Clinical trial NCT03104374
Conditions: Psoriatic Arthritis
Keywords: Arthritis Psoriasis Anti-Rheumatic Anti-inflammatory Joint disease Musculoskeletal disease
Sponsor: AbbVie
Start date: 2017-05-01; Completion date: 2024-09-30
Enrollment: 642 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 multicenter study that includes two periods. Period 1 is designed to compare the safety, tolerability, and efficacy of ABT-494 Dose A once daily (QD) and Dose B QD versus placebo in participants with moderately to severely active Psoriatic Arthritis (PsA) who have an inadequate response to Biological Disease Modifying Anti-Rheumatic Drug (bDMARDs). Period 2 evaluates the safety, tolerability and efficacy of ABT-494 Dose A QD and Dose B QD in subjects with PsA who have completed Period 1.

Detailed description:

Arms: arm 1: It is administered once daily. arm 2: It is administered once daily. arm 3: It is administered once daily. arm 4: It is administered once daily.
Interventions: intervention 1: Placebo intervention 2: ABT-494
Intervention descriptions: intervention 1: Oral tablet intervention 2: Oral tablet

Protocol documents:
Prot_000.pdf: 
ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
1
1.0
Title Page
Clinical Study Protocol M15-554
A Phase 3, Randomized, Double-Blind, Study 
Comparing Upadacitinib (ABT-494) to Placebo in 
Subjects with Active Psoriatic Arthritis Who Have a 
History of Inadequate Response to at Least One 
Biologic Disease Modifying Anti-Rheumatic Drug 
(bDMARD) – SELECT – PsA 2
Incorporating Administrative Change 1, 2 and 
Amendments 1, 2, 2.01 (VHP Countries), 3, 4, 5, 6 
and 7
AbbVie Investigational
Product:
ABT-494
Date:
01 April 2020
Development Phase:
3
Study Design:
A Phase 3, randomized, double-blind, parallel-group, placebo-controlled, 
multicenter study
EudraCT Number:
2016-004152-30
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  
NCT03104374


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
2
Sponsor/Emergency 
  Contact:
AbbVie 
1 North Waukegan Road
North Chicago, IL 60064
Phone:
Mobile:
Fax:
Email:
Emergency 24 hour Number:
* The specific contact details of the AbbVie legal/regulatory entity (person) within the relevant country are 
provided within the clinical trial agreement with the Investigator/Institution and in the Clinical Trial 
Application with the Competent Authority.
This study will be conducted in compliance with the protocol, Good Clinical Practice and all other 
applicable regulatory requirements, including the archiving of essential documents.
Confidential Information
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
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1.1
Protocol Amendment:  Summary of Changes
Previous Protocol Versions
Protocol 
Date
Original
10 February 2017
Amendment 1
27 February 2017
Amendment 2
03 March 2017
Administrative Change 1
19 May 2017
Amendment 2.01 (VHP Countries)
21 June 2017
Amendment 3
07 July 2017
Amendment 4
23 March 2018
Administrative Change 2
15 November 2018
Amendment 5
14 January 2019
Amendment 6
04 October 2019
The purpose of this amendment is to:
●
Apply administrative changes throughout protocol
Rationale:  Revised text to improve consistency and readability, and/or 
provide clarification.
!
Update Section 3.2 Benefits and Risks, paragraph 4
Rationale:  To update safety information regarding risk of pregnancy in 
female partners of male subjects.
●
Update Section 5.2.3.2 Permitted Background Therapy, paragraph 4
Rationale:  To ensure subject safety by clarifying that oral corticosteroid dose 
may not exceed the maximum dose (equivalent to prednisone ≤10 mg/day) 
defined in the inclusion criteria, Section 5.2.1.
●
Update Section 5.3.1.1 Study Procedures, Hepatitis Screening, Last Bullet
Rationale:  Where mandated that testing should be performed every 12 weeks, 
clarified that HBV DNA PCR may be tested at unscheduled visits. 
●
Update Section 5.3.1.1 Study Procedures, Hepatitis Screening, Figure 2
footnote


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
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Rationale:  Where mandated that testing should be performed every 12 weeks, 
clarified that HBV DNA PCR may be tested at unscheduled visits.
●
Update Section 5.4.1 Discontinuation of Individual Subjects
Rationale: To clarify that the development of gastrointestinal perforation due 
to appendicitis or mechanical injury will not require study drug 
discontinuation as these types of events differ from those of potential concern 
with IL-6 inhibition.
Rationale:  To add an additional safety precaution for subjects, given the 
recent concerns raised for the JAK inhibitor class regarding thrombosis risk.
●
Update Section 5.5.7 Drug Accountability
Rationale: Verification of study drug receipt is done in the IRT and paper 
documents are no longer required nor kept in site files.
●
Update Section 6.1.7 Toxicity Management
Rationale: To clarify that the development of gastrointestinal perforation due 
to appendicitis or mechanical injury will not require study drug 
discontinuation as these types of events differ from those of potential concern 
with IL-6 inhibition.
Rationale:  To add an additional safety precaution for subjects, given the 
recent concerns raised for the JAK inhibitor class regarding thrombosis risk.
Rationale:  To clarify when additional eCRFs are required in the management 
of select laboratory abnormalities.
●
Update Table 4, Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values
Rationale: To clarify guidelines for toxicity management and maintain subject 
safety.
●
Update Section 6.1.9 Cardiovascular Adjudication Committee 
Rationale: To clarify that the cardiovascular adjudication committee also 
assesses potential embolic and thrombotic AEs.
●
Update Appendix B, List of Protocol Signatories
Rationale:  To update a title in the List of Protocol Signatories.
●
Update Appendix C, Study Activities, Other Central Lab tests


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
5
Rationale:  To remove the 'X' from Week 12 and Week 24 to clarify that these 
timepoints are only relevant for Hepatitis B testing for Japan or where 
mandated by local requirements.
●
Update Appendix C, Study Activities, Footnote w 
Rationale:  Where mandated that testing should be performed every 12 weeks, 
clarified that HBV DNA PCR may be tested at unscheduled visits.
An itemized list of all changes made to this protocol under this amendment can be found 
in Appendix H.


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
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1.2
Synopsis
AbbVie Inc.
Protocol Number:  M15-554
Name of Study Drug:  ABT-494
Phase of Development:  3
Name of Active Ingredient:  ABT-494
Date of Protocol Synopsis:  01 April 2020
Protocol Title:  A Phase 3, Randomized, Double-Blind, Study Comparing Upadacitinib (ABT-494) to 
Placebo in Subjects with Active Psoriatic Arthritis Who Have a History of Inadequate Response to at 
Least One Biologic Disease Modifying Anti-Rheumatic Drug (bDMARD) – SELECT – PsA 2
Objectives:  
Period 1
1.
To compare the efficacy of ABT-494 15 mg once daily (QD) and 30 mg QD versus placebo for the 
treatment of signs and symptoms in subjects with moderately to severely active Psoriatic Arthritis 
(PsA) who have an inadequate response to bDMARDs (Bio-IR).
2.
To compare the safety and tolerability of ABT-494 15 mg QD and 30 mg QD versus placebo in 
subjects with moderately to severely active PsA who have an inadequate response to bDMARDs.
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 165 sites
Study Population:  Patients with active PsA despite prior use of at least one bDMARD.
Number of Subjects to be Enrolled:  Approximately 630
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 period followed by an 
additional 32 weeks of blinded 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 in subjects with 
moderately to severely active PsA who have an inadequate response to bDMARDs (Bio-IR).  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 630 subjects at approximately 165 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 treatment followed by 32 weeks of treatment blinded to 
the dose of ABT-494 (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); and a 
30-day follow-up call or visit.


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M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
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Methodology (Continued):
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, and number of prior failed (had an inadequate 
response to) biologic DMARDs (1 vs > 1), except for subjects from Japan, for which randomization will 
be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA) only, and then will be 
randomized in a 2:2:1:1 ratio to one of four treatment groups:
Group 1:  ABT-494 15 mg QD (N = 210) 
Group 2:  ABT-494 30 mg QD (N = 210) 
Group 3:  Placebo followed by ABT-494 15 mg QD (N = 105)
Group 4:  Placebo followed by ABT-494 30 mg QD (N = 105)
No more than approximately 40% of subjects will be enrolled with < 3% BSA extent of psoriasis and no 
more than approximately 30% of subjects will be enrolled with prior failure of more than 1 biologic 
DMARD.
Subjects will receive oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or matching placebo) until 
the end of the study or they discontinue study drug.
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 will continue to receive ABT-494 15 mg QD or ABT-494 30 mg QD, respectively, 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 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 bDMARD prior to the Screening visit and must have 
discontinued all bDMARDs prior to the first dose of study drug.  No background non-biologic DMARD 
therapy is required during participation in this study.  For subjects who are on non-biologic DMARD 
therapy at baseline (methotrexate (MTX), sulfasalazine (SSZ), leflunomide (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 
Sections 5.2.3.1 and 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.  
At Week 24, all subjects allocated to placebo at Baseline will be switched to blinded ABT-494 
(randomized at baseline to either 15 mg QD or 30 mg QD) treatment regardless of clinical response.


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
8
Methodology (Continued):
After the last subject completes 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.
Diagnosis and Main Criteria for Inclusion/Exclusion:  
Main Inclusion:  
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.
Diagnosis of active plaque psoriasis or documented history of plaque psoriasis
5.
Subject has had an inadequate response (lack of efficacy after a minimum 12 week duration of 
therapy) or intolerance to treatment with at least 1 bDMARD
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 
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.
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
Duration of Treatment:  152 weeks


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
9
Criteria for Evaluation:
Efficacy:
The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12.
The key multiplicity adjusted secondary efficacy endpoints (each dose of ABT-494 versus placebo) are:
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;
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with ≥ 3% BSA 
psoriasis at baseline);
4.
Change from baseline in SF-36 PCS at Week 12;
5.
Change from baseline in FACIT-Fatigue Questionnaire at Week 12; 
6.
Proportion of subjects achieving Minimal Disease Activity (MDA) at Week 24;
7. 
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 of Disease Activity NRS, 
PGA of Disease Activity NRS, HAQ-DI, or hs CRP.
The proportion of subjects achieving MDA will be determined based on subjects fulfilling 5 of 
7 outcome measures:  TJC ≤ 1; SJC ≤ 1; PASI ≤ 1 or BSA-Ps ≤ 3%; patient assessment of pain 
≤1.5 (0 – 10 NRS); PtGA-disease activity ≤ 2 (0 – 10 NRS); HAQ-DI score ≤ 0.5; and tender entheseal 
points ≤1.
The following outcome measures will be assessed at scheduled time points other than those specified for 
the primary and key secondary variables:
!
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;
o
Change from baseline in Patient's Global Assessment (PtGA) – Disease Activity;
o
Change from baseline in Patient's Assessment of Pain Numerical Rating Scale (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 LEI;
!
Proportion of subjects with resolution of enthesitis sites included in the LEI;


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M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
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Criteria for Evaluation (Continued):
Efficacy (Continued):
!
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-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).


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
11
Criteria for Evaluation (Continued):
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.
Criteria for Evaluation (Continued):
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 the global analysis, comparisons of the primary and key secondary efficacy endpoints will be made 
between the ABT-494 15 mg QD and 30 mg QD groups versus the combined placebo groups for all 
subjects.  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.
For binary endpoints, frequencies and percentages will be reported for each treatment group.  Pairwise 
comparisons for each of the ABT-494 treatment groups to the combined placebo groups will be 
conducted using the Cochran-Mantel-Haenszel test adjusting for main stratification factors.
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 to 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.
Long-Term Efficacy for Period 1 and Period 2 Combined:
Long-term efficacy by time point will be summarized using descriptive statistics.


ABT-494
M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
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Statistical Methods (Continued):
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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M15-554 Protocol Amendment 7
EudraCT 2016-004152-30
13
1.3
List of Abbreviations and Definition of Terms
Abbreviations
ACR
American College of Rheumatology
ADL
Activities of Daily Living
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALC
Absolute Lymphocyte Count
ALT
ALT
ANC
Absolute Neutrophil Count
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
bDMARD
Biological Disease Modifying Anti-Rheumatic Drug
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
DAPSA
Disease Activity In Psoriatic Arthritis


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DAS
Disease Activity Score
DMARD
Disease Modifying Anti-Rheumatic Drug
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EDC 
Electronic Data Capture
EDTA
Edetic acid (ethylenediaminetetraacetic acid)
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
IRB
Institutional Review Board


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15
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)
PRO
Patient-Reported Outcome


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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
T2T
Treat-To-Target
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 .....................................................................................................6
1.3
List of Abbreviations and Definition of Terms........................................13
2.0
Table of Contents...................................................................18
3.0
Introduction ...........................................................................23
3.1
Differences Statement..............................................................................29
3.2
Benefits and Risks....................................................................................29
4.0
Study Objective......................................................................31
5.0
Investigational Plan...............................................................31
5.1
Overall Study Design and Plan:  Description ..........................................31
5.2
Selection of Study Population..................................................................38
5.2.1
Inclusion Criteria .....................................................................................38
5.2.2
Exclusion Criteria ....................................................................................40
5.2.3
Prior, Concomitant, and Prohibited Therapy ...........................................45
5.2.3.1
Prior Therapy ...........................................................................................46
5.2.3.2
Permitted Background Therapy ...............................................................46
5.2.3.3
Prohibited Therapy...................................................................................48
5.2.3.4
Rescue Therapy........................................................................................52
5.2.4
Contraception Recommendations ............................................................53
5.3
Efficacy and Safety Assessments/Variables ............................................56
5.3.1
Efficacy and Safety Measurements Assessed ..........................................56
5.3.1.1
Study Procedures .....................................................................................56
5.3.1.2
Optional Samples for Exploratory Research and Validation 
Studies......................................................................................................78
5.3.2
Drug Concentration Measurements .........................................................79
5.3.2.1
Measurement Methods.............................................................................80
5.3.3
Efficacy Variables....................................................................................80
5.3.3.1
Primary Variables ....................................................................................80
5.3.3.2
Key Secondary Variables.........................................................................81
5.3.3.3
Additional Variables ................................................................................82


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5.3.4
Safety Variables.......................................................................................84
5.3.5
Pharmacokinetic Variables ......................................................................84
5.3.6
Exploratory Research and Validation Studies Variables.........................84
5.4
Removal of Subjects from Therapy or Assessment.................................85
5.4.1
Discontinuation of Individual Subjects....................................................85
5.4.2
Discontinuation of Entire Study...............................................................87
5.5
Treatments................................................................................................87
5.5.1
Treatments Administered.........................................................................87
5.5.2
Identity of Investigational Product(s) ......................................................88
5.5.2.1
Packaging and Labeling...........................................................................88
5.5.2.2
Storage and Disposition of Study Drug(s) ...............................................88
5.5.3
Method of Assigning Subjects to Treatment Groups...............................89
5.5.4
Selection and Timing of Dose for Each Subject......................................90
5.5.5
Blinding....................................................................................................91
5.5.5.1
Blinding of Investigational Product.........................................................91
5.5.5.2
Blinding of Data for Data Monitoring Committee (DMC)......................92
5.5.6
Treatment Compliance.............................................................................92
5.5.7
Drug Accountability.................................................................................92
5.6
Discussion and Justification of Study Design..........................................93
5.6.1
Discussion of Study Design and Choice of Control Groups....................93
5.6.2
Appropriateness of Measurements...........................................................94
5.6.3
Suitability of Subject Population .............................................................94
5.6.4
Selection of Doses in the Study ...............................................................95
6.0
Complaints .............................................................................96
6.1
Medical Complaints.................................................................................96
6.1.1
Definitions................................................................................................97
6.1.1.1
Adverse Event..........................................................................................97
6.1.1.2
Serious Adverse Events ...........................................................................98
6.1.1.3
Adverse Events of Special Interest ..........................................................99
6.1.2
Adverse Event Severity..........................................................................100
6.1.3
Relationship to Study Drug....................................................................101
6.1.4
Adverse Event Collection Period...........................................................101
6.1.5
Serious Adverse Event Reporting and Malignancy Reporting..............102


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6.1.6
Pregnancy...............................................................................................104
6.1.7
Toxicity Management ............................................................................105
6.1.8
Data Monitoring Committee and Trial Monitoring Committee.............110
6.1.9
Cardiovascular Adjudication Committee...............................................110
6.2
Product Complaint .................................................................................110
6.2.1
Definition ...............................................................................................110
6.2.2
Reporting................................................................................................111
7.0
Protocol Deviations..............................................................111
8.0
Statistical Methods and Determination of Sample 
Size ........................................................................................112
8.1
Statistical and Analytical Plans..............................................................112
8.1.1
Analysis Populations..............................................................................113
8.1.1.1
Full Analysis Set (FAS).........................................................................113
8.1.1.2
Per Protocol Analysis Set.......................................................................113
8.1.1.3
Safety Analysis Set ................................................................................113
8.1.2
Subject Accountability, Disposition and Study Drug Exposure............114
8.1.2.1
Subject Accountability...........................................................................114
8.1.2.2
Subject Disposition ................................................................................114
8.1.2.3
Study Drug Exposure.............................................................................114
8.1.3
Analysis of Demographic and Baseline Characteristics ........................115
8.1.4
Efficacy Analysis ...................................................................................115
8.1.4.1
Primary Efficacy Variable .....................................................................115
8.1.4.2
Key Secondary Efficacy Variables ........................................................116
8.1.4.3
Additional Efficacy Variables................................................................116
8.1.4.4
Multiplicity Control for the Primary and Key Secondary 
Endpoints ...............................................................................................116
8.1.4.5
Imputation Methods...............................................................................117
8.1.4.6
Long-Term Efficacy for Period 1 and Period 2 Combined....................117
8.1.5
Safety Analyses......................................................................................118
8.1.5.1
General Considerations..........................................................................118
8.1.5.2
Analysis of Adverse Events...................................................................118
8.1.5.2.1
Treatment-Emergent Adverse Events (TEAE) ......................................118
8.1.5.2.2
Serious Adverse Events and Death ........................................................119


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8.1.5.3
Analysis of Laboratory and Vital Sign Data..........................................120
8.1.6
Pharmacokinetic and Exposure-Response Analyses .............................120
8.2
Determination of Sample Size ...............................................................121
8.3
Randomization Methods ........................................................................121
9.0
Ethics.....................................................................................122
9.1
Independent Ethics Committee (IEC) or Institutional Review 
Board (IRB) ...........................................................................................122
9.2
Ethical Conduct of the Study .................................................................122
9.3
Subject Information and Consent...........................................................123
9.3.1
Informed Consent Form and Explanatory Material ...............................124
9.3.2
Revision of the Consent Form and Explanatory Material .....................124
10.0
Source Documents and Case Report Form 
Completion ...........................................................................124
10.1
Source Documents .................................................................................124
10.2
Case Report Forms.................................................................................125
11.0
Data Quality Assurance ......................................................127
12.0
Use of Information...............................................................127
13.0
Completion of the Study .....................................................128
14.0
Investigator's Agreement....................................................130
15.0
Reference List ......................................................................131
List of Tables
Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and 
Inducers....................................................................................................50
Table 2.
Clinical Laboratory Tests.........................................................................67
Table 3.
Identity of Investigational Product...........................................................88
Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values..................................................................................107
List of Figures
Figure 1.
Study Design............................................................................................35
Figure 2.
Interpretation and Management of HBV Serologic Test Results ............70


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Figure 3.
Adverse Event Collection ......................................................................102
List of Appendices
Appendix A.
Responsibilities of the Clinical Investigator ..........................................137
Appendix B.
List of Protocol Signatories....................................................................139
Appendix C.
Study Activities......................................................................................140
Appendix D.
Study Activities – Optional Samples for Exploratory Research or 
Validation Studies..................................................................................147
Appendix E.
Latent TB Risk Assessment Form Example ..........................................148
Appendix F.
The CASPAR Criteria............................................................................149
Appendix G.
Local Requirements ...............................................................................150
Appendix H.
Protocol Amendment:  List of Changes.................................................154


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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,8 depression, and anxiety than healthy subjects,9 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, 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 
musculoskeletal symptoms is composed of nonsteroidal anti-inflammatory drugs 


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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,1 psoriasis,33 and ankylosing 
spondylitis34), 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 (NCT TBD) 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 the safety, tolerability, and efficacy of ABT-494 in 
subjects with PsA who have had an inadequate response to at least one bDMARD.
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.  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.36-46  
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 (with tofacitinib) support further 
development of ABT-494 in Phase 3 in subjects with PsA.
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 the calculated safety margins for 
human fetal exposure with seminal fluid transfer, there is judged to be no risk to the 
pregnancy of female partners of male subjects who are treated with upadacitinib.
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.


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4.0
Study Objective
Period 1
1.
To compare the efficacy of ABT-494 15 mg once daily (QD) and 30 mg QD versus 
placebo for the treatment of signs and symptoms in subjects with moderately to 
severely active PsA who have an inadequate response or intolerance to bDMARDs 
(Bio-IR). 
2.
To compare the safety and tolerability of ABT-494 15 mg QD and 30 mg QD 
versus placebo in subjects with moderately to severely active PsA who have an 
inadequate response or intolerance to bDMARDs.
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 period followed by an additional 32 weeks of blinded 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 in subjects with moderately to severely active 
PsA who have an inadequate response to bDMARDs (Bio-IR).  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.


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The study is designed to enroll approximately 630 subjects at approximately 165 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 treatment followed by 
32 weeks of treatment blinded to dose of ABT-494 (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); and a 30-day follow-up call or 
visit.
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, and number of prior 
failed (had an inadequate response to) biologic DMARDs (1 vs > 1), except for subjects 
from Japan, for which randomization will be stratified by extent of psoriasis (≥ 3% body 
surface area [BSA] or < 3% BSA) only, and then randomized in a 2:2:1:1 ratio to one of 
four treatment groups: 
Group 1:  ABT-494 15 mg QD (N = 210)
Group 2:  ABT-494 30 mg QD (N = 210)
Group 3:  Placebo followed by ABT-494 15 mg QD (N = 105)
Group 4:  Placebo followed by ABT-494 30 mg QD (N = 105)
No more than approximately 40% of subjects will be enrolled with < 3% BSA extent of 
psoriasis and no more than approximately 30% of subjects will be enrolled with prior 
failure of more than 1 biologic DMARD.
Subjects will receive oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or matching 
placebo) until the end of the study or they discontinue study drug.


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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 3 years).  Subjects will 
continue study treatment as assigned in Period 1.  Subjects will continue to receive 
ABT-494 15 mg QD or ABT-494 30 mg QD, respectively, 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 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 bDMARD prior to the Screening visit 
and must have discontinued all bDMARDs prior to the first dose of study drug.  No 
background non-biologic DMARD therapy is required during participation in this study.  
For subjects who are on non-biologic DMARD therapy at baseline (methotrexate (MTX), 
sulfasalazine (SSZ), leflunomide (LEF), apremilast, hydroxychloroquine (HCQ), 
bucillamine or iguratimod), non-biologic DMARDs should have been started ≥12 weeks 
prior to 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 


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joint, 1 trigger point, 1 tender point, 1 bursa, or 1 enthesis as described in Section 5.2.3.4
(Rescue Therapy).
At Week 24, all subjects allocated to placebo at Baseline will be switched to blinded 
ABT-494 (randomized at baseline to either 15 mg QD or 30 mg QD) treatment regardless 
of clinical response.  
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-
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.
A schematic of the overall study design is shown in Figure 1 below.


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Figure 1.
Study Design
a.
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.
b.
At Week 24, all placebo subjects will switch to ABT-494 15 mg QD or 30 mg QD (1:1 ratio) regardless of 
response.
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.  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.  


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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), 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.  X-rays of 
hands and feet may be repeated although will not be required during re-screening.
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 3 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. 


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The last dose of oral study drug is taken the day prior to the Week 152 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, 
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.
Follow-Up Period 
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 study drug to obtain information on any new 


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or ongoing AEs and to collect vital signs and clinical laboratory tests.  The 30 day follow-
up visit is not required for subjects who discontinued study drug and continued study 
participation with completion of at least one study visit approximately 30 days after last 
dose of study drug.
5.2
Selection of Study Population
It is anticipated that approximately 630 subjects with active PsA despite prior use of at 
least one bDMARD will be randomized at approximately 165 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).
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.
Diagnosis of active plaque psoriasis or documented history of plaque psoriasis.
5.
Subject has had an inadequate response (lack of efficacy after a minimum 12 week 
duration of therapy) or intolerance to treatment with at least 1 bDMARD. 
6.
Subjects must have discontinued all bDMARDs prior to the first dose of study 
drug.  Subjects who need to discontinue bDMARDs 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:
●
≥ 4 weeks for etanercept;


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●
≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, 
tocilizumab, and ixekizumab;
●
≥ 16 weeks for secukinumab;
●
≥ 12 weeks for ustekinumab;
●
≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pretreatment 
level or normal reference range (local lab) if pretreatment levels are not 
available.
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.
●
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 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 weeks 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 
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).


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10.
Women of childbearing potential (refer to Section 5.2.4), must not have a positive 
serum pregnancy test at the Screening Visit and must have a negative urine 
pregnancy test at the Baseline Visit prior to study drug dosing. 
Note:  Subjects with a borderline serum pregnancy test at Screening must have a 
serum pregnancy test ≥ 3 days later to document continued lack of a positive result. 
11.
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 30 days after the last dose of study drug.  
●
Additional local requirements may apply.  Refer to Appendix G for local 
requirements.
12.
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 – 9
To select the appropriate subject population
10, 11
The effect of ABT-494 on pregnancy and reproduction is unknown
12
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 Janus Kinase (JAK) inhibitor (including but not limited to 
ruxolitinib, tofacitinib, baricitinib, and filgotinib). 


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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.
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 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;
●
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 Japan or where mandated by local requirements);
○
HCV:  HCV ribonucleic acid (RNA) detectable in any subject with 
anti-HCV antibody (HCV Ab).


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5.
Underlying medical diseases or problems including but not limited to the 
following:
●
History of any of the following cardiovascular conditions:
○
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 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.
6.
Use of the following concomitant psoriasis treatments within the specified 
timeframe prior to Baseline Visit:
●
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:


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○
Bland (without beta or alpha hydroxy acids, urea or salicyclic acids) 
emollients
○
Low potency (Class VI or VII) topical corticosteroids on the palms, soles, 
face, inframammary area and groin only.
○
Topical anti-itch treatments with no expected effect on psoriatic skin 
lesions.
7.
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).
8.
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 study drug. 
9.
Subject has received oral or parenteral Traditional Chinese Medicines within 
4 weeks prior to Baseline, has received opioid analgesics (except for tramadol or 
combination of acetaminophen and codeine or hydrocodone which are allowed) 
within 1 week prior to Baseline, or used of inhaled marijuana within 2 weeks prior 
to Baseline.
10.
History of an allergic reaction or significant sensitivity to constituents of the study 
drugs (or its excipients) and/or other products in the same class.
11.
History of any fibromyalgia, any arthritis with onset prior to age 17 years, or 
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.


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12.
History of clinically significant (per Investigator's judgment) drug or alcohol abuse 
within the last 6 months preceding the Baseline Visit.
13.
Female subject who is pregnant, breastfeeding or is considering becoming pregnant 
during the study or within 30 days after the last dose of study drug.  
14.
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/1.73m2;
●
Total white blood cell count (WBC) < 2,500/μL;
●
Absolute neutrophil count (ANC) < 1,500/μL;
●
Platelet count < 100,000/μL;
●
Absolute lymphocyte count < 800/μL; 
●
Hemoglobin < 10 g/dL.
15.
Active skin disease other than psoriasis that would interfere with the assessment of 
psoriasis.
16.
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.
17.
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.
18.
Consideration by the Investigator, for any reason, that the subject is an unsuitable 
candidate to receive ABT-494.


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The Rationale for the Exclusion Criteria
1 – 3, 11
To select the appropriate subject population
13
The impact of ABT-494 on pregnancies is unknown
4 – 10, 12, 14 – 18 
To ensure safety of the subjects throughout the study
5.2.3
Prior, Concomitant, and Prohibited Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, 
vitamins and/or herbal supplements including folic acid) that the subject is receiving 
within 28 days prior to Screening 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. 
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.  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.
The AbbVie Therapeutic Area Medical Director (TA MD) should be contacted if there are 
any questions regarding concomitant or prior therapy(ies).


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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 bDMARDs (e.g., no response, inadequate response, 
loss of response) or intolerance to bDMARDs.
5.2.3.2
Permitted Background Therapy
In Period 1, if subjects are on background DMARDs they should continue on their stable 
background 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 
permitted 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 
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 


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(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 oral 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 
described in Section 5.2.3.4 (Rescue Therapy).  Corticosteroid injections should be 


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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) or 
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)
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 used 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
Carbamazepine
Conivaptan
Phenytoin
Grapefruit (fruit or juice)
Rifampin (Rifampicin)
Indinavir
St. John's Wort
Itraconazole
Rifapentine
Ketoconazole
Lopinavir/Ritonavir
Mibefradil
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Saquinavir
Telaprevir
Telithromycin
Troleandomycin
Voriconazole
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):


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●
buprenorphine
●
codeine 
●
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.


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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 
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 


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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).  
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 an follicle-stimulating hormone (FSH) level 
> 40 mIU/mL.


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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.
●
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 30 days after the last dose of 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).


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●
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).
●
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 G 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.


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


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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.
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 subject's 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.


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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 
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 Visit and Week 56.  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.


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Subjects can have a repeat ECG at any time during the study as warranted based on the 
opinion of the Investigator.
X-Rays of the Hands and Feet
If Item 5 of the CASPAR (Appendix F) criteria needs to be verified for a subject to meet 
eligibility, prior x-rays (no time limit) of any combination of bilateral hands and feet with 
images and/or report available to the site can be used to document juxta-articular new 
bone formation.  There is no need to have a full set of x-rays of both hands and both feet 
as a single image could fulfill this criterion. 
If no prior x-rays (images and/or report) are available, subjects are required to have x-rays 
of both hands and feet at screening in order to document all items of the CASPAR criteria. 
If prior x-rays are available, but do not demonstrate radiographic evidence of juxta-
articular new bone formation, subjects may have repeat x-rays of both hands and feet at 
screening if at least 12 weeks has passed since the prior exam. 
The Investigator or their qualified delegate should read the x-rays of the hands and feet.  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:
●
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, 


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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;
●
Still borderline ≥ 3 days later, this will be considered documentation of 
continued lack of a positive result and the subject can be enrolled into the 
study in the absence of clinical suspicion of pregnancy and other pathological 
causes of borderline results.
In Period 1, a urine pregnancy test will be performed for all women of childbearing 
potential at the Baseline Visit prior to the first dose of study drug and at all subsequent 


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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 
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.


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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.
If a QuantiFERON-TB Gold Test cannot be performed by the Central Lab at Screening 
and a subject had a negative PPD test within 90 days prior to Screening and source 
documentation is available, TB testing by PPD Skin Test does not need to be repeated, 
provided nothing has changed in the subject's medical history to warrant a repeat test.  
These cases may be discussed with the AbbVie 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 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 


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laboratory if not locally available) to confirm the positive test result.  If the 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 are 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 
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 


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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.
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.


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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 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.
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. 


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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. 
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.
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 


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assessment for a particular test will be defined as the last measurement prior to the initial 
dose of study drug.
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
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 
Advanced lipid testingd
Specific gravity
Ketones
pH
Protein
Glucose
Blood
Urobilinogen
Bilirubin
Leukocytes
Nitrites
Microscopic examination, 
if needed
Central Lab Tests:
Serum Pregnancy
(bHCG) teste
HBsAgf
HBsAbf
HBcAbf
HBV DNA PCR reflex
onlyf
HCV Abf
HCV RNA reflex onlyf
Rheumatoid Factorf
Anti-CCP antibodiesf
QuantiFERON-TB Goldg
hs-CRPh
FSHii
beta-D-glucanj
HIV Abk
Local Lab Tests:
Urine pregnancy testl
ESR
Varicella antibody, if 
indicated
B cells, 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.
Samples for advanced lipid testing may be stored for batch testing and may include Apo A1, Apo B, and/or other 
lipid particle tests.
e.
A serum pregnancy test will be performed for all female subjects of childbearing potential at the Screening Visit 
and if post-baseline urine pregnancy is positive.


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Table 2.
Clinical Laboratory Tests (Continued)
f.
At Screening only.  For 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–.  
g.
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).
h.
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.
i.
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.
j.
Japan only.  If the result from the central lab is indeterminate or otherwise not interpretable, a local lab may be 
used.
k.
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. 
l.
A urine pregnancy test will be performed for all female subjects 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 


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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 
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), a positive test result for HBs Ab is expected, 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. 


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●
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 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 approximately every 12 weeks.  HBV DNA PCR 
testing every 12 weeks is not necessary when the subject has a history of HBV 
vaccine and HBs Ab+ and HBc Ab–.  If necessary, HBV DNA PCR may be 
tested at unscheduled visits.
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 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 approximately every 12 weeks.  HBV DNA 
PCR testing every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs Ab+ and 
HBc Ab–. If necessary, HBV DNA PCR may be tested at unscheduled visits.


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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.  
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 2:2:1:1 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 = 210)
●
Group 2:  ABT-494 30 mg QD (N = 210)
●
Group 3:  Placebo followed by ABT-494 15 mg QD (N = 105)
●
Group 4:  Placebo followed by ABT-494 30 mg QD (N = 105)
No more than approximately 40% of subjects will be enrolled with < 3% BSA extent of 
psoriasis and no more than approximately 30% of subjects will be enrolled with prior 
failure of more than 1 biologic DMARD.
Randomization will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or 
< 3% BSA), current use of at least 1 DMARD, and number of prior failed (had an 
inadequate response to) biologic DMARDs (1 vs >1), except for subjects from Japan, for 


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which randomization 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 for all study drug 
administered outside of the study visit (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. 
All relevant dosing information will be entered into the eCRF at each 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 final visit and maintained at 
the site as source documentation.
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


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●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue)
●
Disability Index of the Health Assessment Questionnaire (HAQ-DI)
●
Patient's Assessment of Pain Numeric Rating Scale (0 – 10 NRS)
●
Patient's Global Assessment (PtGA) of Disease Activity Numeric Rating Scale 
(0 – 10 NRS)
●
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.
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 
assessments, 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)
●
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 


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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 (PGA) of Disease Activity Numerical Rating Scale (NRS)
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.
Psoriasis Assessments
Psoriasis Area Severity Index (PASI)47
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.


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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:
1.
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.  
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.


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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 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 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.
Dactylitis
Leeds Dactylitis Index (LDI47)
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 


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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.
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.


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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.
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. 
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.


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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 for investigations including, but not limited to, targeted protein 
and metabolomic analyses
The procedures for obtaining and documenting informed consent are discussed in 
Section 9.3.
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 dosing;


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●
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 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 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.
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 of 
Disease Activity (NRS), PGA of Disease Activity (NRS), HAQ-DI, or hs-CRP.


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5.3.3.2
Key Secondary Variables
The key multiplicity adjusted secondary efficacy endpoints (each dose of ABT-494 versus 
placebo) are:
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;
3.
Psoriasis Area Severity Index (PASI) 75 response at Week 16 (for subjects with 
≥3% BSA psoriasis at baseline);
4.
Change from baseline in SF-36 PCS at Week 12;
5.
Change from baseline in FACIT-Fatigue Questionnaire at Week 12; 
6.
Proportion of subjects achieving Minimal Disease Activity (MDA) at Week 24;
7.
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 of Disease Activity NRS, PGA of 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 
assessment of pain ≤ 1.5 (0 – 10 NRS); PtGA-disease activity ≤ 2 (0 – 10 NRS); HAQ-DI 
score ≤ 0.5; and tender entheseal points ≤ 1.


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5.3.3.3
Additional Variables
The following outcome measures will be assessed when obtained at the scheduled time 
points in Appendix C other than those specified for the primary and key secondary 
variables:
●
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; 
●
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 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);


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●
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-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.


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●
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.
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 and Validation Studies Variables
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.


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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.  Samples may then be 
used to validate putative biomarker signatures obtained from a prospective study, leading 
to the development of diagnostic tests.
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


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●
The subject becomes pregnant while on study drug
●
Malignancy, except for localized NMSC or carcinoma in-situ of the cervix
●
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
●
Subject develops a gastrointestinal perforation (other than due to appendicitis 
or mechanical injury)
●
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, a 30-day follow-up visit (or phone call if a visit is not possible) after the 
last dose of study drug may be completed to determine the status of any ongoing 
AEs/SAEs, the occurrence of any new AEs/SAEs, and medications used to treat 


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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 
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 is one active study drug in this study:  ABT-494. 


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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.
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 Product(s)
The individual study drug information is presented in Table 3.
Table 3.
Identity of Investigational Product
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
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.  Each kit will be labeled as required 
per country requirements.  Labels must remain affixed to the kits.  All blank spaces on the 
label will be completed by the site staff prior to dispensing to the subjects.
5.5.2.2
Storage and Disposition of Study Drug(s)
ABT-494 must be stored at controlled room temperature (15° to 25°C/59° to 77°F).  The 
investigational products are for investigational use only and are to be used only within the 


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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 2:2:1:1 ratio to one of four treatment 
groups at Baseline (Day 1) as follows:
●
Group 1:  ABT-494 15 mg QD (N = 210)
●
Group 2:  ABT-494 30 mg QD (N = 210)
●
Group 3:  Placebo followed by ABT-494 15 mg QD (N = 105)
●
Group 4:  Placebo followed by ABT-494 30 mg QD (N = 105)
No more than approximately 40% of subjects will be enrolled with < 3% BSA extent of 
psoriasis and no more than approximately 30% of subjects will be enrolled with prior 
failure of more than 1 biologic DMARD.
Subjects will receive oral study drug QD (ABT-494 15 mg, ABT-494 30 mg, or matching 
placebo) until the end of the study or they discontinue study drug.
Randomization will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or 
< 3% BSA), current use of at least 1 DMARD, and number of prior failed (had an 
inadequate response to) biologic DMARDs (1 vs > 1), except for subjects from Japan, for 


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which randomization 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 
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). 
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 


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notify their study site physician, and the subject should be discontinued from 
study drug treatment.  
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 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.
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.


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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.
A DMC charter will be prepared for the safety data review outside of the protocol and will 
describe the roles and responsibilities of the DMC members, frequency of data reviews, 
and relevant safety data to be assessed. 
Communications from the DMC to the Study Teams will not contain information that 
could potentially unblind the team to subject treatment assignments.
5.5.6
Treatment Compliance
The investigator or his/her designated and qualified representatives will 
administer/dispense study drug only to subjects enrolled in the study in accordance with 
the protocol.  The study drug must not be used for reasons other than that described in the 
protocol.
Subject dosing will be recorded on a subject diary.  Subjects will be instructed to return all 
drug containers (even if empty) to the study site personnel at each clinic visit.  The study 
site personnel will document compliance in the study source documents.
5.5.7
Drug Accountability
The Investigator or his/her representative will verify in the IRT that study drug supplies 
are received intact and in the correct amounts.


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In addition, an IRT will be used to document investigational product accountability 
including but not limited to date received, the lot number, kit number(s), date dispensed, 
subject number, and the identification of the person dispensing the drug. 
All empty/used study drug packaging will be inventoried by the site.  Empty/used study 
drug packaging should be returned by the subject at each visit for accountability and 
compliance purposes and new packaging issued as necessary.  Site staff will complete 
study drug accountability via IRT, source documents, subject dosing diaries, and by 
visually inspecting the packaging whenever possible.  
After drug accountability has been completed 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 
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 period followed by an additional 32 weeks of blinded 
treatment (Weeks 24 – 56).  Period 1 is designed to compare the safety, tolerability and 


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efficacy of ABT-494 15 mg QD and 30 mg QD versus placebo subjects with moderately 
to severely active PsA and have an inadequate response to biologic DMARDs (Bio-IR).  
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.  
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 an unblinded 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.
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 bDMARD 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 classification criteria with symptoms for at least 6 months.  


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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.
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 3 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 
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.


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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.
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 
Sections 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 


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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 
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 


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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.
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).


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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 serious adverse events with the outcome of death, the date and cause of death will be 
recorded on the appropriate case report form.
6.1.1.3
Adverse Events of Special Interest
The following 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;


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●
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. 
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 refer 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.


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6.1.3
Relationship to Study Drug
The investigator will use the following definitions to assess the relationship of the AE to 
the use of study drug:
Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is sufficient evidence 
(information) to suggest a causal relationship.
No Reasonable Possibility
After consideration of factors including timing of the 
event, biologic plausibility, clinical judgment, and 
potential alternative causes, there is insufficient
evidence (information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being 
related to the study drug will be considered "associated."  Events assessed as having no 
reasonable possibility of being related to study drug will be considered "not associated."  
In addition, when the investigator has not reported a causality or deemed it not assessable, 
AbbVie will consider the event associated.
If an investigator's opinion of no reasonable possibility of being related to study drug is 
given, another 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 30 days following 
discontinuation of study drug 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.






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Phone:  
The sponsor will be responsible for Suspected Unexpected Serious Adverse Reactions 
(SUSAR) reporting for the Investigational Medicinal Product (IMP) in accordance with 
Directive 2001/20/EC.  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.
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 following the 
last dose of 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 30 days after the last 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 


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collection of any pregnancy-specific information and the pregnancy will be followed to 
outcome.
6.1.7
Toxicity Management
The toxicity management of the AEs including AESIs consists of safety monitoring 
(review of AEs on an ongoing basis, and periodic/ad hoc review of safety issues by a 
safety data monitoring committee), interruption of study drug dosing with appropriate 
clinical management if applicable, and discontinuation of the subjects from study drug.  
The management of specific AEs and laboratory parameters is described below.
For subjects who 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 


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treatment.  If the diagnosis of gastrointestinal perforation is confirmed (other than due to 
appendicitis or mechanical injury), the subject must be discontinued from study drug.
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.  For subjects with ongoing 
laboratory abnormalities which require data entry into an eCRF, an additional eCRF 
related to subsequent laboratory abnormalities is only required if the subject has relevant 
changes in history (e.g., new onset signs or symptoms) or laboratory values which have 


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returned to normal reference range or its Baseline value followed by subsequent 
laboratory abnormalities meeting toxicity guidelines (considered a new event). 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.
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 or the hemoglobin value remains in 
the normal reference range, 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.
!
Interrupt study drug if confirmed < 500/μL by repeat testing with 
new sample. If value returns to normal reference range or its 
Baseline value, restarting study drug is allowed if there is an 
alternative etiology identified; documentation should include reason 
that rechallenge is expected to be safe for the subject. Study drug 
should be discontinued if no alternative etiology can be found.
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): 
o
ALT > 5 × ULN OR 
o
ALT or AST > 3 × ULN if an alternative cause is not readily 
identified.
!
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.


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Table 4.
Specific Toxicity Management Guidelines for Abnormal 
Laboratory Values (Continued)
Laboratory Parameter
Toxicity Management Guideline
AST or ALT 
(Continued)
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 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 elevations > 3 ULN, complete the 
appropriate supplemental hepatic eCRF(s).
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:
●
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.
●
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, the study drugs should be interrupted 
1 week prior to the planned surgery.
●
After surgery, allow reintroduction of study drug 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 and Trial Monitoring Committee
An external DMC will review unblinded safety data.  See Section 5.5.5.2 for details.
6.1.9
Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess potential cardiovascular, embolic and thrombotic AEs in a blinded 
manner as defined by the Cardiovascular Adjudication Committee charter.
6.2
Product Complaint
6.2.1
Definition
A Product Complaint is any Complaint (see Section 6.0 for the definition) related to the 
biologic or drug component of the product.
For a product this may include, but is not limited to, damaged/broken product or 
packaging, product appearance whose color/markings do not match the labeling, labeling 
discrepancies/inadequacies in the labeling/instructions (example:  printing illegible), 
missing components/product, or packaging issues.
Any information available to help in the determination of causality to the events outlined 
directly above should be captured.


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6.2.2
Reporting
Product Complaints concerning the investigational product must be reported to the 
Sponsor within 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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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.
Complete 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 a 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.


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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, 
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 oral study drug plus 1 day.
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.


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8.1.3
Analysis of Demographic and Baseline Characteristics
Demographic and baseline characteristics will be summarized by treatment group and 
overall for the FAS.  For the purpose of this analysis, baseline data for each subject will 
be the data collected immediately prior to the first dose of study drug.
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.


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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.
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 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 Mixed-Effects Model 
Repeated Measures (MMRM) with fixed effects of treatment group, visit, treatment-by-
visit interaction and the baseline measurements.
8.1.4.3
Additional Efficacy Variables
Additional efficacy variables as listed in Section 5.3.3.3 will be summarized for all visits, 
including visits beyond Week 24.  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.  
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.48,49  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 two-sided α of 0.025 for each dose.  Continued testing 


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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.
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 discontinuation.
Mixed Model Repeated Measures (MMRM):  The MMRM includes treatment, visit, 
and treatment-by-visit interaction as fixed effects, and baseline as covariate.
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 continuous key 
secondary endpoints.  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.   
8.1.4.6
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 30 days following the last dose of study drug 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:
●
All AEs


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●
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 AEs of special interest 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 630 for this study provides at least 90% power for a 20% 
difference in ACR20 response rate (assuming a placebo ACR20 response rate of 20%).  It 
will also provide at least 90% power for the majority of the key secondary endpoints.  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 2:2:1:1 ratio 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, and number of prior failed (had an 
inadequate response to) biologic DMARDs (1 vs > 1), except for subjects from 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 for details.


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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 
Harmonisation (ICH) guidelines, applicable regulations and guidelines governing clinical 
study conduct and the ethical principles that have their origin in the Declaration of 
Helsinki.  Responsibilities of the clinical investigator are specified in Appendix A.


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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 
his/her consent and the samples have already been tested, those results will still remain as 
part of the overall research data.


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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 
automated instruments, microfiches, photographic negatives, microfilm or magnetic 
media, and/or x-rays.  Data collected during this study must be recorded on the 
appropriate source documents.
The investigator(s)/institution(s) will permit study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s), providing direct access to source data documents.


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10.2
Case Report Forms
Case report forms (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 
principal investigator will review the eCRFs for completeness and accuracy and provide 
his or her electronic signature and date to eCRFs as evidence thereof.
Medidata will provide access to the EDC system for the duration of the trial through a 
password-protected method of internet access.  Such access will be removed from 
investigator sites at the end of the site's participation in the study.  Data from the EDC 
system will be archived on appropriate data media (CD-ROM, etc.) and provided to the 


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investigator at that time as a durable record of the site's eCRF data.  It will be possible for 
the investigator to make paper printouts from that media.
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.
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 


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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 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 
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 


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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 
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.


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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.


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14.0
Investigator's Agreement
1.
I have received and reviewed the Investigator's Brochure for ABT-494.
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 in Subjects with Active Psoriatic 
Arthritis Who Have a History of Inadequate Response to at Least 
One Biologic Disease Modifying Anti-Rheumatic Drug (bDMARD) 
– SELECT – PsA 2
Protocol Date:
01 April 2020
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)


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15.0
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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(4):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 


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subjects with active rheumatoid arthritis [abstract].  Arthritis Rheum.  
2010;2172 (Suppl 10):62.
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 D, van der Heijde YC, Chen M, 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;79 (Suppl 2):74.
42.
Genovese J. Kremer O, Zamani C, 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.  2105;75 (Suppl 2):74.
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, et al.  Tofacitinib or adalimumab 
versus placebo in rheumatoid arthritis.  N Engl J Med.  2012;367(6):508-19.
45.
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.
46.
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.
47.
Hochberg Y.  A sharper bonferroni procedure for multiple tests of significance.  
Biometrika.  1988;75(4):800-2.
48.
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.
49.
Bretz F, Maurer W, Brannath W.  A graphical approach to sequentially rejective 
multiple test procedures.  Stat Med.  2009;28(4):586-604. 


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50.
Burmester GR, Blanco R, Charles-Schoeman C, et al.  Tofacitinib (CP-690,550) in 
combination with methotrexate in patients with active rheumatoid arthritis with an 
inadequate response to tumour necrosis factor inhibitors:  a randomised phase 3 
trial.  Lancet.  2013;381(9865):451-60.


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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 140 
(Every
12 Wks)
Wk 
152 
or 
PD
30 Day 
F/U 
Visit/ 
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
Informed Consentc 
X
Inclusion/Exclusion 
Criteria
X
X
CASPAR
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-Rayj,k
Xj
Xk
Xk
Xk
Bilateral X-rays of hands 
and feetl
X
Serum Pregnancy Test at 
central labm
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
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
Local Urine Pregnancy 
Testn,o
X
X
X
X
X
X
X
X
X
X
Xo
Xo
Xo
Xo
X
X
Latent TB risk factor 
questionnairep
X
X
Xp
X
Central lab QuantiFeron 
TB Gold test (and local 
PPD skin test if 
required)q
X
X
Xq
Xq
Central lab testsr
  hs-CRPs
  Clinical Chemistryt
  Hematology (CBC)t
  Urinalysisu
  FSHff
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xgg
Central lab testsr
  Total cholesterol
  HDL-C
  LDL-C
  Triglycerides
  Advanced lipid testings
X
X
X
X
ESR (local lab)
X
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
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
Other Central Lab tests
  HIV Screeningv
  Hepatitis Bw and C
  Screening
  Rheumatoid factor
  Anti-CCP antibodies
X
Blood samples for 
ABT-494 PK assayx,y
Xx
Xx
Xy
Xy
Xy
Xy
Xy
Xy
Xy
Xy
Subject questionnairesee
HAQ-DI
Patient-Pain
PtGA-disease activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Subject questionnairesee
SF-36
EQ-5D-5L
FACIT-F
WPAI
BASDAI
X
X
X
X
X
X
X
Subject Questionnairez,ee
SAPS
X
X
X
X
X
Xz
X
Tender and Swollen Joint 
counts
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PGA-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
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
HRU
X
X
X
X
X
X
X
BSA Psoriasisz
X
X
X
X
X
X
Xz
X
PASIz
X
X
X
X
X
X
Xz
X
sIGAz
X
X
X
X
X
X
Xz
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
Psoriatic Spondylitis 
Assessment
X
Adverse Event 
Assessment 
Xaa
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
Dispense Study Drug and 
Subject Diarybb
X
X
X
X
X
X
Xbb
X
X
X
X
X
X
Calculation of TJC/SJC 
responsescc,dd 
Xcc
Xcc
Xdd
Xdd
Xdd
Xdd
Xdd
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.


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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 visit (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 30 day follow-up visit is not required for subjects who discontinued study drug and continued study participation with completion of 
at least one study visit approximately 30 days after last dose of study drug.
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) and at the Wk 152 visit.  A symptom-
directed physical exam may be performed when necessary.
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.
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).
k.
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. 
l.
There is no need to have a full set of x-rays of both hands and both feet as a single image could fulfill this criterion.  If no prior x-rays (images and/or report) are available, 
subjects are required to have x-rays of both hands and feet at screening in order to document all items of the CASPAR criteria.  If prior x-rays are available, but do not 
demonstrate radiographic evidence of juxta-articular new bone formation, subjects may have repeat x-rays of both hands and feet at screening if at least 12 weeks has passed 
since the prior exam.


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m.
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.
n.
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.
o.
If time between visits is longer than 1 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.
p.
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.
q.
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.
r.
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.
s.
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.  Samples for advanced lipid testing may be stored for batch testing and may include Apo A1, Apo B, and/or other lipid particle tests.
t.
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.
u.
A urine dipstick macroscopic urinalysis will be completed by the central laboratory at all required visits.  A microscopic analysis will be performed in the event the dipstick 
results show leukocytes, nitrite, protein, ketones, or blood greater than negative or glucose greater than normal. 


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v.
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.
w.
For 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 approximately every 12 weeks.  HBV DNA PCR testing every 12 weeks is not necessary when the subject has a history of HBV vaccine and HBs Ab+ and HBc 
Ab–. If necessary, HBV DNA PCR may be tested at unscheduled visits.
x.
At Week 2 and Week 4 visits, PK samples should be collected prior to 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. 
y.
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.
z.
PASI, BSA-Ps, sIGA, and SAPS are to be done at Week 80, Week 104, and Week 128 (every 24 weeks after Week 56).
aa.
Collect serious AEs and protocol-related nonserious AEs that occur after a subject signs the informed consent; prior to the first dose of study drug.
bb. At Week 24, all placebo subjects will be randomized to blinded ABT-494 regardless of clinical response.
cc.
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).
dd. 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.
ee.
Prior to other procedures.
ff.
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).
gg. 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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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 140 
(Every
12 Wks)
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
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 
proteininvestigatioins 
sample (urine)a,b,c,d
X
X
X
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.
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, however it is not required.  It must be recorded whether the subject has fasted or not at 
the time of collection.
d.
An effort should be made to collect prior to dosing.


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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.
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 G.
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 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 an 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.
●
If the FSH is tested and the result is consistent with post-menopausal status, 
contraception is not required.


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●
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 or two highly effective methods.  That is effective from Study 
Day 1 (or earlier) 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 
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 


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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 an FSH level > 40 mIU/mL.
A woman who does not meet the definition of postmenopausal or permanently surgically 
sterile is considered of childbearing potential and is required to practice at least one of the 
following highly effective methods of birth control that is effective from Study Day 1 (or 
earlier) through at least 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 Study Day 1.
●
Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation, initiated at least 30 days prior to Study 
Day 1.
●
Bilateral tubal occlusion/ligation.


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●
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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Appendix H.
Protocol Amendment:  List of Changes
The summary of changes is listed in Section 1.1.
Specific Protocol Changes
Section 3.2  Benefits and Risks
Fourth paragraph, last sentence previously read:
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.
Has been changed to read:
Based on the calculated safety margins for human fetal exposure with seminal fluid 
transfer, there is judged to be no risk to the pregnancy of female partners of male subjects 
who are treated with upadacitinib.
Section 5.2.3.2  Permitted Background Therapy
Fourth paragraph, first sentence previously read:
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.  
Has been changed to read:
In addition, at Week 36 (after Week 36 assessments have been performed) and thereafter, 
initiation of or change in oral 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.


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Section 5.2.3.2  Permitted Background Therapy
Fourth paragraph, last sentence previously read:
Doses of non-biologic DMARDs may not exceed maximums defined above and in 
inclusion criteria (Section 5.2.1).
Has been changed to read:
Doses of non-biologic DMARDs and oral corticosteroids may not exceed maximums 
defined above and in inclusion criteria (Section 5.2.1).
Section 5.3.1.1  Study Procedures
Subsection Hepatitis Screening
Heading "Hepatitis B:"
Third paragraph, last bullet previously read:
For 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 are HBs Ab+ and HBc Ab–.
Has been changed to read:
For 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 approximately every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccine and HBs Ab+ and HBc Ab–.  If 
necessary, HBV DNA PCR may be tested at unscheduled visits.
Figure 2.  Interpretation and Management of HBV Serologic Test Results
Figure note "**" previously read:
For 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–.


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Has been changed to read:
For 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 approximately every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccine and HBs Ab+ and HBc Ab–. If 
necessary, HBV DNA PCR may be tested at unscheduled visits.
Section 5.4.1  Discontinuation of Individual Subjects
Eleventh bullet previously read:
Subject develops a gastrointestinal perforation
Has been changed to read:
Subject develops a gastrointestinal perforation (other than due to appendicitis or 
mechanical injury)
Section 5.4.1  Discontinuation of Individual Subjects
Add:  new last bullet
Confirmed diagnosis of deep vein thrombosis, pulmonary embolus or non-cardiac, non-
neurologic arterial thrombosis.
Section 5.5.7  Drug Accountability
First paragraph previously read:
The Investigator or his/her representative will verify that study drug supplies are received 
intact and in the correct amounts.  This will be documented by signing and dating the 
Proof of Receipt or similar document and by registering the arrival of drug through the 
IRT.  The original Proof of Receipt Note and the IRT confirmation sheet will be kept in 
the site files as a record of what was received.


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Has been changed to read:
The Investigator or his/her representative will verify in the IRT that study drug supplies 
are received intact and in the correct amounts.
Section 6.1.7  Toxicity Management
Fifth paragraph, last sentence previously read:
If the diagnosis of gastrointestinal perforation is confirmed, the subject must be 
discontinued from study drug.
Has been changed to read:
If the diagnosis of gastrointestinal perforation is confirmed (other than due to appendicitis 
or mechanical injury), the subject must be discontinued from study drug.
Section 6.1.7  Toxicity Management
Ninth paragraph
Add:  new last sentence
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.
Section 6.1.7  Toxicity Management
Eleventh paragraph
Add:  new third sentence
For subjects with ongoing laboratory abnormalities which require data entry into an 
eCRF, an additional eCRF related to subsequent laboratory abnormalities is only required 
if the subject has relevant changes in history (e.g., new onset signs or symptoms) or 
laboratory values which have returned to normal reference range or its Baseline value 
followed by subsequent laboratory abnormalities meeting toxicity guidelines (considered 
a new event).


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Table 4.  Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory parameter "Hemoglobin"
Third bullet previously read:
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.
Has been changed to read:
If hemoglobin decreases ≥ 3.0 g/dL from Baseline and an alternative etiology is known or 
the hemoglobin value remains in the normal reference range, the subject may remain on 
study drug at the investigator's discretion.
Table 4.  Specific Toxicity Management Guidelines for Abnormal Laboratory Values
Laboratory parameter "Absolute neutrophil count (ANC)"
Last bullet previously read:
Discontinue study drug if confirmed < 500/μL by repeat testing with new sample.
Has been changed to read:
Interrupt study drug if confirmed < 500/μL by repeat testing with new sample.  If value 
returns to normal reference range or its Baseline value, restarting study drug is allowed if 
there is an alternative etiology identified; documentation should include reason that 
rechallenge is expected to be safe for the subject.  Study drug should be discontinued if no 
alternative etiology can be found.
Section 6.1.9  Cardiovascular Adjudication Committee
Previously read:
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.


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Has been changed to read:
An independent committee of physician experts in cardiovascular adjudication will be 
utilized to assess potential cardiovascular, embolic and thrombotic AEs in a blinded 
manner as defined by the Cardiovascular Adjudication Committee charter.
Appendix B.  List of Protocol Signatories
Previously read:
Name
Title
Functional Area
Immunology Therapeutic Area
Immunology Therapeutic Area
Pharmacovigilance and Patient Safety
Statistics
Statistics
Clinical Pharmacology and 
Pharmacometrics
Clinical Program Development
Has been changed to read:
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 "Other Central Lab tests" 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
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
Other Central Lab tests
  HIV Screeningv
  Hepatitis B and C
  Screening
  Rheumatoid factor
  Anti-CCP antibodies
X
Xw
Xw


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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 140 
(Every
12 Wks)
Wk 
152 
or 
PD
30 Day 
F/U 
Visit/ 
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
Other Central Lab tests
  HIV Screeningv
  Hepatitis Bw and C
  Screening
  Rheumatoid factor
  Anti-CCP antibodies
X


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Appendix C.  Study Activities
Table note "w." previously read:
For 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–.  
Has been changed to read:
For 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 approximately every 12 weeks.  HBV DNA PCR testing every 12 weeks is not 
necessary when the subject has a history of HBV vaccine and HBs Ab+ and HBc Ab–. If 
necessary, HBV DNA PCR may be tested at unscheduled visits.

SAP_001.pdf: 
Upadacitinib
M15-554 – Statistical Analysis Plan
Version 2.0 – 02 Oct 2019
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1.0
Title Page
Statistical Analysis Plan
Study M15-554
A Phase 3, Randomized, Double-Blind, Study 
Comparing Upadacitinib (ABT-494) to Placebo in 
Subjects with Active Psoriatic Arthritis Who Have a 
History of Inadequate Response to at Least 
One Biologic Disease Modifying Anti-Rheumatic Drug 
(bDMARD) – SELECT – PsA 2
Date:  02 Oct 2019
Version 2.0
NCT03104374


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M15-554 – Statistical Analysis Plan
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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..................................................................7
4.3
Sample Size................................................................................................9
4.4
Week 24 Analysis and Data Base Lock...................................................10
4.5
Data Monitoring Committee (DMC) Activities.......................................10
5.0
Analysis Populations and Analysis Windows .....................10
5.1
Analysis Populations................................................................................10
5.2
Analysis Windows ...................................................................................11
6.0
Demographics, Baseline Characteristics, Medical 
History, and Previous/Concomitant Medications ..............15
6.1
Demographics and Baseline Characteristics............................................15
6.2
Medical History .......................................................................................18
6.3
Prior Treatment and Concomitant Medications.......................................18
6.4
Protocol Deviations..................................................................................19
7.0
Patient Disposition.................................................................19
8.0
Study Drug Exposure and Compliance...............................21
8.1
Study Drug Exposure...............................................................................21
8.2
Compliance ..............................................................................................22
9.0
Efficacy Analysis....................................................................22
9.1
General Considerations............................................................................22
9.1.1
Efficacy Analysis at Different Phases of the Study.................................22
9.1.2
Handling of Missing Data and Intercurrent Events .................................23
9.2
Efficacy Analysis Through Week 24.......................................................24
9.2.1
Primary Efficacy Analysis of the Primary Efficacy Endpoint.................24
9.2.2
Supplementary Analysis of the Primary Efficacy Endpoint ....................25
9.2.3
Key Secondary Efficacy Analyses...........................................................26
9.2.4
Efficacy Analyses for Additional Endpoints ...........................................29


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9.2.5
Handling of Multiplicity ..........................................................................32
9.2.6
Efficacy Subgroup Analysis ....................................................................34
9.3
Long-Term Efficacy Analysis..................................................................34
9.4
Efficacy Variables Definitions and Conventions.....................................36
9.4.1
ACR Criteria ............................................................................................36
9.4.2
Joint Evaluation .......................................................................................39
9.4.3
Patient's Global Assessment of Disease Activity Numeric Rating 
Scale (NRS) .............................................................................................40
9.4.4
Physician's Global Assessment of Disease Activity Numeric 
Rating Scale (NRS)..................................................................................41
9.4.5
Patient's Assessment of Pain Numeric Rating Sale (NRS)......................41
9.4.6
Disease Activity Score (DAS28) .............................................................41
9.4.7
Disease Activity in Psoriatic Arthritis (DAPSA) Score...........................42
9.4.8
PsA Disease Activity Score (PASDAS) ..................................................42
9.4.9
Disability Index of Health Assessment Questionnaire (HAQ-DI)...........44
9.4.10
Static Investigator Global Assessment of Psoriasis (sIGA).....................44
9.4.11
Psoriasis Area Severity Index (PASI)......................................................45
9.4.12
Minimum Disease Activity for PsA.........................................................46
9.4.13
Self-Assessment of Psoriasis Symptoms (SAPS)....................................47
9.4.14
Leeds Dactylitis Index (LDI) and Dactylitis Count.................................47
9.4.15
Leeds and SPARCC Enthesitis Indices and Total Enthesitis Count........47
9.4.16
Body Surface Area (BSA) – Psoriasis .....................................................49
9.4.17
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 
and Morning Stiffness Score....................................................................50
9.4.18
Modified Psoriatic Arthritis Response Criteria (PsARC)........................50
9.4.19
Ankylosing Spondylitis Disease Activity Score (ASDAS) .....................51
9.4.20
FACIT-Fatigue Questionnaire (FACIT-F)...............................................52
9.4.21
EuroQoL-5D (EQ-5D-5L) .......................................................................52
9.4.22
Form SF-36v2 ..........................................................................................53
9.4.23
Work Productivity and Activity Impairment Questionnaire 
Psoriatic Arthritis (WPAI) .......................................................................53
9.4.24
Health Resource Utilization (HRU) Questionnaire .................................55
10.0
Safety Analysis.......................................................................56


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10.1
General Considerations............................................................................56
10.2
Analysis of Adverse Events.....................................................................58
10.2.1
Analysis of Adverse Events Prior to Protocol-Defined Treatment 
Switching .................................................................................................58
10.2.1.1
Adverse Events Overview........................................................................58
10.2.1.2
Adverse Events by System Organ Class and Preferred Term..................59
10.2.1.3
TEAEs by Maximum Severity.................................................................59
10.2.1.4
TEAEs by Relationship............................................................................60
10.2.1.5
Frequent (≥ 2%) Adverse Events and Reasonably Possibly 
Related Adverse Events by System Organ Class and Preferred 
Term.........................................................................................................60
10.2.1.6
Adverse Events of Special Interest ..........................................................60
10.2.2
Analysis of Long-Term Adverse Event Rates .........................................63
10.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................64
10.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................64
10.2.2.3
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure by SOC and PT.....................................................65
10.2.2.4
Listing of Serious Adverse Events (Including Deaths) and 
Adverse Events Leading to Study Drug Discontinuation ........................65
10.3
Analysis of Laboratory Data....................................................................65
10.3.1
Variables and Units..................................................................................65
10.3.2
Analysis of Laboratory Data Through Week 24......................................67
10.3.2.1
Assessment of Clinical Laboratory Variables..........................................67
10.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................68
10.3.2.3
Assessment of Potentially Clinical Significant Laboratory Values.........69
10.3.2.4
Assessment of Liver Elevations...............................................................69
10.3.3
Analysis of Long-Term Laboratory Data.................................................70
10.3.3.1
Assessment of Clinical Laboratory Variables..........................................70
10.3.3.2
Assessment of Potentially Clinical Significant Laboratory Values .........70
10.3.3.3
Assessment of Liver Elevations...............................................................71
10.4
Analysis of Vital Signs ............................................................................72


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10.4.1
Variables and Criteria Defining Abnormality..........................................72
10.4.2
Analysis of Vital Signs Through Week 24 ..............................................72
10.4.3
Analysis of Long-Term Vital Signs.........................................................72
11.0
References...............................................................................73
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) ..................................12
Table 2.
Analysis Windows for Efficacy Analysis for Period 1 (for SF-36, 
EQ-5D-5L, FACIT-F, WPAI, BASDAI, HRU and Derived 
Endpointsa)...............................................................................................13
Table 3.
Analysis Windows for Safety Analysis for Period 1 (for Total 
Cholesterol, HDL-C, LDL-C, Triglycerides, Advanced Lipid 
Testinga)...................................................................................................13
Table 4.
Analysis Windows for Efficacy Analysis for Period 1 (for 
BSA-Psoriasis, PASI, sIGA, LDI, LEI, SPARCC Enthesitis Index 
and Derived Endpointsa) ..........................................................................14
Table 5.
Analysis Windows for Efficacy Analysis for Period 1 (for SAPS) .........14
Table 6.
Subgroups for Efficacy Analysis .............................................................34
Table 7.
Anatomical Joints Assessed for Calculation of Tender and 
Swollen Joint Counts (TJC68 and SJC66)...............................................40
Table 8.
Anatomical Joints for DAS28 (CRP) Calculation ...................................42
Table 9.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................61
Table 10.
List of Laboratory Variables....................................................................66
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Findings..........72
List of Figures
Figure 1.
Study Design..............................................................................................9
Figure 2.
Graphical Multiple Testing Procedure.....................................................33


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List of Appendices
Appendix A.
SAS Procedure for Mantel-Haenszel Test ...............................................75
Appendix B.
Tipping Point Analysis for ACR20 at Week 12 ......................................76
Appendix C.
Tipping Point Analysis for Key Secondary Continuous Endpoint ..........77
Appendix D.
Exposure Adjusted AE Rate Difference and Normal 
Approximation Based 95% Confidence Interval (Liu, F et al.  
20065).......................................................................................................80


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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 M15-554.  It provides 
details to further elaborate statistical methods as outlined in the protocol.  
Pharmacokinetic and biomarker analyses will be performed separately and 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
1.
To compare the efficacy of upadacitinib 15 mg once daily (QD) and 30 mg QD 
versus placebo for the treatment of signs and symptoms in subjects with 
moderately to severely active Psoriatic Arthritis (PsA) who have an inadequate 
response to biologic DMARDs (Bio-IR).
2.
To compare the safety and tolerability of upadacitinib 15 mg QD and 30 mg QD
versus placebo in subjects with moderately to severely active PsA who have an 
inadequate response to biologic DMARDs.
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-


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controlled period followed by an additional 32 weeks of blinded active 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 in subjects with moderately to 
severely active PsA who have an inadequate response to bDMARDs (Bio-IR).  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 630 subjects at approximately 165 study 
centers worldwide to meet scientific and regulatory objectives without enrolling an undue 
number of subjects in alignment with ethical considerations.  
Subjects who meet eligibility criteria will be randomized in a 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 = 210)
●
Group 2:  Upadacitinib 30 mg QD, N = 210)
●
Group 3:  Placebo, N = 105 (Day 1 to Week 24) →Upadacitinib 15 mg QD 
(Week 24 and thereafter)
●
Group 4:  Placebo, N = 105 (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), and number of prior failed 
biologic DMARDs (1 vs > 1), except for subjects from Japan, for which randomization 
will be stratified by extent of psoriasis (≥ 3% body surface area [BSA] or < 3% BSA) 
only.


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A schematic of the overall study design is shown in Figure 1 below.  For a more detailed 
description of the study design, refer to Section 5.0 of the most up-to-date version of the 
study protocol.
Figure 1.
Study Design
a.
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 of the most up-to-date version of the study protocol.
b.
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 630 for this study provides at least 90% power for a 20% 
difference in ACR20 response rate (assuming a placebo ACR20 response rate of 20%).  It 
will also provide at least 90% power for the majority of the key secondary endpoints.  All 
power and sample size calculations are performed at a two-sided significance level of 
0.025 and accounting for a 10% dropout rate.


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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 initial 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.
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 have 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 
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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 
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. 


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The visit window and the target study day for each protocol-specified visit in Period 1 are 
displayed in Table 1 to Table 5 (depending on the different visit schedules of different 
endpoints).  Visit windows for protocol-specified visits in Period 2 are defined similarly. 
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, Advanced Lipid 
Testinga)
Protocol Specified 
Visit Week
Lower Bound
Target Day
Upper Bound
Baseline
–99
1b
1
4
2
29
57
12
58
85
127
24
128
169
Min (211, first dose date 
from Week 24 dispensed kit)
a.
Advanced lipid testing is exploratory and may not be performed and/or be reported in the CSR.
b.
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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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)
●
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


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●
Number of prior non-biologic DMARDs (0, 1, 2, ≥ 3)
●
Number of prior biologic DMARDs (0, 1, 2, ≥ 3)
●
Number of prior biologic DMARDs other than anti-TNF (0, 1, 2, ≥ 3)
●
Number of prior anti-TNFs (0, 1, 2, ≥ 3)
●
Number of prior failed biologic DMARDs (0, 1, 2, ≥ 3)
●
Current use of at least 1 non-biologic DMARD at baseline (Yes or No)
●
Current NSAID use at baseline (Yes or No)
●
Current Corticosteroid use 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)
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 assessment of disease activity (0 - 10 NRS)
●
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)


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●
Erythrocyte sedimentation rate (ESR)
●
Psoriatic arthritis disease activity score (PASDAS)
●
Disease Activity In Psoriatic Arthritis (DAPSA) score
●
Presence of Dactylitis (defined as 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 (defined as 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)
●
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)
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) 


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●
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 body 
systems and conditions/diagnoses as captured on the CRF.  The body systems will be 
presented in alphabetical order and the conditions/diagnoses will be presented in 
alphabetical order within each body system.  The number and percentage of subjects with 
a particular condition/diagnosis will be summarized for each randomized treatment group 
as well as overall.  Subjects reporting more than one condition/diagnosis within a body 
system will be counted only once for that body system.  No statistical comparison will be 
performed for medical history reporting.
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.  
This includes medications with a start date between first study drug administration and 
last study drug administration + 1 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 
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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.
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.


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Period 1
The number and percentage of subjects who completed Period 1 and prematurely 
discontinued in Period 1 will be summarized by randomized treatment group, separately 
by study drug completion/discontinuation and by study participation 
completion/discontinuation, with the reason for discontinuation collected from the 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 entered Period 2 will be summarized 
by randomized treatment group.
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
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.  


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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
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.
Exposure to upadacitinib and placebo is defined as last dose date minus first dose date 
plus 1 day.
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


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●
≥ 1 month
●
≥ 3 months
●
≥ 6 months
●
≥ 9 months
●
≥ 12 months
●
≥ 18 months
●
≥ 2 years
●
≥ 2.5 years
8.2
Compliance
Study drug compliance will be summarized for each treatment group at Week 24.  The 
compliance is defined as the number of tablets taken (i.e., the difference between the 
number of tablets dispensed and the number of tablets returned) during the subject's 
participation up to Week 24 divided by the number of days that the subject was 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 Through Week 24
Efficacy analysis by randomized treatment groups (upadacitinib 15 mg QD, upadacitinib 
30 mg QD and the combined placebo group) will be performed on efficacy data up to 
Week 24.  No protocol-defined treatment switching will occur prior to the time point.  


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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:
1.
Placebo →Upadacitinib 15 mg QD
2.
Placebo →Upadacitinib 30 mg QD
3.
Upadacitinib 15 mg QD
4.
Upadacitinib 30 mg QD
Descriptive statistics and 95% confidence intervals will be provided for all treatment 
sequences.
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


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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 
unstructured variance covariance matrix will be used.  The parameter estimations are 
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 key continuous 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 (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 intent-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 
randomized to each upadacitinib dose group and received study drug to those who are 
randomized to placebo and received study drug.  


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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 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 
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.


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9.2.3
Key Secondary Efficacy Analyses
The following is a list of ranked key secondary endpoints:
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 SF-36 PCS at Week 12;
5.
Change from baseline in FACIT-Fatigue at Week 12; 
6.
Proportion of subjects achieving Minimal Disease Activity (MDA) at Week 24;
7.
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. 


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For secondary endpoints applicable only for sub-populations, the estimands will be 
constructed similarly but based on the subject sub-population, as defined in the below 
table. 
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
For MDA 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 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.  Supplementary analysis using AO data 
handling will also be conducted for binary endpoints. 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 
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.


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Continuous Endpoints
For 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.
The supplementary analysis for ranked 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 


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at random (MNAR).  Details of the tipping point analysis for continuous endpoints are 
outlined in Appendix C.
9.2.4
Efficacy Analyses for Additional Endpoints
Additional efficacy analysis includes the following endpoints at the scheduled time points 
other than those specified for the primary and key secondary variables:
●
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;
●
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 (defined as LDI = 0) (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 
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●
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 > 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;
●
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);


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●
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).
For binary endpoints, frequencies and percentages will be reported for each treatment 
group.  NRI will be used for primary analysis.  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 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 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 and the combined placebo group will be provided using 
MMRM model as described in Section 9.2.3, with fixed effects of treatment, visit, 
treatment-by-visit interaction, the stratification factor of current DMARD use (yes/no) and 


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the continuous fixed covariates of baseline measurement.  The nominal p-value will be 
provided.
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.
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 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.  Adjusted p-values for 
the primary and ranked key secondary endpoints will be provided based on the testing 
procedure. 
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 
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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9.2.6
Efficacy Subgroup Analysis
The primary efficacy endpoint will be examined in the subgroups listed in Table 6 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.
Table 6.
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 failed 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)


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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
●
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


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●
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
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
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, and maximum for continuous endpoints; and 
frequencies and percentages with 95% CI using normal approximation for binary 
endpoints.  These efficacy analyses will be based on AO data.  Plot for each randomized 
treatment group sequence over time will be provided for key endpoints.
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.
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).


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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 high-sensitivity CRP (hsCRP)
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. 
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.


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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 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:
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.


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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 "as 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 "as 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 7 are assessed in this study for both the left and right side of 
the body.


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Table 7.
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 will assess whether a particular joint was "tender or 
painful" where presence of tenderness is scored as "1" and the absence of tenderness is 
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 the 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 the 
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 Global 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 PsA 
using hsCRP or ESR measurement, respectively.  The DAS28 provides a score between 
0 and 10, indicating arthritis disease activity at the time of measurement.
DAS28 (CRP) and DAS28 (ESR) is calculated based on Tender Joint Count, Swollen 
Joint Count, PtGA of Disease Activity (0-100), 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 8.
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 PtGA 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), PtGA of Disease Activity (0-10 NRS), and
hsCRP (in mg/dL).
DAPSA = SJC66 + TJC68 + Pt pain (0-10 NRS) + PtGA (0-10 NRS) + hsCRP (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.
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.


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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 is 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
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.


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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 category there is an 
AIDS OR DEVICES companion variable 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 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 subject 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 assessment, 
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). 
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.


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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
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, 


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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 an item is missing, PASI is not scored.
PASI 75 (PASI 50, PASI 90, PASI 100) response is achieved 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, 
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 


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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 dactylitis 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 finals 
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.
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 


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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 modified PsARC is a PsA-specific composite responder index.  To achieve response, 
a subject 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)
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 × PtGA + 0.073 × peripheral 
pain/swelling + 0.058 × duration of morning stiffness + 0.579 × 
Ln(hs-CRP+1).
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 
any observed component is missing in a window, then the observed ASDAS score will be 
missing.


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ASDAS score is categorized by 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 Scale 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).  
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.


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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) was developed to measure 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:
!∀
#
∃%
&
∋
(
4
2
2
100
Q
Q
Q


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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).
○
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.


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●
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 or 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 unit of time (e.g., subject-
year) under observation in each variable (i.e., the number of unscheduled PsA-related 
health care professional visits, the number of emergency room visits, the number of 
hospital admissions and the total number of days in hospital) as follows:


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●
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.
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 through Week 24, 
and long-term safety analysis.
Safety Analysis Through Week 24
Standard safety analyses by the "as treated" treatment groups of upadacitinib 15 mg QD, 
upadacitinib 30 mg QD, and the combined placebo group 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 
treatment groups.  All continuous laboratory parameters and vital signs variables at each 
visit will be summarized by 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 treatment groups.  Missing safety data 
will not be imputed.  Treatment comparations of upadacitinib versus placebo will be 


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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.
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


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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 study drug.
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 will be tabulated by 
SOC and 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 PT 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 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 9 below.  Adjudicated 
cardiovascular events will be summarized and presented by treatment group using the 
CAC adjudicated categories.


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Table 9.
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"
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 
Perforation” 
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 9.
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 event rates 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 which 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 which 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.
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 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 categories 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 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


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10.2.2.3
Adverse Events of Special Interest Rates per 
100 Patient-Years of Study Drug Exposure by SOC and PT
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 MedDRA PT, 
for each of the AESI listed in Section 10.2.1.6.  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 10.
List of Laboratory Variables
Laboratory Variables
Hematology
White Blood Cell (WBC) Count
Red Blood Cell (RBC) Count
Hemoglobin
Hematocrit
Platelet 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 10.
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 Through Week 24
The laboratory data will be summarized by the treatment groups (upadacitinib 15 mg QD, 
upadacitinib 30 mg QD, and the combined placebo group).
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 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 5.0.  For the parameters with 
no quantitative grading available in version 5.0, CTCAE version 4.03 will be used.  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 5.0.  For the parameters with 
no quantitative grading available in version 5.0, CTCAE version 4.03 will be used.  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 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


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●
AST ≥ 10 × ULN
●
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 2 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 11.
Table 11.
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 Through 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, 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 groups.
10.4.3
Analysis of Long-Term 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 signs 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.  Introduction to stratified analysis.  In:  Rothman KJ, 
Greeland S, Lash TL, editors.  Modern Epidemiology, 3rd Edition.  Philaphdelphia:  
Lippincott Williams & Wilkins; 2008.
3.
Carpenter JR, Kenward MG.  Multiple Imputation and Its Application.  New York:  
John Wiley & Sons; 2013.
4.
Ratitch B, Lipkovich O'Kelly M.  Combining analysis results from multiply 
imputed categorical data.  In:  Conference Proceedings from PharmaSUG 2013.  
Paper SP03.  Chicago, IL:  May 12 - 15; 2013. 


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5.
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,3 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.4  These transformed results will be then 
aggregated using Rubin's method to get P-values.  


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Appendix C.
Tipping Point Analysis for Key Secondary Continuous Endpoint
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 the 
key secondary continuous endpoint HAQ-DI.
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on each upadacitinib dose group 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.
For a given pair of shift parameters, the SAS code example is as follows:
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'));


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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-biological DMARD gender, race, and regions.  WEEK_2, WEEK_4, WEEK_8, WEEK_12 
denote the observed values at each visit.  &SJ1 and &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 model 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;      
    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;


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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.


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Appendix D.
Exposure Adjusted AE Rate Difference and Normal Approximation 
Based 95% Confidence Interval (Liu, F et al.  20065)
Assume the occurrence of TEAE of special interest follows a Poisson 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 
Poisson 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
 −  ± ⍺/
where  = /
 + /
