; and a 70-day follow-up call.
Section 5.1  Overall Study Design and Plan:  Description
Twelfth paragraph, second sentence previously read:
Subjects who complete the Week 56 visit (end of Period 1) will enter the long-term 
extension portion of the study, Period 2 (total treatment up to approximately 3 years).  
Has been changed to read:
Subjects who complete the Week 56 visit (end of Period 1) will enter the long-term 
extension portion of the study, Period 2 (total treatment up to approximately 5 years).  


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Section 5.1  Overall Study Design and Plan:  Description
Seventeenth paragraph previously read:
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 24, Week 56, Week 104, and 
Week 152/Premature discontinuation.
Has been changed to read:
Each subject will undergo a maximum of 6 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 24, Week 56, Week 104, Week 152, 
and Week 260/Premature discontinuation.


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Figure 1.  Study Design
Previously read:
a.
All subjects will receive x-rays of hands and feet at Screening, Wk 24, Wk 56, Wk 104, and Wk 152/PD.
b.
At Week 16 rescue therapy will be offered to, subjects classified as non-responders (defined as not achieving at 
least 20% improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 
and Week 16) as described in Section 5.2.3.4.  
c.
At Week 24, all placebo subjects will switch to ABT-494 15 mg QD or 30 mg QD (1:1 ratio) regardless of 
response.


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Has been changed to read:
a.
All subjects will receive x-rays of hands and feet at Screening, Wk 24, Wk 56, Wk 104, 152, and Wk 260/PD.
b.
At Week 16 rescue therapy will be offered to, subjects classified as non-responders (defined as not achieving at 
least 20% improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 
and Week 16) as described in Section 5.2.3.4.  
c.
At Week 24, all placebo subjects will switch to ABT-494 15 mg QD or 30 mg QD (1:1 ratio) regardless of 
response.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Period 2 (Long-Term Extension Period [Up to a Total Treatment 
Duration of Approximately 3 Years])
Subsection title previously read:
Period 2 (Long-Term Extension Period [Up to a Total Treatment Duration of 
Approximately 3 Years])


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Has been changed to read:
Period 2 (Long-Term Extension Period [Up to a Total Treatment Duration of 
Approximately 5 Years])
Section 5.1  Overall Study Design and Plan:  Description
Subsection Period 2 (Long-Term Extension Period [Up to a Total Treatment 
Duration of Approximately 3 Years])
Last sentence previously read:
The last dose of oral study drug is taken the day prior to the Week 152 visit.
Has been changed to read:
The last dose of oral study drug is taken the day prior to the Week 260 visit.
Section 5.1  Overall Study Design and Plan:  Description
Subsection Follow-Up Period
First sentence previously read:
Subjects who complete the last visit of Period 2 (Week 152) will have a follow-up visit 
approximately 30 days after the last dose of oral study drug to obtain information on any 
new or ongoing AEs and to collect vital signs and clinical laboratory tests.  
Has been changed to read:
Subjects who complete the last visit of Period 2 (Week 260) will have a follow-up visit 
approximately 30 days after the last dose of oral study drug to obtain information on any 
new or ongoing AEs and to collect vital signs and clinical laboratory tests.  
Section 5.3.1.1  Study Procedures
Subsection X-Rays of the Hands and Feet
First paragraph previously read:
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 


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meet the quality requirements) at Screening, Week 24, Week 56, Week 104, and 
Week 152/Premature discontinuation.
Has been changed to read:
Each subject will undergo a maximum of 6 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 24, Week 56, Week 104, Week 152, 
and Week 260/Premature discontinuation.
Section 5.3.1.1  Study Procedures
Subsection TB Testing/TB Prophylaxis
Second paragraph
Add:  new last sentence
At annual evaluations, questions on the TB risk assessment form should be answered 
considering the previous year when the timeframe is not indicated in the question.
Section 5.3.1.1  Study Procedures
Subsection Clinical Laboratory Tests
Add:  new fifth paragraph
In cases of state-of emergency or pandemic situations, local laboratories may be used to 
collect laboratory samples per instructions from AbbVie, as local regulations allow.
Section 5.3.1.1  Study Procedures
Subsection Randomization and Drug Assignment
Heading "Study Drug Dispensing, Dosing, and Compliance"
First paragraph, third sentence previously read:
Subjects will maintain a diary for all study drug administered (i.e., at home) to capture 
dosing dates and times.  
Has been changed to read:
Subjects will maintain a diary through Week 151 for all study drug administered (i.e., at 
home) to capture dosing dates and times.  


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Section 5.3.1.1  Study Procedures
Subsection Randomization and Drug Assignment
Heading "Study Drug Dispensing, Dosing, and Compliance"
First paragraph
Add:  new last sentence
Diaries will not be dispensed beyond Week 140; dosing compliance will be captured 
during the drug accountability process for each subject in the IRT system.
Section 5.3.1.1  Study Procedures
Subsection Randomization and Drug Assignment
Heading "Study Drug Dispensing, Dosing, and Compliance"
Add:  new second paragraph
In cases of state-of emergency or pandemic situations, study drug may be shipped directly 
to subjects per instructions from AbbVie, as local regulations allow.
Section 5.3.1.1  Study Procedures
Subsection Subject Diary
Last sentence previously read:
The completed diaries will be collected at the subject's final visit and maintained at the 
site as source documentation.
Has been changed to read:
The completed diaries will be collected at the subject's Week 152 visit and maintained at 
the site as source documentation.  Diaries will not be dispensed beyond Week 140; 
concomitant medication use and AEs will be documented in the subject's source 
documentation during study visits and recorded on the applicable eCRF.


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Section 5.3.1.1  Study Procedures
Subsection Patient Questionnaires
Add:  new last paragraph
In cases of state-of emergency or pandemic situations, PROs may be administered on 
paper or over the telephone directly to subjects by site personnel within the study visit 
window per instructions from AbbVie, as local regulations allow.
Section 5.5.4  Selection and Timing of Dose for Each Subject
Second paragraph, first sentence previously read:
Each subject's dosing schedule should be closely monitored by the site at each study visit 
by careful review of the subject's diary.  
Has been changed to read:
Each subject's dosing schedule should be closely monitored by the site at each study visit 
through Week 151 by careful review of the subject's diary.  
Section 5.5.4  Selection and Timing of Dose for Each Subject
Second paragraph
Add:  new last sentence
Diaries will not be dispensed beyond Week 140; dosing compliance will be captured 
during the drug accountability process for each subject in the IRT system.
Section 5.5.6  Treatment Compliance
Last paragraph, first sentence previously read:
Subject dosing will be recorded on a subject diary.  
Has been changed to read:
Subject dosing will be recorded on a subject diary through Week 151.  


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Section 5.5.6  Treatment Compliance
Last paragraph
Add:  new last paragraph
Dosing compliance will be captured during the drug accountability process for each 
subject in the IRT system.
Section 5.6.4  Selection of Doses in the Study
First paragraph, first sentence previously read:
The doses of ABT-494 selected for this study, 15 mg QD and 30 mg QD, dosed up to 
approximately 3 years, are expected to be efficacious with an acceptable safety profile.  
Has been changed to read:
The doses of ABT-494 selected for this study, 15 mg QD and 30 mg QD, dosed up to 
approximately 5 years, are expected to be efficacious with an acceptable safety profile.  
Section 6.1.5  Serious Adverse Event and Malignancy Reporting
"Immunology Safety Team," "Bldg." previously read:
Has been changed to read:
Section 9.3  Subject Information and Consent
Add:  new last paragraph
In cases of state-of emergency or pandemic situations, verbal consent may be obtained 
prior to adaptations to substantial changes in study conduct, according to local 
regulations.


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Section 10.2  Case Report Forms
Subsection Electronic Patient Reported Data:
Add:  new fourth paragraph
In cases of state-of emergency or pandemic situations, PROs may be administered within 
the study visit window on paper or over the telephone by site personnel directly to 
subjects per instructions from AbbVie, as local regulations allow.


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Appendix C.  Study Activities
Previously read:
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 140 
(Every 
12 Wks)
Wk 
152 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 981
D 
1065
D
1095
D 
1121
Informed Consentc
X
Inclusion/Exclusion Criteria
X
X
CASPAR Criteria
X
Medical/Surgical Historyd
X
X
Vital Signse/Weight/Heightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol/Nicotine Use
X
Prior/Concomitant Therapyg
X
X
X
X
X
X
X
X
X
X
X
Xg
X
X
X
X
X
Physical Examh
X
X
X
X
Xh
X
12-Lead ECG
Xi
X
Xi
Chest X-Rayk,l
Xk
Xl
Xl
Xl
Bilateral X-Rays of Hands and Feetm,n
Xm, n
Xm
Xm
Xm
Xm
Xm
Serum Pregnancy Test at Central Labo
X
Local Urine Pregnancy Testp,q
X
X
X
X
X
X
X
X
X
X
Xq
Xq
Xq
Xq
X
X
Latent TB Risk Factor Questionnairer
X
X
Xr
X
Central Lab QuantiFeron TB Gold Test 
(and Local PPD Skin Test if Required)s
X
X
Xs
Xs


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Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 140 
(Every 
12 Wks)
Wk 
152 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 981
D 
1065
D
1095
D 
1121
Central Lab Testst
hs-CRPu
Clinical Chemistryv
Hematology (CBC)v
Urinalysisw
FSHx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xhh
Central Lab Testt
Total Cholesterol
HDL-C
LDL-C
Triglycerides
X
X
X
X
ESR (Local Lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Central Lab Tests
HIV Screeningj
Hepatitis B and C
Screening
Rheumatoid Factor 
Anti-CCP Antibodies
ANA/Reflex Anti-dsDNA
X
Xy
Xy
Blood Samples for ABT-494 PK 
Assayz,aa
Xz
Xz
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Subject Questionnairesbb
HAQ-DI
Patient-Pain
PtGA-Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 140 
(Every 
12 Wks)
Wk 
152 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 981
D 
1065
D
1095
D 
1121
Subject Questionnairesbb
SF-36
EQ-5D-5L
FACIT-F
WPAI
BASDAI 
X
X
X
X
X
X
X
Subject Questionnairebb,cc
SAPS
X
X
X
X
X
Xcc
X
Tender and Swollen Joint Counts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Psoriatic Spondylitis Question
X
PGA-Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRU
X
X
X
X
X
X
X
BSA Psoriasiscc
X
X
X
X
X
X
Xcc
X
PASIcc
X
X
X
X
X
X
Xcc
X
sIGAcc
X
X
X
X
X
X
Xcc
X
Leeds Dactylitis Index (LDI)
X
X
X
X
X
X
X
X
Leeds/SPARCC Enthesitis Indicies 
(LEI)
X
X
X
X
X
X
X
X
Adverse Event Assessmentdd
Xdd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X


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Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 140 
(Every 
12 Wks)
Wk 
152 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 981
D 
1065
D
1095
D 
1121
Dispense Study Drug and Subject 
Diaryee
X
X
X
X
X
X
X
X
X
X
X
X
X
Calculation of TJC/SJC Responsesff,gg
Xff
Xff
Xgg
Xgg
Xgg
Xgg
Xgg
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
a.
These visits every 12 weeks are at:  Wk 68, Wk 80, Wk 92, Wk 104, Wk 116, Wk 128, and Wk 140.
b.
This on-site visit is 30 days after the last dose of study drug.  For those subjects who prematurely discontinue from the study (withdrawal of informed consent) a 30-day 
follow-up phone call (and not an on-site visit) 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 phone call is to take place 70 days after the last dose of study drug.  The 70-day follow-up phone call is also for 
those subjects who prematurely discontinue from the study (withdrawal of informed consent).  Subjects completing the study on OL therapy will only be required to have the 
30-day follow-up visit if on oral study drug and the 70-day follow-up call if on injectable study drug.  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 or 70 days after last dose of 
study drug, respectively.  
c.
Obtain informed consent prior to performing any study related procedures.
d.
Note herpes zoster, herpes zoster vaccination, and hepatitis B vaccination status in medical history.
e.
Blood pressure, pulse rate, body temperature, body weight, and respiratory rate should be performed before blood draws are performed.
f.
Height will be measured at Screening visit only (with shoes off).
g.
For concomitant medications, at Week 36 (after Week 36 assessments have been performed), per Investigator judgment, may add non-biologic DMARDs (concomitant use of 
up to 2 non-biologic DMARDs, except the combination of MTX and leflunomide), or increase DMARD dose.
h.
For Period 1 (up to and including Week 56 visit), a full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when 
necessary.  For Period 2 (after Week 56), a full physical exam is required approximately every 24 weeks (Wk 80, Wk 104, and Wk 128 visits) and at the Wk 152/PD visit.  A
symptom-directed physical exam may be performed when necessary.


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i.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required; provided all protocol-required documentation is available 
and nothing has changed in the subject's health status since the time of the test that warrants a repeat test.  If required by country regulatory authorities, an annual ECG will be 
performed.
j.
HIV testing will be performed at Screening.  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.
k.
The screening chest x-ray will not be required if a subject had a previously normal chest-x-ray (posterior-anterior and lateral views) within 90 days of Screening, provided that 
all protocol-required documentation is available at the site and nothing has changed in the subject's health status since the time of the test that warrants a repeat test (refer to 
Section 5.3.1.1 for specific requirements).
l.
Obtain a chest x-ray annually for subjects with one or more TB risk factors as identified by the TB risk assessment form, subjects living in areas endemic for TB, and subjects 
with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.  In the case a subject prematurely discontinues from the study drug a chest x-ray 
should not be performed if it has been less than 48 weeks since the last examination.
m.
X-rays of hands and feet will be performed for all subjects at Screening, Wk 24, Wk 56, Wk 104, and Wk 152/PD visits.  All subjects who fail to attain at least 20% 
improvement in either or both TJC and SJC at Week 12 and Week 16 will have an x-ray examination at Week 16.  An x-ray examination at Week 16 is not required for 
subjects with at least a 20% improvement in either or both TJC and SJC at Week 12 and Week 16.  All subjects will receive x-rays of hands and feet if they discontinue from 
the study or from study drug at Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained during Period 1 or at least 24 weeks during Period 2.
n.
Randomization is permitted prior to results of the central reading of hand and foot x-rays for eligibility if a subject has an elevated hs-CRP available from the central 
laboratory and all other criteria are met.
o.
For all women of childbearing potential, collect serum for pregnancy test at Screening and if any urine pregnancy test is positive at any time during the study.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If serum pregnancy test comes back borderline, a repeat test is necessary (pregnancy is an exclusion 
criterion).  If 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.  Refer to 
Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
p.
For all female subjects of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits.  More frequent pregnancy tests will be performed 
throughout the study if required per local/country requirements.  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 study drug treatment.  Refer to Section 5.3.1.1
Study Procedures Pregnancy Test for additional details.


ABT-494
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q.
If time between visits is longer than one month, then collect the results of the monthly at home urine pregnancy test between scheduled visits.  If a urine pregnancy test is 
positive, the subject must stop dosing, come into the clinic and have blood drawn for a serum pregnancy test that will be analyzed at the central laboratory.  A pregnant or 
breastfeeding female will not be eligible for participation or continuation in this study.  The monthly at home tests between scheduled on-site visits are to occur at Weeks 40, 
48, 52, 60, 64, 72, 76, 84, 88, 96, 100, 108, 112, 120, 124, 132, 136, 144, and 148.
r.
Latent TB risk factor questionnaire will be obtained at Screening and annually thereafter through study participation.  Refer to Section 5.3.1.1 for specific requirements for TB 
testing and TB Prophylaxis.
s.
TB testing will be performed at Screening and annually thereafter through study participation.  In the case a subject prematurely discontinues from the study drug TB testing 
should not be performed if it has been less than 48 weeks since the last test was obtained.  Refer to Section 5.3.1.1 for specific requirements for TB testing and TB 
Prophylaxis.
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.
Starting from Baseline (Day 1) the hs-CRP results will not be reported to the Sponsor, Investigator, study site personnel, or the subject.  For safety evaluations of signs and 
symptoms of infection and management of adverse events, the investigator may locally test procalcitonin.  Results of tests such as hs-CRP, and procalcitonin 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 hs-
CRP, CRP, or serial procalcitonin tests reported to the investigator until a subject is known to receive upadacitinib or until treatment allocation is unblinded will be recorded 
as protocol deviations.
v.
If required by country regulatory authorities, subjects who initiate or increase dose of MTX during the study should undergo ALT, AST, creatinine and CBC testing every 
4 weeks for a 12-week period.
w.
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.
x.
FSH should be tested at Screening 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 in Section 5.2.4).
y.
For China and Japan, or where mandated by local requirements:  for subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening, the HBV-DNA PCR test 
should be performed again every 12 weeks.  Retesting every 12 weeks is not necessary for subjects that have a history of HBV vaccine and HBs Ab+ and HBc Ab–.  
z.
At Week 2 and Week 4 visits, PK samples should be collected prior to oral study drug dosing and the subjects should take the study drug dose at the clinic after collecting the 
PK blood sample.  However, if the subject normally takes the study 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.
aa.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.  Collect PK samples at Week 8, Week 12, Week 16, Week 20, 
Week 24, Week 32, Week 56, and at PD visit only for subjects who prematurely discontinue from study drug treatment prior to Week 56.  No PK sample collection is 
required at Week 152.
bb. Prior to other study visit procedures.  
cc.
PASI, BSA-Ps, sIGA, and SAPS are to be done at Week 80, Week 104, and Week 128 (every 24 weeks after the Week 56 visit).


ABT-494
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dd. Collect serious adverse events and protocol-related non-serious AEs that occur after a subject signs the informed consent; prior to the first dose of study drug.
ee.
At Week 24, all placebo subjects will be switched to blinded ABT-494 regardless of clinical response.
ff.
At Week 16, subjects who do not achieve ≥ 20% improvement in either or both TJC and SJC compared to baseline at both Weeks 12 and 16 will be offered rescue therapy 
(see Section 5.2.3.4).
gg. Starting at Week 36, subjects who failed to show at least 20% improvement in either or both TJC and SJC compared to baseline at 2 consecutive visits will be discontinued 
from study drug treatment.
hh. Only blood chemistry and hematology.
Note:
Visit window is ± 3 days for the first 36 weeks and ± 7 days for the remainder of the study.  Any of the procedures may be performed at an unscheduled visit at 
the discretion of the Investigator.


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Has been changed to read:
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Informed Consentc
X
Inclusion/Exclusion Criteria
X
X
CASPAR Criteria
X
Medical/Surgical Historyd
X
X
Vital Signse/Weight/Heightf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Alcohol/Nicotine Use
X
Prior/Concomitant Therapyg
X
X
X
X
X
X
X
X
X
X
X
Xg
X
X
X
X
X
Physical Examh
X
X
X
X
Xh
X
12-Lead ECG
Xi
X
Xi
Chest X-Rayk,l
Xk
Xl
Xl
Xl
Bilateral X-Rays of Hands and Feetm,n
Xm, n
Xm
Xm
Xm
Xm
Xm
Serum Pregnancy Test at Central Labo
X
Local Urine Pregnancy Testp,q
X
X
X
X
X
X
X
X
X
X
Xq
Xq
Xq
Xq
X
X
Latent TB Risk Factor Questionnairer
X
X
Xr
X
Central Lab QuantiFeron TB Gold Test 
(and Local PPD Skin Test if Required)s
X
X
Xs
Xs


ABT-494
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211
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Central Lab Testst
hs-CRPu
Clinical Chemistryv
Hematology (CBC)v
Urinalysisw
FSHx
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xhh
Central Lab Testt
Total Cholesterol
HDL-C
LDL-C
Triglycerides
X
X
X
X
ESR (Local Lab)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Other Central Lab Tests
HIV Screeningj
Hepatitis B and C
Screening
Rheumatoid Factor 
Anti-CCP Antibodies
ANA/Reflex Anti-dsDNA
X
Xy
Xy
Blood Samples for ABT-494 PK 
Assayz,aa
Xz
Xz
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Xaa
Subject Questionnairesbb
HAQ-DI
Patient-Pain
PtGA-Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


ABT-494
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EudraCT 2016-004130-24
212
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Subject Questionnairesbb
SF-36
EQ-5D-5Ljj
FACIT-F
WPAIjj
BASDAI 
X
X
X
X
X
X
X
Subject Questionnairebb,cc
SAPS
X
X
X
X
X
Xcc
X
Tender and Swollen Joint Counts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Psoriatic Spondylitis Question
X
PGA-Disease Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HRU
X
X
X
X
X
X
X
BSA Psoriasiscc
X
X
X
X
X
X
Xcc
X
PASIcc
X
X
X
X
X
X
Xcc
X
sIGAcc
X
X
X
X
X
X
Xcc
X
Leeds Dactylitis Index (LDI)
X
X
X
X
X
X
X
X
Leeds/SPARCC Enthesitis Indicies 
(LEI)
X
X
X
X
X
X
X
X
Adverse Event Assessmentdd
Xdd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X


ABT-494
M15-572 Protocol Amendment 6
EudraCT 2016-004130-24
213
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68a to 
Wk 248 
(Every 
12 Wks)
Wk 
260 
or PD
30 Day 
F/U 
Visit/ 
Callb
70-
Day 
F/U 
Callb
D –35 to
D –1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 1737
D 
1821
D
1851
D 
1877
Dispense Study Drug and Subject 
Diaryee
X
X
X
X
X
X
X
X
X
X
X
X
Xkk
Calculation of TJC/SJC Responsesff,gg
Xff
Xff
Xgg
Xgg
Xgg
Xgg
Xgg
Subject Diary Review
X
X
X
X
X
X
X
X
X
X
X
X
Xkk
a.
These visits every 12 weeks are at:  Wk 68, Wk 80, Wk 92, Wk 104, Wk 116, Wk 128, Wk 140, Wk 152, Wk 164, Wk 176, Wk 188, Wk 200, Wk 212, Wk 224, Wk 236, 
Wk 248.
b.
This on-site visit is 30 days after the last dose of study drug.  For those subjects who prematurely discontinue from the study (withdrawal of informed consent) a 30-day 
follow-up phone call (and not an on-site visit) 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 phone call is to take place 70 days after the last dose of study drug.  The 70-day follow-up phone call is also for 
those subjects who prematurely discontinue from the study (withdrawal of informed consent).  Subjects completing the study on OL therapy will only be required to have the 
30-day follow-up visit if on oral study drug and the 70-day follow-up call if on injectable study drug.  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 or 70 days after last dose of 
study drug, respectively.  
c.
Obtain informed consent prior to performing any study related procedures.
d.
Note herpes zoster, herpes zoster vaccination, and hepatitis B vaccination status in medical history.
e.
Blood pressure, pulse rate, body temperature, body weight, and respiratory rate should be performed before blood draws are performed.
f.
Height will be measured at Screening visit only (with shoes off).
g.
For concomitant medications, at Week 36 (after Week 36 assessments have been performed), per Investigator judgment, may add non-biologic DMARDs (concomitant use of 
up to 2 non-biologic DMARDs, except the combination of MTX and leflunomide), or increase DMARD dose.
h.
For Period 1 (up to and including Week 56 visit), a full physical exam is required at the visits indicated.  A symptom-directed physical exam may be performed when 
necessary.  For Period 2 (after Week 56), a full physical exam is required approximately every 24 weeks (Wk 80, Wk 104, Wk 128, Wk 152, Wk 176, Wk 200, Wk 224 visits) 
and at the Wk 260/PD visit.  A symptom-directed physical exam may be performed when necessary.


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i.
For subjects with a normal ECG taken within 90 days of Screening, a repeat ECG at Screening will not be required; provided all protocol-required documentation is available 
and nothing has changed in the subject's health status since the time of the test that warrants a repeat test.  If required by country regulatory authorities, an annual ECG will be 
performed.
j.
HIV testing will be performed at Screening.  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.
k.
The screening chest x-ray will not be required if a subject had a previously normal chest-x-ray (posterior-anterior and lateral views) within 90 days of Screening, provided that 
all protocol-required documentation is available at the site and nothing has changed in the subject's health status since the time of the test that warrants a repeat test (refer to 
Section 5.3.1.1 for specific requirements).
l.
Obtain a chest x-ray annually for subjects with one or more TB risk factors as identified by the TB risk assessment form, subjects living in areas endemic for TB, and subjects 
with a newly positive QuantiFERON-TB Gold test (and/or PPD skin test) after baseline.  In the case a subject prematurely discontinues from the study drug a chest x-ray 
should not be performed if it has been less than 48 weeks since the last examination.
m.
X-rays of hands and feet will be performed for all subjects at Screening, Wk 24, Wk 56, Wk 104, Wk 152 and Wk 260/PD visits.  All subjects who fail to attain at least 20% 
improvement in either or both TJC and SJC at Week 12 and Week 16 will have an x-ray examination at Week 16.  An x-ray examination at Week 16 is not required for 
subjects with at least a 20% improvement in either or both TJC and SJC at Week 12 and Week 16.  All subjects will receive x-rays of hands and feet if they discontinue from 
the study or from study drug at Week 12 or later and it has been at least 12 weeks from when x-rays were last obtained during Period 1 or at least 24 weeks during Period 2.
n.
Randomization is permitted prior to results of the central reading of hand and foot x-rays for eligibility if a subject has an elevated hs-CRP available from the central 
laboratory and all other criteria are met.
o.
For all women of childbearing potential, collect serum for pregnancy test at Screening and if any urine pregnancy test is positive at any time during the study.  If the serum 
pregnancy test is positive the subject is considered a screen failure.  If serum pregnancy test comes back borderline, a repeat test is necessary (pregnancy is an exclusion 
criterion).  If 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.  Refer to 
Section 5.3.1.1 Study Procedures Pregnancy Test for additional details.
p.
For all female subjects of childbearing potential, collect urine for pregnancy test at Baseline and all subsequent visits.  More frequent pregnancy tests will be performed 
throughout the study if required per local/country requirements.  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 study drug treatment.  Refer to Section 5.3.1.1
Study Procedures Pregnancy Test for additional details.


ABT-494
M15-572 Protocol Amendment 6
EudraCT 2016-004130-24
215
q.
If time between visits is longer than one month, then collect the results of the monthly at home urine pregnancy test between scheduled visits.  If a urine pregnancy test is 
positive, the subject must stop dosing, come into the clinic and have blood drawn for a serum pregnancy test that will be analyzed at the central laboratory.  A pregnant or 
breastfeeding female will not be eligible for participation or continuation in this study.  The monthly at home tests between scheduled on-site visits are to occur at Weeks 40, 
48, 52, 60, 64, 72, 76, 84, 88, 96, 100, 108, 112, 120, 124, 132, 136, 144, 148, 156, 160, 168, 172, 180, 184, 192, 196, 204, 208, 216, 220, 228, 232, 240, 244, 252, and 256.
r.
Latent TB risk factor questionnaire will be obtained at Screening and annually thereafter through study participation.  Refer to Section 5.3.1.1 for specific requirements for TB 
testing and TB Prophylaxis.
s.
TB testing will be performed at Screening and annually thereafter through study participation.  In the case a subject prematurely discontinues from the study drug TB testing 
should not be performed if it has been less than 48 weeks since the last test was obtained.  Refer to Section 5.3.1.1 for specific requirements for TB testing and TB 
Prophylaxis.
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.
Starting from Baseline (Day 1) the hs-CRP results will not be reported to the Sponsor, Investigator, study site personnel, or the subject.  For safety evaluations of signs and 
symptoms of infection and management of adverse events, the investigator may locally test procalcitonin.  Results of tests such as hs-CRP, and procalcitonin 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 hs-
CRP, CRP, or serial procalcitonin tests reported to the investigator until a subject is known to receive upadacitinib or until treatment allocation is unblinded will be recorded 
as protocol deviations.
v.
If required by country regulatory authorities, subjects who initiate or increase dose of MTX during the study should undergo ALT, AST, creatinine and CBC testing every 
4 weeks for a 12-week period.
w.
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.
x.
FSH should be tested at Screening 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 in Section 5.2.4).
y.
For China and Japan, or where mandated by local requirements:  for subjects with HBs Ab+ and/or HBc Ab+ and negative HBV DNA at Screening, the HBV-DNA PCR test 
should be performed again every 12 weeks.  Retesting every 12 weeks is not necessary for subjects that have a history of HBV vaccine and HBs Ab+ and HBc Ab–. If 
necessary, HBV DNA PCR may be tested at unscheduled visits.
z.
At Week 2 and Week 4 visits, PK samples should be collected prior to oral study drug dosing and the subjects should take the study drug dose at the clinic after collecting the 
PK blood sample.  However, if the subject normally takes the study 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.
aa.
PK samples should be collected at any time during the visit.  Subject should follow the regular dosing schedule.  Collect PK samples at Week 8, Week 12, Week 16, Week 20, 
Week 24, Week 32, Week 56, and at PD visit only for subjects who prematurely discontinue from study drug treatment prior to Week 56.  No PK sample collection is 
required at Week 260.
bb. Prior to other study visit procedures.  


ABT-494
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EudraCT 2016-004130-24
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cc.
PASI, BSA-Ps, sIGA, and SAPS are to be done at Week 80, Week 104, and Week 128 (every 24 weeks after the Week 56 visit).
dd. Collect serious adverse events and protocol-related non-serious AEs that occur after a subject signs the informed consent; prior to the first dose of study drug.
ee.
At Week 24, all placebo subjects will be switched to blinded ABT-494 regardless of clinical response.
ff.
At Week 16, subjects who do not achieve ≥ 20% improvement in either or both TJC and SJC compared to baseline at both Weeks 12 and 16 will be offered rescue therapy 
(see Section 5.2.3.4).
gg. Starting at Week 36, subjects who failed to show at least 20% improvement in either or both TJC and SJC compared to baseline at 2 consecutive visits will be discontinued 
from study drug treatment.
hh. Only blood chemistry and hematology.
jj.
After Week 152, administer these questionnaires every 6 months: EQ-5D-5L, WPAI.
kk. After the Week 140 visit, Dosing Diaries will no longer be dispensed.
Note:
Visit window is ± 3 days for the first 36 weeks and ± 7 days for the remainder of the study.  Any of the procedures may be performed at an unscheduled visit at 
the discretion of the Investigator.
Appendix D.  Study Activities – Optional Samples for Exploratory Research or Validation Studies
Header row previously read:
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68 to 
Wk 140 
(Every 
12Wks)
Wk 152 
or PD
D – 35 
to D – 1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to 
D 981
D
1065


ABT-494
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217
Has been changed to read:
Activity
SCR
BL
Wk 
2
Wk 
4
Wk 
8
Wk 
12
Wk 
16
Wk 
20
Wk 
24
Wk 
28
Wk 
32
Wk 
36
Wk 
44
Wk 
56
Wk 68 to 
Wk 248 
(Every 
12 Wks)
Wk 260 
or PD
D – 35 
to D – 1
D
1
D 
15
D 
29
D 
57
D 
85
D 
113
D 
141
D 
169
D 
197
D 
225
D 
253
D 
309
D 
393
D 477 to
D 1737
D
1821

SAP_001.pdf: 
Upadacitinib
M15-572 – Statistical Analysis Plan
Version 3.0 – 12 Dec 2019
1
1.0
Title Page
Statistical Analysis Plan
Study M15-572
A Phase 3, Randomized, Double-Blind, Study 
Comparing Upadacitinib (ABT-494) to Placebo and to 
Adalimumab in Subjects with Active Psoriatic 
Arthritis Who Have a History of Inadequate 
Response to at Least One Non-Biologic Disease 
Modifying Anti-Rheumatic Drug (DMARD) – SELECT –
PsA 1
Date:  12 Dec 2019
Version 3.0
NCT03104400


Upadacitinib
M15-572 – Statistical Analysis Plan
Version 3.0 – 12 Dec 2019
2
2.0
Table of Contents
1.0
Title Page..................................................................................1
2.0
Table of Contents.....................................................................2
3.0
Introduction .............................................................................7
4.0
Study Objectives, Design and Procedures.............................7
4.1
Study Objectives ........................................................................................7
4.2
Overall Study Design and Plan..................................................................8
4.3
Sample Size..............................................................................................10
4.4
Week 24 Analysis and Data Base Lock...................................................11
4.5
Data Monitoring Committee (DMC) Activities.......................................11
5.0
Analysis Populations and Analysis Windows .....................12
5.1
Analysis Populations................................................................................12
5.2
Analysis Windows ...................................................................................12
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............17
6.1
Demographics and Baseline Characteristics............................................17
6.2
Medical History .......................................................................................20
6.3
Prior Treatment and Concomitant Medications.......................................21
6.4
Protocol Deviations..................................................................................21
7.0
Patient Disposition.................................................................22
8.0
Study Drug Exposure and Compliance...............................23
8.1
Study Drug Exposure...............................................................................23
8.2
Compliance ..............................................................................................25
9.0
Efficacy Analysis....................................................................25
9.1
General Considerations............................................................................25
9.1.1
Efficacy Analysis at Different Phases of the Study.................................25
9.1.2
Handling of Missing Data and Intercurrent Events .................................26
9.2
Efficacy Analysis through Week 24 ........................................................27
9.2.1
Primary Efficacy Analysis of the Primary Efficacy Endpoint.................27
9.2.2
Supplementary Analysis of the Primary Efficacy Endpoint ....................28
9.2.3
Key Secondary Efficacy Analyses...........................................................29
9.2.4
Efficacy Analyses for Additional Endpoints ...........................................35


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9.2.5
Handling of Multiplicity ..........................................................................39
9.2.6
Efficacy Subgroup Analysis ....................................................................42
9.3
Long-Term Efficacy Analysis..................................................................43
9.4
Efficacy Variables Definitions and Conventions.....................................45
9.4.1
ACR Criteria ............................................................................................45
9.4.2
Joint Evaluation .......................................................................................48
9.4.3
Patient's Global Assessment of Disease Activity Numeric Rating 
Scale (NRS) .............................................................................................49
9.4.4
Physician's Global Assessment of Disease Activity Numeric 
Rating Scale (NRS)..................................................................................50
9.4.5
Patient's Assessment of Pain Numeric Rating Sale (NRS)......................50
9.4.6
Disease Activity Score (DAS28) .............................................................50
9.4.7
Disease Activity in Psoriatic Arthritis (DAPSA) Score...........................51
9.4.8
PsA Disease Activity Score (PASDAS) ..................................................52
9.4.9
Disability Index of Health Assessment Questionnaire (HAQ DI)...........53
9.4.10
Static Investigator Global Assessment of Psoriasis (sIGA).....................53
9.4.11
Psoriasis Area Severity Index (PASI)......................................................54
9.4.12
Minimum Disease Activity for PsA.........................................................55
9.4.13
Self-Assessment of Psoriasis Symptoms (SAPS)....................................56
9.4.14
Leeds Dactylitis Index (LDI) and Dactylitis Count.................................56
9.4.15
Leeds and SPARCC Enthesitis Indices and Total Enthesitis Count........57
9.4.16
Body Surface Area (BSA) – Psoriasis .....................................................58
9.4.17
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
and Morning Stiffness Score....................................................................59
9.4.18
Modified Psoriatic Arthritis Response Criteria (PsARC)........................59
9.4.19
Ankylosing Spondylitis Disease Activity Score (ASDAS) .....................60
9.4.20
FACIT-Fatigue Questionnaire (FACIT-F)...............................................61
9.4.21
EuroQoL-5D (EQ-5D-5L) .......................................................................61
9.4.22
Form SF-36v2 ..........................................................................................62
9.4.23
Work Productivity and Activity Impairment Questionnaire 
Psoriatic Arthritis (WPAI) .......................................................................62
9.4.24
Health Resource Utilization (HRU) Questionnaire .................................64
9.4.25
Modified PsA Sharp/van der Heijde Score (SHS)...................................65


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10.0
Safety Analysis.......................................................................70
10.1
General Considerations............................................................................70
10.2
Analysis of Adverse Events.....................................................................72
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined Treatment 
Switching .................................................................................................72
10.2.1.1
Adverse Events Overview........................................................................72
10.2.1.2
Adverse Events by System Organ Class and Preferred Term..................73
10.2.1.3
TEAEs by Maximum Severity.................................................................73
10.2.1.4
TEAEs by Relationship............................................................................74
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term.........................................................................................................74
10.2.1.6
Adverse Events of Special Interest ..........................................................74
10.2.2
Analysis of Long-Term Adverse Event Rates .........................................77
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................78
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................78
10.2.2.3
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................79
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................79
10.3
Analysis of Laboratory Data....................................................................79
10.3.1
Variables and Units..................................................................................79
10.3.2
Analysis of Laboratory Data by Week 24................................................81
10.3.2.1
Assessment of Clinical Laboratory Variables..........................................81
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................82
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory Values .........83
10.3.2.4
Assessment of Liver Elevations...............................................................83
10.3.3
Analysis of Long-Term Laboratory Data.................................................84
10.3.3.1
Assessment of Clinical Laboratory Variables..........................................84
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory Values .........84
10.3.3.3
Assessment of Liver Elevations...............................................................85


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10.4
Analysis of Vital Signs ............................................................................86
10.4.1
Variables and Criteria Defining Abnormality..........................................86
10.4.2
Analysis of Vital Signs by Week 24 ........................................................86
10.4.3
Long-Term Analysis of Vital Signs.........................................................86
11.0
References...............................................................................87
List of Tables
Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components, TJC28, SJC28, ESR and Derived Endpointsa) and 
Safety Analysis for Period 1 (for Lab Values [Clinical Chemistry, 
Hematology, Urinalysis] and Vital Signs/Weight) ..................................14
Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for SF-36, 
EQ-5D-5L, FACIT-F, WPAI, BASDAI, HRU and Derived 
Endpointsa)...............................................................................................15
Table 3.
Analysis Windows for Safety Analysis for Period 1 (for Total 
Cholesterol, HDL-C, LDL-C, Triglycerides) ..........................................15
Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for 
BSA-Psoriasis, PASI, sIGA, LDI, LEI, SPARCC Enthesitis Index 
and Derived Endpointsa) ..........................................................................16
Table 5.
Analysis Windows for Efficacy Analysis for Period 1 (for SAPS) .........16
Table 6.
Analysis Windows for Efficacy Analysis for Period 1 (for X-Rays 
of Hands and Feet)...................................................................................17
Table 7.
Subgroups for Efficacy Analysis .............................................................43
Table 8.
Anatomical Joints Assessed for Calculation of Tender and 
Swollen Joint Counts (TJC68 and SJC66)...............................................49
Table 9.
Anatomical Joints for DAS28 (CRP) Calculation ...................................51
Table 10.
Range of Total SHS Score, Erosion Score and Joint Space 
Narrowing ................................................................................................66
Table 11.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................75
Table 12.
List of Laboratory Variables....................................................................80
Table 13.
Criteria for Potentially Clinically Significant Vital Sign Findings..........86


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List of Figures
Figure 1.
Study Design............................................................................................10
Figure 2.
Graphical Multiple Testing Procedure.....................................................41
List of Appendices
Appendix A.
SAS Procedure for Mantel-Haenszel Test ...............................................89
Appendix B.
Tipping Point Analysis for ACR20 at Week 12 ......................................90
Appendix C.
Three Arm Approach to Non-Inferiority (NI) Testing ............................91
Appendix D.
Details of Supplementary Analyses for Ranked Secondary 
Continuous Endpoints..............................................................................92
Appendix E.
Exposure Adjusted AE Rate Difference and Normal 
Approximation Based 95% Confidence Interval6....................................97


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3.0
Introduction
This statistical analysis plan (SAP) describes the statistical analyses to be completed by 
the Data and Statistical Science Department for upadacitinib Study M15-572.  It provides 
details to further elaborate statistical methods as outlined in the protocol.  
Pharmacokinetic and biomarker analyses will be performed separately and the 
corresponding analysis plan is documented separately are not in the scope of this SAP.
Unless noted otherwise, all analyses will be performed using SAS version 9.2 or later 
(SAS Institute Inc., Cary, NC 27513) under the UNIX operating system.
4.0
Study Objectives, Design and Procedures
4.1
Study Objectives
Period 1
Primary Objective
1.
To compare the efficacy of upadacitinib 15 mg once daily (QD) and 30 mg QD 
versus placebo and versus adalimumab (ADA) 40 mg every other week (eow) for 
the treatment of signs and symptoms in subjects with moderately to severely active 
Psoriatic Arthritis (PsA) who have an inadequate response or intolerance to 1 or 
more non-biologic DMARD (DMARD-IR).
Secondary Objective
2.
To compare the efficacy of upadacitinib 15 mg QD and 30 mg QD versus placebo 
for the prevention of structural progression in subjects with moderately to severely
active PsA who have an inadequate response or intolerance to 1 or more non-
biologic DMARD (DMARD-IR).
3.
To compare the safety and tolerability of upadacitinib 15 mg QD and 30 mg QD 
versus placebo and versus adalimumab in subjects with moderately to severely


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active PsA who have an inadequate response or intolerance to 1 or more non-
biologic DMARD (DMARD-IR).
Period 2
To evaluate the long-term safety, tolerability and efficacy of upadacitinib 15 mg QD and 
30 mg QD in subjects with PsA who have completed Period 1.
4.2
Overall Study Design and Plan
This is a Phase 3 multicenter study that includes two periods.  Period 1 is 56 weeks in 
duration and includes a 24-week randomized, double-blind, parallel-group, placebo-
controlled and active-comparator controlled period followed by an additional 32 weeks of 
blinded active comparator-controlled treatment (Weeks 24 – 56).  Period 1 is designed to 
compare the safety, tolerability, and efficacy of upadacitinib 15 mg QD and 30 mg QD 
versus placebo and versus adalimumab 40 mg every other week (eow) in subjects with 
moderately to severely active PsA who have an inadequate response to non-biologic 
DMARDs (DMARD-IR).  Period 1 is also designed to compare the efficacy of 
upadacitinib 15 mg QD and 30 mg QD versus placebo for the prevention of structural 
progression.  Period 2 is an open-label (blinded until the last subject completes the last 
visit of Period 1), long-term extension of up to a total treatment duration of approximately 
3 years to evaluate the safety, tolerability and efficacy of upadacitinib 15 mg QD and 
30 mg QD in subjects with PsA who have completed Period 1.
The study is designed to enroll approximately 1640 subjects at approximately 350 study 
centers worldwide to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  
The study duration will include a 35-day screening period; a 56-week blinded period 
which includes 24 weeks of double-blind, placebo-controlled and active comparator-
controlled treatment followed by 32 weeks of active comparator-controlled treatment 
(Period 1); a long-term extension period of up to a total treatment duration of 


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approximately 3 years ([blinded to sites and investigators until the last subject completes 
the last visit of Period 1] Period 2); and a 30-day follow-up call or visit; and a 70-day 
follow-up call.  Subjects who meet eligibility criteria will be randomized in a 
2:2:2:1:1 ratio using an Interactive Response Technology (IRT) to receive double-blind 
study drug in one of the following treatment groups:
●
Group 1:  Upadacitinib 15 mg QD, N = 410 (Day 1 to Week 24) → 
Upadacitinib 15 mg QD (Week 24 and thereafter)
●
Group 2:  Upadacitinib 30 mg QD, N = 410 (Day 1 to Week 24) → 
Upadacitinib 30 mg QD (Week 24 and thereafter)
●
Group 3:  Adalimumab (40 mg eow) (N = 410)
●
Group 4:  Placebo, N = 205 (Day 1 to Week 24) → Upadacitinib 15 mg QD 
(Week 24 and thereafter)
●
Group 5:  Placebo, N = 205 (Day 1 to Week 24) → Upadacitinib 30 mg QD 
(Week 24 and thereafter)
Randomization will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or 
< 3% BSA), current use of at least 1 DMARD (Yes or No), presence of dactylitis, and 
presence of enthesitis, except for subjects from China and Japan, for which randomization 
will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA) 
only.  See Section 5.5.3 of protocol for details.
A schematic of the overall study design is shown in Figure 1 below.


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Figure 1.
Study Design
a.
All subjects will receive x-rays of hands and feet at Screening, Wk 24, Wk 56, Wk 104, and Wk 152/PD.
b.
At Week 16 rescue therapy will be offered to subjects classified as non-responders (defined as not achieving at 
least 20% improvement in either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 
and Week 16) as described in Protocol Section 5.2.3.4.
c.
At Week 24, all placebo subjects will switch to Upadacitinib 15 mg QD or 30 mg QD (1:1 ratio) regardless of 
response.
4.3
Sample Size
The planned total sample size of approximately 1640 for this study (with 
2:2:2:1:1 randomization ratio for upadacitinib 15 mg, upadacitinib 30 mg, adalimumab 
40 mg eow and placebo subjects) provides at least 90% power for a 20% difference in 
ACR20 response rate (assuming a placebo ACR20 response rate of 30%).  It will also 
provide at least 90% power for the majority of the key secondary endpoints.  With the
given sample size, there is approximately 90% power to detect a standardized effect size 
of 0.26 in change from baseline in SHS for each upadacitinib dose group versus the 
combined placebo group at Week 24.  This sample size will also provide at least 85%
power for evaluating non-inferiority for each upadacitinib dose group vs. adalimumab in 


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ACR20 response rate at Week 12 assuming 50% ACR20 response rates for adalimumab 
and upadacitinib and 30% ACR20 response rates for placebo.  All power and sample size 
calculations are performed at a two-sided significance level of 0.025 and accounting for a 
10% dropout rate.
4.4
Week 24 Analysis and Data Base Lock
After the last subject completes the Week 24 study visit, an unblinded analysis will be 
conducted for the purpose of regulatory submission.  To maintain integrity of the trial 
during the blinded 56-week period (Period 1), study sites and subjects will remain blinded 
until all subjects have reached Week 56.
4.5
Data Monitoring Committee (DMC) Activities
An independent external Data Monitoring Committee (DMC) is used to review unblinded 
safety data at regular intervals during the conduct of the study.  The DMC will provide 
recommendation to an AbbVie Point of Contact on whether to continue, modify, or 
terminate studies after each review.  When needed, high-level unblinded efficacy data 
may also be requested by the DMC and be reviewed so that the DMC can assess 
benefit:risk of any emerging safety differences.
An unblinded interim efficacy analysis will also be conducted by an independent external 
DMC after at least 600 subjects have completed the Week 12 Visit or have prematurely 
discontinued from the study.  The interim analysis is to assess if the study met the pre-
defined No-Go boundary for the primary endpoint ACR20.  A futility recommendation 
will be made only when both the upadacitinib 15 mg and 30 mg QD doses meet the 
futility criteria.  To address potential practical regulatory and statistical concerns, a small 
alpha of 0.0001 will be spent for the interim analysis and the final analysis will be 
performed at level 0.0499. The overall Type I error rate is controlled at 0.05. However, 
in no circumstance should a decision be made to stop the trial early for superiority in 
efficacy of ABT-494 versus either adalimumab or placebo. Details of the interim efficacy 
analysis are described in the DMC SAP and details of the decision making rules are
specified in the DMC charter.


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5.0
Analysis Populations and Analysis Windows
5.1
Analysis Populations
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.
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 deviations that are determined to have a 
potential impact on the primary efficacy endpoint up to Week 12 in Period 1 of the study.  
Additional analysis of the primary efficacy endpoint will be conducted on the Per Protocol 
analysis set, in order to evaluate the impact of major protocol deviations.
Protocol deviations with potential to affect the primary efficacy endpoint (key ICH 
deviations and other clinically significant non-ICH deviations) will be identified prior to 
the Week 24 database lock.
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 will be analyzed "as treated," regardless of the 
treatment randomized.  "As treated" is determined by the treatment the subject received 
during the majority of the subject's drug exposure time in the analysis period.
5.2
Analysis Windows
Definition of Study Days (Days Relative to the First Dose of Study Drug)
Study Days are calculated for each collection date relative to the date of the first dose of 
study drug.  It is defined as the number of days between the date of the first dose of study 
drug and the collection date.  Study days are negative values when the collection date of 


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interest is prior to the first study drug dose date.  Study days are positive values when the 
collection date of interest is on or after the first study drug dose date.  The day of the 
first dose of study drug is defined as Study Day 1, while the day prior to the first study 
drug dose is defined as Study Day –1 (there is no Study Day 0).  Study days are used to 
map actual study visits to the protocol-specified study visits.
Definition of Analysis Windows
The following rules will be applied to assign actual subject visits to protocol-specified 
visits.  For each protocol-specified study visit, a target study day will be identified to 
represent the corresponding visit along with a window around the target day.  Windows 
will be selected in a non-overlapping fashion so that a collection date does not fall into 
multiple visit windows.  If a subject has two or more actual visits in one visit window, the 
visit closest to the target day will be used for analysis.  If two visits are equidistant from 
the target day, then the later visit will be used for analysis. 
The visit window and the target study day for each protocol-specified visit in Period 1 are 
displayed in Table 1, Table 2, Table 3, Table 4, Table 5 and Table 6 (depending on the 
different visit schedules of different endpoints).  Visit windows for protocol-specified 
visits in Period 2 are defined similarly.


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Table 1.
Analysis Windows for Efficacy Analysis for Period 1 (for ACR 
Components, TJC28, SJC28, ESR and Derived Endpointsa) and 
Safety Analysis for Period 1 (for Lab Values [Clinical Chemistry, 
Hematology, Urinalysis] and Vital Signs/Weight)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1b
1
2
2
15
22
4
23
29
43
8
44
57
71
12
72
85
99
16
100
113
127
20
128
141
155
24
156
169
Min (183, first dose date from 
Week 24 dispensed kit)
28
Min (183, first dose date from 
Week 24 dispensed kit) + 1
197
211
32
212
225
239
36
240
253
281
44
282
309
351
56
352
393
435
a.
ACR20/50/70 response rates, DAS28 (CRP), DAS28 (ESR), PsARC, DAPSA, proportion of subjects achieving a 
clinically meaningful improvement in HAQ-DI (≥ 0.35).
b.
Day of first dose of study drug.


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Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for SF-36, 
EQ-5D-5L, FACIT-F, WPAI, BASDAI, HRU and Derived 
Endpointsa)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1b
1
12
2
85
127
24
128
169
Min (211, first dose date from 
Week 24 dispensed kit)
36
Min (211, first dose date from 
Week 24 dispensed kit) + 1
253
323
56
324
393
435
a.
PASDAS, BASDAI 50 response rates, Change from baseline in Morning stiffness (mean of BASDAI Questions 5 
and 6), ASDAS, proportion of subjects with ASDAS Inactive Disease, proportion of subjects with ASDAS Major 
Improvement, proportion of subjects with ASDAS Clinically Important Improvement.
b.
Day of first dose of study drug.
Table 3.
Analysis Windows for Safety Analysis for Period 1 (for Total 
Cholesterol, HDL-C, LDL-C, Triglycerides)
Protocol Specified 
Visit Week
Lower 
Bound
Target Day
Upper Bound
Baseline
–99
1a
1
4
2
29
57
12
58
85
127
24
128
169
Min (211, first dose date from Week 24 dispensed kit)
a.
Day of first dose of study drug.


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Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for
BSA-Psoriasis, PASI, sIGA, LDI, LEI, SPARCC Enthesitis Index 
and Derived Endpointsa)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1b
1
12
2
85
99
16
100
113
141
24
142
169
Min (211, first dose date from 
Week 24 dispensed kit)
36
Min (211, first dose date from 
Week 24 dispensed kit) + 1
253
323
56
324
393
435
a.
MDA, dactylitis count/total enthesitis count, proportion of subjects with resolution of dactylitis/enthesitis (out of 
all sites, or the sites included in SPARCC or LEI), PAISI75/90/100, proportion of subjects achieving a static 
Investigator Global Assessment of psoriasis (sIGA) score of 0 or 1 and at least a 2-point improvement from 
baseline.  
b.
Day of first dose of study drug.
Table 5.
Analysis Windows for Efficacy Analysis for Period 1 (for SAPS)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
16
2
113
141
24
142
169
Min (211, first dose date from 
Week 24 dispensed kit)
36
Min (211, first dose date from 
Week 24 dispensed kit) + 1
253
323
56
324
393
435
a.
Day of first dose of study drug.


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Table 6.
Analysis Windows for Efficacy Analysis for Period 1 (for X-Rays of 
Hands and Feet)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1a
1
16b
2
113
141
24
142
169
197 
36c
198
253
323
56
324
393
435
a.
Day of first dose of study drug.
b. 
Week 16 x-rays will be performed for all subjects who met the protocol specified rescue criteria at Week 16 
(i.e., not achieving at least 20% improvement in either or both TJC68 and SJC66 at both Week 12 and Week 16).
c.
Not protocol specified visit for x-ray assessment, but will be used to capture unscheduled or PD x-rays.
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications
6.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics information will be collected at the Baseline 
visit of the study and will be summarized for the FAS.  The number of observations, 
mean, standard deviation, median, minimum and maximum will be summarized for 
continuous variables.  Categorical or discrete variables will be summarized via 
frequencies and percentages.  Summary statistics will be computed for each treatment 
group and overall.
Main Demographic and Baseline Characteristics
●
Sex (male, female)
●
Age (years)
●
Age Categories (< 65, ≥ 65 – 75, ≥ 75 years)
●
Race (White, Black or African American, American Indian or Alaska Native, 
Native Hawaiian or Other Pacific Islander, Asian, Other)


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●
Geographic Region (North America, Western Europe and Oceania, Eastern 
Europe, Latin-America, Asia, and Other)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
●
Weight (kg)
●
Height (cm)
●
Body Mass Index (BMI) (kg/m2)
●
Body Mass Index (BMI) Category (kg/m2) (BMI < 25, BMI ≥ 25)
PsA Medical History, Prior and Baseline Treatments
●
Duration of PsA symptoms in years
●
Duration of PsA diagnosis in years
●
Rheumatoid Factor (RF) status:  Positive or Negative
●
Anti-CCP status:  Positive or Negative
●
Number of prior non-biologic DMARDs (0, 1, 2, ≥ 3)
●
Current use of at least 1 non-biologic DMARD at baseline (Yes or No)
●
Concomitant non-biologic DMARD at baseline (MTX alone, MTX and other 
non-biologic DMARD, non-biologic DMARD other than MTX)
●
Current NSAID use at baseline (Yes or No)
●
Current Corticosteroid use at baseline (Yes or No)
Baseline Disease Characteristics
●
Tender joint count (TJC68) defined as the number of tender joints out of 
68 assessed joints
●
Swollen joint count (SJC66) defined as the number of swollen joints out of 
66 assessed joints
●
Physician's global assessment of Disease Activity Numeric Rating Scale 
(0 - 10 NRS)
●
Patient's assessment of pain (0 - 10 NRS)
●
Patient's global assessment of disease activity (0 - 10 NRS)


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●
Health Assessment Questionnaire Disability Index (HAQ-DI)
●
High sensitivity C-reactive protein (hsCRP) 
●
Categories for hsCRP:  equal or below vs. above ULN (2.87 mg/L) 
●
Body Surface Area (BSA) with Psoriasis (as categorical with < 3%, ≥ 3%) 
●
Body Surface Area (BSA) with Psoriasis (as continuous for subjects with 
BSA-Ps > 0%)
●
Static Investigator Global Assessment of Psoriasis (sIGA) (as a categorical 
variable) 
●
Psoriasis Area and Severity Index (PASI) score (for subjects with ≥ 3% Body 
Surface Area (BSA) psoriasis)
●
Erythrocyte sedimentation rate (ESR)
●
Psoriatic arthritis disease activity score (PASDAS)
●
Disease Activity In Psoriatic Arthritis (DAPSA) score
●
Presence of Dactylitis (LDI > 0)
●
Leeds Dactylitis Index (LDI) (out of subjects with presence of dactylitis
(LDI > 0))
●
Total dactylitis count (out of subjects with presence of dactylitis (LDI > 0))
●
Presence of enthesitis (total enthesitis count > 0)
●
Total enthesitis count (out of subjects with presence of enthesitis (total 
enthesitis count > 0))
●
Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index 
(out of subjects with SPARCC Enthesitis Index > 0)
●
Leeds Enthesitis Index (LEI) (out of subjects with LEI > 0)
●
DAS28 [CRP]
●
DAS28 [ESR]
●
Presence of Psoriatic Spondylitis
●
Ankylosing Spondylitis Disease Activity Score (ASDAS) (out of subjects with 
presence of psoriatic spondylitis)
●
Bath AS Disease Activity Index (BASDAI) (out of subjects with presence of 
psoriatic spondylitis)


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●
Morning stiffness (mean of BASDAI Questions 5 and 6) 
●
Morning stiffness severity 0 - 10 (BASDAI Question 5)
●
Morning stiffness duration 0 - 10 (BASDAI Question 6)
●
Radiographic endpoints:
○
Presence of ≥ 1 erosion
○
Total modified PsA Sharp/van der Heijde Score (SHS) score
○
Erosion score
○
Joint space narrowing score
Patient Report Outcomes at Baseline
●
Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue 
●
36-Item Short Form Health Survey (SF-36) Version 2:  physical component 
summary, mental component summary, and the 8 sub-domain scores
●
EuroQol-5D-5L (EQ-5D-5L) index and VAS score 
●
Work Productivity and Activity Impairment (WPAI) 
●
Self-Assessment of Psoriasis Symptoms (SAPS) 
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [user, ex-user, non-user, unknown]
●
Alcohol Use [drinker, ex-drinker, non-drinker, unknown]
6.2
Medical History
Medical history data will be summarized and presented for FAS population using System 
Organ Class (SOC) and Preferred Term (PT) as in the Medical Dictionary for Regulatory 
Activities (MedDRA) dictionary.  The number and percentage of subjects with a 
particular PT will be summarized for each randomized treatment group as well as overall.  
Subjects reporting more than one PT within a SOC will be counted only once for that 
SOC.  No statistical comparison will be performed for medical history reporting.


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6.3
Prior Treatment and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for FAS.  Prior medications are those medications taken prior to 
the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  
Medications taken on the day of the first dose of study drug are not counted as prior 
medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug for 
the subjects on upadacitinib and placebo, and within 14 days of the last dose of study drug
for the subjects on adalimumab, respectively.  This includes medications with a start date 
between first study drug administration and last study drug administration + 1 or 14 day, 
as well as, medications with a start date prior to first dose of study drug and which are 
ongoing after first dose of study drug.  Medications taken on the day of the first dose of 
study drug are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
6.4
Protocol Deviations
Protocol deviations based on ICH deviation criteria are categorized as follows:
1.
Those who entered the study even though they did not satisfy the entry criteria
2.
Those who developed withdrawal criteria during the study and were not withdrawn
3.
Those who received the wrong treatment or incorrect dose, and
4.
Those who received an excluded or prohibited concomitant medication.
The protocol deviations listed above will be summarized and listed by treatment group.


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7.0
Patient Disposition
The following will be summarized by randomized treatment group as well as overall:
●
number of subjects randomized,
●
number of subjects included in key analysis populations (Full Analysis Set and 
Per Protocol Analysis Set for efficacy analysis, Safety Analysis Set for safety 
analysis),
●
number of subjects who completed Period 1 study participation,
●
number of subjects who entered Period 2,
●
number of subjects who completed overall study (Period 1 and Period 2) 
participation (if applicable).
Premature discontinuation details will be further summarized separately for Period 1 and 
Period 2 as follows.
Period 1
The number and percentage of subjects completed Period 1 and prematurely discontinued 
in Period 1 will be summarized by randomized treatment group, separately by study drug 
and study participation completion/discontinuation, with the reason for discontinuation 
collected from CRF by the following categories:
●
Adverse event (AE)
●
Withdrew consent
●
Lost to follow-up
●
Lack of efficacy
●
Other.
In addition, the number and percentage of subjects who entered Period 2 will also be 
summarized by randomized treatment group.


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For Week 24 reporting, this summary will also be presented for study drug 
completion/discontinuation by Week 24.
Period 2
Period 2 patient dispositions and reason for discontinuation will be summarized with the 
same categories as given above for Period 1 for overall total and by treatment in Period 2 
defined as follows:
1.
Upadacitinib 15 mg QD
2.
Upadacitinib 30 mg QD
3.
Adalimumab 40 mg EOW
Among the subjects who entered Period 2 participation (regardless of whether subject 
entered Period 2 on study drug), the number and percentage of subjects who completed 
and prematurely discontinued study participation in Period 2 will be summarized.  
Among the subjects who entered Period 2 on study drug, the number and percentage of 
subjects who completed and prematurely discontinued study drug in Period 2 will be 
summarized.
8.0
Study Drug Exposure and Compliance
8.1
Study Drug Exposure
For short term up to Week 24, the duration of exposure to study drug will be summarized 
for the safety analysis set by the randomized treatment groups.
For long term, the duration of exposure to study drug will be summarized for the safety 
analysis set by the following groups.
1.
Upadacitinib 15 mg QD


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This includes upadacitinib 15 mg QD exposure from subjects starting on 
upadacitinib 15 mg QD and subjects switching from placebo to upadacitinib 15 mg 
QD.
2.
Upadacitinib 30 mg QD
This includes upadacitinib 30 mg QD exposure from subjects starting on 
upadacitinib 30 mg QD and subjects switching from placebo to upadacitinib 30 mg 
QD.
3.
Adalimumab 40 mg EOW
Exposure to upadacitinib and placebo is defined as last dose date minus first dose date 
plus 1 day.  Exposure to adalimumab is defined as last dose date minus first dose date plus 
14 days.
The duration of exposure to study drug will be summarized for each group as specified 
above, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values.  In addition, the number and percentage of subjects exposed to study 
drug will be summarized for the following cumulative duration intervals.
●
≥ 2 weeks
●
≥ 1 month
●
≥ 3 months
●
≥ 6 months
●
≥ 9 months
●
≥12 months
●
≥ 18 months
●
≥ 2 years
●
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8.2
Compliance
Study drug compliance will be summarized for each treatment group at Week 24.  The 
summary will be performed for UPA/PBO tablets and ADA/PBO injections separately.  
For tablets, 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 up to Week 24 divided by the number of days that the subject was 
in the Treatment Phase up to Week 24.  For injections, compliance is defined as the 
number of ADA injections administered during the subject's participation up to Week 24
divided by the number of injections planned during the subject's participation in the 
Treatment Phase up to Week 24.
9.0
Efficacy Analysis
9.1
General Considerations
There are two sets of planned efficacy analysis:  efficacy analysis through Week 24 and 
long-term efficacy analysis.  Unless otherwise noted, all efficacy analyses will be carried 
out using the FAS population.
9.1.1
Efficacy Analysis at Different Phases of the Study
Efficacy Analysis by Week 24
Standard efficacy analysis by randomized treatment groups (upadacitinib 15 mg QD, 
upadacitinib 30 mg QD, adalimumab 40 mg EOW and the combined placebo groups) will 
be performed on efficacy data up to Week 24.  No protocol-defined treatment switching 
will occur prior to the time point.  Formal statistical inference will be generated, and 
results from this set of analysis will be used as the key efficacy findings of this study.
Long-Term Efficacy Analysis
Long-term efficacy analysis will be performed on As Observed data (defined in 
Section 9.1.2) by randomized treatment group sequence as described below:


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1.
Placebo →Upadacitinib 15 mg QD
2.
Placebo →Upadacitinib 30 mg QD
3.
Upadacitinib 15 mg QD
4.
Upadacitinib 30 mg QD
5.
Adalimumab 40 mg EOW
Descriptive statistics and 95% confidence intervals will be provided for all treatment 
sequences.  In addition, comparisons between each upadacitinib dose and adalimumab 
(treatment sequences 3, 4, and 5) will be provided up to Week 56.
9.1.2
Handling of Missing Data and Intercurrent Events
Non-Responder Imputation (NRI) Approach
The NRI approach will handle data for binary endpoints as follows. 
●
Subjects who prematurely discontinue from study drug will be considered as 
non-responders for all subsequent visits after discontinuation.  
●
In addition, any subject with any missing value for the binary endpoints at a 
specific visit will be treated as non-responder for that visit. 
NRI data handling will be used for the primary estimand (refer to Section 9.2.1) for the 
binary endpoints.  
Mixed-Effects Model Repeated Measures (MMRM)
The repeated measure analysis will be conducted using mixed models including observed 
data at all visits.  For the MMRM analysis, data collected after premature discontinuation 
of study drug will be excluded.  The mixed model includes the categorical fixed effects of 
treatment, visit, treatment-by-visit interaction, the stratification factor current DMARD 
use (yes/no) and the continuous fixed covariates of baseline measurement.  An 
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based on the assumption of data being missing at random (MAR) and using the method of 
restrictive maximum likelihood (REML).  MMRM will be used for the primary estimand 
of the non-radiographic continuous endpoints (refer to Section 9.2.3).
Linear Extrapolation for Radiographic Data 
For radiographic data (i.e., SHS-based endpoints), linear extrapolation will be applied to 
subjects with missing data including those due to premature discontinuation of study drug 
or meeting the rescue criteria, where the missing x-ray at the time point of interest will be 
imputed assuming a linear relationship across visits. Linear extrapolation will be used to 
facilitate the primary estimand for radiographic endpoints (refer to Section 9.2.3).
As Observed (AO)
The AO data handling 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 AO 
analysis for that visit.  Regardless of premature discontinuation of study drug or use of 
rescue medication, all observed data will be used in the analysis.  The AO data handling 
will be used to facilitate the supplementary analysis for both binary and continuous 
endpoints including radiographic endpoints (refer to Section 9.2.2 and Section 9.2.3 where 
the corresponding supplementary estimands for the primary and ranked secondary 
endpoints are described respectively).
The intention-to-treat (ITT) principle for the analysis using AO data, AO (with 
imputation), where additional missing data will be imputed as non-responders, will be 
used for the supplementary analysis of the primary and key secondary binary endpoints.
9.2
Efficacy Analysis through Week 24
9.2.1
Primary Efficacy Analysis of the Primary Efficacy Endpoint
The primary efficacy endpoint is ACR20 response at Week 12. The primary estimand is 
the difference in the proportion of PsA patients who achieved ACR20 response at
Week 12 and did not discontinue study drug by Week 12, comparing those who are 


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randomized to each upadacitinib dose group and received study drug to those who are 
randomized to placebo and received study drug.  
Analysis of the primary endpoint will be conducted on the FAS based on randomized 
treatment groups (upadacitinib 15 mg QD, upadacitinib 30 mg QD versus the combined 
placebo groups).  Point estimate and 95% CI using normal approximation will be 
provided for the response rate for each randomized treatment group.  Comparisons of the 
primary endpoint will be made between each upadacitinib dose and the combined placebo 
group using the Cochran-Mantel-Haenszel test (CMH) (refer to Appendix A) adjusting for 
the main stratification factor of current DMARD use (yes/no).  Point estimate, 95% CI 
using normal approximation and p-value for the treatment comparison will be presented.  
Nominal p-values constructed using the CMH test will be provided. The multiplicity 
adjusted (as described in Section 9.2.5) testing results (significant or not significant) will 
also be provided.  NRI data handling will be used to facilitate the primary estimand. In 
addition, the number and percentage of non-responders by the intercurrent events, such as 
discontinuation of study drug prior to or at Week 12 or missing Week 12 ACR 
measurement will be summarized.
9.2.2
Supplementary Analysis of the Primary Efficacy Endpoint
For the primary efficacy endpoint, the same CMH analysis as detailed in Section 9.2.1
will be repeated using As Observed (AO) data handling without any imputation as 
supplementary analysis. This will be conducted on the FAS based on randomized 
treatment groups. The corresponding estimand for the supplementary analysis is the 
difference in the proportion of PsA patients who achieved ACR20 response at Week 12, 
regardless of whether the subject had discontinued study drug by Week 12, comparing 
each upadacitinib dose group vs placebo. The analysis will be conducted for those who 
are randomized, received study drug and have the efficacy measurement at Week 12 visit. 
In addition to the supplementary analysis based on AO data, to explore various missing 
data assumptions including missing not at random (MNAR), tipping point analysis will 
also be performed for the primary endpoint by multiple imputations using logistic 


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regression, allowing the imputed ACR response rate to systematically vary from 0% to 
100% in both upadacitinib and placebo, respectively.  Details of the tipping point analysis 
are outlined in Appendix B.  Supportive analysis will also be conducted on the Per 
Protocol Analysis Set using the CMH model and NRI data handling.
9.2.3
Key Secondary Efficacy Analyses
The following is a list of ranked key secondary endpoints (upadacitinib versus placebo if 
not otherwise specified):
1.
Change from baseline in HAQ-DI at Week 12;
2.
Static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 1 and at least a 
2-point improvement from baseline at Week 16 (for subjects with baseline 
sIGA ≥2);
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with 
≥3% BSA psoriasis at baseline);
4.
Change from baseline in modified PsA Sharp/van der Heijde Score (SHS) at 
Week 24;
5.
Proportion of subjects achieving MDA at Week 24;
6.
Proportion of subjects with resolution of enthesitis (LEI = 0) at Week 24 (for 
subjects with baseline presence of enthesitis (LEI > 0));
7.
ACR 20 response rate at Week 12 (non-inferiority of upadacitinib vs adalimumab);
8.
Change from baseline in SF-36 PCS at Week 12;
9.
Change from baseline in FACIT-Fatigue at Week 12;
10.
ACR 20 response rate at Week 12 (superiority of upadacitinib vs. adalimumab);
11.
Proportion of subjects with resolution of dactylitis (LDI = 0) at Week 24 (for 
subjects with baseline presence of dactylitis (LDI > 0));


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12.
Change from baseline in Patient's Assessment of Pain NRS at Week 12 (superiority 
of upadacitinib vs. adalimumab);
13.
Change from baseline in HAQ-DI at Week 12 (superiority of upadacitinib vs. 
adalimumab);
14.
Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS) at 
Week 16.
Additional key secondary efficacy endpoints are:
1.
ACR50/70 response at Week 12;
2.
ACR20 response at Week 2.
Binary Endpoints
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  For the ranked secondary endpoints at the time point of interest, the primary 
estimand is the same as that for the primary efficacy endpoint as defined in Section 9.2.1, 
except for the definition of the efficacy measurement.
For the key secondary endpoints applicable only for sub-population, the estimands will be 
constructed similarly but based on the sub-population, as defined in the below table.


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Endpoint
Sub-population
Static Investigator Global Assessment 
(sIGA) of Psoriasis of 0 or 1 and at least a 
2-point improvement from baseline at 
Week 16
Subjects with baseline sIGA ≥2 are 
included in the analysis
Psoriasis Area Severity Index (PASI) 75 
response at Week 16
Subjects with ≥3% BSA psoriasis at 
baseline are included in the analysis
Proportion of subjects with resolution of 
enthesitis (LEI = 0) at Week 24
Subjects with baseline LEI > 0 are 
included in the analysis
Proportion of subjects with resolution of 
dactylitis at Week 24
Subjects with baseline LDI > 0 are 
included in the analysis
For MDA at Week 24, resolution of enthesitis at Week 24 and resolution of dactylitis at 
Week 24, in addition to the NRI data handling as defined in Section 9.1.2, subjects who 
meet the rescue criteria (i.e., not achieving at least 20% improvement in either or both 
tender joint count (TJC) and swollen joint count (SJC) at both Week 12 and Week 16) 
will also be treated as non-responders. The corresponding primary estimand is the 
difference in the proportion of patients who achieved MDA/resolution of 
enthesitis/resolution of dactylitis at Week 24, and who did not discontinue study drug and 
did not initiate rescue therapy by Week 24. The comparison is for each upadacitinib dose 
group vs placebo for patients randomized and treated with at least one dose of study drug.  
NRI data handling will be used to analyze the primary estimand for binary endpoints. 
Supplementary analysis using AO data handling will also be conducted. The 
corresponding supplementary estimand is the same as defined in Section 9.2.2 except for 
the definition of the efficacy measurement.
Point estimate and 95% CI using normal approximation will be provided for the response 
rate for each randomized treatment group.  Treatment comparisons will be made between 


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each upadacitinib dose and the combined placebo group using the Cochran-Mantel-
Haenszel test (refer to Appendix A).  The CMH test adjusts for the main stratification
factor of current DMARD use (yes/no).  Point estimate, 95% CI using normal 
approximation and the p-value for the treatment difference will be presented.    
For ACR20 response at Week 12, analysis will be conducted to assess the non-inferiority 
of each upadacitinib dose versus adalimumab on the placebo-subtracted treatment 
difference using Koch's 3-arm test statistic as described in Appendix C.  The test aims to 
show that upadacitinib preserves at least 50% of the placebo-subtracted adalimumab 
effect.  If statistical significance is achieved for the non-inferiority assessment, superiority 
of upadacitinib versus adalimumab will be tested for ACR20 subsequently as described in 
Section 9.2.5.  
Non-Radiographic Continuous Endpoints
For non-radiographic continuous endpoints, the estimand is the difference in mean change 
from baseline at the protocol defined time point (e.g., HAQ-DI at Week 12) under the 
assumption that patients with missing data, including those due to premature 
discontinuation of study drug, can have their measurements at the protocol defined time 
point predicted by their observed data and the observed data for other patients for their 
respective assessments during follow-up. The comparison is for each upadacitinib dose 
group vs placebo for patients randomized and treated with at least one dose of study drug. 
To analyze the primary estimand for the continuous ranked secondary efficacy endpoints, 
statistical inference will be conducted using the MMRM model and the associated data 
handling as described in Section 9.1.2, with fixed effects of treatment, visit, treatment-by-
visit interaction, the stratification factor of current DMARD use (yes/no) and the 
continuous fixed covariate of baseline measurement.  The LS mean and 95% CI for each 
randomized treatment group and the LS mean treatment difference, the associated 95% CI 
and the p-value between each upadacitinib dose group and the combined placebo group 
will be provided.  For change from baseline in Patient's Assessment of Pain NRS and 


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change from baseline in HAQ-DI at Week 12, superiority of upadacitinib vs. adalimumab 
will also be tested using the same MMRM model. 
The supplementary analysis for ranked non-radiographic secondary continuous endpoints 
will be conducted using AO data handling and using the analysis of covariance 
(ANCOVA) model with treatment and the stratification factor of current DMARD use 
(yes/no) as the fixed factors and the corresponding baseline values as the covariates. The 
corresponding estimand is the difference in the mean change from baseline in the efficacy 
endpoints at the protocol defined time point regardless of treatment discontinuation or use 
of rescue medication, comparing each upadacitinib dose group vs placebo. The analysis 
will be conducted for those who are randomized, received study drug and have the 
efficacy measurement at the protocol defined time point.  
For the key continuous endpoint change from baseline in HAQ-DI at Week 12, tipping 
point analysis will also be conducted using multiple imputation (MI) as additional 
supplementary analysis to explore various missing data assumptions including missing not 
at random (MNAR). Details of the tipping point analysis for continuous endpoints are 
outlined in Appendix D.
Radiographic Endpoints
For change from baseline in SHS at Week 24, statistical inference will be conducted using 
ANCOVA model and the associated data handling as described in Section 9.1.2 with 
treatment and the stratification factor of current DMARD use (yes/no) as the fixed factors 
and the corresponding baseline values as the covariates.  The primary estimand for the x-
ray assessment is the difference in the mean change from baseline in SHS score at 
Week 24, under the assumption that patients with missing data, including those due to 
premature discontinuation of study drug or use of rescue medication, can have their 
measurements at Week 24 predicted using their SHS score from the baseline window and 
the Week 16 window. The comparison will be between each upadacitinib dose group vs 
placebo for patients randomized and treated with at least one dose of study drug.


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To incorporate the uncertainty of a single imputation, the Multiple Imputation (MI) 
analysis will be conducted as a sensitivity analysis.  The proposed MI model for the 
change from baseline in SHS score will be based on the linearity assumption for the 
subjects with missing data including those due to premature discontinuation of study drug 
or meeting the rescue criteria. More specifically, the regression method will be used 
where missing Week 24 observations will be imputed by regression upon all previous 
visits including baseline and Week 16, stratified by treatment group. The imputation 
model will also include baseline demographics and key baseline characteristics as 
appropriate. Analysis of covariance (ANCOVA) will be performed on each of the 
multiple imputed datasets. The results will be aggregated across the multiple imputed 
datasets using Rubin's method. The detailed SAS procedure are outlined in Appendix D.
The supplementary analysis will be performed using AO data handling with the same 
ANCOVA model. The corresponding estimand for the AO analysis is the difference in 
the mean change from baseline in SHS score at Week 24, regardless of premature 
discontinuation of study drug or use of rescue medication, comparing each upadacitinib 
dose group vs placebo. The analysis will be conducted for those who are randomized, 
received study drug and have the efficacy measurement at Week 24 visit.
The LS mean and 95% CI for each randomized treatment group and the LS mean 
treatment difference, the associated 95% CI and the p-value between each upadacitinib 
dose group and the combined placebo group will be provided.
In another sensitivity analysis, a random coefficient model will be applied, in which SHS 
measurements are used as the response variable, including measurements at Baseline and 
post-Baseline. The model is specified with a random intercept and a random slope on 
time, and includes treatment, current DMARD use (yes/no), and treatment-by-time 
interaction in the model. The "group" option in PROC MIXED is used to allow for 
heterogeneity among treatment groups in the covariance structure. The coefficient for 
treatment-by-time interaction is used to estimate the difference in rate of progression (per 
24 weeks) comparing upadacitinib and placebo. The rate of progression (per 24 weeks) 
for each group respectively is also estimated using the coefficients for time and treatment-


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by-time interaction.  In case the random coefficient model does not converge, a simplified 
model may be explored by removing the random intercept or fitting a fixed-effect linear 
effect model.
Additionally, in the event that data severely deviates from the normal distribution, non-
parametric analyses such as the ranked ANCOVA may be considered for treatment 
comparison.
9.2.4
Efficacy Analyses for Additional Endpoints
Additional efficacy analysis includes the following endpoints at the scheduled time points 
in Section 5.2 other than those specified for the primary and key secondary variables:
●
Proportion of subjects with no radiographic progression is defined as
○
change from baseline in SHS ≤ 0; 
○
change from baseline in SHS ≤ 0.5.
●
Change from baseline in joint space narrowing score and joint erosion score.
●
Change from baseline in individual components of ACR response
○
Change from baseline in Tender Joint Count (TJC) (0 – 68);
○
Change from baseline in Swollen Joint Count (SJC) (0 – 66);
○
Change from baseline in Physician Global Assessment (PGA) – Disease 
Activity (NRS);
○
Change from baseline in Patient's Global Assessment (PtGA) – Disease 
Activity (NRS);
○
Change from baseline in Patient's Assessment of Pain Numerical Rating 
Scale (NRS);
○
Change from baseline in Health Assessment Questionnaire – Disability 
Index (HAQ-DI);
○
Change from baseline in High-Sensitivity C Reactive Protein (hs-CRP);
●
ACR 20/50/70 response rates;
●
Proportion of subjects achieving MDA;


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●
Change from baseline in Leeds Dactylitis Index (LDI) (for subjects with 
baseline LDI > 0);
●
Change from baseline in dactylitis count (for subjects with baseline LDI > 0);
●
Proportion of subjects with resolution of dactylitis (for subjects with baseline 
LDI > 0);
●
Change from baseline in LEI (for subjects with baseline LEI > 0);
●
Proportion of subjects with resolution of enthesitis defined as LEI = 0 (for 
subjects with baseline LEI > 0);
●
Change from baseline in SPARCC Enthesitis Index (for subjects with baseline 
SPARCC Enthesitis Index > 0);
●
Proportion of subjects with resolution of enthesitis defined as SPARCC 
Enthesitis Index = 0 (for subjects with baseline SPARCC Enthesitis 
Index > 0);
●
Change from baseline in total enthesitis count (for subjects with baseline total 
enthesitis count > 0);
●
Proportion of subjects with resolution of enthesitis defined as total enthesitis 
count = 0 (for subjects with baseline total enthesitis count > 0);
●
PASI 75/90/100 response rates (for subjects with ≥ 3% Body Surface Area 
(BSA) psoriasis at baseline);
●
Proportion of subjects achieving a static Investigator Global Assessment of 
psoriasis (sIGA) score of 0 or 1 and at least a 2-point improvement from 
baseline (for subjects with baseline sIGA ≥ 2);
●
Change from baseline in BSA-Ps (for subjects with baseline BSA-Ps > 0);
●
Modified Psoriatic Arthritis Response Criteria (PsARC) response rate;
●
Change from baseline in Disease Activity Score 28 (DAS28) (CRP);
●
Change from baseline in DAS28 (ESR);
●
Change from baseline in PsA Disease Activity Score (PASDAS);
●
Change from baseline in Disease Activity In Psoriatic Arthritis (DAPSA) 
score;
●
Change from baseline in Short Form 36 (SF-36) Health;


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●
Change from baseline in Functional Assessment of Chronic Illness Therapy 
(FACIT)-Fatigue;
●
Change from baseline in EuroQol-5D-5L (EQ-5D-5L) index and VAS score;
●
Change from baseline in Work Productivity and Activity Impairment (WPAI);
●
Cumulative Health Resource Utilization (HRU);
●
Change from baseline in Self-Assessment of Psoriasis Symptoms (SAPS);
●
Change from baseline in Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI) (out of subjects with presence of psoriatic spondylitis at baseline);
●
BASDAI 50 response rates (out of subjects with presence of psoriatic 
spondylitis at baseline);
●
Change from baseline in Morning stiffness (mean of BASDAI Questions 5 and 
6);
●
Change from baseline in Morning stiffness severity 0 - 10 (BASDAI 
Question 5)
●
Change from baseline in Morning stiffness duration 0 - 10 (BASDAI 
Question 6)
●
Change from baseline in Ankylosing Spondylitis Disease Activity Score 
(ASDAS) (out of subjects with presence of psoriatic spondylitis at baseline);
●
Proportion of subjects with ASDAS Inactive Disease (out of subjects with 
presence of psoriatic spondylitis at baseline);
●
Proportion of subjects with ASDAS Major Improvement (out of subjects with 
presence of psoriatic spondylitis at baseline);
●
Proportion of subjects with ASDAS Clinically Important Improvement (out of 
subjects with presence of psoriatic spondylitis at baseline);
●
Proportion of subjects achieving a clinically meaningful improvement in 
HAQ-DI (≥0.35).
Non Radiographic Endpoints
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  NRI will be used for primary analysis. For enthesitis and dactylitis related


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endpoints at Week 24, in addition to the NRI data handling as defined in Section 9.1.2, 
subjects who meet the rescue criteria (i.e., not achieving at least 20% improvement in 
either or both tender joint count (TJC) and swollen joint count (SJC) at both Week 12 and 
Week 16) will also be treated as non-responders. AO will be used as supplementary
analysis.  Point estimate and 95% CI using normal approximation will be provided for the 
response rate for each randomized treatment group.  Treatment comparisons will be made 
between each upadacitinib dose to the combined placebo group and to the adalimumab 
group using the CMH (refer to Appendix A) test adjusting for the main stratification 
factor of current DMARD use (yes/no).  Point estimate, 95% CI using normal 
approximation and the nominal p-value for the treatment difference will be presented.
For non-radiographic continuous endpoints, the LS mean and 95% CI for each 
randomized treatment group and the LS mean treatment difference, the associated 95% CI 
and the p-value between each upadacitinib dose group to the combined placebo group and 
to the adalimumab group will be provided using MMRM model as described in 
Section 9.2.3.2, with fixed effects of treatment, visit, treatment-by-visit interaction, the 
stratification factor of current DMARD use (yes/no) and the continuous fixed covariates 
of baseline measurement.  The nominal p-value will be provided. For enthesitis and 
dactylitis related endpoints at Week 24, exploratory analysis accounting for potential 
influential outliers may be performed.
For change from baseline in each of the seven ACR components, the ANCOVA model 
using AO data handling as described in Section 9.2.3 will be conducted as supplementary 
analysis, with treatment and the stratification factor of current DMARD use (yes/no) as 
the fixed factors and the corresponding baseline values as the covariates. Nominal p-
values will be provided.
Radiographic Endpoints
For proportion of subjects with no radiographic progression at Week 24, point estimate 
and 95% CI of the response rate for each randomized treatment group will be provided.  
Comparisons will be made between the upadacitinib 15 mg QD and 30 mg QD group and 


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the combined placebo group using the CMH (refer to Appendix A) test adjusting for 
current DMARD use (yes/no).  Point estimate, 95% CI and nominal p-value for the 
treatment comparison will be presented.  Non-progression will be derived using both 
linear extrapolation imputation and AO.
For change from baseline in joint space narrowing score and joint erosion score at 
Week 24, linear extrapolation analysis and AO analysis will be performed similarly as 
described in Section 9.2.3.
In the linear extrapolation analysis for Week 56 radiographic endpoints, the missing 
Week 56 data will be imputed via linear extrapolation using available post-baseline x-ray 
data in the latest analysis window prior to Week 56.  For placebo subjects who switched 
to upadacitinib at Week 24, their Week 56 x-ray data will be imputed via linear 
extrapolation using Week 24 x-ray data.  In the AO analysis, the observed Week 56 
measurements will be used regardless of treatment switching.  Similar statistical inference 
approach as Week 24 analysis by original randomized treatment group will be used.
Nominal p-values will be provided.
9.2.5
Handling of Multiplicity
The overall type I error rate of the primary and ranked key secondary endpoints for the 
two doses will be strongly controlled using a graphical multiple testing procedure [1].  
Specifically, the testing will utilize the endpoint sequence of primary endpoint followed 
by the ranked key secondary endpoints in the order as specified in Section 9.2.3, and will 
begin with testing the primary endpoint using α/2 for each dose (α = 0.0499 accounting 
for 0.0001 spending after interim futility analysis).  Continued testing will follow a pre-
specified α transfer path which includes downstream transfer along the endpoint sequence 
within each dose as well as cross-dose transfer.
The graph for the testing procedures is provided in Figure 2.  In the graph, the arrows 
specify the α transfer paths.  Once an endpoint is rejected (i.e., deemed significant) at its 
assigned significance level, its significance level will be transferred to subsequent 


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endpoint(s) following the arrow(s).  The numbers on the arrows denote the weights for 
transferring significance levels.  Specifically, the weight 1 denotes 100% transfer of 
significance level.


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Figure 2.
Graphical Multiple Testing Procedure


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Figure 2.
Graphical Multiple Testing Procedure (Continued)
9.2.6
Efficacy Subgroup Analysis
The primary efficacy endpoint will be examined in the subgroups listed in Table 7 below.  
Treatment difference between each upadacitinib dose and the combined placebo group 
will be presented with point estimate and 95% confidence interval using normal 
approximation.  No p-value will be provided for subgroup analysis.


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Table 7.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 65, ≥ 65 - < 75, ≥ 75 years (if sample size allows)
Sex
Male or Female
BMI
< 25 kg/m2 or ≥ 25 kg/m2
Race
White, Non-white
Geographic region
North America, Western Europe and Oceania, Eastern 
Europe, Latin-America, Asia, and Other
Duration of PsA diagnosis
≤ 5, > 5 - ≤ 10, > 10 years
Baseline hsCRP
≤ ULN or > ULN
Number of prior non-biologic DMARDs
≤ 1, > 1
Current use of non-biologic DMARDs 
Yes or No
9.3
Long-Term Efficacy Analysis
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Week 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 56 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) and DAS28 (ESR)
●
PsARC response rate
●
Change from baseline in DAPSA
●
Proportion of subjects achieving a clinically meaningful improvement in 
HAQ-DI (≥0.35)
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Week 12, 24, 36, 56 and every 12 weeks thereafter until completion of the study:
●
Change from baseline in EQ-5D-5L index and VAS score
●
Change from baseline in FACIT-Fatigue
●
Change from baseline in SF-36


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●
Change from baseline in WPAI
●
Change from baseline in BASDAI
●
Cumulative HRU
●
Change from baseline in PASDAS
●
BASDAI 50 response rates
●
Change from baseline in ASDAS
●
Proportion of subjects with ASDAS Inactive Disease
●
Proportion of subjects with ASDAS Major Improvement
●
Proportion of subjects with ASDAS Clinically Important Improvement
Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Week 12, 16, 24, 36, 56 and every 12 weeks thereafter until completion of the study:
●
Change from baseline in BSA-Ps
●
PASI 75/90/100 response rates
●
Static Investigator Global Assessment (sIGA) of Psoriasis of 0 or 1 and at least 
a 2-point improvement from baseline 
●
Proportion of subjects achieving Minimal Disease Activity (MDA)
●
Change from baseline in LDI
●
Change from baseline in LEI
●
Change from baseline in SPARCC enthesitis index
●
Change from baseline in dactylitis count
●
Proportion of subjects with resolution of dactylitis
●
Proportion of subjects with resolution of enthesitis sites included in the LEI
●
Proportion of subjects with resolution of enthesitis sites included in the 
SPARCC Enthesitis Index
●
Change from baseline in total enthesitis count
●
Proportion of subjects with resolution of enthesitis


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Assessments to evaluate long-term efficacy will be analyzed for the following measures at 
Week 16, 24, 36, 56 and every 12 weeks thereafter until completion of the study:
●
Change from baseline in SAPS
Additionally, assessments to evaluate long-term radiographic change will be analyzed for 
the following measures at Week 24, 56, 104, and 152/PD visits: 
●
Change from baseline in SHS 
●
Change from baseline in joint space narrowing score and joint erosion score 
●
Proportion of subjects with no radiographic progression (defined as change 
from baseline in SHS ≤ 0);
Descriptive statistics will be provided for each randomized treatment group sequence as 
defined in Section 9.1.1.  These include the number of observations, mean, standard 
deviation, 95% CI, median, minimum, Q1, Q3 and maximum for continuous endpoints; 
and frequencies and percentages with 95% CI using normal approximation for binary 
endpoints.  Plot for each randomized treatment group sequence over time will be provided 
for key endpoints.  Additionally, treatment comparisons between each upadacitinib dose 
versus adalimumab will be made for efficacy endpoints for the originally randomized 
upadacitinib groups and adalimumab group.  Point estimate, nominal p value and 95% CI 
will be provided up to Week 56.  These efficacy analyses will be based on data and NRI 
for AO data for non-radiographic endpoints. For radiographic related endpoints, the 
analysis will be based on linear extrapolation imputation and AO data.
9.4
Efficacy Variables Definitions and Conventions
9.4.1
ACR Criteria
ACR criteria are a commonly used standard criteria set mentioned in the FDA industry 
guidance to evaluate the effectiveness of investigational drug in reduction of disease 
activity.  It is a composite measurement calculated based on the improvement over a set of 
core measurements.


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ACR20 is defined as at least 20% improvement (compared to baseline values) in tender 
and swollen joint counts and at least 20% improvement in 3 of the remaining 5 core set 
measures (subject assessment of pain, subject global assessment of disease activity, 
physician global assessment of disease activity, subject assessment of physical function 
and acute phase reactant hsCRP).
ACR50 and ACR70 are similarly defined with at least 50% and 70% improvement, 
respectively.
A subject will be classified as an ACR20 (ACR50, ACR70) responder, if the following 
conditions are met:
1.
≥ 20% (50%, 70%) improvement from baseline in tender joint count (TJC68) and
2.
≥ 20% (50%, 70%) improvement from baseline in swollen joint count (SJC66) and
3.
≥ 20% (50%, 70%) improvement from baseline in at least 3 of the following 5:
●
patient's assessment of pain
●
patient's global assessment of disease activity (PtGA)
●
physician's global assessment of disease activity (PGA)
●
patient's self-assessment of physical function (i.e., measured by Health 
Assessment Questionnaire HAQ-DI score)
●
Acute-phase reactant value CRP
Seven components are included in the ACR response criteria.  Missing values for a 
component can occur due to data collection issues for a particular form, a missed visit or 
dropout from the study.  Depending on the pattern of the missing components, ACR 
responses may be or may not be determined for a visit date using (partially) observed 
values only.  In the case when ACR responses cannot be determined for any visit date 
within a visit window, partially observed data from different visit dates within the same 
visit window can be combined to determine ACR responses for the visit window.


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To maximize the utilization of observed information at certain visits and be scientifically 
as robust as possible, the principle to calculate ACR response is to minimize imputation 
whenever possible.  "As Observed" ACR response will be calculated first based on a 
derived visit window instead of the nominal visit identifier (e.g., Week 6 visit) collected 
from the CRF.
To calculate "as observed" ACR responses:
Identify the observed component 20% improvement indicator (0/1/missing), 1 means 
achieving ≥ 20% improvement from baseline and 0 means < 20% improvement from 
baseline.
ACR20 = 0 if TJC indicator = 0 OR SJC indicator = 0 OR at least 3 out of 5 components 
improvement indicators = 0;
ACR20 = 1 if TJC indicator = 1 AND SJC indicator = 1 AND at least 3 out of 
5 components improvement indicators = 1.
For all other cases, "as observed" ACR20 = missing since ACR20 cannot be determined.   
The following table illustrates examples for as-observed ACR calculations. 
Example
TJC 
68
SJC 
66
Component 1 Component 2 Component 3 Component 4 Component 5
ACR20-
Response?
A
1
1
1
1
1
.
.
Yes
B
1
0
1
1
1
1
1
No
C
.
0
.
.
.
.
.
No
D
1
.
1
1
1
1
1
.
E
1
1
0
0
0
1
1
No
F
.
.
0
0
0
.
.
No
G
1
1
1
1
0
0
.
.
Legend:  1 = ≥ 20% improved compared to baseline; 0 = < 20% improved compared to baseline; "." missing
Derived visit windowing Rule for ACR Response Calculation:  
To identify the component value in a visit window:  


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ACR component values will first be determined at each date within a visit window. 
ACR component values at each date will be combined to determine the "as observed" 
ACR composite score at each date in each window.
After this calculation, if multiple non-missing ACR composite scores are available within 
a given visit window, the non-missing ACR composite score closest to the target day will 
be used.  If two composite scores have the same distance from the target day, the later one 
will be used.  The corresponding date will be used as the "observed" ACR response date 
in the derived efficacy dataset.
If a non-missing ACR composite score is not available for any day within a given visit 
window, the windowed component values for that visit will be used to calculate the ACR 
composite score for that visit window (component value windowing follow the same rules 
as in steps described above).  Date of TJC will be used as the "observed" ACR date in the 
derived efficacy dataset.
The following rules are applied for the NRI imputation for the ACR responses. 
Non-Responder Imputation (NRI):
●
Step 1:  all missing components will be imputed using LOCF, and then the 
ACR composite score can be calculated
●
Step 2:  if the ACR composite score cannot be determined by step 1, the ACR 
composite score will be imputed as 0.  In addition, subjects who prematurely 
discontinue from the study drug will be considered as non-responders 
(ACR = 0) for all subsequent visits after the discontinuation date.
9.4.2
Joint Evaluation
Anatomical joints are evaluated for swelling and tenderness at every study visit.  The 
34 anatomical joints in Table 8 are assessed in this study for both the left and right side of 
the body.


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Table 8.
Anatomical Joints Assessed for Calculation of Tender and Swollen 
Joint Counts (TJC68 and SJC66)
Temporomandibular
Sternoclavicular
Acromio-clavicular
Shoulder
Elbow
Wrist
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal III
Metacarpophalangeal IV
Metacarpophalangeal V
Thumb Interphalangeal
Proximal Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V
Distal
Interphalangeal II
Distal
Interphalangeal III
Distal
Interphalangeal IV
Distal
Interphalangeal V
Hipa
Knee
Ankle
Tarsus
Metatarsophalangeal I
Metatarsophalangeal II
Metatarsophalangeal III
Metatarsophalangeal IV
Metatarsophalangeal V
Great Toe/Hallux
Interphalangeal II
Interphalangeal III
Interphalangeal IV
Interphalangeal V
a.
Hip joints are not assessed for swelling.
At each study visit, a joint evaluator assessed whether a particular joint was "tender or 
painful" where presence of tenderness was scored as "1" and the absence of tenderness 
was scored as "0," provided the joint was not replaced ("9") or could not be assessed 
("NA") due to other reasons (e.g., post-corticosteroid joint injection).  The total tender 
joint count (TJC68), which is based on 68 joints, will be derived as the sum of all "1s" and 
proportional extrapolation will be used to impute joint counts for the joints that are 
replaced or not assessed.  A similar method will be followed for the derivation of total 
swollen joint count (SJC66), which is based on 66 joints as the hip joints are excluded.  
Thus, the range for TJC68 will be 0 to 68 and 0 to 66 for SJC66.
9.4.3
Patient's Global Assessment of Disease Activity Numeric 
Rating Scale (NRS)
The subject will assess his/her disease activity using a Patient's Global Assessment of 
Disease NRS.  The range is 0 to 10 with no activity being indicated by 0 and severe 
activity by 10.


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9.4.4
Physician's Global Assessment of Disease Activity Numeric 
Rating Scale (NRS)
The physician will assess Patient's disease activity at the time of visit using a Physician's 
Global Assessment of Disease NRS.  The range is 0 to 10 with no activity being indicated 
by 0 and severe activity by 10.
9.4.5
Patient's Assessment of Pain Numeric Rating Sale (NRS)
The subject will assess his/her pain using the Patient's Assessment Pain NRS.  The range 
is 0 to 10 with no activity being indicated by 0 and severe activity by 10.
9.4.6
Disease Activity Score (DAS28)
DAS28 (CRP) and DAS28 (ESR) are composite indices to assess disease activity in RA 
using hsCRP or ESR measurement, respectively.  The DAS provides a score between 0 
and 10, indicating how active the rheumatoid arthritis is at the time of measurement.
DAS28 (CRP) and DAS28 (ESR) can be calculated based on Tender Joint Count, Swollen 
Joint Count, Patient's Global Assessment of Disease Activity (PtGA) (in mm), and hsCRP 
(in mg/L) or ESR (mm/hr).
DAS28 (CRP) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.36 × ln(hsCRP& + 1) 
+ 0.014 × PtGA» + 0.96
DAS28 (ESR) = 0.56 × √(TJC28*) + 0.28 × √(SJC28**) + 0.70 × ln(ESR#) + 0.014 
× PtGA»
where √is square root and ln is natural log.
*
TJC28 refers to the Subject's total Tender Joint Count out of the provided 28 evaluated joints.
**
SJC28 refers to the Subject's total Swollen Joint Count out of the provided 28 evaluated joints.
&
hsCRP refers to the high-sensitivity c-reactive protein lab value.  hsCRP unit in the DAS28 (CRP) equation is 
expressed as mg/L.
#
ESR refers to the Erythrocyte sedimentation rate.  ESR unit in the DAS28 (ESR) equation is expressed as mm/hr.
»
PtGA refers to the Patient's Global Assessment of Disease Activity.


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Table 9.
Anatomical Joints for DAS28 (CRP) Calculation
Shoulder
Elbow
Wrist
Thumb Interphalangeal
Metacarpophalangeal I
Metacarpophalangeal II
Metacarpophalangeal III
Metacarpophalangeal IV
Metacarpophalangeal V
Proximal 
Interphalangeal II
Proximal 
Interphalangeal III
Proximal 
Interphalangeal IV
Proximal 
Interphalangeal V
Knee
As Patient's Global Assessment of Disease Activity is collected with the scale of 
0 - 10 NRS, the variable needs to be multiplied by 10 before being used the DAS28 
formula.
To calculate observed DAS28 scores, the observed component value will be calculated
first.  Then the components will be included in the calculation per the DAS formula 
selected.  If any observed component is missing in a window, then the observed DAS28 
score will be missing.
9.4.7
Disease Activity in Psoriatic Arthritis (DAPSA) Score
DAPSA is a continuous endpoint that measures the disease activity in psoriatic arthritis.  
DAPSA consists of five components:  Tender Joint Count 68, Swollen Joint Count 66, 
Patient's Assessment of Pain (0 - 10 NRS), Patient's Global Assessment of Disease 
Activity (0 - 10 NRS), and hsCRP (in mg/dL).
DAPSA = SJC66 + TJC68 + Pt pain (0 - 10 NRS) + PtGA (0 - 10 NRS) + CRP (in 
mg/dL)
To calculate observed DAPSA scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the DAPSA formula.  If 
any observed component is missing in a window, then the observed DAPSA score will be 
missing.


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9.4.8
PsA Disease Activity Score (PASDAS)
PASDAS is a continuous scale of combined joint, dactylitis and enthesitis assessments, 
physician and patient global assessments for arthritis, SF36-PCS, and hsCRP 
measurements.
PASDAS  = (((0.18 √(PGA)) + 0.159 √(PtGA) – 0.253 √(SF36-PCS) + 0.101 ln 
(SJC66 + 1) + 0.048 ln (TJC68 + 1) + 0.23 ln (Leeds Enthesitis Index + 1) + 0.37 ln 
(Tender Dactylitis Count + 1) + 0.102 ln (hsCRP + 1) + 2) * 1.5,
where √is square root and ln is natural log.  PtGA is on the scale of 0 – 100 and PGA is 
on the scale of 0 – 100. As PtGA and PGA are collected with the scale of 0 - 10 NRS, 
their values need to be multiplied by 10 before being used in the PASDAS formula.
SF36-PCS is the physical component scale in SF36 instrument.  The unit for hsCRP is 
mg/L.
The tender dactylitis count is based on the dactylitis assessment.  The count can be 
calculated by summing the digits with a "presence of tenderness" score = 1.
The Leeds Enthesitis Index (LEI) evaluates enthesitis at 6 most commonly involved 
entheseal sites, as indicated in the table below.  The LEI is calculated by taking the sum of 
the scores from the 6 sites. The LEI ranges from 0 to 6.  
Tenderness in Left
Tenderness in Right
YES = 1
NO = 0
Not 
assessed = NA
YES = 1
NO = 0
Not 
assessed = NA
1
Lateral 
epicondyle
2
Achilles tendon 
insertion
3
Medial femoral 
condyle


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To calculate observed PASDAS scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the PASDAS formula.  
If any observed component is missing in a window, then the observed PASDAS score will 
be missing.
9.4.9
Disability Index of Health Assessment Questionnaire 
(HAQ DI)
HAQ-DI is a self-reported patient outcome measurement.  It is calculated as the mean of 
the scores from 8 following categories with a range 0 – 3:  Dressing and Grooming, 
Rising, Eating, Walking, Hygiene, Reach, Grip, and Activities.  Higher scores reflect 
greater disability. 
The maximum score for all the questions in each category is considered as the score for 
the category.  The HAQ-DI takes into account the subject's use of aids or devices or 
assistance in the scoring algorithm for a disability category.  For each of the 
eight disability categories there is an AIDS OR DEVICES companion variable(s) that is 
used to record the type of assistance, if any, a subject uses for his/her usual activities.  If 
aids or devices and/or assistance from another person are checked for a disability 
category, the score for this category is set to 2 (much difficulty), if the original score is 
0 (no difficulty) or 1 (some difficulty).  The HAQ-DI is then calculated by summing the 
adjusted categories scores and dividing by the number of categories answered.  The 
HAQ-DI cannot be calculated if the patient does not have scores for at least 6 categories.
9.4.10
Static Investigator Global Assessment of Psoriasis (sIGA)
The sIGA is a 5 point score ranging from 0 to 4, based on the investigator's assessment of 
the average elevation, erythema, and scaling of all psoriatic lesions.  The assessment is 
considered "static" which refers to the patients disease state at the time of the assessments, 
without comparison to any of the patient's previous disease states, whether at Baseline or 
at a previous visit.  A lower score indicates less severe psoriasis (0 = clear, 1 = almost 
clear, 2 = mild, 3 = moderate and 4 = severe).


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A binary clinical endpoint based on sIGA is considered in this study.  It is the proportion 
of subjects achieving a sIGA score of 0 or 1 and at least a 2-point improvement from 
baseline.  This endpoint is calculated among the subjects with baseline sIGA score ≥ 2.
9.4.11
Psoriasis Area Severity Index (PASI)
Psoriasis Area Severity Index (PASI) has four anatomic sites – head, upper extremities, 
trunk, and lower extremities – which are assessed for erythema, induration and 
desquamation using a 5-point scale:
●
0 = no symptoms
●
1 = slight
●
2 = moderate
●
3 = marked
●
4 = very marked
Based on the extent of lesions in a given anatomic site, the area affected is assigned a 
numerical value:
●
0 = no involvement
●
1 = < 10%
●
2 = 10% – 29%
●
3 = 30% – 49%
●
4 = 50% – 69%
●
5 = 70% – 89%
●
6 = 90% – 100%
Since the head, upper extremities, trunk and lower extremities correspond to 
approximately 10, 20, 30 and 40% of body surface area, respectively; the PASI score is 
calculated using the formula:
PASI = 0.1(Eh + Ih + Dh)Ah + 0.2(Eu + Iu + Du)Au + 0.3(Et + It + Dt)At + 0.4(El + Il + Dl)Al


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where E, I, D, and A denote erythema, induration, desquamation, and area, respectively, 
and h, u, t, and l denote head, upper extremities, trunk, and lower extremities, 
respectively.  PASI scores range from 0.0 to 72.0 with the highest score representing 
complete erythroderma of the severest possible degree.  Typically scores of 3 or less 
represent mild disease, scores over 3 and up and including 15 represent moderate disease 
and scores over 15 are considered to be associated with severe disease.
If one item is missing, PASI is not scored.
PASI 75 (PASI 50, PASI 90, PASI 100) responder is reached if there is at least a 75% 
(50%, 90%, 100%) reduction in PASI score (≥ PASI 75/50/90/100 response) at a visit 
relative to the Baseline PASI score.
PASI is summarized in subjects with ≥ 3% BSA (Body Surface Area) psoriasis 
involvement at baseline. 
9.4.12
Minimum Disease Activity for PsA
A patient is classified as in MDA when 5 of the following 7 criteria are met:
●
TJC68 ≤ 1
●
SJC66 ≤ 1
●
PASI ≤ 1 or BSA-Ps ≤ 3%
●
Patient's assessment of pain ≤ 1.5 (0 - 10 NRS) 
●
Patient's Global Assessment of disease activity ≤ 2 (0 - 10 NRS)
●
HAQ-DI score ≤ 0.5
●
Leeds Enthesitis Index ≤ 1
MDA response can be determined if at least 5 of the 7 criteria are met (responder), or if at 
least 3 of the 7 criteria are not met (non-responder).  Selection of multiple MDA 
responses within one visit window follows the same rules as ACR.  Missing values for 
each component can occur due to data collection issues for a particular form, a missed 
visit or dropout from the study.  Depending on the pattern of the missing components, 


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MDA responses may be or may not be determined for a visit date using (partially) 
observed values only.  In the case when MDA responses cannot be determined for any 
visit date within a visit window, partially observed data from different visit dates within 
the visit window can be combined to determine MDA responses for the visit window.
9.4.13
Self-Assessment of Psoriasis Symptoms (SAPS)
The Self-Assessment of Psoriasis Symptoms (SAPS) contains 11 symptom-focused items.  
Each item is scored from 0 to 10, with 0 being least severe and 10 being most severe.  The 
total score is generated by summing the 11 items.  The total score ranges from 0 to 110.
9.4.14
Leeds Dactylitis Index (LDI) and Dactylitis Count
The Leeds Dactylitis Index (LDI) is a score based on finger circumference and tenderness, 
assessed and summed across all dactylitic digits.  The presence of dactylitic digit is 
defined as at least one affected AND tender digit with circumference increase over 
reference digit ≥ 10%.  For each of 20 digits of a subject, a digit final score needs to be 
calculated first.  For an unaffected digit, the digit final score is set to be 0.  For an affected 
digit, the digit final score is calculated as (A/B-1)*100*C if A/B ≥ 1.1, and digit final 
score = 0 if A/B ≤ 1.1, where A denotes the circumference of the digit, B the reference 
circumference, and C the tenderness score.  The reference circumference can be either the 
circumference of the unaffected contralateral digit if available, or from a reference table if 
otherwise.  LDI is the sum of the digit final scores over all 20 digits.
The dactylitis count will be calculated as the number of digits (hands and feet) with 
presence of dactylitis.  The count ranges from 0 to 20.  
The proportion of subjects with resolution of dactylitis is defined as the proportion of 
subjects with LDI = 0.


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9.4.15
Leeds and SPARCC Enthesitis Indices and Total Enthesitis 
Count
For the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index 
16 sites are evaluated as indicated in rows 1 – 8 in the table below.  Tenderness on 
examination is recorded as either present (coded as 1), absent (coded as 0), or not assessed 
for each site.  The SPARCC enthesitis index is calculated by taking the sum of the scores 
from the 16 sites.  The SPARCC score ranges from 0 to 16.
The Leeds Enthesitis Index evaluates enthesitis at the 6 entheseal sites indicated in rows 2, 
7 and 9 in the table below.  Tenderness on examination is recorded as either present 
(coded as 1), absent (coded as 0), or not assessed for each of the 6 sites.  The LEI is 
calculated by taking the sum of the scores from the 6 sites.  The LEI ranges from 0 to 6.
The total enthesitis count is calculated by taking the sum of the tenderness scores from all 
18 sites in the table below.
The proportion of subjects with resolution of enthesitis sites included in the LEI is defined 
as the proportion of subjects with LEI = 0; the proportion with resolution of the SPARCC 
Enthesitis Index and of the total enthesitis count are similarly defined.


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Tenderness in Left
Tenderness in Right
Present 
= 1
Absent 
= 0
Not assessed 
= NA
Present 
= 1
Absent 
= 0
Not assessed 
= NA
1
Medial 
epicondyle
2
Lateral 
epicondyle
3
Supraspinatus 
insertion into the 
greater tuberosity 
of humerus
4
Greater 
trochanter
5
Quadriceps 
insertion into 
superior border 
of patella
6
Patellar ligament 
insertion into 
inferior pole of 
patella or tibial 
tubercle
7
Achilles tendon 
insertion into 
calcaneum
8
Plantar fascia 
insertion into 
calcaneum
9
Medial femoral 
condyle
9.4.16
Body Surface Area (BSA) – Psoriasis
The subject's right or left hand should be selected as the measuring device.  For purposes 
of clinical estimation, the total surface of the palm plus five digits will be assumed to be 
approximately equivalent to 1%.  Measurement of the total area of involvement by the 
physician is aided by imagining if scattered plaques were moved so that they were next to 
each other and then estimating the total area involved.


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9.4.17
Bath Ankylosing Spondylitis Disease Activity Index 
(BASDAI) and Morning Stiffness Score
The BASDAI is composed of 6 items investigating 5 domains (fatigue, spinal pain, joint 
pain/swelling, areas of localized tenderness, morning stiffness), with 1 item for each of 
the first four domains and 2 items for the last domain (morning stiffness).  Each item is 
scored on a 0 - 10 NRS.  A lower score indicates less disease activity.
Scoring of the BASDAI is as follows:
1.
Measure each item of the BASDAI in NRS (out of a total of 10)
2.
BASDAI Score = 0.2*(Item1 + Item2 + Item3 + Item4 + 0.5*Item5 + 0.5* Item6)
The BASDAI Score ranges from 0 – 10.  If one of the 5 items (Questions 1 – Question 4, 
inflammation) is missing, then the score is the mean of the 4 non-missing items (total of 
4 non-missing items divided by 4).  If more than 1 of the 5 items is missing, then the 
BASDAI score is missing.
Note:  Question 5 and Question 6 jointly constitute Item 5 (inflammation).  If both 
Questions 5 and 6 are missing, and questions 1 through 4 are non-missing, then only 
one item will be considered missing.  The BASDAI score can still be calculated as the 
mean of Questions 1 – 4.  However, if, for example, both Question 6 and Question 1 are 
missing, then 2 items will be considered missing, as the inflammation calculation would 
be incomplete.  The BASDAI score would then be considered missing in this case.
The Morning Stiffness Score is the average of BASDAI questions 5 and 6 and it ranges 
from 0 – 10.  
9.4.18
Modified Psoriatic Arthritis Response Criteria (PsARC)
The PsARC was developed as a PsA-specific composite responder index.  To achieve 
response, a patient must achieve 2 of the following 4 items, one of which has to be a 
Tender Joint Count 68 or Swollen Joint Count 66, and no worsening of any measure: 


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●
≥ 30% improvement in TJC68
●
≥ 30% improvement in SJC66
●
Improvement in PtGA of Disease Activity NRS
●
Improvement in PGA of Disease Activity NRS
Four components are included in the PsARC criteria.  Missing values for each component 
can occur due to data collection issues for a particular form, a missed visit or dropout 
from the study.  In the case when PsARC responses cannot be determined for any visit 
date within a visit window, partially observed data from different visit dates within the 
visit window can be combined to determine PsARC responses for the visit window.
9.4.19
Ankylosing Spondylitis Disease Activity Score (ASDAS)
The Ankylosing Spondylitis Disease Activity Score (ASDAS) is a composite index to 
assess disease activity in AS.  It combines five disease activity variables.  Parameters used 
for the calculation of ASDAS:
1.
Patient's assessment of total back pain (BASDAI Question 2)
2.
PtGA of disease activity (0 - 10 NRS)
3.
Peripheral pain/swelling (BASDAI Question 3)
4.
Duration of morning stiffness (BASDAI Question 6)
5.
High-sensitivity C-reactive protein (hs-CRP) in mg/L.
Calculation of ASDAS:
ASDAShs-CRP =
0.121 × total back pain + 0.110 × patient global + 0.073 × peripheral 
pain/swelling + 0.058 × duration of morning stiffness + 0.579 
× Ln(hs-CRP+1).okie
To calculate observed ASDAS scores, the observed component value will be calculated 
first.  Then the components will be included in the calculation per the ASDAS formula.  If 


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any observed component is missing in a window, then the observed ASDAS score will be 
missing.
ASDAS score is categorized in to the following ASDAS Disease Activity States:
●
ASDAS Inactive Disease: ASDAS < 1.3
●
ASDAS Moderate Disease:  1.3 ≤ ASDAS < 2.1
●
ASDAS High Disease:  2.1 ≤ ASDAS ≤ 3.5
●
ASDAS Very High Disease: ASDAS > 3.5
ASDAS Response categories are defined as follows:
●
ASDAS Major Improvement (a change from baseline ≤ –2.000)
●
ASDAS Clinically Important Improvement (a change from baseline ≤–1.100)
9.4.20
FACIT-Fatigue Questionnaire (FACIT-F)
The FACIT Fatigue Questionnaire is a 13-item tool that measures an individual's level of 
fatigue during their usual daily activities over the past week.  The level of fatigue is 
measured on a four point scale (4 = not at all fatigued to 0 = very much fatigued).  The 
Fatigue scale ranges from 0 to 52, with higher scores indicating less fatigue. 
Item score for each item is calculated by either subtracting from 4 or adding 0 depending 
on whether it is a reversal item or not.  FACIT Fatigue is then calculated by adding up all 
item scores, multiplying by 13 and dividing by the number of items answered.  If less than 
7 items are answered, the scale will not be computed.
9.4.21
EuroQoL-5D (EQ-5D-5L)
EQ-5D measures 5 dimensions of health status (mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression) with 5 levels per dimension (no problems, slight 
problems, moderate problems, severe problems, and extreme problems corresponding to 
Level 1 to Level 5 respectively) and includes the EQ Visual Analogue Scale (EQ VAS).  


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The 5 dimensions of health status are converted into a single index value.  The change 
from baseline of the index value and the EQ VAS will be analyzed and reported.  UK 
scoring algorithm will be used.
9.4.22
Form SF-36v2
The 36-Item Short Form, Version 2 (SF-36v2) health survey consists of 36 general health 
questions.  It has 2 components:  physical and mental.  For each component, a 
transformed summary score is calculated using 8 sub domains:  physical functioning, role-
physical, bodily pain, general health, vitality, social functioning, role-emotional, and 
mental health.
The coding and scoring for the SF-36 will use the software provided by QualityMetrics.
9.4.23
Work Productivity and Activity Impairment Questionnaire 
Psoriatic Arthritis (WPAI)
The Work Productivity and Activity Impairment Questionnaire:  Psoriatic Arthritis, V2.0 
(WPAI) measures the effect of overall health and specific symptoms on productivity at 
work and outside of work.  It consists of 6 questions.  A lower WPAI score indicates an 
improvement.  The WPAI is collected at the designated study visits listed in the protocol.  
The WPAI coding and scoring methods are described in the following:
The 6 measures will be derived based on the responses from the 6 questions.  The 4 main 
impairment scores (S1 to S4) are expressed as percent impairment based on the 
6 questions.
Scores:
S0.
Employment:  defined below in missing data handling conventions
S1.
Absenteeism:  Percent work time missed due to PsA: 


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!∀
#
∃%
&
∋
(
4
2
2
100
Q
Q
Q
S2.
Presenteeism:  Percent impairment while working due to PsA: 
!∀
#
∃%
&
( 10
5
100
Q
S3.
Percent overall work impairment due to PsA:
!
∀
#
∃
%
&
(
)
∗
+
,
−
.
∋
/
∋
∋
(
10
5
4
2
2
1
4
2
2
100
Q
Q
Q
Q
Q
Q
Q
S4.
Percent activity impairment due to PsA: 
!∀
#
∃%
&
( 10
6
100
Q
S5.
Did subject miss work (defined below).  This is needed to derive the 
proportion of subjects who missed work.
Missing Data Handling Conventions
When calculating the WPAI:  PsA scores, the following computational notes should be 
followed.
●
Define Employment as a binary YES or NO variable where YES corresponds 
to "Employed" and NO corresponds to "Not Employed."
○
A subject will be considered "employed" at a given visit if Q1 = YES or 
Q2 > 0 or Q4 > 0.
○
A subject will be considered "unemployed" at a given visit if Q1 = NO and 
no positive hours recorded under Q2 and Q4 (i.e., if Q1 = NO AND Q2 ≤ 0 
AND Q4 ≤ 0, then UNEMPLOYED).


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○
Employment status for a subject will be considered "missing" at a given 
visit if Q1 = missing and no positive hours recorded under Q2 and Q4.
●
If a subject is "unemployed" or employment status is "missing," then S1, S2, 
and S3 will be set to "missing."
●
If Q2 = 0 and Q4 = 0 are missing then Q2/(Q2 + Q4) = missing 
(i.e., S1 = missing).
●
If Q2 = 0 and Q4 = 0, then set S3 to missing.
●
If Q2 is missing or Q4 is missing, then set S1 and S3 to missing.
●
If Q4 = missing, then DO NOT set Q5 = missing.
●
If Q5 is missing, then apply the following rules:
○
If Q2 > 0, Q4 = 0, and Q5 = missing, then S3 = 100%.
○
If Q2 = 0, Q4 > 0, and Q5 = missing, then S3 is missing.
○
If Q2 > 0, Q4 > 0, and Q5 = missing, then S3 is missing.
●
Determine if a subject missed work (based on Q2) in order to analyze the 
proportion of subjects who missed work:
○
Create a binary (yes or no) "missed work" variable.
○
A subject will be considered as yes to missed work if Q2 is greater than 0.
○
If Q2 = missing, then MISSED WORK = missing.
○
If Q2 > 0, then MISSED WORK = "yes."
○
If Q2 = 0, then MISSED WORK = "no."
Therefore, the proportion of subjects who missed work will be counted 
based on the number of subjects with MISSED WORK = YES.
9.4.24
Health Resource Utilization (HRU) Questionnaire
The HRU questionnaire contains three questions regarding health care utilization in the 
following categories:  unscheduled health care professional visits, emergency room visits, 
and hospital admissions.  The data gathered from the HRU questionnaire will be used to 
calculate the individual cumulative number of utilizations per time (e.g., subject-year) 
under observation in each variable (i.e., the number of unscheduled PsA-related health 


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care professional visits, the number of emergency room visits, the number of hospital 
admissions and the total number of days in hospital) as follows:
●
Time under observation for a subject will be defined as "date of last visit with 
non-missing HRU – date of baseline visit."
●
The number of utilizations after baseline will be summed up for each subject.
To determine cumulative HRU over all subjects, the ratio of the total number of 
utilizations (i.e., over all subjects) and the total time under observation (i.e., over all 
subjects) will be calculated across all subjects in each treatment group.  HRU will be 
analyzed as observed only.
9.4.25
Modified PsA Sharp/van der Heijde Score (SHS)
Radiographic outcomes will be assessed and scored according to Sharp's method (van der 
Heijde modification for PsA) centrally by two qualified readers who will be blinded to 
site number, subject number, treatment allocation, time sequence and clinical response.
Calculation of the SHS Score
To obtain the total SHS score, scores for erosions and JSN in both the hands and feet will 
be added together.
The following considerations are applied before score summation: 
●
Osteolysis in the form of pencil-in-cup:  Osteolysis of the proximal phalanx 
and the base of the distal phalanx resulting in a pencil like proximal phalanx 
covered by cup like base of the distal phalanx.  Pencil-in-cup will be scored as 
"P" where applicable. 
●
Gross Osteolysis:  Osteolysis of the phalanx resulting in a loss of the normal 
joint structure, usually accompanied by shortening of the length of the 
phalanx.  Gross osteolysis will be scored as "G" where applicable. 


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For the purpose of summing total scores, "G" or "P" assigned by the IRC reviewers will 
be associated with a maximum score per feature (JSN and erosion score) per location in 
analyses of radiographic scores.
Not Visible and Surgically Modified Joints/Bones
If a joint or bone is not visible (e.g., poor film quality, missing imaging, severe 
misalignment, flexion deformity, dislocation) at the timepoint, the individual joint or bone 
will be coded as Not Visible (N).  If radiographs at the timepoint show a joint or bone 
with surgical fusion, replacement (prosthesis), or amputation, then the joint or bone will 
be scored Surgically Modified (S). 
For joints and bones with end stage disease, scores N and S should not be used.
The range of scores is summarized below.
Table 10.
Range of Total SHS Score, Erosion Score and Joint Space 
Narrowing 
Hands
Feet
Total
(Hands and Feet)
Erosion Score Range
0 – 200
0 – 120
0 – 320
Joint Space Narrowing Range
0 – 160
0 – 48
0 – 208
Total SHS Range for Erosion and JSN
0 – 360
0 – 168
0 – 528
Erosion Assessment
Erosions will be assessed in each hand (20 locations per hand) and foot (6 locations per 
foot).  The locations assessed in the SHS method include:
Hands:
●
4 Distal inter-phalangeal joints (2 - 5)
●
5 Metacarpo-Phalangeal Joints (1 - 5)
●
4 Proximal Inter-Phalangeal Joints (2 - 5)


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●
Inter-Phalangeal Joint of the thumb
●
Proximal first Metacarpal Bone
●
Radius Bone
●
Ulnar Bone
●
Trapezium and Trapezoid (as one unit; multangular)
●
Navicular Bone
●
Lunate Bone
Feet:
●
5 Metatarso-phalangeal joints (1 - 5)
●
Inter-phalangeal joint of the first toe
Joint Space Narrowing Assessment
Joint space narrowing (JSN) will be assessed in each hand (20 locations per hand) and 
foot (6 locations per foot).  The locations assessed in the SHS method include:
●
Hand Joints:
○
4 Distal inter-phalangeal joints (2 - 5)
○
4 Proximal inter-phalangeal joints (2 - 5)
○
5 Metacarpo-phalangeal joints (1 - 5)
○
Interphalangeal Joint of thumb (IP)
○
3 Carpo-metacarpal joints (3 - 5)
○
Radio-carpal joint 
○
Multangular-navicular joint 
○
Capitate-navicular-lunate joint 
●
Foot Joints:
○
5 Metatarso-phalangeal joints
○
Inter-phalangeal joint of first toe


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For each Joint and Bone assessed, scores range as follows:
●
Erosions:  0 – 5 (hands/wrists) or 0 – 10 (feet) to characterize the extent of 
erosions (where 0 denotes no erosion).
●
Joint Space Narrowing:  0 – 4 to characterize the extent of Joint Space 
Narrowing (JSN) (where 0 denotes no narrowing).
Erosion and JSN scores for each reader are calculated by taking the sum of the left and 
right joints as shown below.
Right
Left
i
Reader 
Erosion
Erosion
Erosion
∋
0
Right
Left
i
Reader 
JSN
JSN
JSN
∋
0
for i = 1, 2.
Thus, the maximum erosion score for the hands is 200. The maximum erosion score for 
the feet is 120.  Thus, the total erosion score for hands/wrists and feet is 320.
The maximum score for JSN in all 40 hand joints is 160.  The maximum score for JSN in 
all 12 feet joints is 48.  Thus, the total JSN score for hand and feet is 208.
Since two independent readers evaluate each film, the mean score will be calculated for 
the two readers from the individual erosion and JSN scores as shown below:
2
Erosion
Erosion
Erosion
Joint 
Reader2
Reader1 ∋
0
2
JSN
JSN
JSN
Reader2
Reader1 ∋
0


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The SHS for each reader is defined as the sum of the erosion and JSN scores:
SHSReader i = ErosionReader i + JSNReader i for i = 1, 2.
The average modified SHS from the two readers will be used for all x-ray endpoint 
calculations.
  = 	
 + 	

2
Handling of Missing Joints in the SHS Derivation
If a score at any location/joint is missing, the method described below will be used for 
deriving SHS.
●
If the score for a location/joint is missing at Baseline, this joint will not 
contribute to the calculation of SHS for this subject at any visit within the 
reading session (even if the score for this location/joint is available at post-
baseline visits).
●
If the score for a location/joint is missing at all post-baseline visits within a 
reading session, this joint will not contribute to the calculation of SHS for this 
subject at any visit within the reading session (even if the score for this 
location/joint is available at Baseline).
●
If the score for a location/joint is available at Baseline and at least one post-
baseline visit, missing scores for this joint at any other post-baseline visit will 
be imputed assuming no progression from the previous time point with 
available score. 
Adjudication Process
Two reviewers will independently review the images.  Adjudication will occur for all 
subjects with a discrepancy of ≥│8 units│ between the two reviewers' SHS change 
scores, in which case another reviewer, different from the reviewers who performed 
primary assessments, will make a third, independent assessment.


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For the calculation of SHS, the score of two closest reads (out of the 
two primary reviewers and the adjudicator) will be used.  In the case of equal distance, the 
average of the three reads will be used.
10.0
Safety Analysis
10.1
General Considerations
Safety analyses will be carried out using the Safety Analysis Set by "as treated" treatment 
groups.  There are two sets of planned safety analysis:  safety analysis by Week 24, and 
long-term safety analysis.
Safety Analysis through Week 24
Standard safety analysis by the "as treated" treatment groups of upadacitinib 15 mg QD, 
upadacitinib 30 mg QD, adalimumab 40 mg EOW and combined placebo groups will be 
performed on safety data up to Week 24.  No protocol-defined treatment switching will 
occur prior to this time point.
The standard safety analyses will include reporting of adverse events (AEs), laboratory, 
and vital signs measurements.  Frequency tables of subjects with treatment-emergent 
adverse events (TEAEs) by system organ class (SOC) and by preferred term (PT) as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be provided by 
as-treated treatment groups.  Mean changes from baseline in all continuous laboratory 
parameters and vital signs variables at each visit will be summarized by "as treated" 
treatment groups.  Frequency tables of subjects meeting criteria for potentially clinically 
significant vital sign values and for potentially clinically significant laboratory values will 
be provided by as-treated treatment groups.  Missing safety data will not be imputed.
Treatment comparison of upadacitinib versus placebo and ADA will be provided for key 
safety endpoints including overview of AE, overview of AE of special interest, change 
from baseline in selected laboratory parameters, and potentially clinically significant 
laboratory values.  Treatment difference and corresponding 95% CI will be provided.


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Long-Term Safety Analysis
Long-term safety analyses that account for protocol-defined treatment switching include 
reporting of AE rate adjusted by cumulative exposure, descriptive summary in laboratory 
parameters and vital sign variables by visit, and rate of potentially clinically significant 
laboratory and vital signs values.  The treatment-emergent adverse event (TEAE) rate per 
100 patient-years of exposure will be presented by actual treatment received at the time of 
AE (as described in Section 10.2.2).  Listing of subjects with TEAEs by SOC and PT will 
be provided.  Summary statistics for laboratory parameters and vital signs variables at 
each visit will be presented by "as treated" treatment group sequences defined below.  
Frequency tables and listings of subjects meeting criteria for potentially clinically 
significant vital sign values and for potentially clinically significant laboratory values will 
be provided by actual treatment received at the time of event.  Missing safety data will not 
be imputed.
"As treated" treatment group sequences are defined as follows:
1.
Placebo →Upadacitinib 15 mg QD
2.
Placebo →Upadacitinib 30 mg QD
3.
Upadacitinib 15 mg QD
4.
Upadacitinib 30 mg QD
5.
Adalimumab 40 mg EOW
Treatment comparisons of upadacitinib versus ADA will be provided for key safety 
endpoints including overview of AE, overview of AESI, selected lab parameters, and 
potentially clinically significant laboratory values.  Treatment difference and 
corresponding 95% CI will be provided.


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10.2
Analysis of Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is after the first dose of study drug, and no more than 30 days after the last dose 
of upadacitinib and placebo, and 70 days after the last dose of adalimumab.
Events where the onset date is the same as the study drug start date are assumed to be 
treatment-emergent, unless the study drug start time and the adverse event start time are 
collected and the adverse event start time is prior to the study drug start time.  If an 
incomplete onset date was collected for an adverse event, the event will be assumed to be 
treatment-emergent unless there is other evidence that confirms that the event was not 
treatment-emergent (e.g., the event end date was prior to the study drug start date).
Adverse event data will be presented by SOCs and PTs using MedDRA Version 19.1 or 
most up to date version, which will be sorted in alphabetical order by SOC and PT.
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined 
Treatment Switching
10.2.1.1
Adverse Events Overview
The number and percentage of subjects experiencing TEAEs will be summarized by 
treatment groups for the following AE categories.
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs with a reasonable possibility of being related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
Deaths (includes all deaths – treatment-emergent and non-treatment-emergent)
Additional AE summaries may be considered for tabulation/summary based on 
recommendations from Clinical and Safety as deemed appropriate.


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10.2.1.2
Adverse Events by System Organ Class and Preferred Term
The number and percentage of subjects experiencing adverse events a will be tabulated by 
SOC and MedDRA PT by treatment groups.  The SOCs will be presented in alphabetical 
order, and the PTs will be presented in alphabetical order within each SOC.
The following summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs with a reasonable possibility of being related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity tables and most 
related incident for the relationship tables).  Subjects reporting more than one type of 
adverse event within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.
10.2.1.3
TEAEs by Maximum Severity
TEAEs will also be summarized by maximum severity by treatment groups.  If a subject 
has an AE with an unknown severity, then the subject will be counted in the severity 
category of unknown, even if the subject has another occurrence of the same event with a 
severity present.  The only exception is if the subject has another occurrence of the same 
AE with the highest CTCAE grade; in this case, the subject will be counted under the 
highest CTCAE grade for the term in question.


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10.2.1.4
TEAEs by Relationship
TEAEs will also be summarized by relationship to upadacitinib, adalimumab and placebo, 
as assessed by the investigator, by treatment groups.  If a subject has a TEAE with an 
unknown relationship, then the subject will be counted in the relationship category of 
"unknown," even if the subject has another occurrence of the same event with a 
relationship present.  The only exception is if the subject has another occurrence of the 
same TEAE with a relationship assessment of "reasonable possibility."  In this case, the 
subject will be counted under the "reasonable possibility" category.
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and 
Preferred Term
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the treatment groups will be summarized by SOC and PT separately.
10.2.1.6
Adverse Events of Special Interest
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented by treatment groups in overview as well as using SOC and PT.  The AESI 
categories will be identified by the following search criteria per Standard MedDRA 
Queries (SMQs)/Company MedDRA Queries (CMQs) in Table 11 below.  Adjudicated 
cardiovascular events will be summarized and presented by treatment group using the 
CAC adjudicated categories.


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Table 11.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches
AESI
Type of MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
excluding Tuberculosis and 
Herpes Zoster
CMQ
"Opportunistic Infection excluding 
Tuberculosis and Herpes Zoster"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
"Malignant tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Narrow
Skin Malignant tumours (Narrow
SMQ) removing Melanoma CMQ
Malignancy excluding NMSC
"Malignant tumours" SMQ 
removing NMSC output
Lymphoma
SMQ
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders"
Gastrointestinal Perforations
Output from 
Medical Review of 
Events Identified 
by the 
"Gastrointestinal 
Perforations" SMQ 
Narrow Search
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia"
Herpes Zoster
CMQ
"Herpes Zoster"
Creatine Phosphokinase (CPK) 
Elevation
PT
Search only for the PT of "Blood 
creatine phosphokinase increased"
Renal Dysfunction
SMQ
Narrow
"Acute Renal, Failure"
Active Tuberculosis
CMQ
"Active Tuberculosis"


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Table 11.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches 
(Continued)
AESI
Type of MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Adjudicated cardiovascular 
events
Output from CAC
MACE*
Cardiovascular Death
Non-fatal Myocardial 
Infarction
Non-fatal Stroke
Other Adjudicated 
Cardiovascular Events
Undetermined/Unknown 
Cause of Deaths
Adjudicated Thrombotic
Events
Output from CAC
VTE**
Deep Vein 
Thrombosis
Pulmonary Embolism
Other Venous Thrombosis
Arterial Thromboembolic 
Events
(non-cardiac, 
non-neurologic)
CAC = Cardiovascular Adjudication Committee; CMQ = company MedDRA query; PT = preferred term; 
SMQ = standard MedDRA query
*
MACE; Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction 
and non-fatal stroke.
**
VTE:  Venous thromboembolic events, defined as deep vein thrombosis (DVT) and pulmonary embolism (PE) 
(fatal and non-fatal).
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.


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10.2.2
Analysis of Long-Term Adverse Event Rates
Long-term adverse events will be analyzed using event rates adjusted by cumulative 
exposure and will be based on the actual treatment received at the time of AE occurrence.  
The detailed treatment groups are defined as follows.
1.
Any upadacitinib 15 mg QD
This includes AEs occurred under upadacitinib 15 mg QD exposure from subjects 
starting on upadacitinib 15 mg QD and subjects switching from placebo to 
upadacitinib 15 mg QD.
2.
Any upadacitinib 30 mg QD
This includes AEs occurred under upadacitinib 30 mg QD exposure from subjects 
starting on upadacitinib 30 mg QD and subjects switching form placebo to 
upadacitinib 30 mg QD.
3.
Any adalimumab 40 mg EOW
Exposure-Adjusted Event Rate (EAER)
To adjust for potentially different follow-up time between treatment groups, EAER will 
be provided. For the purpose of event rate calculation, the numerator will be the total 
number of AEs reported for the event (i.e., a subject can contribute more than one event to 
the numerator) and the denominator will be the total exposure time among subjects under 
the treatment group. The number of AEs reported (numerator), the total number of years 
of study drug exposure (denominator), and the exposure-adjusted AE event rate per 
100 patient-years, calculated as ([numerator/denominator])*100, will be presented for 
each treatment group. The EAER will be the main approach to evaluate AEs in the long-
term analysis.
The exposure adjusted incidence rate (censored at the time of first event) may be 
conducted for selected AESI endpoints as appropriate for long-term analysis.


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10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
An overview of AEs per 100 patient-years of study exposure will be presented by 
treatment group for the following AE categories.
●
All TEAEs 
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events 
●
TEAEs reasonably possibly related to study drug
●
TEAEs of special interest
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
Deaths (includes all deaths – treatment-emergent and non-treatment-emergent)
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
For each treatment group, the TEAE rate per 100 patient-years of exposure will be 
calculated overall, for each SOC and each PT, for each of the following events:
●
All TEAEs 
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events 
●
TEAEs with a reasonable possibility of being related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death


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10.2.2.3
Adverse Events of Special Interest Rates per
100 Patient-Years of Study Drug Exposure
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented for each treatment group in overview as well as using SOC and PT.  The AESI 
categories will be identified per Standard MedDRA Queries (SMQs)/Company MedDRA 
Queries (CMQs).  Adjudicated cardiovascular events will be summarized and presented 
by treatment group using the CAC adjudicated categories.
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation
All serious adverse events (SAEs), deaths, and adverse events leading to discontinuation 
of study drug will be listed.
10.3
Analysis of Laboratory Data
10.3.1
Variables and Units
All laboratory parameters to be collected in this study are listed below.  Laboratory 
parameters will be reported using the standard international (SI) units.


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Table 12.
List of Laboratory Variables
Laboratory Variables
Hematology
White Blood Cell (WBC) Count
Red Blood Cell (RBC) Count
Hemoglobin
Hematocrit
Platelets count
Neutrophils
Basophils
Eosinophils
Lymphocytes
Monocytes
Bands
Chemistry
Total Bilirubin
Alkaline Phosphatase (ALP)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Sodium
Potassium
Calcium
Inorganic Phosphorus
Creatine Phosphokinase (CPK)
Chloride
Bicarbonate


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Table 12.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry (Continued)
Cholesterol
LDL cholesterol
HDL cholesterol
LDL/HDL ratio
Cholesterol/HDL ratio
Urinalysis
Specific Gravity
pH
Protein
Glucose
Ketones
Blood
Microscopic Examination (if needed)
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Other
hs-CRP
ESR
10.3.2
Analysis of Laboratory Data by Week 24
The laboratory data will be summarized by the "as treated" treatment groups 
(Upadacitinib 15 mg QD, Upadacitinib 30 mg QD, ADA 40 mg EOW and combined 
placebo groups).
10.3.2.1
Assessment of Clinical Laboratory Variables
Analyses of hematology, chemistry, and urinalysis variables which are measured 
longitudinally will be performed by visits and by treatment groups.  For analysis at each 


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visit, the following summary statistics of visit values will be presented for each treatment 
group:  sample size, mean, standard deviation, minimum, median, and maximum.  
An ANOVA model with treatment as a factor will be used to compare change from 
baseline between different treatment groups for selected laboratory parameters.  Mean 
difference from placebo/ADA and associated 95% CIs will be presented.  The analysis 
applies to the following laboratory parameters of clinical interest:  hemoglobin, platelets, 
lymphocytes, neutrophils, creatinine, ALT, AST, creatine phosphokinase (CPK), LDL, 
HDL, total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol, and total 
cholesterol.
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables
The baseline and post-baseline laboratory observations will be categorized as Grade 0, 
Grade 1, Grade 2, Grade 3, and Grade 4 and shifts from baseline grade to worst on-
therapy grade will be summarized.  Toxicity grading scale is based on National Cancer 
Institute Common Toxicity Criteria (NCI CTC) AE version 4.03. Shift tables from 
Baseline according to the grades will be provided for laboratory variables.
For LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides, the following 
categories according to National Cholesterol Education Program (NCEP) Adult Treatment 
Panel III (ATP III) guidelines will be used.
●
LDL cholesterol (< 3.36, ≥ 3.36 and < 4.14, ≥ 4.14 mmol/L)
●
HDL cholesterol (< 1.03, ≥ 1.03 mmol/L)
●
Total cholesterol (< 5.17, ≥ 5.17 and < 6.21, ≥ 6.21 mmol/L)
●
Triglycerides (< 1.69, ≥ 1.69 and < 2.26, ≥ 2.26 mmol/L)
Note that the minimum/maximum category is used, rather than the category of the 
minimum/maximum value.  The two may be different due to variation in the reference 
range.


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No statistical tests will be performed for this analysis.
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory 
Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 2, Grade 3, Grade 4 and ≥Grade 3(if applicable), with a grade 
worsening compared to baseline.  Toxicity grading scale is based on National Cancer 
Institute Common Toxicity Criteria (NCI CTC) AE version 4.03. The number and 
percentage of subjects meeting the criteria for potentially clinically significant laboratory 
values will be summarized by treatment groups.
10.3.2.4
Assessment of Liver Elevations
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (bilirubin 
elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., significant 
elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a potential for 
the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized by treatment groups:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN


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●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
10.3.3
Analysis of Long-Term Laboratory Data
10.3.3.1
Assessment of Clinical Laboratory Variables
Analyses of hematology, chemistry, and urinalysis variables which are measured 
longitudinally will be performed by visits and by treatment group sequences as described 
in Section 10.1.  For each analysis, the following summary statistics of visit values will be 
presented for each treatment group sequence:  sample size, mean, standard deviation, 
minimum, median and maximum.
Analyses will be performed for change from baseline in hemoglobin, lymphocytes, 
neutrophils, creatinine, and creatine phosphokinase (CPK).
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory 
Values
Long-term laboratory data will be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinical significant laboratory values and by 
the actual treatment received at the time of the event occurrence.  The treatment groups 
are the same as the ones for long-term AE analysis as described in Section 10.2.2.  
A subject can be counted under different treatment groups if he/she was on placebo from 
baseline to Week 24 and then started upadacitinib 15 or 30 mg at Week 24 and 
experienced potentially clinical significant laboratory values under different treatment 
groups.


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In the evaluation of potentially clinically significant laboratory values, the baseline value 
will be determined by the last non-missing measurement recorded on or before the date of 
the first dose of study drug in the corresponding treatment group (which may be different 
than the first dose of study drug received in the study).  For example, for a subject who 
started on placebo and switched to upadacitinib 15 mg QD at Week 24, lab values under 
upadacitinib 15 mg QD exposure would be evaluated against the baseline value defined as 
the last non-missing measurement recorded on or before the date of the first dose of 
upadacitinib 15 mg QD.
A listing of all subjects with any laboratory determination meeting CTCAE criteria of 
Grade 3 or above with a grade worsening compared to baseline will be provided.  For 
each of these subjects, the whole course of the respective parameter will be listed.
10.3.3.3
Assessment of Liver Elevations
The frequencies and percentages of subjects with post-baseline liver-specific function test 
values that meet the following criteria of potential clinical interest will be summarized by 
the actual treatment received at the time of the event occurrence, as described in 
Section 10.2.2.
A subject can be counted under different treatment groups if he/she was on placebo from 
baseline to Week 24 and then started upadacitinib 15 or 30 mg at Week 24 and 
experienced potentially clinical significant laboratory values under different treatment 
groups.
A listing of potentially clinically significant liver elevations based on criteria specified 
above will be provided.  For each of these subjects, the whole course of the respective 
parameter will be listed.


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10.4
Analysis of Vital Signs
10.4.1
Variables and Criteria Defining Abnormality
Vital sign variables include sitting systolic blood pressure, sitting diastolic blood pressure, 
pulse rate, and weight.  The criteria for potentially clinically significant vital sign findings 
are presented in Table 13.
Table 13.
Criteria for Potentially Clinically Significant Vital Sign Findings
Vital Sign
Category
Criteria for Potential Clinically Significant Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Pulse
Low
Value ≤ 50 bpm and decrease ≥ 15 bpm from Baseline
High
Value ≥ 120 bpm and increase ≥ 15 bpm from Baseline
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
10.4.2
Analysis of Vital Signs by Week 24
Analyses of vital sign variables which are measured longitudinally will be performed by 
visits and by the treatment groups of upadacitinib 15 mg QD, upadacitinib 30 mg QD, 
adalimumab 40 mg EOW, and the combined placebo group.  For each analysis, the 
following summary statistics will be presented for each treatment group:  sample size, 
mean, standard deviation, minimum, median, and maximum.  
The number and percentage of subjects meeting the criteria for potentially clinically 
significant vital sign values will be summarized by treatment group.
10.4.3
Long-Term Analysis of Vital Signs
Analyses of vital signs variables which are measured longitudinally will be performed by 
visits and by treatment group sequences as described in Section 10.1.  For each analysis, 


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the following summary statistics will be presented for each treatment group:  sample size, 
mean, standard deviation, minimum, median, and maximum.
Long-Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for potentially clinical significant vital sign values and by the 
actual treatment received at the time of the event occurrence.  The treatment groups are 
the same as the ones for long-term AE analysis as described in Section 10.2.2.  A subject 
can be counted under different treatment groups if he/she was on placebo from baseline to 
Week 24 and then started upadacitinib 15 or 30 mg at Week 24 and experienced 
potentially clinical significant laboratory values under different treatment groups.  In the 
evaluation of potentially clinically significant vital sign values, the baseline value will be 
determined by the last non-missing measurement recorded on or before the date of the 
first dose of study drug in the corresponding treatment group, similarly as described in 
Section 10.3.3.2.
A listing of all subjects with any vital sign values meeting the criteria for potentially 
clinically significant vital signs will be provided.  For each of these subjects, the whole 
course of the respective parameter will be listed.
11.0
References
1.
Bretz F, Maurer W, Brannath W, et al.  A graphical approach to sequentially 
rejective multiple test procedures.  Stat Med.  2009;28(4):586-604.
2.
Greenland S, Rothman KJ, Lash TL.  Introduction to stratified analysis.  In:  
Rothman KJ, Greeland S, Lash TL, editors.  Modern Epidemiology.  3rd Ed.  
Philaphdelphia:  Lippincott Williams & Wilkins; 2008.
3.
Koch GG.  Comments on 'current issues in non-inferiority trials'.  Stat Med.  
2008;27(3):333-42.
4.
Carpenter JR, Kenward MG.  Multiple Imputation and Its Application.  New York:  
John Wiley & Sons; 2013.


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5.
Ratitch B, Lipkovich I, O'Kelly M.  Combining analysis results from multiply 
imputed categorical data.  In:  Conference Proceedings from PharmaSUG 2013.  
May 12-15, 2013; Chicago, IL. Paper SP03.
6.
Liu GF, Wang J, Liu K, et al.  Confidence intervals for an exposure adjusted 
incidence rate difference with application to clinical trials.  Stat Med.  
2006;25(8):1275-86.


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Appendix A.
SAS Procedure for Mantel-Haenszel Test
A SAS procedure, the Proc Freq, will be used to compute the statistics using the Mantel-
Haenszel method.2  Risk difference, 95% CI and p value will be provided through the 
program.
SAS code example:
title 'Placebo vs ABT-494 30 mg QD';
proc freq data= wk12_nri;
where TRTP='Placebo'|TRTP='ABT-494 30 mg QD';
table TRTP*aval/ nopercent nocol chisq riskdiff(cl=wald) 
alpha=0.05;
run;
title2 'For p-values';
proc freq data=wk12_nri;
where TRTP='Placebo'|TRTP='ABT-494 30 mg QD';
tables DMARDBL*TRTP*aval/ cmh;
run;


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Appendix B.
Tipping Point Analysis for ACR20 at Week 12
To assess the robustness of the primary analysis using NRI data handling, tipping point 
analysis is conducted on the primary endpoint ACR20.  The analysis is conducted on the 
FAS using As Observed data handling.
The tipping point analysis will be performed by multiple imputations using logistic 
regression, allowing the imputed ACR response rate to systematically vary from 0% to 
100% in both upadacitinib and placebo, respectively.  This will be accomplished by 
modifying the predicted probabilities for the responses through shifting the log odds 
ratios,4 then directly sampling the missing ACR20 response from the Bernoulli 
distribution with the modified probabilities.
For each pair of shift parameters, the same CMH method used for the primary endpoint 
will be performed on each of the multiple imputed datasets to obtain the results for each 
comparison of the upadacitinib treatment group versus the placebo group.  Because chi-
square distribution of CMH test statistic is skewed from the normal distribution, to 
combine the results from the CMH test using Rubin's method, a transformation will be 
conducted to normalize the CMH statistic.5  These transformed results will be then 
aggregated using Rubin's method to get P-values.


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Appendix C.
Three Arm Approach to Non-Inferiority (NI) Testing
Let parameters T, R and P represent the ACR20 response rates for an upadacitinib dose 
group, the adalimumab group, and the combined placebo group respectively and let n be 
the sample size per group (as all groups have an equal sample size).  Let α denote the 
type 1 error rate and β denote the type 2 error rate (so 1-β is the test power).  The null and 
alternative hypotheses of non-inferiority testing have the form:
:  − ≤−(1 −)( −)  .  :  − > −(1 −)( −).
 is a pre-specified fraction of reference drug effect to be retained by test drug, and it is 
set to be 50% in this NI comparison.  Using the three-arm approach, both  − and  −
 are estimated from the current clinical trial.  The three-arm approach test statistic has 
the following form:
 =
 ! − " + (1 −)( " − #)
$ !(1 − !)
%
+  "(1 − ")
%
+ (1 −) #(1 − #)
%
,
where  !,  " and  # are the sample ACR20 response rates for the upadacitinib dose group, 
the adalimumab group, and the combined placebo group respectively.  The null 
hypothesis is rejected at a two-sided ' level if  > (/ , where (/ is the upper '/2
percentile of the standard normal distribution.


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Appendix D.
Details of Supplementary Analyses for Ranked Secondary 
Continuous Endpoints
Tipping Point Analysis for Key Secondary Non-Radiographic Continuous Endpoints
To assess the impact of potential departures from the missing-at-random assumption, 
tipping point analyses are conducted as a sensitivity check for change from baseline in 
key secondary non-radiographic continuous endpoints at the protocol defined primary 
time point.
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on the upadacitinib treatment groups and the placebo group are allowed to vary 
independently.  In addition, the focus is on scenarios where missing outcomes on 
upadacitinib are worse than the imputed values on upadacitinib, while missing outcomes 
on placebo are better than the imputed values on placebo.  Missing values are 
first imputed via MI under MAR (where the MI imputation is performed upon AO data), 
and then a shift parameter is applied to the imputed values (a different shift parameter 
may be specified for each treatment group).  This is implemented by PROC MI using the 
MNAR statement.
More specifically, PROC MI using the fully conditional specification (FCS) method will 
be performed to impute any missing value and therefore does not rely on a monotone 
missing pattern. In fact, the FCS method can handle any arbitrary missing data pattern. 
Treatment is included in the FCS imputation model to enable sampling conditional on 
treatment groups. Additionally, the imputation model includes stratification factor of 
current use of non-biologic DMARD (yes/no), gender, race (white vs. non-white), age, 
baseline BMI, geographic regions, duration of PsA diagnosis and the baseline value of the 
endpoints of interest, as well as longitudinal response observed at any other visits. The 
SAS code example is as follows:
For a given pair of shift parameters, the SAS code example is as follows:


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PROC MI DATA=DATA_WIDE OUT=DATA_WIDE_BOUNDED NIMPUTE=20 
SEED=12345;  
     CLASS TRTP &COVCAT;     
     FCS;
  By trtp;
     
     VAR &COVCON &COVCAT WEEK_2 WEEK_4 WEEK_8 WEEK_12;  
MNAR ADJUST (WEEK_12 / SHIFT=&SJ1 
ADJUSTOBS=(TRTP='PLACEBO'));
MNAR ADJUST (WEEK_12 / SHIFT=&SJ2 ADJUSTOBS=(TRTP='UPA 
15MG'));
RUN; 
Note:
The input dataset is in wide format.  TRTP denotes the treatment group. &COVCON denotes 
baseline continuous covariates including baseline age, baseline BMI, duration of PsA diagnosis 
and baseline value of the endpoint of interest. &COVCAT denotes categorical covariates 
including current use of non-biologic DMARD, gender, race, and regions.  WEEK_2, 
WEEK_4, WEEK_8, WEEK_12 denote the observed values at each visit.  &SJ1and &SJ2 
denote the shift parameters for the placebo group and upadacitinib 15 MG group respectively.
In cases where the shifted values are smaller than the minimum or larger than maximum 
value of the endpoint, (i.e., out of range), the minimum or maximum value of the endpoint 
is used in further analysis steps.  For each pair of shift parameters, the SAS procedure 
PROC MIXED is used for ANCOVA analysis with Huber-White sandwich errors which 
includes the fixed effects of treatment, the stratification factor of current DMARD use and 
the continuous fixed covariate of baseline measurement on each of the multiple imputed 
datasets to obtain the results for each upadacitinib treatment group versus the placebo 
group comparison.  These results will be aggregated using Rubin's method to get p-values.  
If one pair of shift parameters are found to just reverse the study conclusion, in terms of p-
value larger than 0.05 (the original p-value < 0.05), then the shift parameters are identified 
as the tipping point.  The results for a grid of shift parameter combinations are provided in 
tabular format.
The SAS code example of the data imputation step for tipping point analysis using MI is 
provided above. The SAS code example for the analysis and results combination step 
using PROC MIXED and PROC MIANALYZE is as follows:
PROC MIXED DATA=ALL EMPIRICAL;      


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    ODS OUTPUT LSMEANS=MIXEDLSMEANS DIFFS=DIFF;      
    BY Shift1 Shift2 _IMPUTATION_;      
    CLASS TRTP STRATA USUBJID;    
    MODEL CHG = BASELINE TRTP STRATA / SOLUTION;      
LSMEANS TRTP / CL PDIFF DIFF; 
Repeated/subject = USUBJID;
RUN;
DATA DIFF1; 
    SET DIFF;      
    COMPARISON= TRTP||' VS '||LEFT(_TRTP); 
RUN; 
PROC SORT DATA=DIFF1; BY COMPARISON Shift1 Shift2 _IMPUTATION_; RUN;
PROC MIANALYZE DATA=DIFF1;      
    ODS OUTPUT PARAMETERESTIMATES=GROUP_OUTPUT;      
    BY comparison shift1 shift2;      
    MODELEFFECTS ESTIMATE;      
    STDERR STDERR; 
RUN; 
/* Comparison of “UPA 15 mg” vs. “Placebo” */
data miparm1;
set GROUP_OUTPUT;
if comparison='1            VS            2' then output miparm1;
run;
proc transpose data=miparm1(keep= Shift1 Shift2 Probt)
out=wide_miparm1;
by shift1;
id shift2;
var Probt;
run;
Note:
The input dataset ALL includes all (# of shift1 parameters) * (# of shift2 parameters) * (# of imputations in 
MI) imputed datasets.  TRTP denotes the treatment group and STRATA denotes the stratification factor used 
in analysis.  CHG denotes the change from baseline value and BASELINE denotes the baseline value.
MI Analysis for Radiographic Continuous Endpoints
The MI analysis will impute missing data multiple times under appropriate random 
variation and thus generate multiple imputed "pseudo-complete" datasets. The imputation 
assumes of missing at random (MAR). ANCOVA will be performed on each of the 
multiple imputed datasets. The results will be aggregated across the multiple imputed 
datasets using Rubin's method. The SAS procedure PROC MI with the monotone 


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statement and REGRESSION method is used. Before applying PROC MI, MCMC is 
applied where necessary to augment data into monotone missing pattern. The SAS code 
example for PROC MI is as follows:
PROC MI DATA=DATA_WIDE OUT=OUTMI NIMPUTE=1 SEED=12345;     
     
     
     Mcmc impute = monotone;      
     VAR &COVCON base aval; 
By trtp;       
RUN;
PROC MI DATA=DATA_WIDE OUT=OUTMI NIMPUTE=20 SEED=12345;     
     
     CLASS &COVCAT;     
     MONOTONE;     
     VAR &COVCON &COVCAT base aval; 
By trtp;       
RUN;
Note:
The input dataset is in wide format.  TRTP denotes the treatment group. &COVCON denotes baseline 
continuous covariates including baseline age, baseline BMI, duration of PsA diagnosis and baseline value of 
the endpoint of interest. &COVCAT denotes categorical covariates including current use of non-biologic 
DMARD, gender, race and regions. WEEK_16, WEEK_24 denote the observed values at each visit.
PROC MIXED DATA=ALL;      
    ODS OUTPUT LSMEANS=MIXEDLSMEANS DIFFS=DIFF;      
    BY_IMPUTATION_;      
    CLASS TRTP STRATA;    
    MODEL CHG = BASELINE TRTP STRATA / SOLUTION;      
LSMEANS TRTP / CL PDIFF DIFF; 
RUN;
DATA DIFF1; 
    SET DIFF;      
    COMPARISON= TRTP||' VS '||LEFT(_TRTP); 
RUN; 
PROC SORT DATA=DIFF1; BY COMPARISON_IMPUTATION_; RUN;
PROC MIANALYZE DATA=MIXEDLSMEANS1;
ODS OUTPUT PARAMETERESTIMATES=GROUP_OUTPUT;
BY TRTP;
MODELEFFECTS ESTIMATE;


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STDERR STDERR;
RUN;
PROC MIANALYZE DATA=DIFF1;      
    ODS OUTPUT PARAMETERESTIMATES=GROUP_OUTPUT;      
    BY comparison;      
    MODELEFFECTS ESTIMATE;      
    STDERR STDERR; 
RUN; 
Note:
The input dataset ALL includes all 20 imputed datasets. TRTP denotes the treatment group and STRATA 
denotes the stratification factor used in analysis.  CHG denotes the change from baseline value and 
BASELINE denotes the baseline value.


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Appendix E.
Exposure Adjusted AE Rate Difference and Normal Approximation 
Based 95% Confidence Interval6
Assume the occurrence of TEAE of special interest follows a Possion distribution and let 
λ denote the rate of occurrence of TEAE under the total exposure time for a treatment 
group.  Let n1 and n2 be the number of AEs reported in an upadacitinib dose group and the 
combined placebo group, respectively.  Let T1 and T2 be the total number of days exposed 
to study drug summed across all treated subjects in an upadacitinib dose group and the 
combined placebo group.  Under the assumption that n1 and n2 follow independent 
Possion distribution with parameters λ1T1 and λ2T2, the *+= n1/T1 and *+= = n2/T2.  So the 
exposure adjusted TEAE rate difference can be estimated by
, = *+ − *+
Using normal approximation, the 95% confidence interval can be calculated by
*+ − *+ ± ⍺//0
Where /1 = 2%/
 + %/