A Phase 3 Randomized, Placebo-Controlled, Double-Blind Program to Evaluate Efficacy and Safety of Upadacitinib in Adult Subjects With Axial Spondyloarthritis Followed by a Remission-Withdrawal Period
Phase: PHASE3
Conditions: Spondyloarthritis
Sponsor: AbbVie



  
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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
9
2.1
BACKGROUND AND RATIONALE
9
2.2
BENEFITS AND RISKS TO SUBJECTS
10
3
OBJECTIVES AND ENDPOINTS
11
3.1
OBJECTIVES
11
3.2
PRIMARY ENDPOINT
12
3.3
SECONDARY ENDPOINTS
12
3.4
ADDITIONAL ENDPOINTS
14
3.5
PATIENT EXPERIENCE DATA (PED)
18
3.6
SAFETY ENDPOINTS
18
3.7
PHARMACOKINETIC ENDPOINTS
18
3.8
BIOMARKER RESEARCH
18
4
INVESTIGATIONAL PLAN
19
4.1
OVERALL STUDY DESIGN AND PLAN
19
4.2
DISCUSSION OF STUDY DESIGN
22
5
STUDY ACTIVITIES
23
5.1
ELIGIBILITY CRITERIA
23
5.2
CONTRACEPTION RECOMMENDATIONS
29
5.3
PROHIBITED MEDICATIONS AND THERAPY
30
5.4
PRIOR AND CONCOMITANT THERAPY
34
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
39
5.6
FOLLOW-UP FOR SUBJECT WITHDRAWAL FROM STUDY
41
5.7
STUDY DRUG
41
5.8
RANDOMIZATION/DRUG ASSIGNMENT AND BLINDING
42
5.9
PROTOCOL DEVIATIONS
44
5.10 TB TESTING/TB PROPHYLAXIS
44
6
SAFETY CONSIDERATIONS
47
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6.1
COMPLAINTS AND ADVERSE EVENTS
47
6.2
TOXICITY MANAGEMENT
51
6.3
DATA MONITORING COMMITTEE
55
7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
55
7.1
STATISTICAL AND ANALYTICAL PLANS
55
7.2
DEFINITION FOR ANALYSIS POPULATIONS
56
7.3
STATISTICAL ANALYSES FOR EFFICACY
56
7.4
STATISTICAL ANALYSES FOR SAFETY
59
7.5
INTERIM ANALYSIS
59
7.6
MULTIPLICITY ADJUSTMENT AND OVERALL TYPE I ERROR CONTROL
59
7.7
SAMPLE SIZE DETERMINATION
62
8
ETHICS
62
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD
62
8.2
ETHICAL CONDUCT OF THE STUDY
63
8.3
SUBJECT CONFIDENTIALITY
63
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
64
10 DATA QUALITY ASSURANCE
64
11 COMPLETION OF THE STUDY
64
12 REFERENCES
64
LIST OF TABLES
TABLE 1.
EXAMPLES OF COMMONLY USED STRONG CYP3A INHIBITORS AND INDUCERS
33
TABLE 2.
DESCRIPTION OF STUDY DRUG
42
TABLE 3.
SPECIFIC TOXICITY MANAGEMENT GUIDELINES FOR ABNORMAL LABORATORY VALUES 
(FOR STUDY 1 AND STUDY 2 AND REMISSION-WITHDRAWAL PERIOD)
53
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LIST OF FIGURES
FIGURE 1.
STUDY SCHEMATIC
21
FIGURE 2.
STUDY 1 (BDMARD-IR AS):  RESCUE THERAPY AND PERMANENT STUDY DRUG 
DISCONTINUATION PARAMETERS
37
FIGURE 3.
STUDY 2 (NR-AXSPA): RESCUE THERAPY AND PERMANENT STUDY DRUG DISCONTINUATION 
PARAMETERS
38
FIGURE 4.
TESTING SEQUENCE FOR STUDY 1 (BDMARD-IR AS)
60
FIGURE 5.
TESTING SEQUENCE FOR STUDY 2 (NR-AXSPA)
61
FIGURE 6.
STUDY SCHEMATIC
88
LIST OF APPENDICES
APPENDIX A.
STUDY SPECIFIC ABBREVIATIONS AND TERMS
68
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
71
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
72
APPENDIX D.
ACTIVITY SCHEDULE
73
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
84
APPENDIX F.
OPEN-LABEL EXTENSION FOR APPLICABLE COUNTRIES
86
APPENDIX G.
OPERATIONS MANUAL
90
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted
Spondyloarthritis (SpA) is represented by a group of diseases that share common genetic, clinical, and 
radiographic features.7,8  Adult SpA patients are commonly categorized by the 2 predominant 
manifestations of disease:  either axial spondyloarthritis (axSpA), which primarily involves the spine and 
sacroiliac (SI) joints, or peripheral SpA, which primarily involves peripheral joints.  Axial spondyloarthritis
encompasses a spectrum of inflammatory involvement of the axial skeleton.  Also, based on the 
Assessment of SpondyloArthritis international Society (ASAS) axSpA criteria, the disease can be further 
divided into 2 categories by radiographic findings:  1) non-radiographic axial spondyloarthritis (nr-
axSpA), which is axSpA that does not meet the 1984 modified New York imaging criteria, and 2) 
ankylosing spondylitis (AS), which by definition meets the modified New York criteria.9  Patients with nr-
axSpA and AS share common epidemiological, genetic, and clinical disease characteristics, particularly 
with regard to disease activity, and similar response to treatment.10,11  The presence of sacroiliitis on 
plain radiographs of at least Grade 2 bilateral or Grade 3 unilateral are required by the modified New 
York criteria for the classification of AS.
Per international treatment recommendations, nonsteroidal anti-inflammatory drugs (NSAIDs) are the 
first-line therapy in axSpA.2,12  After failure of 2 NSAIDs given over a maximum of 4 weeks, biologic 
disease-modifying antirheumatic drugs (bDMARDs) are the next recommended treatment option.  
Analgesics are also considered standard of care treatment for patients with pain from axSpA and are in 
line with current treatment guidelines.  In axSpA, conventional synthetic disease-modifying 
antirheumatic drugs (csDMARDs) and long-term corticosteroids are not efficacious and therefore not 
recommended for treatment of axial symptoms.2
The prevalence of AS differs between regions and has been estimated to be up to 0.5%13,14,15 with similar 
estimated prevalence rates for nr-axSpA, resulting in an overall prevalence for axSpA in the United 
States (US) of approximately up to 1% or even higher in the overall population.16,17  In contrast to other 
regions of the world, the prevalence in Japan has only been estimated to be 0.0065%.18
There remains a significant unmet medical need in the treatment of axSpA as only approximately 45% to 
50% of patients show an ASAS40 response and only approximately 15% to 20% achieve a state of 
remission in biologic-naïve patients, and response rates are even less in axSpA patients who had an 
inadequate response to bDMARDs (bDMARD-inadequate responders [bDMARD-IR]).19,20,21,22  To date, 
there have been no oral targeted therapies approved for the treatment of axSpA.  Data from patients 
with rheumatoid arthritis (RA) suggest that an oral therapy could provide a preferred administration 
alternative to injectable biologic medications.23  Evidence from Phase 2 studies with the Janus kinase 
(JAK) inhibitors, tofacitinib or filgotinib, suggests that inhibition of JAK-mediated pathways may be a 
promising approach for the treatment of subjects with AS.24,25
More selective JAK inhibitors may decrease the risk for infection (including viral reactivation) and/or 
malignancy that are observed with pan JAK inhibitors or less selective JAK inhibitors.  Upadacitinib is a 
novel oral selective and reversible JAK inhibitor being developed for axSpA and treatment of other 
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immune-mediated inflammatory diseases including RA, Crohn's disease, ulcerative colitis, atopic 
dermatitis, psoriatic arthritis (PsA), giant cell arteritis, and juvenile idiopathic arthritis.  In the Phase 2/3 
study in AS (Study M16-098, SELECT-AXIS 1), the primary endpoint (ASAS40 at Week 14) was met with a 
statistically significantly higher ASAS40 response in the upadacitinib 15 mg once daily (QD) group 
compared to the placebo group.26  Through Week 64, no new safety risks were identified.1
Per international treatment recommendations, the treatment goal in axial SpA is to achieve remission or 
Low Disease Activity (LDA).2,3,12,27 One important clinical question in axial SpA patients who achieve 
clinical remission on a certain drug treatment is whether the remission can be sustained even after the 
drug is withdrawn.
Clinical Hypothesis for Study 1 (bDMARD-IR AS)
Upadacitinib is expected to provide better efficacy compared to placebo and is expected to be well 
tolerated in adult subjects with active AS who are bDMARD-IR.
Clinical Hypothesis for Study 2 (nr-axSpA)
Upadacitinib is expected to provide better efficacy compared to placebo and is expected to be well 
tolerated in adult subjects with active nr-axSpA.
Rationale for Master Protocol Approach
Study Protocol M19-944 is a global, multicenter, protocol ("master protocol") with a common screening 
platform for determining subject eligibility into 2 separate studies with many overlapping eligibility 
criteria within the same protocol.  The ability to use a common screening platform is considered to be 
one of the main advantages of incorporating these 2 studies into a single protocol, resulting in a 
decreased patient burden during screening and a more efficient recruitment of subjects and use of 
resources.  A subject who is a bDMARD-IR in screening may be eligible for and randomized into 1 of the 
2 studies without the need to screen-fail and rescreen for the other study.  The requirement for subjects 
to meet the modified New York criteria using confirmation of radiographic evidence by a central reader 
is necessary for eligibility into the AS study; however, those subjects who do not meet these 
radiographic criteria may still be eligible for the nr-axSpA study.
Although this protocol includes a common screening process and other operational elements 
(Appendix G) for Study 1 and Study 2, randomization and data collection will be conducted for each 
study independently.  There is no overlap in subject population, nor is there a shared control group.  
Each study has its own objective, hypothesis testing, and adequate power for primary and secondary 
endpoints.  The analyses and reporting for the 2 studies will therefore be separate.  The success of each 
study in its corresponding subject population will be determined separately and independently of the 
other study.  Each study represents a standalone study for regulatory purposes with the ability to report 
interim and final data independently.
2.2 Benefits and Risks to Subjects
Primary results from the ongoing upadacitinib Phase 2/3 Study M16-098 (SELECT-AXIS 1) in 
bDMARD-naïve AS demonstrated superior efficacy of upadacitinib with an acceptable safety profile at 
the selected dose for Phase 3 (15 mg QD) compared to placebo (data on file).  Since AS and nr-axSpA are 
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conditions along the spectrum of axSpA and patients with either condition share similar disease 
characteristics and similar response to treatment (see Section 2.1),10,11 it is expected that the safety 
profiles of upadacitinib in the bDMARD-IR AS and nr-axSpA populations would be similar.28  The 
available long-term safety data from the Phase 3 RA studies with upadacitinib did not show any new 
significant safety concerns compared to the marketed JAK inhibitors.29  The findings of an increased risk 
of infections, herpes zoster, and abnormal laboratory changes have been observed (e.g., increases in 
serum transaminases, lipids, and creatine phosphokinase [CPK], small mean decreases from Baseline in 
hemoglobin, and small mean changes from Baseline in absolute lymphocyte count [ALC]) with 
upadacitinib therapy.  The incidence rates of other clinically important adverse events (AEs) such as 
cardiovascular events, malignancies, and mortality reported during the RA studies were within the 
expected range for the general population or for a population of patients with moderately to severely 
active RA.30  Events of deep vein thrombosis and pulmonary embolism have been reported in patients 
receiving JAK inhibitors including upadacitinib.
When treated with available therapies, safety events are typically fewer in AS patients compared to RA 
or PsA patients.28,31,32,33  The reason for fewer safety events might be due to the fact that patients with 
axSpA are, on average, younger, use fewer concomitant immunosuppressants given that corticosteroids 
and csDMARDs are not efficacious and not recommended for the treatment of axial symptoms (see 
Section 2.1), and generally have fewer comorbidities such as hypertension, hypercholesterolemia, or 
diabetes.34,35
The results of genetic toxicology testing indicate that upadacitinib is not genotoxic; however, 
upadacitinib is teratogenic based on animal studies, which necessitates avoidance of pregnancy in 
females 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 upadacitinib can be found in the current Investigator's Brochure.30
Taken together, the safety and efficacy data from upadacitinib studies to date show a favorable 
benefit:risk profile for upadacitinib and support the continued investigation of upadacitinib in adult 
subjects with active axSpA including bDMARD-IR AS (Study 1) and nr-axSpA (Study 2).
In view of the coronavirus disease 2019 (COVID-19) pandemic, the benefit:risk profile of various 
immunomodulatory therapies on COVID-19 is being evaluated.  At this time, the effects of upadacitinib 
on the course of COVID-19 are not well defined.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives
Double-Blind Period:

To evaluate the efficacy of upadacitinib compared with placebo on reduction of signs and 
symptoms in adult subjects with active axSpA including bDMARD-IR AS (Study 1) and nraxSpA
(Study 2);
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
To assess the safety and tolerability of upadacitinib in adult subjects with active axSpA including 
bDMARD-IR AS (Study 1) and with nraxSpA (Study 2).
Open-Label Extension Period:
To evaluate the safety and tolerability of upadacitinib in extended treatment in adult subjects with 
active axSpA including bDMARD-IR AS who have completed the Double-Blind Period (Study 1) and with 
nr-axSpA who have completed the Double-Blind Period (Study 2).
Remission-Withdrawal Period:
To evaluate the maintenance of disease control after withdrawal of upadacitinib in those who achieved 
ASDAS < 1.3 at Week 104 and ASDAS < 2.1 at Week 88.
3.2 Primary Endpoint
Study 1 (bDMARD-IR AS):
The primary endpoint is ASAS40 response at Week 14.
Study 2 (nr-axSpA):
The primary endpoint is ASAS40 response at Week 14.
3.3 Secondary Endpoints
Study 1 (bDMARD-IR AS): 
The multiplicity-controlled secondary endpoints at Week 14 are:
1.
Change from Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
2.
Change from Baseline in magnetic resonance imaging (MRI) Spondyloarthritis Research 
Consortium of Canada (SPARCC) score (spine);
3.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 response;
4.
ASAS20 response;
5.
ASDAS Inactive Disease (ID) (ASDAS score < 1.3);
6.
Change from Baseline in Patient's Assessment of Total Back Pain (Total Back Pain);
7.
Change from Baseline in Patient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain);
8.
ASDAS LDA (ASDAS score < 2.1);
9.
Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI);
10. ASAS partial remission (PR) (an absolute score of ≤ 2 units for each of the 4 domains identified in 
ASAS40);
11. Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL);
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12. Change from Baseline in ASAS Health Index (HI);
13. Change from Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin);
14. Change from Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES).
Additional secondary endpoint at Week 14: 

Change from Baseline in MRI SPARCC score (SI joints).
Study 2 (nr-axSpA):
The multiplicity-controlled secondary endpoints at Week 14 (unless otherwise noted) are:
1.
Change from Baseline in ASDAS;
2.
Change from Baseline in MRI SPARCC score (SI joints);
3.
BASDAI 50 response;
4.
ASDAS ID (ASDAS score < 1.3);
5.
Change from Baseline in Patient's Assessment of Total Back Pain (Total Back Pain);
6.
Change from Baseline in Patient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain);
7.
ASDAS LDA (ASDAS score < 2.1);
8.
ASAS PR (an absolute score of ≤ 2 units for each of the 4 domains identified in ASAS40);
9.
Change from Baseline in BASFI;
10. Change from Baseline in ASQoL;
11. Change from Baseline in ASAS HI;
12. ASAS20 response;
13. Change from Baseline in BASMIlin;
14. Change from Baseline in MASES;
15. ASAS40 response at Week 52 (for European Union [EU]/European Medicines Agency [EMA] 
regulatory purposes).
For US/Food and Drug Administration (FDA) regulatory purposes, the last multiplicity-controlled 
secondary endpoint is change from Baseline in MASES.
Additional secondary endpoints are:

Change from Baseline in MRI SPARCC score (spine) at Week 14;

Initiation of rescue between Week 24 and Week 52;

ASDAS Major Improvement (a change from Baseline of ≤ –2.0) at Week 52 (for EU/EMA 
regulatory purposes);
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
ASDAS ID (ASDAS score < 1.3) at Week 52 (for EU/EMA regulatory purposes);

ASDAS LDA (ASDAS score < 2.1) at Week 52 (for EU/EMA regulatory purposes).
3.4 Additional Endpoints
Study 1 (bDMARD-IR AS):
Additional endpoints are the following measurements assessed at scheduled time points other 
than those specified for the primary and secondary endpoints:
Binary variables:

ASAS20 response;

ASAS40 response;

BASDAI 50 response;

ASAS PR;

ASDAS ID (ASDAS score < 1.3);

ASDAS LDA (ASDAS score < 2.1);

ASDAS Major Improvement (a change from Baseline of ≤ –2.0);

ASDAS Clinically Important Improvement (a change from Baseline of ≤ –1.1);

Discontinuation of opioids among subjects with opioid use at Baseline.
Change from Baseline in:

ASAS HI;

ASDAS;

ASQoL;

BASDAI and BASDAI components including mean of question 5 and 6 of the BASDAI;

BASFI;

BASMIlin;

High sensitivity C-reactive protein (hsCRP);

EuroQoL-5D-5L (EQ-5D-5L);

Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);

MASES;

Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with conventional radiograph;

MRI SPARCC score of SI joints;

MRI SPARCC score of spine;
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
Patient's Assessment of Total Back Pain (Total Back Pain);

Patient's Assessment of Nocturnal Back Pain (Nocturnal Back Pain);

Patient's Global Assessment of Pain;

Physician's Global Assessment of Disease Activity (PGA);

Patient's Global Assessment of Disease Activity (PtGA);

36-Item Short Form Health Survey (SF-36);

Tender joint count (TJC) and swollen joint count (SJC); 

Work Productivity and Activity Impairment (WPAI);

NSAID score;

Physical Activity Assessment (step count, physical activity, and spinal range of motion tasks) as 
measured by a wearable device (except in countries where the digital health technology device 
is not available or is not allowed to be used in the study by the local regulatory authority).
Additional endpoint relating to the assessment of disease flare for subjects on upadacitinib treatment
who achieve an ASDAS C-reactive protein (CRP) < 1.3 at Week 52 and an ASDAS (CRP) < 2.1 at Week 40:

Time to flare during Week 52 to Week 104
Study 2 (nr-axSpA): 
Additional endpoints are the following measurements assessed at scheduled time points other 
than those specified for the primary and secondary endpoints:
Binary variables:

ASAS20 response;

ASAS40 response;

BASDAI 50 response;

ASAS PR;

ASDAS ID (ASDAS score < 1.3);

ASDAS LDA (ASDAS score < 2.1);

ASDAS Major Improvement (a change from Baseline of ≤ –2.0);

ASDAS Clinically Important Improvement (a change from Baseline of ≤ –1.1);

Discontinuation of opioids among subjects with opioid use at Baseline.
Change from Baseline in:

ASAS HI;

ASDAS;
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
ASQoL;

BASDAI and BASDAI components including mean of question 5 and 6 of the BASDAI;

BASFI;

BASMIlin;

hsCRP;

EQ-5D-5L;

FACIT-F; 

MASES;

mSASSS with conventional radiograph;

MRI SPARCC score of SI joints;

MRI SPARCC score of spine;

Total Back Pain;

Nocturnal Back Pain;

Patient's Global Assessment of Pain;

PGA;

PtGA;

SF-36;

TJC and SJC;

WPAI;

NSAID score.
Additional endpoint relating to the assessment of disease flare for subjects in the upadacitinib group 
who achieved an ASDAS (CRP) < 1.3 at Week 52 and an ASDAS (CRP) < 2.1 at Week 40:

Time to flare during Week 52 to Week 104
Study 1 and Study 2: Remission-Withdrawal Period
Additional endpoint relating to the assessment of disease flare:

Time to flare during the withdrawal period 
Additional endpoints assessed at scheduled visits during the withdrawal period:
Binary variables:

ASDAS (CRP) ID/LDA 

ASDAS (CRP) Major Improvement/Clinically Important Improvement
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
ASAS 40/20/PR

BASDAI 50
Change from baseline (of Double-Blind Period) in:

ASDAS (CRP) (and components)

BASDAI (and components)

Total back pain

BASFI

PtGA

Patient's Global Assessment of Pain

Nocturnal back pain

ASAS HI

TJC/SJC

BASMIlin

MASES

PGA
Additional endpoints assessed at scheduled visits during re-treatment of upadacitinib after disease flare:
Binary variables:

ASDAS (CRP) ID/LDA

ASDAS (CRP) Major Improvement/Clinically Important Improvement

ASAS 40/20/PR

BASDAI 50
Change from re-treatment baseline (i.e., at the time of flare) in:

ASDAS (CRP) (and components)

BASDAI (and components)

Total back pain

BASFI

PtGA

Patient's Global Assessment of Pain

Nocturnal back pain

ASAS HI
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
TJC/SJC

BASMIlin

MASES

PGA
3.5 Patient Experience Data (PED)
PED will be collected for Study 1 and Study 2 at each subject's Baseline Visit only.
3.6 Safety Endpoints
Study 1 and Study 2 will be analyzed and reported independently for safety.  The following safety 
evaluations will be performed during Study 1 and Study 2:  treatment-emergent adverse events (TEAEs), 
serious adverse events (SAEs), AE of special interest (AESI), AEs leading to discontinuation, vital signs, 
laboratory tests, and physical examination findings.
3.7 Pharmacokinetic Endpoints
Study 1 and Study 2 will be analyzed and reported independently for pharmacokinetic (PK) endpoints.  
PK samples will be collected from approximately 30% of subjects at select sites at the visits indicated in 
Appendix D.  Using the data available from these subjects, a nonlinear mixed-effects modeling approach 
will be used to estimate the population central values and the empirical Bayesian estimates of the 
individual values of upadacitinib oral clearance (CL/F) and apparent volume of distribution (V/F).  
Additional parameters may be estimated if useful in the interpretation of the data.  Data from these 
studies may be combined with data from other studies for the population PK analyses.
3.8 Biomarker Research
Optional samples for biomarker research will be collected in Study 1 and Study 2 as described in 
Appendix D to evaluate known and/or novel disease-related or drug-related biomarkers.  Types of 
biomarkers may include nucleic acids, proteins, lipids, and/or metabolites.  The objective of the research 
is to analyze samples for biomarkers that will help to understand axSpA, related conditions, and 
response to treatment with upadacitinib or similar compounds.  Research may also include changes in 
epigenetics, gene expression, and proteomics that may associate with axSpA, related conditions, or the 
subject's response to treatment.  This research is exploratory in nature, and the results may not be 
included with clinical study reports.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a global Phase 3, multicenter, protocol with a common screening platform and other operational 
elements of study conduct.  The master protocol includes 2 independent studies for subjects with active 
axSpA including bDMARD-IR AS (Phase 3 study, Study 1) and nr-axSpA (Phase 3 study, Study 2).
Although this protocol includes a common screening process and other operational elements of study 
conduct for Study 1 and Study 2, randomization and data collection will be conducted for each study 
independently.  The analyses and reporting for the 2 studies will also be separate.  Each study 
represents a standalone study which may be reported individually for regulatory purposes.
Study 1 (bDMARD-IR AS) is comprised of a 35-day Screening Period; a 14-week randomized, 
double-blind, parallel-group, placebo-controlled period (the Double-Blind Period); a 90-week open-label, 
long-term extension period (the Open-Label Extension Period); and a 30-day Follow-Up Visit (F/U Visit).
Study 2 (nr-axSpA) is comprised of a 35-day Screening Period; a 52-week randomized, double-blind, 
parallel-group, placebo-controlled period (the Double-Blind Period); a 52-week open-label, long-term 
extension period (the Open-Label Extension Period); and a 30-day F/U Visit.
For both studies, a 30-day F/U phone call may be performed in place of a visit to determine the status of 
any ongoing AEs/SAEs or the occurrence of any new AEs/SAEs is required; these subjects will be 
considered as having completed the study.
Up to and including Week 14 of each study, a ± 3 day window is permitted around scheduled study 
visits.  After Week 14 of each study, a ± 7 day window is permitted around scheduled study visits.  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).
In the Double-Blind Period, subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups:
Study 1 (bDMARD-IR AS):

Group 1:  upadacitinib 15 mg QD (N = 193)

Group 2:  placebo QD (N = 193)
Study 2 (nr-axSpA):

Group 1:  upadacitinib 15 mg QD (N = 152)

Group 2:  placebo QD (N = 152)
Subjects in the placebo group will be switched to upadacitinib 15 mg QD at Week 14 in the Open-Label 
Extension Period for Study 1 (bDMARD-IR AS) and to upadacitinib 15 mg QD at Week 52 in the 
Open-Label Extension Period for Study 2 (nr-axSpA).
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The AbbVie study team will be unblinded to perform the Week 14 primary analysis for both studies.  
Reporting will be performed independently for Study 1 and Study 2.  For Study 1 and Study 2, the 
unblinding will take place after all subjects in the study have completed the Week 14 visit or have 
prematurely discontinued prior to Week 14.  For both Study 1 and Study 2, sites and subjects will remain 
blinded to the Double-Blind Period treatment assignments for the duration of the study.
Information on the Data Monitoring Committee (DMC) and Cardiovascular Adjudication Committee 
(CAC) are described in Section 6.3 and Section 6.1, respectively.
See Section 5 for information regarding eligibility criteria and Section 5.8 for information on
stratification.
The schematic of Study 1 and Study 2 is shown in Figure 1.  Further details regarding study procedures 
are located in the operations manual (Appendix G).
For subjects in Japan only: Upon marketing approval of upadacitinib for the treatment of nr-axSpA in 
Japan, M19-944 Study 1 and Study 2 will be changed from Phase 3 studies to post-marketing clinical 
studies in Japan.
Remission-Withdrawal Period
Subjects in Study M19-944 from both Study 1 (AS bDMARD-IR) and Study 2 (nr-axSpA) who reach Week 
104 on study drug (upadacitinib 15 mg QD) will be assessed whether they are in remission, with an 
ASDAS (CRP) < 1.3 at Week 104 and an ASDAS (CRP) < 2.1 at Week 88.
Subjects in remission at Week 104 will be eligible for the Remission-Withdrawal Period.  Subjects will be 
followed without study drug treatment and assessed for disease flare through Week 152.  Flare is 
defined as an ASDAS (CRP) ≥ 2.1 at 2 consecutive visits, which are at least 2 weeks apart, or an ASDAS 
(CRP) > 3.5 at one visit.  Subjects who flare will receive open-label upadacitinib 15 mg QD from the time 
of flare for 24 weeks (re-treatment) or longer per local country requirements (See Appendix F for more 
details).
Subjects who do not flare, will be followed without upadacitinib treatment until Week 152.
Subjects who are not in remission at Week 104 will complete the study after the 30 day follow-up visit 
OR, if applicable, will have the option to enter open-label treatment with upadacitinib until a predefined 
time period only per local country requirements (See Appendix F).
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Figure 1.
Study Schematic
AS = ankylosing spondylitis; ASAS = Assessment of SpondyloArthritis International Society; DB = double-blind; bDMARD-IR = biologic disease-modifying antirheumatic drug 
inadequate responder; MRI = magnetic resonance imaging; nr-axSpA = non-radiographic axial spondyloarthritis; PBO = placebo; QD = once daily; SI = sacroiliac; UPA = upadacitinib; 
Wk = week
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4.2 Discussion of Study Design
Master Protocol Design
The Study M19-944 master protocol utilizes a common screening platform to operationally streamline 
the screening and enrollment of similar but noncompeting subject populations into independent studies 
within the master protocol.  Please refer to Section 2.1 for the rationale for the master protocol 
approach.
Choice of Control Group
Placebo control will be used in Study 1 and Study 2.  Comparative studies utilizing a double-blind, 
placebo-control design provides an unbiased assessment of the efficacy and safety profile of 
upadacitinib.
Appropriateness of Measurements
Standard statistical, clinical, and laboratory procedures will be utilized in Study 1 and Study 2.  All 
efficacy measurements are standard for assessing disease activity in subjects with AS or nr-axSpA.  All 
clinical and laboratory procedures are standard and generally accepted.
Suitability of Subject Population
The intended study populations are subjects with active AS who are bDMARD-IR (Study 1) or with active 
nr-axSpA (Study 2).  These 2 specific populations chosen were based on the unmet medical need of 
these subjects.  Key entry criteria are to enroll adult female and male subjects who are at least 18 years 
of age with a clinical diagnosis of AS, meet the modified New York Criteria for AS, and are without total 
spinal ankylosis (Study 1) or with a clinical diagnosis of nr-axSpA fulfilling the 2009 ASAS classification 
criteria for axSpA but not meeting the radiologic criterion of the modified New York criteria for AS and 
have objective signs of active inflammation on MRI of SI joints or based on hsCRP > upper limit of normal 
(ULN) (Study 2).  Eligible study subjects for both studies must have a BASDAI score ≥ 4 and a Total Back 
Pain score ≥ 4 based on a 0 – 10 numerical rating scale (NRS) at the Screening and Baseline Visits.  
Subjects who enter a study on permitted concomitant medication(s) must have been on a stable dose 
for the amount of time specified in the eligibility criteria (Section 5.1) prior to the Baseline Visit.
Selection of Doses in the Study
Study 1 and Study 2 will evaluate 1 dose of upadacitinib (15 mg QD) versus placebo.  Dose selection was
informed by results of the Phase 2/3 study of upadacitinib in AS (Study M16-098, SELECT-AXIS 1) 
including exposure-response analyses from that study, as well as the results from the exposure-response 
analyses conducted based on data from upadacitinib Phase 2 and Phase 3 studies in RA
(Studies M13-537, M13-550, M13-549, M13-542, M15-555, M14-465, and M13-545).
In Study M16-098, upadacitinib 15 mg QD was studied versus placebo over a period of 14 weeks in 
subjects with active AS who failed treatment with NSAIDs and who were bDMARD-naïve.  The study met 
its primary endpoint, ASAS40 response at Week 14.  No new safety risks were identified in this study.  
Efficacy and safety data in Japanese subjects were overall consistent with global data in this study.
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Exposure-response relationships between upadacitinib plasma exposures (average concentrations [Cavg]) 
and ASAS response rates (i.e., ASAS20 and ASAS40) and safety variables (i.e., herpes zoster infections; 
pneumonia; any infection; serious infections; decrease in hemoglobin, lymphocytes, or neutrophils from 
Baseline; and increase in platelet counts from Baseline) were evaluated using data from Study M16-098.  
Results of these analyses showed that upadacitinib Cavg values with the 15 mg QD dose were associated 
with higher ASAS20 and ASAS40 response rates compared to placebo, with no evidence of 
exposure-dependent increase in ASAS20 or ASAS40 response within subjects treated with upadacitinib.36
These results indicate that upadacitinib exposures resulting from the 15 mg QD dose maximize efficacy 
in subjects with AS.
Similarly, evaluation of exposure-response relationships between upadacitinib plasma exposures and 
safety variables indicated no exposure-dependent changes in the occurrence of safety events, except for 
decrease in hemoglobin levels by > 1 g/dL compared to Baseline.  Similar to results previously observed 
in subjects with RA, higher upadacitinib exposures (especially those associated with the 30 mg QD dose) 
were associated with higher incidence of hemoglobin decrease of > 1 g/dL.
Overall, results from Study M16-098 (including exposure-response evaluations) indicate that 
upadacitinib 15 mg QD provides the optimal balance of efficacy and safety in treatment of AS.
Likewise, exposure-responseanalyses of upadacitinib Phase 2 and 3 studies in RA have previously shown 
that upadacitinib 15 mg QD dosing result in near maximal efficacy in RA, with 30 mg QD dosing resulting
in only modest incremental efficacy benefit (≤ 5% increase in American College of Rheumatology or 
LDA/clinical remission responses from 15 mg QD to 30 mg QD across all populations).37   More 
importantly, these results were consistent across subjects with inadequate response to a csDMARD 
(csDMARD-IR) and bDMARD-IR populations and whether upadacitinib is used as monotherapy or on 
background treatment of csDMARDs.
Overall, AS patients and nr-axSpA patients show similar and comparable response to treatment.  For this 
reason, treatment recommendations were published for axSpA as a whole including AS and 
nr-axSpA.19,38,39  Based on the historically similar treatment responses in AS patients and nr-axSpA 
patients, and the consistent benefit:risk profile for upadacitinib 15 mg QD dose across the different RA 
populations, the 15 mg QD dose was selected for both AS and nr-axSpA populations and is expected to 
provide optimal benefit:risk balance.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria specific to each study in order to be included in the 
study.
Study 1:  bDMARD-IR AS specific criteria:
1. Subject must have a clinical diagnosis of AS and subjects must meet the modified New York 
criteria for AS.
2. Subject must not have total spinal ankylosis.
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3. Subject must have been previously exposed to 1 or 2 bDMARDs (at least 1 tumor necrosis 
factor [TNF] inhibitor or 1 interleukin [IL]-17 inhibitor), and the subject must have discontinued 
the bDMARD therapy due to either lack of efficacy (after at least 12 weeks of treatment with a 
bDMARD at an adequate dose) or intolerance (irrespective of treatment duration).  Prior 
exposure to a 2nd bDMARD is allowed for no more than 30% of subjects.  Subjects who have had 
lack of efficacy to 2 bDMARDs (including both a TNF inhibitor and IL-17 inhibitor) are not eligible.
Study 2:  nr-axSpA-specific criteria:
4. Subject must have a clinical diagnosis of nr-axSpA fulfilling the 2009 ASAS classification criteria 
for axSpA but not meeting the radiologic criterion of the modified New York criteria for AS.
5. Subjects with or without prior exposure to a bDMARD may be enrolled.

For the subset of subjects with prior bDMARD exposure (at least 20%, but not exceeding 
35% of total enrolled subjects), prior treatment with at most 1 bDMARD (either 1 TNF 
inhibitor or 1 IL-17 inhibitor) is allowed, and the subject must have discontinued the 
bDMARD due to either lack of efficacy (after at least 12 weeks of treatment with a bDMARD 
at an adequate dose) or intolerance (irrespective of treatment duration).  Subjects who have 
had lack of efficacy to both a TNF inhibitor and IL-17 inhibitor are not eligible.
6. Subject must have objective signs of active inflammation consistent with axSpA on MRI of SI 
joints or hsCRP > ULN at Screening.
The following eligibility criteria are applicable for Study 1 and Study 2:
Consent and Demographics
7. Subject must be able to understand and willing to adhere to all protocol requirements and 
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.
8. Subject must be an adult male or female, at least 18 years of age at Screening.
Disease Activity and Prior and Concomitant Treatment
9. Subject must meet the following scores at Screening and Baseline Visits:

BASDAI score ≥ 4 and

Total Back Pain score ≥ 4 based on a 0 – 10 NRS.
10. Subject has had an inadequate response to at least 2 NSAIDs over an at least 4-week period 
in total at maximum recommended or tolerated doses, or subject has an intolerance to or 
contraindication for NSAIDs as defined by the Investigator.
11. The washout period for biologics prior to the first dose of study drug is specified below:

≥ 4 weeks for etanercept;
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
≥ 8 weeks for adalimumab, infliximab, certolizumab, golimumab, abatacept, tocilizumab, 
and ixekizumab;

≥ 12 weeks for ustekinumab;

≥ 16 weeks for secukinumab;

≥ 1 year for rituximab OR ≥ 6 months if B cells have returned to pre-treatment level or 
normal reference range (central lab) if pre-treatment levels are not available;

≥ 12 weeks or at least 5 times the mean terminal elimination half-life, whichever is longer, 
for other biologics.
12. If entering the studyon the following concomitant csDMARDs,subject must be on a stable
dose as indicated below for at least 28 days prior to the Baseline Visit.  A combination of up to 
2 background csDMARDs is allowed EXCEPT the combination of methotrexate (MTX) and
leflunomide.

MTX (≤25 mg/week); or

Sulfasalazine (≤3 g/day); or

Hydroxychloroquine(≤400 mg/day); or

Chloroquine (≤400 mg/day); or

Leflunomide (≤20 mg/day); or

Apremilast (≤60 mg/day).
13. If entering the studyon concomitant oral corticosteroids,subject must be on a stable dose of
prednisone (≤10 mg/day) or oral corticosteroid equivalent for at least 14 days prior to the
Baseline Visit.
14. If entering the studyon concomitant NSAIDs, tramadol, combinationof 
acetaminophen/paracetamol and codeine or combination of acetaminophen/paracetamol and 
hydrocodone, and/or non-opioid analgesics, subject must be on stable dose(s) for at least
14 days prior to the Baseline Visit.
15. Subject must not have been exposed to any JAK inhibitor (including but not limited to 
upadacitinib [Rinvoq®], tofacitinib [Xeljanz®], baricitinib [Olumiant®], filgotinib, ruxolitinib 
[Jakafi®], abrocitinib [PF04965842], and peficitinib [Smyraf®]).
16. Subject must not have used the following prohibited concomitant treatments within the 
specified timeframe prior to Baseline Visit:

Intra-articular joint injections, spinal/paraspinal injection(s), or parenteral administration of 
corticosteroids (including intramuscular and intravenous injections) within 28 days prior to 
the Baseline Visit.  Inhaled or topical corticosteroids are allowed;

Any other csDMARDs (other than those allowed per eligibility criterion 12), including 
thalidomide, within 28 days or 5 half-lives (whichever is longer) of the drug prior to the 
Baseline Visit;

Opioid analgesics (except for combination of acetaminophen/paracetamol and codeine or 
combination of acetaminophen/paracetamol and hydrocodone which are allowed) within 
14 days prior to the Baseline Visit.
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17. Subject must not have received a live vaccine within 28 days (or longer if required locally) 
prior to the first dose of study drug or have expected need of live vaccination during study 
participation including at least 30 days (or longer if required locally) after the last dose of study 
drug.
18. Subject must have no systemic use of known strong cytochrome P450 3A (CYP3A) inhibitors 
from Screening through the end of study drug administration or strong CYP3A inducers 30 days 
prior to study drug administration through the end of study drug administration (refer to Table 1
is Section 5.3 for examples of commonly used strong CYP3A inhibitors and inducers).  Subjects 
must not use herbal therapies or other traditional medicines with unknown effects on CYP3A
from Screening through the end of study drug administration.
19. Subject must not have been treated with any investigational drug of chemical or biologic 
nature within a minimum of 30 days or 5 half-lives of the drug (whichever is longer) prior to the 
first dose of study drug or is currently enrolled in another interventional study.
20. Subject must not have a history of an allergic reaction or significant sensitivity to 
constituents of the study drug (and its excipients) and/or other products in the same class.
Contraception
21. For all females of childbearing potential:  must not have a positive serum pregnancy test at 
the Screening Visit and must have a negative urine pregnancy test at Baseline prior to the 
first dose of study drug (local practices may require serum pregnancy testing at Baseline).  
Subjects with a borderline pregnancy test at Screening must have absence of clinical suspicion of 
pregnancy or other pathological causes of borderline results and a serum pregnancy 
test ≥3 days later to document continued lack of a positive result (unless prohibited by local 
requirements).
22. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control that is effective from Study Day 1 through at least 30 days after the last dose of 
study drug (local practices may require 2 methods of birth control).  Female subjects of 
nonchildbearing potential do not need to use birth control.
23. Females must not be pregnant, breastfeeding, or considering becoming pregnant during the 
study or for approximately 30 days after the last dose of study drug.
Laboratory Values
24. Laboratory values must meet the following criteria within the Screening Period prior to the 
first dose of study drug:

Serum aspartate transaminase (AST) ≤ 2 × ULN;

Serum alanine aminotransferase (ALT) ≤ 2 × ULN;

eGFR by simplified 4-variable Modification of Diet in Renal Disease (MDRD) 
formula ≥30 mL/min/1.73 m2;

Total white blood cell (WBC) count ≥ 2,500/μL;

Absolute neutrophil count (ANC) ≥ 1,200/μL;
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
Platelet count ≥ 100,000/μL;

ALC ≥ 750/μL;

Hemoglobin ≥ 9 g/dL.
Subject History
25. Subject is judged to be in good health as determined by the Principal Investigator, based 
upon the results of medical history, laboratory profile, physical examination, chest x-ray (CXR), 
and a 12-lead electrocardiogram (ECG) performed during Screening.
26. Subject must not have a history of clinically significant (per Investigator's judgment) drug or 
alcohol abuse within the last 6 months.
27. Subject must have no current or past history of infection including:

Recurrent or disseminated (even a single episode) herpes zoster;

Disseminated (even a single episode) herpes simplex;

Human immunodeficiency virus (HIV) defined as confirmed positive anti-HIV antibody (Ab) 
test;

Active tuberculosis (TB) or meets TB exclusionary parameters (specific requirements for TB 
testing are provided in Section 5.10);

For subjects in Japan only:  Positive result of beta-D-glucan (screening for Pneumocystis 
jirovecii infection) or 2 consecutive indeterminate results of beta-D-glucan during the 
Screening Period;

Active infection(s) requiring treatment with intravenous anti-infectives within 30 days, or 
oral/intramuscular 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;

Confirmed COVID-19:  the Baseline Visit must be at least 14 days from onset of 
signs/symptoms or positive SARS-CoV-2 test; symptomatic subjects must have recovered, 
defined as resolution of fever without use of antipyretics and improvement in symptoms;

Suspected COVID-19:  subjects with signs/symptoms suggestive of COVID-19, known 
exposure, or high risk behavior should undergo molecular (e.g., polymerase chain reaction 
[PCR]) testing to rule out SARS-CoV-2 infection or must be asymptomatic for 14 days from a 
potential exposure;

Subject must not have evidence of:

Hepatitis B virus (HBV):  hepatitis B surface antigen (HBs Ag) positive (+) test or detected 
sensitivity on the HBV DNA PCR qualitative test for subjects who are hepatitis B core Ab 
(HBc Ab) positive (+) (and for Hepatitis B surface Ab positive [+] subjects where 
mandated per local requirements);

Hepatitis C virus (HCV):  HCV RNA detectable in any subject with anti-HCV Ab.
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28. Subject must not have any of the following medical diseases or disorders:

Recent (within past 6 months) cerebrovascular accident, myocardial infarction, coronary 
stenting;

History of an organ transplant which requires continued immunosuppression;

History of gastrointestinal (GI) perforation (other than appendicitis or mechanical 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 or gastric bypass surgery; subjects with a history of gastric 
banding/segmentation are not excluded;

History of any malignancy except for successfully treated non-melanoma skin cancer (NMSC) 
or localized carcinoma in situ of the cervix;

History of inflammatory arthritis of different etiology other than axial SpA (including but not 
limited to RA, PsA, mixed connective tissue disease, systemic lupus erythematosus, reactive 
arthritis, scleroderma, polymyositis, dermatomyositis), or any arthritis with onset prior to 
17 years of age;

Fibromyalgia (currently with active symptoms);

Extra-articular manifestations (e.g., psoriasis, uveitis, or inflammatory bowel disease) that 
are not clinically stable for at least 30 days prior to study entry.
29. There must be no reason the Investigator believes that the subject is an unsuitable 
candidate to participate in the study or receive study drug or would place the subjects at risk by 
participating in the study.
Remission-Withdrawal Period Specific Criteria:
30. Subject must be on study drug upon completion of the Open-Label Extension Period of 
Study 1 or Study 2 through Week 104.
31. Subject must achieve ASDAS (CRP) < 1.3 at Week 104 and ASDAS (CRP) < 2.1 at Week 88.
32. Subject must voluntarily sign and date an informed consent to participate in the Remission
Withdrawal Period, approved by an IEC/IRB.
33. Subject must not have a newly suspected/acquired medical condition and/or initiate a new 
medication since the last dose of study drug that would have precluded his/her enrollment into 
the main study.
34. There must be no reason the Investigator believes that the subject is an unsuitable 
candidate to participate in the remission-withdrawal period or receive study drug or would 
place the subjects at risk by continuing to participate in the study.
35. Subjects must be willing to keep background axSpA medications stable during the 
Remission-Withdrawal Period (including withdrawal and re-treatment phases, if applicable).
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5.2 Contraception Recommendations
Contraception Requirements for Females Only
Subjects must follow the following contraceptive guidelines as specified:

Females, Non-Childbearing Potential

Females do not need to use birth control during or following study drug treatment if 
considered of non-childbearing potential due to meeting any of the following criteria:

Postmenopausal, age > 55 years with no menses for 12 or more months without an 
alternative medical cause.

Postmenopausal, age ≤ 55 years with no menses for 12 or more months without an 
alternative medical cause AND a follicle-stimulating hormone (FSH) level > 40 IU/L.

Permanently surgically sterile (bilateral oophorectomy, bilateral salpingectomy, or 
hysterectomy).

Females of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug and for at 
least 30 days after the last dose of study drug.  Females must commit to one of the following 
methods of birth control:

Combined (estrogen- and progestogen-containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation initiated at 
least 30 days prior to study Baseline Day 1.

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1.

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure) (For Japan:  bilateral tubal 
ligation).

Intrauterine device.

Intrauterine hormone-releasing system.

Vasectomized sexual partner (the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject).

Practice true abstinence (unless not acceptable per local practices), defined as:  
refraining from heterosexual intercourse when this is in line with the preferred and 
usual lifestyle of the subject (periodic abstinence [e.g., calendar, ovulation, 
symptothermal, post-ovulation methods] and withdrawal are not acceptable).
If required per local practices, females of childbearing potential must commit to using 2 methods of 
contraception (either 2 highly effective methods or 1 highly effective method combined with 1 effective 
method).  Effective methods of birth control are the following:
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
Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action, initiated at least 30 days prior to Study Day 1.

Male or female condom with or without spermicide.

Cap, diaphragm, or sponge with spermicide.

A combination of male condom with a cap, diaphragm, or sponge with spermicide (double 
barrier method).
Contraception recommendations related to use of concomitant therapies prescribed per standard of 
care should be based on the local label.
For subjects in Japan only: After marketing approval of upadacitinib for the treatment of nr-axSpA, 
contraception requirements should be followed per Japan label in both M19-944 Study 1 and Study 2.
5.3 Prohibited Medications and Therapy
JAK Inhibitors
Prior and concomitant oral and topical exposure to any other JAK inhibitors (including but not limited to 
the investigational drug, upadacitinib [Rinvoq®]; tofacitinib [Xeljanz®]; baricitinib [Olumiant®]; filgotinib; 
ruxolitinib [Jakafi®]; abrocitinib [PF-04965842]; and peficitinib [Smyraf®]) is not allowed.
Targeted Biologic Therapies
Concomitant biologic therapies and biosimilar versions of biologic drugs are prohibited during treatment 
with study drug and in the Remission-Withdrawal Period.  Examples of biologic therapies include but are 
not limited to the following:

Abatacept

Adalimumab

Anakinra

Belimumab

Bimekizumab

Certolizumab pegol

Dupilumab

Efalizumab

Etanercept

Golimumab

Guselkumab

Infliximab

Ixekizumab
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
Natalizumab

Rituximab

Risankizumab

Secukinumab

Tildrakizumab

Tocilizumab

Ustekinumab
Other Non-Biologic Systemic Therapy
Initiation of additional systemic immunomodulating therapy for the treatment of axSpA is prohibited 
during treatment with study drug outside of rescue parameters (refer to Section 5.4) and in the 
Remission-Withdrawal Period.
Corticosteroids
Spinal/paraspinaland SI joint injection(s) or parenteral administration of corticosteroids (including 
intramuscular and intravenous injections) or prednisone (or oral corticosteroid equivalents) > 10 mg/day 
are not allowed during treatment with study drug outside of rescue parameters (refer to Section 5.4)
and in the Remission-Withdrawal Period; the following exceptions apply:  short-term use (≤10 days) of 
corticosteroids for conditions that are not related to axSpA, such as exacerbation of asthma or chronic 
obstructive pulmonary disease, allergic reactions, or serious infection when additional corticosteroids 
may be required to prevent adrenal insufficiency, a total of up to 100 mg of prednisolone or equivalent 
is allowed during each study.
Investigational Drugs
Subjects who have been treated with any investigational drug within 30 days or 5 half-lives of the drug 
(whichever is longer) prior to the first dose of study drug are excluded from participation in the studies.  
Investigational drugs are also prohibited during the studies including the Remission-Withdrawal Period.
Vaccines
If the subject and Investigator choose to receive/administer live vaccines, these vaccinations must be 
completed (per local label) at least 28 days (or longer if required locally) before first dose of study drug.  
Live vaccinations are prohibited during study participation prior to Week 14 for Study 1 (bDMARD-IR AS) 
and prior to Week 52 for Study 2 (nr-axSpA), including at least 30 days (or longer if required locally) after 
the last dose of study drug.  After Week 14 for Study 1 (bDMARD-IR AS) and after Week 52 for Study 2 
(nr-axSpA), if a live vaccine must be administered during participation, study drug must be held for at 
least 14 days prior to the vaccination and at least 30 days after the vaccination (or longer if required 
locally).  Live vaccinations are prohibited during re-treatment in the Remission-Withdrawal Period.
If the live herpes zoster vaccine is to be administered and there is no known history of primary varicella 
(chicken pox), preexisting immunity to varicella should be confirmed with Ab testing at or prior to 
Screening and prior to administration of the herpes zoster vaccine.  If screening varicella Ab testing is 
negative, the live herpes zoster vaccine should not be administered.
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Examples of live vaccines include, but are not limited to, the following:

Monovalent live influenza A (H1N1) (intranasal);

Seasonal trivalent live influenza (intranasal);

Zostavax (herpes zoster, live attenuated);

Rotavirus;

Varicella (chicken pox);

Measles-mumps-rubella or measles-mumps-rubella-varicella;

Oral polio vaccine;

Smallpox;

Yellow fever;

Bacille Calmette-Guérin;

Typhoid (oral).
Administration of inactivated (non-live) vaccines is permitted prior to or during each study according to 
local practice guidelines.  Examples of common vaccines that are inactivated, toxoid, or biosynthetic 
include, but are not limited to, injectable influenza vaccine, pneumococcal, Shingrix (zoster vaccine, 
recombinant, adjuvanted), and pertussis (Tdap) vaccines.
Strong CYP3A Inhibitors or Inducers
Systemic use of known strong CYP3A inhibitors (includes over-the-counter or prescription medicines, 
vitamins and/or herbal supplements) is not permitted from Screening through the end of study drug 
administration and use of strong CYP3A inducers is not permitted from 30 days prior to study drug 
administration through the end of study drug administration.  Table 1 includes examples of commonly 
used strong CYP3A inhibitors and inducers.  In addition, herbal therapies and other traditional medicines 
with unknown effects on CYP3A are not permitted from Screening through the end of study drug 
administration.
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Table 1.
Examples of Commonly Used Strong CYP3A Inhibitors and Inducers
Strong CYP3A Inhibitors
Strong CYP3A Inducers
Boceprevir 
Cobicistat 
Clarithromycin 
Conivaptan 
Grapefruit (fruit or juice)
Indinavir 
Itraconazole 
Ketoconazole 
Lopinavir/Ritonavir 
Mibefradil 
Nefazodone 
Nelfinavir 
Posaconazole 
Ritonavir 
Saquinavir 
Telaprevir 
Telithromycin 
Troleandomycin 
Voriconazole
Avasimibe
Carbamazepine 
Phenytoin
Rifampin 
Rifapentine 
St. John's Wort
For subjects enrolled in the Remission-Withdrawal Period, use of strong CYP3A inhibitors or inducers are 
prohibited while taking study drug.
Opiates
High potency opiates are not permitted during the study (i.e., Double-Blind Period and Open-Label 
Extension Period and Remission-Withdrawal Period), and subjects must have discontinued use at least 
14 days prior to the first dose of study drug.  High-potency opiates include but are not limited to:

oxycodone;

oxymorphone;

fentanyl;

levorphanol;

buprenorphine;

methadone;

hydromorphone;

morphine;

meperidine.
Combination of acetaminophen/paracetamol and codeine or combination of 
acetaminophen/paracetamol and hydrocodone are allowed.
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Elective and Emergency Surgeries
For elective and emergency surgeries, the following rules will apply:

If the subject must undergo emergency surgery, study drug should be interrupted at the time of 
the surgery.  After emergency surgery, allow reintroduction of study drug once the physician has 
examined the surgical site and determined that it has healed and there is no sign of infection.

Elective surgery, and interruption of study drug for such a surgery, will not be allowed for 
Study 1 (bDMARD-IR) and Study 2 (nr-axSpA) until after the primary endpoint visit at Week 14 
for the respective study has been completed.  For Study 1 and Study 2, if the subject undergoes 
elective surgery, the study drug should be interrupted at least 1 week prior to the planned 
surgery.  Allow reintroduction of study drug once the physician has examined the surgical site 
and determined that it has healed and there is no sign of infection.
5.4 Prior and Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins and/or herbal 
supplements) that the subject is receiving at the time of Screening, and/or receives during a study, must 
be recorded along with the reason for use, date(s) of administration including start and end dates, and 
dosage information including dose, route, and frequency on the appropriate electronic case report form 
(eCRF).  Also, medications taken for axSpA since date of diagnosis (based on subject recollection and 
available medical records) should be entered into the appropriate eCRF inclusive of the dates of first and 
last dose, maximum dosage taken, and route of administration.
Allowed Therapies:
Methotrexate, sulfasalazine (SSZ), hydroxychloroquine, chloroquine, or leflunomide are allowed during 
each study, but subjects must be on a stable dose of MTX (≤25 mg/week) or SSZ (≤3 g/day) or
hydroxychloroquine(≤400 mg/day) or chloroquine (≤400 mg/day) or leflunomide (≤20 mg/day) for at
least 28 days prior to the Baseline Visit.  A combinationof up to 2 background csDMARDs is allowed
EXCEPT the combinationof MTX and leflunomide.  For Study 1, subjects should stay on their stable 
background csDMARD therapy until after their Week 24 Visit unless the subject meets the rescue 
criterion at Week 24, at which time they may add or modify background csDMARD therapy as outlined 
in the Addition or Modification of Medication for axSpA subsection below.  For Study 2, subjects should 
stay on their stable background csDMARD therapy until after their Week 52 Visit unless the subject 
meets the rescue criterion between Week 24 and Week 52, at which time they may add or modify 
background csDMARD therapy as outlined in the Addition or Modification of Medication for axSpA 
subsection below.  At any time in Study 1 and Study 2, the csDMARD dose may be decreased for safety 
reasons.
Oral corticosteroids are allowed during each study, but subjects must be on a stable dose of prednisone
(≤10 mg/day) or oral corticosteroidequivalent for at least 14 days prior to the Baseline Visit.  See
Section 5.3 for short-term use (≤10 days) of corticosteroids for conditions that are not related to axSpA.
NSAIDs, tramadol, combinationof acetaminophen/paracetamol and codeine or combination of 
acetaminophen/paracetamol and hydrocodone, and/or non-opioid analgesics are allowed during each 
study, but subjects must be on stable dose(s) for at least 14 days prior to the Baseline Visit.
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For subjects on concomitant NSAID therapy, the NSAID eCRF should be completed.
Until at least Week 24 in Study 1 or at least until Week 52 in Study 2, subjects should continue on their 
stable doses of NSAIDs, tramadol, combination acetaminophen/paracetamol and codeine or 
combination or acetaminophen/paracetamol and hydrocodone, and/or non-opioid analgesics; oral 
corticosteroids (equivalent to prednisone ≤10 mg/day); or inhaled corticosteroids.  At any time, the 
dose of NSAIDs, tramadol, combination of acetaminophen/paracetamol and codeine or combination of 
acetaminophen/paracetamol and hydrocodone, and/or non-opioid analgesics, or oral corticosteroids 
may be decreased or interrupted for safety reasons.

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, until at least 
Week 24 in Study 1 or at least until Week 52 in Study 2 unless the subject meets the rescue 
criterion between Week 24 and Week 52.

If not taking any of the above at Baseline, these must not be initiated except where permitted 
by protocol.

If taking any of the above at Baseline on an as-needed basis (PRN), they should continue to use 
them for the same reason and same dose each time but they should not be taken within 
24 hours prior to any study visit to avoid bias in outcome measurements.
For Study 1, one intra-articular corticosteroid injection for a peripheral joint will be allowed up to the 
Week 14 Visit; however, the joint injection should be avoided within 21 days prior to the Week 14 Visit 
to avoid confounding effects of systemic absorption of intra-articular corticosteroids.  Starting at 
Week 14 (after Week 14 assessments have been performed) and thereafter, peripheral intra-articular, 
trigger point or tender point, intra-bursa, and intra-tendon sheath injections of corticosteroids are 
allowed at the Investigator's discretion (dosage and frequency per standard of care).  Once a peripheral 
joint is injected, it will be considered not evaluable/assessable ("NA") during the 90 days following 
injection.
For Study 2, one intra-articular corticosteroid injection for a peripheral joint will be allowed up to the 
Week 14 Visit; however, the joint injection should be avoided within 21 days prior to the Week 14 Visit 
to avoid confounding effects of systemic absorption of intra-articular corticosteroids.  Starting at 
Week 14 (after Week 14 assessments have been performed) and thereafter, peripheral intra-articular, 
trigger point or tender point, intra-bursa, and intra-tendon sheath injections of corticosteroids are 
allowed at the Investigator's discretion (dosage and frequency per standard of care); however, joint 
injections should be avoided within 21 days prior to the Week 52 Visit.  Once a peripheral joint is 
injected, it will be considered "NA" during the 90 days following injection.
During the Remission-Withdrawal Period peripheral intra-articular, trigger point or tender point, intra-
bursa, and intra-tendon sheath injections of corticosteroids are allowed at the Investigator's discretion 
(dosage and frequency per standard of care); however, joint injections should be avoided within 21 days 
prior to the next Visit. Once a peripheral joint is injected, it will be considered not evaluable/assessable 
("NA") during the 90 days following injection.
See Section 5.3 for permitted vaccines.
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Any questions regarding concomitant or prior therapy should be raised to the AbbVie Therapeutic Area 
Medical Director (TA MD)/AbbVie emergency contact.  Information regarding potential drug interactions 
with upadacitinib can be located in the upadacitinib Investigator's Brochure.30
Addition or Modification of Medication for axSpA
Study 1 (bDMARD-IR AS):
Rescue Therapy:
After visit assessments have been performed at Week 24, subjects who do not achieve an ASAS20 
response at both the Week 18 and Week 24 Visits should add or modify any of the following background 
axSpA medications per local label (Figure 2):

NSAIDs, acetaminophen/paracetamol, low potency opioid medications (tramadol or 
combination of acetaminophen/paracetamol and codeine or combination of 
acetaminophen/paracetamol and hydrocodone); and/or

MTX, SSZ, hydroxychloroquine, chloroquine, leflunomide, apremilast (concomitant use of up to 
2 csDMARDs except the combination of MTX and leflunomide); and/or

Prednisone (≤10 mg/day) (or oral corticosteroid equivalent) and/or a corticosteroid burst with 
no more than 3 consecutive days of systemic corticosteroids (including intramuscular and 
intravenous injections) (maximum dose of 0.5 mg/kg/day of prednisone or its equivalent).
Investigator or site staff will determine the subjects' ASAS20 response based on the values presented in 
the data capture systems.
After Week 24 (e.g., at Week 32 through Week 104 visits), addition or modification of background axSpA 
medications listed above can be made per Investigator judgment regardless of the disease activity status 
(Figure 2).
If rescue therapy is escalated to targeted biologic therapies including but not limited to a TNF inhibitor 
or IL-17 inhibitor (refer to Section 5.3), then study drug treatment must be permanently discontinued 
prior to initiation of the bDMARD therapy for safety reasons (refer to Section 5.5).
Disease Activity Criteria for Permanent Study Drug Discontinuation:
At Week 32 and through Week 104, subjects without an ASAS20 response at any 2 consecutively 
scheduled visits will be permanently discontinued from study drug treatment (e.g., Week 24 and 
Week 32 with discontinuation at Week 32; or at Week 40 and Week 52 with discontinuation at 
Week 52), unless an alternative etiology exists to influence the individual domains of the ASAS20 
response criteria (such as trauma, injury, or infection affecting the subject's ability to accurately perform 
pain, function, or global self-assessments of axial SpA disease activity) as documented by the 
Investigator (Figure 2).
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Figure 2.
Study 1 (bDMARD-IR AS):  Rescue Therapy and Permanent Study Drug 
Discontinuation Parameters
Study 2 (nr-axSpA):
Rescue Therapy:
After visit assessments have been performed at Week 24 and through Week 52, subjects who do not 
achieve an ASAS20 response at any 2 consecutively scheduled visits should be rescued with standard of 
care (e.g., Week 18 and Week 24 with rescue at Week 24; or Week 32 and Week 40 with rescue at 
Week 40) as follows (Figure 3):
1.
Add or modify any of the following background axSpA medications listed below per standard of 
care (per local label) without initiation of a bDMARD:

NSAIDs, acetaminophen/paracetamol, low potency opioid medications (tramadol or 
combination of acetaminophen/paracetamol and codeine or combination of 
acetaminophen/paracetamol and hydrocodone); and/or

MTX, SSZ, hydroxychloroquine, chloroquine, leflunomide, apremilast (concomitant use of up 
to 2 csDMARDs except the combination of MTX and leflunomide); and/or

Prednisone (≤ 10 mg/day) (or oral corticosteroid equivalent) and/or a corticosteroid burst 
with no more than 3 consecutive days of systemic corticosteroids (including intramuscular 
and intravenous injections) (maximum dose of 0.5 mg/kg/day of prednisone or its 
equivalent).

Subjects may continue concomitant use of study drug if background medications remain 
within allowed parameters (refer to Section 5.4, Allowed Therapies).
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OR
2.
Modify axSpA medications per standard of care (per local label) with initiation of a bDMARD:

TNF inhibitor or IL-17 inhibitor.

Subjects must permanently discontinue study drug prior to initiation of the bDMARD 
therapy for safety reasons (refer to Section 5.3 and Section 5.5).
Investigator or site staff will determine the subjects' ASAS20 response based on the values presented in 
the data capture systems.
After Week 52 (e.g., at Week 64 through Week 104 visits), addition or modification of axSpA 
medications listed above can be made per Investigator judgment regardless of the disease activity status 
(Figure 3).
Disease Activity Criteria for Permanent Study Drug Discontinuation:
At Week 64 and through Week 104, subjects without an ASAS20 response at any 2 consecutively 
scheduled visits will be permanently discontinued from study drug treatment (e.g., Week 52 and 
Week 64 with discontinuation at Week 64; or at Week 76 and Week 88 with discontinuation at 
Week 88), unless an alternative etiology exists to influence the individual domains of the ASAS20 
response criteria (such as trauma, injury, or infection affecting the subject's ability to accurately perform 
pain, function, or global self-assessments of axial SpA disease activity) as documented by the 
Investigator (Figure 3).
Figure 3.
Study 2 (nr-axSpA):  Rescue Therapy and Permanent Study Drug 
Discontinuation Parameters
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Background Medication During Remission-Withdrawal Period:
Starting at Week 104, subjects entering the Remission-Withdrawal Period, should keep their axSpA
related background medication stable (including withdrawal and retreatment phases, as applicable).
COVID-19 Pandemic-Related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected non-live vaccines (e.g., mRNA, non-replicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during screening or 
the treatment period, as long as components of the vaccine are not contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an individual 
discussion between the treating physician and the subject.
The potential impact of upadacitinib on SARS-CoV-2 vaccination is unknown.  Therefore, study drug 
should be administered as follows:

The first dose of upadacitinib during the Remission-Withdrawal Period, when possible, is 
preferred not to be given within ± 7 days from the SARS-CoV-2 vaccine administration.
Note:  The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the complete 
treatment course.
These recommendations may be subject to change based on the evolving knowledge around the use of 
SARS-CoV-2 vaccines in patients with axSpA and as more data are collected in real-world scenarios and 
clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF.  Refer to the 
Operations Manual for instructions on reporting any adverse events associated with the COVID-19 
vaccine (Appendix G).
5.5 Withdrawal of Subjects and Discontinuation of Study
AbbVie may terminate Study 1 and/or Study 2 and/or the Remission-Withdrawal Period prematurely, 
either in its entirety or at any site.  Study 1 and/or Study 2 and/or the Remission-Withdrawal Period will 
be discontinued or terminated in case of an unacceptable risk, any relevant toxicity, or a negative 
change in the benefit:risk assessment.  This might include the occurrence of AEs with a character, 
severity, or frequency that is new in comparison to the existing risk profile.  In addition, data deriving 
from other clinical trials or toxicological studies which negatively influence the benefit:risk assessment 
might cause discontinuation or termination of a study.  The Investigator may also stop a study at their
site if they have safety concerns.  If AbbVie terminates a study for safety reasons, AbbVie will promptly 
notify the Investigator.  Advance notice is not required by either party if a study is stopped due to safety 
concerns.
Subjects can request to be discontinued from participating in a study at any time for any reason.  The 
Investigator may discontinue any subject's participation at any time for any reason.  The AbbVie TA 
MD/Scientific Director may mandate individual subject discontinuation from study drug in case of safety 
concern.
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For each study, subjects must have study drug discontinued immediately if any of the following occur:

The subject requests withdrawal from the study.

The Investigator believes it is in the best interest of the subject.

Abnormal laboratory results or AEs that either meet the criteria for discontinuation of study 
drug as stated in Section 6.2 or as determined by the Investigator or the AbbVie TA MD, that 
rule out safe continuation of the study drug.

Serious infections (e.g., sepsis) which cannot be adequately controlled by anti-infective 
treatment or would put the subject at risk for continuation of the study drug.

Subject is non-compliant with TB prophylaxis (if applicable) or develops active TB at any time 
during the study.

Malignancy, except for localized NMSC or carcinoma in situ of the cervix.

Subject develops a GI perforation (defined as acute, spontaneous perforation of the GI tract that 
requires inpatient medical care or urgent surgical intervention other than appendicitis or 
mechanical injury).  See also Section 6.2 Toxicity Management.

Confirmed diagnosis of deep vein thrombosis, pulmonary embolism or non-cardiac, non-
neurologic arterial thrombosis.

The subject becomes pregnant while on study drug.

Eligibility criteria violation was noted after the subject started study drug, when continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages when continuation of the study drug would 
place the subject at risk.

Subject is significantly non-compliant with study procedures, which would put the subject at risk 
for continued participation in the trial.

For Study 1 (bDMARD-IR AS), at Week 32 and through Week 104, subjects without an ASAS20 
response at any 2 consecutively scheduled visits will be permanently discontinued from study 
drug treatment (e.g., Week 24 and Week 32 with discontinuation at Week 32; or at Week 40 and 
Week 52 with discontinuation at Week 52), unless an alternative etiology exists to influence the 
individual domains of the ASAS20 response criteria (such as trauma, injury, or infection affecting 
the subject's ability to accurately perform pain, function, or global self-assessments of axial SpA 
disease activity) as documented by the Investigator.

For Study 2 (nr-axSpA), at Week 64 and through Week 104, subjects without an ASAS20 
response at any 2 consecutively scheduled visits will be permanently discontinued from study 
drug treatment (e.g., Week 52 and Week 64 with discontinuation at Week 64; or at Week 76 and 
Week 88 with discontinuation at Week 88), unless an alternative etiology exists to influence the 
individual domains of the ASAS20 response criteria (such as trauma, injury, or infection affecting 
the subject's ability to accurately perform pain, function, or global self-assessments of axial SpA 
disease activity) as documented by the Investigator.
Additional requirements related to abnormal laboratory values and selected AESIs are located in 
Section 6.2.
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5.6 Follow-Up for Subject Withdrawal from Study
Discontinuation of Study Drug and Continuation of Study Participation
If a subject prematurely discontinues study drug, the procedures outlined for a Premature 
Discontinuation Visit (PD Visit) should be completed as soon as possible, preferably within 2 weeks, and 
preferably prior to initiation of another therapy.  To minimize missing data for efficacy and safety 
assessments, subjects who prematurely discontinue study drug treatment should continue to be 
followed for all regularly scheduled visits as outlined in the Activity Schedule (Appendix D) and adhere to 
all study procedures except for dispensing study drug, PK sample collection, and blood sample collection 
for optional biomarker research studies, unless subjects have decided to discontinue study participation 
entirely (withdrawal of informed consent).  In addition, all efficacy-driven criteria for addition or 
modification of background medications and study drug discontinuation no longer apply.  If at any point 
a subject no longer wants to provide assessments (withdrawal of informed consent) following 
discontinuation of study drug, a second PD Visit is not required.  Subjects should be advised on the 
continued scientific importance of their data even if they discontinue treatment with study drug early.  
Following discontinuation of study drug, the subject should be treated in accordance with the 
Investigator's best clinical judgment irrespective of whether the subject decides to continue 
participation in a study.
Premature Discontinuation of Study (Withdrawal of Informed Consent)
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the PD Visit should be completed as soon as possible, preferably within 2 weeks, 
and preferably prior to initiation of another therapy.  In addition, if subject is willing, a 30-day F/U Visit 
(or phone call) after the last dose of study drug may be completed to determine the status of any 
ongoing AEs/SAEs or the occurrence of any new AEs/SAEs.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status.  At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
5.7 Study Drug
Study drugs refer to drugs that are used (or can be used) in this study to assess the safety and the 
efficacy of the Investigational Product. Investigators will assess the relationship of AEs to the use of 
study drugs.
Study drug will be taken orally QD, beginning on Day 1 (Baseline), and should be taken at approximately 
the same time each day, with or without food.  Subjects will be instructed to return all drug containers 
(even if empty) to the study site personnel at each study visit; study site personnel will document 
compliance.
Subjects will continue their disease-related concomitant medications therapy as allowed per protocol.  
AbbVie will not supply any disease-related concomitant medication therapy taken during the course of 
each study.
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AbbVie will supply upadacitinib and matching upadacitinib placebo.
All study drug investigational product must be stored at controlled room temperature (15° to 
25°C/59° to 77°F).  Study drug will be packaged in quantities sufficient to accommodate study design.
Each kit will be labeled per local requirements and this label must remain affixed to the kit.  Upon 
receipt, study drug should be stored as specified on the label and kept in a secure location.  Each kit will 
contain a unique kit number.  This kit number is assigned to a subject via interactive response 
technology (IRT) and encodes the appropriate study drug to be dispensed at the subject's corresponding 
study visit.  All blank spaces on the label will be completed by the site staff prior to dispensing to 
subjects.  Study drug will only be used for the conduct of the study.
The individual study drug information is presented in Table 2.
Table 2.
Description of Study Drug
Investigational 
Product
Mode of 
Administration
Dosage Form
Strength
Blinded or 
Open Label
Frequency
Manufacturer
Upadacitinib 
(ABT-494)
Oral
Film-coated 
tablets
15 mg
Blinded for 
Double-Blind 
Period; 
unblinded for 
Open-Label 
Extension 
Perioda
QD
AbbVie
Placebo for 
upadacitinib 
(ABT-494)
Oral
Film-coated 
tablets
Not 
applicable
Blinded for 
Double-Blind 
Perioda
QD
AbbVie
a.
For Study 1 and Study 2, study sites and subjects will remain blinded to the Double-Blind Period treatment assignments for 
the duration of the respective study.
If a subject is unable to come to the study site to pick up their study drug due to COVID-19, a 
direct-to-patient (DTP), study drug shipment can be made from the study site to the subject if allowed 
by local regulations.  AbbVie will submit any required notifications to the regulatory authority as 
applicable.  Refer to the Operations Manual in Appendix G for details on DTP shipment of study drug.
5.8 Randomization/Drug Assignment and Blinding
All subjects will be assigned a unique identification number by the IRT at the screening visit.  For 
subjects who re-screen, the screening number assigned by the IRT at the initial screening visit should be 
used.  The IRT will assign a randomization number that will encode the subject's treatment group 
assignment according to the randomization schedule generated by the statistics department at AbbVie.  
In the Double-Blind Period, subjects will be randomized in a 1:1 ratio to 1 of 2 treatment groups:
Study 1 (bDMARD-IR AS):

Group 1:  Upadacitinib 15 mg QD (N = 193)
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
Group 2:  Placebo QD (N = 193)
Study 2 (nr-axSpA): 

Group 1:  Upadacitinib 15 mg QD (N = 152)

Group 2:  Placebo QD (N = 152)
In Study 1 (bDMARD-IR AS), randomization will be stratified by hsCRP (≤ULN versus > ULN) collected at 
Screening Visit, the class of the prior bDMARD use (1 TNF inhibitor, 1 IL-17 inhibitor, and "other"), and 
geographic region (US/Canada versus Rest of the World excluding Japan and China).  The "other"
category of prior bDMARD use includes exposure to 2 bDMARDs and cannot exceed 30% of subjects.  
Japan and China will each have a separate randomization schedule stratified by hsCRP (≤ULN
versus > ULN) collected at Screening Visit.
In Study 2 (nr-axSpA), randomization will be stratified by MRI and screening hsCRP status (MRI+/hsCRP 
> ULN, MRI+/hsCRP ≤ ULN, and MRI–/hsCRP > ULN) and exposure to bDMARDs (yes versus no).  At least 
20%, but not exceeding 35% of subjects with prior exposure to a bDMARD will be enrolled in Study 2.  
Japan and China will each have a separate randomization schedule stratified by MRI and screening 
hsCRP status (MRI+/hsCRP > ULN, MRI+/hsCRP ≤ ULN, and MRI–/hsCRP > ULN).
Subjects in the placebo group will be switched to upadacitinib 15 mg QD at Week 14 in the Open-Label 
Extension Period for Study 1 (bDMARD-IR AS) and Week 52 in the Open-Label Extension Period for 
Study 2 (nr-axSpA).
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 until the Week 14 primary analysis for Study 1 
(bDMARD-IR AS).  For Study 2 (nr-axSpA), all AbbVie personnel with direct oversight of the conduct and 
management of the trial (with the exception of AbbVie Drug Supply Management Team) will remain 
blinded to each subject's treatment until the Week 14 primary analysis, while the Investigator, study site 
personnel, and the subject will remain blinded to each subject's treatment until after all subjects have 
completed the Week 52 visit or have prematurely discontinued prior to Week 52.  For Study 1 and 
Study 2, sites and subjects will remain blinded to the Double-Blind Period treatment assignments for the 
duration of the respective study.  To maintain the blind, the upadacitinib tablets and placebo tablets 
provided for each study will be identical in appearance.  The IRT will provide access to unblinded subject 
treatment information in the case of a medical emergency.
In the event of a medical emergency 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 the technical support of the IRT vendor via either phone (preferred) or email 
(support@endpointclinical.com).  For country-specific phone numbers, please see the following website:  
http://www.endpointclinical.com/helpdesk/.
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In the event that the blind is broken before notification to the AbbVie TA MD, we request 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 appropriate eCRF.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects.  The Investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations.  If a 
protocol deviation occurs (or is identified including those that may be due to the COVID-19 pandemic),
the Investigator is responsible for notifying IEC/IRB, regulatory authorities (as applicable), and AbbVie.
5.10 TB Testing/TB Prophylaxis
All subjects must be evaluated for TB at Screening and annually.  The results of the TB screening must 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 
questionnaire and tested for TB infection as described below.  The site staff will complete the TB risk 
assessment questionnaire in its entirety (Part I and Part II) and enter the data into the appropriate eCRF.  
The TB risk assessment questionnaire will be completed annually (Part I only) for all subjects, regardless 
of TB test results.
Subjects with a negative TB test and CXR not suggestive of active TB may be enrolled.  Subjects with 
history of active TB may be enrolled if it has been adequately treated with no evidence of current active 
TB; subjects with inadequate documentation of treatment should be cleared by a TB specialist prior to 
enrollment.
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 latent TB (positive TB test 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 Testing:

The QuantiFERON-TB Gold Plus test should be performed at Screening on all subjects unless the 
subject is considered to be TB test positive prior to Screening.  The purified protein derivative 
(tuberculin) (PPD) Skin Test (also known as TB Skin test or Mantoux test) should only be utilized 
when the QuantiFERON-TB Gold Plus test is not possible or if both tests are required per local 
guidelines.

If a subject had a QuantiFERON-TB Gold Plus test within 90 days prior to Screening and source 
documentation is available, TB testing does not need to be performed by the central laboratory 
at Screening provided nothing has changed in the subject's medical history to warrant a repeat 
test.
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
For subjects with only a negative PPD Skin Test available within 90 days prior to Screening, a 
QuantiFERON-TB Gold Plus test is required at Screening.  If the QuantiFERON-TB Gold Plus test is 
not possible and source documentation is available, the PPD Skin Test does not need to be 
repeated provided nothing has changed in the subject's medical history to warrant a repeat test.

For regions that require both PPD and QuantiFERON-TB Gold Plus testing, both will be 
performed.  If either PPD or QuantiFERON-TB Gold Plus is positive, the TB test is considered 
positive.

Subjects with documentation of prior positive result of QuantiFERON-TB Gold Plus test and/or 
PPD Skin Test and/or history of latent or active TB are not required to repeat a TB test at 
Screening or during a study and should be considered TB test positive.

If TB testing is done at Screening for subjects with a prior positive TB test and a positive 
result is reported, the subject is considered TB test positive.

If TB testing is done at Screening in subjects considered at low risk for TB as described below 
and a negative or indeterminate result is reported, the procedure for "Interpretation of a 
positive TB test in low-risk subjects" should be followed OR either prior or concomitant 
treatment for latent TB is required.

If TB testing is done for subjects with a prior positive TB test at the annual evaluation, 
repeated TB prophylaxis is not required for a positive result unless indicated by the subject's 
medical history.

Subjects without history of active or latent TB and having a negative TB test result at Screening 
or the most recent evaluation will undergo annual TB testing by QuantiFERON-TB Gold Plus Test 
and/or PPD Skin Test.

If a site has the capacity to perform both PPD and QuantiFERON-TB Gold Plus Test, and local 
guidelines require only one test to be performed, then the QuantiFERON-TB Gold Plus Test is the 
preferred test.  At a site with capacity to perform both tests, whatever TB test method (i.e., PPD 
or QuantiFERON-TB Gold Plus Test or other Interferon Gamma Release Assay [IGRA]) was 
performed at screening, then the subject should have their annual TB test performed with the 
same test method.

If performed, the PPD Skin Test should be read by a licensed healthcare professional between 
48 and 72 hours after administration.  A subject who does not return within 72 hours will need 
to be rescheduled for another skin test.  The reaction will be measured in millimeters (mm) of 
induration and induration ≥ 5 mm is considered a positive reaction.  The absence of induration 
will be recorded as "0 mm" and not "negative."

Subjects who have an ulcerating reaction to PPD in the past should not be re-exposed and the 
PPD should be considered positive and do not require subsequent testing with either PPD or 
QuantiFERON-TB Gold Plus.

If the QuantiFERON-TB Gold Plus test is indeterminate, then the Investigator should perform a 
local QuantiFERON-TB Gold Plus 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 the study.  If the testing result is negative, then the 
subject is considered to be negative.
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
Interpretation of a positive TB test in low risk subjects:  In cases where the QuantiFERON-TB 
Gold Plus test by the central laboratory is positive and the Investigator considers the subject at 
low risk for TB (i.e., no risk factors identified using the Part I and Part II questions of the TB risk 
assessment questionnaire at Screening or Part I questions annually) and has no clinical suspicion 
of TB, the Investigator may perform a local QuantiFERON-TB Gold Plus test (or repeat testing 
through the central 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 or indeterminate, the test is 
considered positive.

An equivalent IGRA (such as T-SPOT TB test) may be substituted for the QuantiFERON-TB Gold 
Plus.

TB test(s) results will be retained at the site as the original source documentation.
If an annual TB test is newly positive (seroconversion), a CXR needs to be performed as soon as possible 
to aid in distinguishing active versus latent TB and subsequent annual TB follow-up tests are not 
required.  For subjects with seroconversion on an annual TB test, if a CXR cannot be done due to the 
COVID-19 pandemic, the Investigator should contact the AbbVie TA MD to determine if the subject may 
continue on study drug.  CXR should be performed as soon as restrictions allow at the study site or local 
hospital/facility.
If the subject is experiencing signs or symptoms suspicious for TB or something has changed in the 
subject's medical history to warrant investigation and a repeat test before the next scheduled annual TB 
re-test, the case (including the TB test results) should be discussed with the AbbVie TA MD.
TB prophylaxis:
Note:  Rifampicin and Rifapentine are not allowed for TB prophylaxis while on study drug.
At Screening, if the subject has evidence of latent TB infection, prophylactic treatment with isoniazid 
must be initiated at least 2 weeks prior to administration of study drug (or per local guidelines, 
whichever is longer).  If receiving isoniazid prophylaxis during a study, at least 6 months must be 
completed; however, the full course of prophylaxis does not need to be completed prior to the first dose 
of study drug.
Subjects with a prior history of active or latent TB that have documented completion of a full course of 
anti-TB therapy will be allowed to enter a study provided nothing has changed in the subject's medical 
history to warrant repeat treatment.  Prior to the study, a full course of latent TB prophylaxis may be 
achieved with at least 4 months of rifampin, at least 6 months of isoniazid, or at least 3 months of 
combination rifapentine and isoniazid.  For subjects with completion of a full course of anti-TB therapy, 
but insufficient documentation, the Investigator should consult with the AbbVie TA MD.
During a study, subjects with new evidence of latent TB must initiate prophylactic treatment with 
isoniazid immediately 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 as well as laboratory assessment of toxicity to TB prophylaxis.
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At Screening, newly diagnosed latent TB should be entered in the TB Screening eCRF; prior history of 
latent or active TB should be entered into the medical history eCRF.  Any positive TB test after the 
subject has started a study should be reported as an AE of latent TB or active TB (as applicable).  Newly 
initiated prophylactic treatment and prior therapy should be captured in the concomitant/prior 
medications eCRF as appropriate.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
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.  Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the 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 (e.g., printing illegible), missing components/product, or packaging issues.
Product complaints concerning the investigational product must be reported to AbbVie within 24 hours 
of the study site's knowledge of the event.  Product complaints occurring during each study will be 
followed up to a satisfactory conclusion.
Medical Complaints/Adverse Events and Serious Adverse Events
An AE is defined as any untoward medical occurrence in a subject 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.
The Investigators will monitor each subject for clinical and laboratory evidence of AEs on a routine basis 
throughout each study.  All AEs will be followed to a satisfactory conclusion.  Laboratory abnormalities 
and changes in vital signs are considered to be AEs only if they result in discontinuation from the study 
drug, necessitate therapeutic medical intervention, and/or if the investigator considers them to be AEs.
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 
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pre-planned prior to study entry.  However, if the pre-existing condition deteriorates unexpectedly 
during a 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.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie or contract research organization (as appropriate) as an SAE within 24 hours of the 
site being made aware of the SAE (refer to the Reporting Adverse Events and Intercurrent Illnesses 
section of the operations manual for reporting details and contact information):
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 (ADL) of a study subject.  Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Intervention to Prevent 
Serious Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization but based on 
medical judgment may jeopardize the subject and may require 
medical or surgical intervention to prevent any of the outcomes 
listed above (i.e., death of subject, life threatening, hospitalization, 
prolongation of hospitalization, congenital anomaly, or persistent or 
significant disability/incapacity).  Additionally, any elective or 
spontaneous abortion or stillbirth is considered an important 
medical event.  Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room 
or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or 
drug abuse.
All AEs reported from the time of study drug administration until 30 days after discontinuation of study 
drug administration will be collected, whether solicited or spontaneously reported by the subject.  After 
30 days following the last dose of study drug or completion of study treatment, only spontaneously 
reported SAEs will be collected (nonserious AEs will not be collected). In addition, SAEs and protocol-
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related nonserious AEs will be collected from the time the subject signs the study-specific informed 
consent.
AbbVie will be responsible for SUSAR reporting for the Investigational Medicinal Product (IMP) in 
accordance with global and local requirements.  An adverse reaction implies at least a reasonable 
possibility of a causal relationship between a suspected medicinal product and an AE.  An adverse 
reaction, in contrast to an AE, is characterized by the fact that a causal relationship between a medicinal 
product and an occurrence is suspected.  A 'suspected' serious adverse reaction refers to individual SAE 
case reports from clinical trials where a causal relationship between the SAE and the IMP was suspected 
by either the Sponsor or the Investigator, is not listed is the applicable Reference Safety Information, 
and meets one of the following serious criteria:  results in death, is life-threatening, requires 
hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability 
or incapacity, or is a congenital anomaly or birth defect.  All individually reported serious adverse 
reactions are considered suspected.
AEs will be monitored throughout each study to identify any of special interest that may indicate a trend 
or risk to subjects.
Adverse Events of Special Interest
The following AESIs will be monitored during each study:

Serious infections

Opportunistic infections

Herpes Zoster

Active TB

Malignancy (all types)

Adjudicated GI perforations

Anemia

Neutropenia

Lymphopenia

Renal dysfunction

Hepatic disorder

Adjudicated cardiovascular events (e.g., major adverse cardiac events)

Adjudicated embolic and thrombotic events (non-cardiac, non-central nervous system)
Cardiovascular Adjudication Committee
An independent committee of physician experts in cardiovascular adjudication will be utilized to assess 
potential cardiovascular, cerebrovascular, embolic, and thrombotic AEs in a blinded manner as defined 
by the CAC charter.  The CAC charter will be prepared separate from the protocol and will describe the 
objective, scope, frequency, and triggers for data reviews.
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Adverse Event Severity and Relationship to Study Drug
The Investigators will rate the severity of each AE according to the National Cancer Institute CTCAE 
version 4.03, which can be accessed at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50.
If no grading criteria are provided for the reported event, then the event should be graded 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 ADL (instrumental ADL refer to preparing 
meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.)
Severe (Grade 3 – 5)
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL (self-care ADL refers to bathing, dressing and 
undressing, feeding self, using the toilet, taking medications, and not 
bedridden)
Grade 4
Life-threatening consequences; urgent intervention indicated
Grade 5
Death related to AE
The Investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
For causality assessments, events assessed as having a reasonable possibility of being related to the 
study drug will be considered "associated."  Events assessed as having no reasonable possibility of being 
related to study drug will be considered "not associated."  In addition, when the Investigator has not 
reported a causality or deemed it not assessable, AbbVie will consider the event associated.
If an Investigator's opinion of no reasonable possibility of being related to study drug is given, an Other 
cause of event must be provided by the Investigator for the SAE.
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Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy.  If a pregnancy occurs in a study subject, information regarding the 
pregnancy and the outcome will be collected.
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.
Subjects who become pregnant during a study must be discontinued from study drug, but may remain in 
the study (see Section 5.5).
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours of the site becoming aware of the 
event.
6.2 Toxicity Management
The toxicity management of the AEs including AESIs consists of safety monitoring (review of AEs on an 
ongoing basis, and periodic/ad hoc review of safety issues by an Independent Data Monitoring 
Committee), and, if applicable, interruption of study drug dosing with appropriate clinical management 
and/or discontinuation of the subjects from study drug.  The management of specific AEs and laboratory 
parameters is described below.
For subjects who discontinue study drug but continue study participation and are on standard of care 
therapies or are enrolled in the Remission-Withdrawal Period prior to retreatment, these toxicity 
management requirements do not apply (including alerts from the central laboratory) and any 
intolerability to standard of care therapies should be managed by the prescribing physician.
Serious Infections:  Study drug should be interrupted if a subject develops a serious infection.  Study 
drug may be restarted once the infection has been successfully treated.  Subjects who develop active TB 
must be permanently discontinued from study drug.
Herpes Zoster:  If a subject develops herpes zoster, consider temporarily interrupting study drug until 
the episode resolves.
Gastrointestinal Perforation:  If a diagnosis of gastrointestinal perforation is confirmed (other than due 
to appendicitis or mechanical injury), the subject must be permanently discontinued from study drug.
Major cardiovascular event: For subjects who develop a major cardiovascular event (MACE; acute 
myocardial infarction, stroke) while on study drug, the investigator should evaluate the benefit/risk of, 
and discuss with the TA MD whether it is appropriate to continue study drug.
Malignancy:  Subjects who develop malignancy other than localized NMSC or carcinoma in situ of the 
cervix must be permanently discontinued from study drug.  Information including histopathological 
results should be queried for confirmation of the diagnosis.  Periodic skin examination is recommended 
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for patients who are at increased risk for skin cancer. Subjects who develop malignancies should be 
referred to appropriate specialists and managed as per standard of care.
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 embolism or non-cardiac, 
non-neurologic arterial thrombosis is confirmed, the subject must be discontinued from study drug.
COVID-19:  Interrupt study drug in subjects with a confirmed diagnosis of COVID-19. Consider 
interrupting study drug in subjects with signs and/or symptoms and suspicion of COVID-19.  Study drug 
may be restarted once the infection has resolved, or subject is asymptomatic. The COVID-19 eCRF must 
be completed.
Management of Select Laboratory Abnormalities:  For any given laboratory abnormality, the 
Investigator should assess the subject and 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 3 and may require a supplemental eCRF to 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 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 protocol, the repeat testing is to occur as soon as possible.
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Table 3.
Specific Toxicity Management Guidelines for Abnormal Laboratory Values (for 
Study 1 and Study 2 and Remission-Withdrawal Period)
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 confirmed, continue to withhold study drug until hemoglobin value 
returns to ≥ 8 g/dL.
OR

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 
within 3.0 g/dL from Baseline.
ANC

If confirmed < 1000/µL by repeat testing with new sample, interrupt study drug dosing 
until ANC value returns to ≥ 1000/μL.

For confirmed < 500/μL, if value returns to ≥ 1000/μL, 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.
ALC

If confirmed < 500/µL by repeat testing with new sample, interrupt study drug dosing 
until ALC returns to≥ 500/μL.
Total WBC count

If confirmed < 2000/µL by repeat testing with new sample, interrupt study drug dosing 
until WBC count returns to ≥ 2000/μL.
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Laboratory 
Parameter
Toxicity Management Guideline
AST or ALT

Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample and either a total bilirubin > 2 × ULN or an INR > 1.5.

A separate blood sample for INR testing will be needed to measure INR at the time 
of repeat testing for ALT or AST.  A repeat test of INR is not needed for 
determination if above toxicity management criteria are met.

If a CPK value is not available, a CPK should be drawn to exclude AST/ALT elevations 
related to muscle injury.

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 new-onset eosinophilia.

Interrupt study drug if confirmed ALT or AST > 5 × ULN by repeat testing with new 
sample for more than 2 weeks.

If ALT or AST > 8 × ULN, interrupt study drug immediately, confirm by repeat testing 
with a new sample, and contact the TA MD. 
Subjects with HBc Ab+ (irrespective of hepatitis B surface antibody status) and negative HBV 
DNA PCR testing at Screening who develop the following laboratory findings should have 
HBV DNA PCR testing performed within 1 week (based on initial elevated value):

ALT > 5 × ULN OR

ALT or AST > 3 × ULN if an alternative cause is not readily identified

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). Within 1 week of the first episode of a positive 
HBV DNA PCR test, a hepatologist consultation should occur for recommendation regarding 
subsequent treatment.
Subjects who meet any of the above criteria should be evaluated for an alternative etiology 
of the ALT or AST elevation and managed as medically appropriate.  If applicable, the 
alternative etiology should be documented in the eCRF.  If ALT or AST values return to the 
normal reference range or the 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, interrupt study drug and restart study drug 
once serum creatinine returns to ≤ 1.5 × Baseline value.
For the above serum creatinine elevation scenarios, complete the supplemental renal eCRF.
Ab = antibody; ALC = absolute lymphocyte count; ALT = alanine aminotransferase; ANC = Absolute neutrophil count; 
AST = aspartate transaminase; DNA = deoxyribonucleic acid; eCRF = electronic case report form; HBc Ab = hepatitis B core 
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antibody; HBV = Hepatitis B virus; INR = international normalized ratio; PCR = polymerase chain reaction; TA MD = Therapeutic 
Area Medical Director; ULN = upper limit of normal; WBC = white blood cell
6.3 Data Monitoring Committee
For each study, an independent, external DMC will be established for periodic review of unblinded 
safety data and to alert AbbVie to possible safety concerns related to the conduct of the study to ensure 
subject safety.  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 DMC charter will describe the roles and responsibilities of the DMC members, frequency of data 
reviews, and relevant data to be assessed.  Communications from the DMC to the Study Team will not 
contain information that could potentially unblind the team to subject treatment assignments.
7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
Study 1 (bDMARD-IR AS) and Study 2 (nr-axSpA) will be analyzed separately for global submission 
purposes.  The AbbVie study team will be unblinded to perform the primary analysis and reporting for 
each study independently.
For Study 1 (bDMARD-IR AS), the database lock for the primary analysis will occur after all Study 1 
subjects have completed the Week 14 visit or have prematurely discontinued prior to Week 14.
For Study 2 (nr-axSpA), the database lock for the primary analysis will occur after all Study 2 subjects 
have completed the Week 14 visit or have prematurely discontinued prior to Week 14.
The primary analysis for Study 1 and Study 2 will be conducted for the comparisons of the upadacitinib 
group versus the placebo group.  The database lock dates may be different for Study 1 and Study 2.  For 
Study 1 and Study 2, sites and subjects will remain blinded to the placebo-controlled period treatment 
assignments for the duration of the respective study.
Additional analyses will also be conducted for each study independently as follows:

For Study 1 (bDMARD-IR AS), an analysis will be conducted when all subjects in the study have 
completed the Week 104 visit or have prematurely discontinued prior to Week 104.  An 
additional analysis may be conducted for regulatory purposes after all subjects have completed 
the Week 52 visit or have prematurely discontinued prior to Week 52.

For Study 2 (nr-axSpA), an analysis will be conducted after all subjects in the study have 
completed the Week 104 visit or have prematurely discontinued prior to Week 104.  An 
additional analysis will be conducted for regulatory purposes after all subjects have completed 
the Week 52 visit or have prematurely discontinued prior to Week 52.
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Specific details of the statistical analyses will be described and fully documented in the Statistical 
Analysis Plan (SAP) for each study.  For both studies, the SAP will be finalized prior to the Week 14 
database lock of the study.  The statistical analyses will be performed using SAS (SAS Institute Inc., Cary, 
North Carolina, USA).
7.2 Definition for Analysis Populations
The Full Analysis Set (FAS) includes all randomized subjects who received at least 1 dose of study drug.  
Subjects will be included in the analysis based on the treatment group as randomized.  The FAS will be 
used for all efficacy and Baseline analyses.
The Per Protocol Analysis Set represents a subset of the FAS and consists of all FAS subjects who did not 
have any major protocol violations that impact primary efficacy analysis.  The primary endpoint will be 
analyzed in the Per Protocol Analysis Set.  The Per Protocol Analysis Set will be determined prior to the 
respective primary analysis database lock.
The Safety Analysis Set consists of all subjects who received at least 1 dose of study drug.  For the Safety 
Analysis Set, subjects will be assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized.
7.3 Statistical Analyses for Efficacy
All efficacy analyses will be carried out for each study independently.
Analysis of the efficacy endpoints for Study 1 and Study 2 will be conducted on the FAS based on 
randomized treatment group.  Unless otherwise specified, comparisons will be between the 
upadacitinib group and the placebo group.  For each study, the between group comparison will be 
conducted using a two-sided test at significance level α = 0.05.
For binary endpoints, point estimate for the response rate and 95% confidence interval (CI) will be 
reported for each randomized treatment group.  Point estimate, 95% CI, and p-value for treatment 
comparison between upadacitinib and placebo will also be reported.
For continuous endpoints, the means at specified visits, least square means, and 95% CI of change from 
Baseline will be reported for each randomized treatment group.  The least square means of treatment 
difference and associated 95% CI and p-value for treatment comparison between upadacitinib and 
placebo will also be reported.
For primary and secondary binary endpoints, the primary analysis method will use the composite 
estimand framework; the supplementary analysis will use the treatment policy estimand framework. 
For secondary continuous endpoints, the primary analysis method will use the treatment policy 
estimand framework.  Details are outlined below.
Primary Efficacy Analysis
For Study 1 (bDMARD-IR AS), the primary endpoint is ASAS40 response at Week 14.  For Study 2 
(nr-axSpA), the primary endpoint is ASAS40 response at Week 14.  The primary efficacy analysis will use 
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the composite estimand framework, where the Week 14 primary endpoint for both studies is defined as 
a composite endpoint that is achieved if a subject fulfills the following 2 components:  1) Remain in the 
study and on study drug through 14 weeks; and 2) Achieve an ASAS40 response at Week 14.  
Corresponding to this estimand, in the primary analysis, subjects who discontinue study drug prior to 
Week 14 will be treated as non-responders.  Missing data due to COVID-19 will be imputed using 
Multiple Imputation and additional missing data due to other reasons will be treated as non-responders.
All subjects in the FAS will be included in the primary efficacy analysis.  Comparison of the primary 
endpoint will be made between the upadacitinib group and the placebo group using the 
Cochran-Mantel-Haenszel (CMH) test adjusting for the main stratification factor.  For Study 1 
(bDMARD-IR AS), the main stratification factor is hsCRP level (≤ ULN versus > ULN).  For Study 2 
(nr-axSpA), the main stratification factor is MRI and hsCRP status (MRI+/hsCRP > ULN, 
MRI+/hsCRP ≤ULN, and MRI–/hsCRP > ULN).  Rubin's method will be used to combine the results from 
the multiple datasets generated by the Multiple Imputation.  For both studies, the same respective 
analysis will be conducted on the Per Protocol Analysis Set as a supplementary analysis.
Corresponding to the composite estimand, a sensitivity analysis will be conducted.  Subjects who 
discontinue study drug prior to Week 14 will be treated as non-responders.  Additional missing data 
including those due to COVID-19 will also be treated as non-responders.  The same CMH analysis as the 
primary analysis will be conducted.
In addition, the following supplementary analyses will be performed using the treatment policy 
estimand framework.  The same CMH analysis as the primary analysis will be conducted including all 
data as observed, regardless of adherence to study drug, with subjects missing ASAS40 response treated 
as non-responders.  Additional sensitivity analysis using Multiple Imputation may also be conducted to 
handle missing ASAS40 responses.
Secondary Efficacy Analysis
For binary endpoints, similar analyses as for the primary endpoint will be conducted on the FAS.
The primary analysis of continuous endpoints will use the treatment policy estimand framework, 
intending to assess the treatment effect regardless of adherence to study drug.  All subjects in the FAS 
will be included for the analysis.  Comparisons between the upadacitinib group and the placebo group 
will be performed using the Mixed Model for Repeated Measures (MMRM) with treatment group, visit, 
and treatment-by-visit interaction as fixed effects and the corresponding Baseline value and the main 
stratification factor as the covariates.  The same main stratification factors as in the primary endpoint 
analyses will be used.  The MMRM model includes all longitudinal data as observed for subjects in the 
FAS, regardless of adherence to study drug.
For multiplicity-controlled secondary continuous efficacy variables, additional sensitivity analysis will be 
conducted corresponding the treatment policy estimand, where missing data will be imputed using 
Multiple Imputation.  The imputation model will include demographics variables and Baseline disease 
characteristics, as well as longitudinal response observed at any other visits.  The analysis of covariance 
(ANCOVA) model will be performed on each of the multiple imputed datasets adjusting for treatment, 
main stratification factor, and Baseline value.  The ANCOVA results from the multiple imputed datasets 
will be combined using the Rubin's method.
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Additional Efficacy Analyses
Additional efficacy variables will be summarized for all visits.  For efficacy analysis of the 
placebo-controlled period (up to Week 14 in Study 1 [bDMARD-IR] and Week 52 in Study 2 [nr-axSpA]), 
similar statistical methods as for the primary and secondary endpoints will be used.  For binary 
endpoints, comparisons between the upadacitinib group and the placebo group will be performed using 
the CMH test adjusting for the main stratification factor.  Corresponding to the composite estimand, 
subjects who discontinue study drug or use rescue medication will be treated as non-responders for 
visits after study drug discontinuation or initiation of rescue medication.  Missing data will be imputed 
similarly as for the primary endpoint.  A sensitivity analysis will be conducted where all missing data are 
treated as non-responders.  For continuous endpoints, comparisons between the upadacitinib group 
and the placebo group will be performed using the MMRM with treatment group, visit, and treatment-
by-visit interaction as fixed effects and the corresponding Baseline value and the main stratification 
factor as the covariates. Handling of data observed after rescue will be further detailed in the SAP.
Long-term efficacy analysis will be performed similarly as described above, corresponding to the 
composite estimand for binary endpoints and the treatment policy estimand for continuous endpoints.  
For binary endpoints, supplementary analysis using the treatment policy estimand may also be 
conducted on all data as observed.  For efficacy analysis beyond the placebo-controlled period (Week 14 
in Study 1 [bDMARD-IR] and Week 52 in Study 2 [nr-axSpA]), no statistical comparison will be 
performed; descriptive statistics and 95% CIs will be provided.  The analyses will be performed by 
randomized treatment sequence as described below:
1.
Placebo →upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →upadacitinib 15 mg QD
Efficacy Analysis for the Remission-Withdrawal Period
For time to flare during the withdrawal period, the Kaplan-Meier (KM) curve will be provided based on 
as observed data.  Subjects who discontinue the Remission-Withdrawal Period (prior to observed flare) 
will be considered censored.  Subjects who receive retreatment will be considered flared.  The KM 
estimator and associated 95% CIs for the flare-free rate during the withdrawal period will be provided.  
Similar analyses will also be performed for time to flare between Week 52 and Week 104 for Study 1 
and Study 2 as well as for M16-098 (SELECT-AXIS 1).
For analysis of binary endpoints at scheduled visits during the withdrawal period, non-responder 
imputation will be used, where subjects who flare, discontinue the study, or have missing values are 
considered non-responders. For analysis of continuous endpoints, MMRM will be used. For all 
endpoints, analysis based on as observed data will also be performed. Descriptive statistics and 95% CIs 
will be provided.  Data after retreatment will be excluded from these analyses and analyzed separately.
For subjects who receive re-treatment of upadacitinib after disease flare, analysis of endpoints after re-
treatment will be based on data as observed. Change from baseline and improvement response are 
calculated from the retreatment baseline.  Descriptive statistics and 95% CIs will be provided.
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Subgroup Analysis for Efficacy
The analyses for the primary efficacy endpoint for Study 1 and Study 2 will also be performed in 
demographic subgroups, including age, gender, race, weight, 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.  The treatment difference 
between the upadacitinib group and the placebo group will be presented with point estimate and 95% 
CI.  No p-value will be provided for subgroup analysis.
7.4 Statistical Analyses for Safety
All safety analyses will be carried out for each study independently using the Safety Analysis Set for both 
the primary analysis and for the entire study.  Analyses for Study 1 and Study 2 will be based on 
treatments the subjects actually received.  Safety will be assessed by TEAEs, physical examination, 
laboratory assessments, and vital signs.  The descriptive summary of subjects experiencing TEAEs by 
treatment group will be tabulated by the Medical Dictionary for Regulatory Activities primary system 
organ class and preferred term.  In addition, summary of SAEs and TEAEs by severity and relationship to 
study drug as assessed by the Investigator will be provided.  SAEs, severe TEAEs, or TEAEs that lead to 
premature study discontinuation will be listed.  A similar summary will also be performed for AESIs.
The observed values for vital signs, physical examination, and clinical laboratory variables at each visit 
will be summarized.  The number and percentage of subjects meeting the criteria for potentially 
clinically significant laboratory values will be summarized.  Shift of laboratory values from Baseline to 
defined time points will be tabulated.
Missing safety data will not be imputed.
Analysis details will be specified in the SAP.
7.5 Interim Analysis
There are no interim analyses planned for efficacy endpoints.  Information on the interim safety 
monitoring DMC is described in Section 6.3.  A separate DMC charter will be prepared outside of the 
protocol and will describe the roles and responsibilities of the DMC members, frequency of data 
reviews, and relevant data to be assessed.
7.6 Multiplicity Adjustment and Overall Type I Error Control
All efficacy analyses including multiplicity adjustment will be carried out for Study 1 (bDMARD-IR AS) and 
Study 2 (nr-axSpA) separately.  Study 1 and Study 2 will have its own hypothesis testing and overall type 
I error rate control at a level of 0.05 independently.  Since all efficacy comparisons target superior 
efficacy from placebo, this is equivalent to a one-sided test at a level of 0.025.
A fixed sequence testing approach will be employed to control the familywise error rate at 0.05 level for 
the primary and multiplicity-controlled secondary endpoints.  The test starts with the primary endpoint 
using two-sided α = 0.05; significance can be claimed for a lower ranked endpoint only if the previous 
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endpoints in the sequence meet the requirement of significance.  The testing sequence for Study 1 
(bDMARD-IR AS) is shown in Figure 4.  The testing sequence for Study 2 (nr-axSpA) is shown in Figure 5.
Figure 4.
Testing Sequence for Study 1 (bDMARD-IR AS)
Note:
The primary endpoint and all multiplicity-controlled secondary endpoints will be assessed at Week 14.
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Figure 5.
Testing Sequence for Study 2 (nr-axSpA)
*
ASAS40 response at Week 52 is part of the testing sequence for EU/EMA regulatory purposes.  For US/FDA regulatory 
purposes, the testing sequence stops at ΔMASES.
Note:
The primary endpoint and multiplicity-controlled secondary endpoints will be assessed at Week 14 unless otherwise 
noted.
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7.7 Sample Size Determination
The sample size and power were calculated for Study 1 and Study 2 separately.  Power and sample size 
calculations were performed at two-sided significance level of 0.05 and accounting for a 10% dropout 
rate for Week 14 endpoints.
Study 1 (bDMARD-IR AS)
The planned total sample size of 386 subjects for this study (with a 1:1 randomization ratio for placebo 
and upadacitinib 15 mg) provides at least 90% power for the primary endpoint ASAS40 response of 
upadacitinib 15 mg versus placebo using a two-sided Chi-square test at 0.05 level.  For ASAS40, the 
assumed response rates for upadacitinib and placebo are 24% and 6%, respectively.20,26,40  This sample 
size also provides 90% power for ASAS20, with assumed response rates for upadacitinib and placebo of 
41% and 24%, respectively.
In addition, this sample size provides at least 80% power for several of the multiplicity-controlled 
secondary endpoints including change from Baseline in ASDAS, change from Baseline in MRI SPARCC 
score of spine, BASDAI 50 response, ASDAS ID, change from Baseline in Total Back Pain, change from 
Baseline in Nocturnal Back Pain, ASDAS LDA, change from Baseline in BASFI, and ASAS PR.20,26,40
Study 2 (nr-axSpA)
The planned total sample size of 304 for this study (with a 1:1 randomization ratio for placebo and 
upadacitinib 15 mg) provides at least 90% power for the primary endpoint ASAS40 response of 
upadacitinib 15 mg versus placebo using a two-sided Chi-square test at 0.05 level.  For ASAS40 at 
Week 14, the assumed response rates for upadacitinib and placebo are 42% and 17%, 
respectively.38,41,42,43
In addition, this sample size provides at least 80% power for several of the multiplicity-controlled 
secondary endpoints including change from Baseline in ASDAS, change from Baseline in MRI score of SI 
joints, BASDAI 50 response, ASDAS ID, change from Baseline in Total Back Pain, change from Baseline in 
Nocturnal Back Pain, ASDAS LDA, ASAS PR, and Week 52 ASAS40 response (multiplicity-controlled for 
EU/EMA regulatory purposes).38,41,43
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the IEC/IRB for review and approval.  Approval of both the protocol and the informed 
consent form(s) must be obtained before any subject is enrolled.  Any amendment to the protocol will 
require review and approval by the IEC/IRB before the changes are implemented to a study.  In addition, 
all changes to the consent form(s) will be IEC/IRB approved.
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8.2 Ethical Conduct of the Study
Each study will be conducted in accordance with the protocol, operations manual, International Council 
for 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 Investigator are specified in Appendix B.
For subjects in Japan only: After marketing approval of upadacitinib for the treatment of nr-axSpA in 
Japan, M19-944 Study 1 and Study 2 will be conducted in compliance with the Ministerial on Good Post-
marketing Study Practice (GPSP) in Japan.
In cases of COVID-19 pandemic situations leading to difficulties in performing protocol-specified 
procedures, AbbVie will engage with study site personnel in efforts to ensure the safety of subjects, 
maintain protocol compliance, and minimize risks to the integrity of the study while trying to best 
manage subject continuity of care.  This may include alternative methods for assessments (e.g., virtual 
site visits), alternative locations for data collection (e.g., use of a local laboratory instead of a central 
laboratory), and shipping investigational product and/or supplies DTP to ensure continuity of treatment 
where allowed.  Refer to the operations manual for additional details.  In all cases, these alternative 
measures must be allowed by local regulations and permitted by the IRB/IEC.  Investigators should 
notify AbbVie if any urgent safety measures are taken to protect the subjects against any immediate 
hazard.
8.3 Subject Confidentiality
For the protection of personal data, AbbVie has developed a robust security program focused on due 
diligence in design, managed change, and information security governance.  Information Security 
policies govern the Information Security functions including identity and access management, 
operations, infrastructure, application, and third-party security requirements.  The risk-based AbbVie 
Data Classification Tool dictates the level of scrutiny and control required for the relevant activities per 
AbbVie's Information Security policies taking into account the sensitivity of the data.
Before a subject's data are shared with AbbVie, the study investigator and staff will replace any 
information that could directly identify a subject (such as name, address, and contact information) with 
an assigned numerical study identifier or "code" which AbbVie cannot link to that subject's identity in 
order to protect the confidentiality of the data.
AbbVie has a data protection impact assessment program to ensure and document the appropriate 
controls and safeguards stated above are in place for clinical trial data that it controls and maintains and 
these processing activities respect privacy of clinical trial subjects.  AbbVie also maintains robust security 
incident response policies and procedures, including requirements for the containment of any data 
related incidents, the mitigation measures where needed, and notification to authorities or affected 
individuals where required.  During the COVID-19 pandemic, remote monitoring of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
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9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The Investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).  During the COVID-19 pandemic, remote data review and verification of data may be 
employed if allowed by the local regulatory authority, IRB/IEC, and the study site.
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The start-of-study is defined as the date of the first site activated. For Study 1 and Study 2, the 
end-of-study is defined as the date of study participation by the last subject in the last country where 
the study was conducted.  The end-of-study, as it pertains to Study Protocol M19-944, is defined as the 
end-of-study for Study 1 or Study 2, whichever is later.
12
REFERENCES
1.
Deodhar A, van der Heijde D, Sieper J, et al. Efficacy and Safety of Upadacitinib in Patients with 
Active Ankylosing Spondylitis: 1-Year Results from a Randomized, Double-Blind, Placebo-Controlled 
Study with Open-Label Extension [abstract]. Arthritis Rheumatol 2020;72.
2.
van der Heijde D, Ramiro S, Landewe R, et al. 2016 update of the ASAS-EULAR management 
recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978-91.
3.
Smolen JS, Schols M, Braun J, et al. Treating axial spondyloarthritis and peripheral spondyloarthritis, 
especially psoriatic arthritis, to target: 2017 update of recommendations by an international task 
force. Ann Rheum Dis. 2018;77(1):3-17.
4.
Landewé R, Sieper J, Mease P, et al. Efficacy and safety of continuing versus withdrawing 
adalimumab therapy in maintaining remission in patients with non-radiographic axial 
spondyloarthritis (ABILITY-3): a multicentre, randomised, double-blind study. Lancet. 
2018;392(10142):134-44.
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5.
Van den Bosch F, Wei JCC, Nash P, et al. Etanercept withdrawal and re-treatment in patients with 
inactive non-radiographic axial spondyloarthritis at 24 weeks: results of re-embark, an open-label, 
phase IV trial Ann Rheum Dis. 2020;79(70).
6.
Landewé RB, van der Heijde D, Dougados M, et al. Maintenance of clinical remission in early axial 
spondyloarthritis following certolizumab pegol dose reduction. Ann Rheum Dis. 2020;79(7):920-8.
7.
Khan MA. Update on spondyloarthropathies. Annals of Internal Medicine. 2002;136(12):896-907.
8.
Dougados M, Baeten D. Spondyloarthritis. Lancet. 2011;377(9783):2127-37.
9.
Rudwaleit M, van der Heijde D, Landewe R, et al. The development of Assessment of 
SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): 
validation and final selection. Ann Rheum Dis. 2009;68(6):777-83.
10. Baraliakos X, Braun J. Non-radiographic axial spondyloarthritis and ankylosing spondylitis: what are 
the similarities and differences? RMD Open. 2015;1(Suppl 1):e000053.
11. Poddubnyy D, Sieper J. Similarities and differences between nonradiographic and radiographic axial 
spondyloarthritis: a clinical, epidemiological and therapeutic assessment. Curr Opin Rheumatol. 
2014;26(4):377-83.
12. Ward MM, Deodhar A, Akl EA, et al. American College of Rheumatology/Spondylitis Association of 
America/Spondyloarthritis Research and Treatment Network 2015 Recommendations for the 
Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis. Arthritis 
Rheumatol. 2016;68(2):282-98.
13. Braun J, Bollow M, Remlinger G, et al. Prevalence of spondylarthropathies in HLA-B27 positive and 
negative blood donors. Arthritis Rheum. 1998;41(1):58-67.
14. Costantino F, Talpin A, Said-Nahal R, et al. Prevalence of spondyloarthritis in reference to HLA-B27 in 
the French population: results of the GAZEL cohort. Ann Rheum Dis. 2015;74(4):689-93.
15. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other 
rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1):15-25.
16. Reveille JD, Weisman MH. The epidemiology of back pain, axial spondyloarthritis and HLA-B27 in the 
United States. Am J Med Sci. 2013;345(6):431-6.
17. van Tubergen A. The changing clinical picture and epidemiology of spondyloarthritis. Nat Rev 
Rheumatol. 2015;11(2):110-8.
18. Hukuda S, Minami M, Saito T, et al. Spondyloarthropathies in Japan: nationwide questionnaire 
survey performed by the Japan Ankylosing Spondylitis Society. J Rheumatol. 2001;28(3):554-9.
19. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390(10089):73-84.
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20. Sieper J, Deodhar A, Marzo-Ortega H, et al. Secukinumab efficacy in anti-TNF-naïve and anti-TNF-
experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 Study. Ann 
Rheum Dis. 2017;76(3):571-92.
21. Rudwaleit M, Van den Bosch F, Kron M, et al. Effectiveness and safety of adalimumab in patients 
with ankylosing spondylitis or psoriatic arthritis and history of anti-tumor necrosis factor therapy. 
Arthritis Res Ther. 2010;12(3):R117.
22. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. Efficacy and safety of ixekizumab in the treatment 
of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-
blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor 
necrosis factor inhibitors. Arthritis Rheumatol. 2019;71(4):599-611.
23. Alten R, Krüger K, Rellecke J, et al. Examining patient preferences in the treatment of rheumatoid 
arthritis using a discrete-choice approach. Patient Prefer Adherence. 2016;10:2217-28.
24. van der Heijde D, Deodhar A, Wei JC, et al. Tofacitinib in patients with ankylosing spondylitis: a 
phase II, 16-week, randomised, placebo-controlled, dose-ranging study. Ann Rheum Dis. 
2017;76(8):1340-7.
25. van der Heijde D, Baraliakos X, Gensler LS, et al. Efficacy and safety of filgotinib, a selective Janus 
kinase 1 inhibitor, in patients with active ankylosing spondylitis (TORTUGA): results from a 
randomised, placebo-controlled, phase 2 trial. Lancet. 2018;392(10162):2378-87.
26. van der Heijde D, Song IH, Pangan AL, et al. Efficacy and safety of upadacitinib in patients with active 
ankylosing spondylitis (SELECT-AXIS 1): a multicentre, randomised, double-blind, placebo-controlled, 
phase 2/3 trial. Lancet. 2019;394(10214):2108-17.
27. Ward MM, Deodhar A, Gensler LS, et al. 2019 Update of the American College of 
Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment 
Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial 
Spondyloarthritis. Arthritis Rheumatol. 2019;71(10):1599-613.
28. Burmester GR, Panaccione R, Gordon KB, et al. Long-Term Safety of Adalimumab (HUMIRA) in Adult 
Patients from Global Clinical Trials across Multiple Indications: An Updated Analysis in 29,987 
Patients Representing 56,951 Patient-Years [abstract]. Arthritis Rheumatol. 2017;69.
29. Cohen SB, Vollenhoven RV, Winthrop K, et al. THU0167 safety profile of upadacitinib in rheumatoid 
arthritis: integrated analysis from the SELECT Phase 3 clinical program. Ann Rheum Dis. 
2019;78(357).
30. AbbVie. Upadacitinib Investigator's Brochure Edition 11. 18 August 2020.
31. Minozzi S, Bonovas S, Lytras T, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, 
psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis. Expert Opin 
Drug Saf. 2016;15(sup1):11-34.
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32. Kerensky TA, Gottlieb AB, Yaniv S, et al. Etanercept: efficacy and safety for approved indications. 
Expert Opin Drug Saf. 2012;11(1):121-39.
33. Krüger K, Burmester GR, Wassenberg S, et al. Effectiveness and safety of golimumab in patients with 
rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis under real-life clinical conditions: 
non-interventional GO-NICE study in Germany. BMJ Open. 2018;8(6):e021082.
34. Dougados M, Soubrier M, Antunez A, et al. Prevalence of comorbidities in rheumatoid arthritis and 
evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann 
Rheum Dis. 2014;73(1):62-8.
35. Moltó A, Etcheto A, van der Heijde D, et al. Prevalence of comorbidities and evaluation of their 
screening in spondyloarthritis: results of the international cross-sectional ASAS-COMOSPA study. 
Ann Rheum Dis. 2016;75(6):1016-23.
36. Ismail M, Nader A, Winzenborg I, et al. Exposure-response analyses for upadacitinib efficacy and 
safety in ankylosing spondylitis – analyses of the SELECT-AXIS I study [abstract]. Arthritis Rheumatol. 
2019;71(suppl 10):Abstract 1492.
37. Mohamed M, Nader A, Winzenborg I, et al. Exposure-response analyses of upadacitinib efficacy and 
safety in rheumatoid arthritis – analyses of Phase 2 and 3 studies. Ann Rheum Dis. 2019;78:739-40.
38. Landewe R, Braun J, Deodhar A, et al. Efficacy of certolizumab pegol on signs and symptoms of axial 
spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised 
placebo-controlled Phase 3 study. Ann Rheum Dis. 2014;73(1):39-47.
39. Song IH, Weiß A, Hermann KG, et al. Similar response rates in patients with ankylosing spondylitis 
and non-radiographic axial spondyloarthritis after 1 year of treatment with etanercept: results from 
the ESTHER trial. Ann Rheum Dis. 2013;72(6):823-5.
40. Baeten D, Sieper J, Braun J, et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing 
spondylitis. N Engl J Med. 2015;373(26):2534-48.
41. Sieper J, van der Heijde D, Dougados M, et al. Efficacy and safety of adalimumab in patients with 
non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-
1). Ann Rheum Dis. 2013;72(6):815-22.
42. Dougados M, van der Heijde D, Sieper J, et al. Symptomatic efficacy of etanercept and its effects on 
objective signs of inflammation in early nonradiographic axial spondyloarthritis: a multicenter, 
randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2014;66(8):2091-102.
43. Sieper J, van der Heijde D, Dougados M, et al. A randomized, double-blind, placebo-controlled, 
sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial 
spondyloarthritis. Arthritis Rheumatol. 2015;67(10):2702-12.
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APPENDIX A. STUDY SPECIFIC ABBREVIATIONS AND TERMS
Ab
antibody
AE(s)
adverse event(s)
ALT
alanine aminotransferase
AS
ankylosing spondylitis
ASAS
Assessment of SpondyloArthritis international Society
ASDAS
Ankylosing Spondylitis Disease Activity Score
ASQoL
Ankylosing Spondylitis Quality of Life
AST
aspartate transaminase
axSpA
axial spondyloarthritis
BASDAI
Bath Ankylosing Spondylitis Disease Activity Index
BASFI
Bath Ankylosing Spondylitis Functional Index
BASMIlin
Linear Bath Ankylosing Spondylitis Metrology Index
bDMARD-IR
biologic disease-modifying antirheumatic drug inadequate responder(s)
bDMARDs
biologic disease-modifying antirheumatic drugs
CAC
Cardiovascular Adjudication Committee
CI
confidence interval
CMH
Cochran-Mantel-Haenszel
CRF
case report form
CRP
C-reactive protein
csDMARD(s)
conventional synthetic disease-modifying antirheumatic drug(s)
CXR
chest x-ray
CYP3A
cytochrome P450 3A isoform subfamily
DMC
Data Monitoring Committee
DTP
direct-to-patient
EC
Ethics Committee
eCRF
electronic case report form
EMA
European Medicines Agency
EQ-5D-5L
EuroQol 5 Dimensions 5 Levels Health State Instrument
EU
European Union
EudraCT
European Clinical Trials Database
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FDA
Food and Drug Administration
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GCP
Good Clinical Practice
GI
gastrointestinal
GPSP
Good Post-Marketing Study Practice
HI
Health Index
hsCRP
High sensitivity C-reactive protein
ICH
International Council for Harmonisation
ID
Inactive Disease
IEC
Independent Ethics Committee
IGRA
Interferon Gamma Release Assay
IL
interleukin
INR
international normalized ratio
IRB
institutional review board
JAK
Janus kinase
KM
Kaplan-Meier
LDA
Low Disease Activity
MACE
major adverse cardiac event
MASES
Maastricht Ankylosing Spondylitis Enthesitis Score
Min
minimum
mm
millimeters
MMRM
Mixed Model for Repeated Measures
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
NA
not evaluable/assessable
nr-axSpA
non-radiographic axial spondyloarthritis
NSAID(s)
nonsteroidal anti-inflammatory drug(s)
NRS
numeric rating scale
PCR
polymerase chain reaction
PD Visit
Premature Discontinuation Visit
PED
Patient Experience Data
PGA
Physician's Global Assessment of Disease Activity
PK
pharmacokinetics
PPD
purified protein derivative (tuberculin)
PR
partial remission
PRO
patient-reported outcome
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PsA
psoriatic arthritis
PtGA
Patient's Global Assessment of Disease Activity
QD
once daily
QoL
quality of life
RA
rheumatoid arthritis
SAE
serious adverse event
SF-36
36-Item Short Form Health Survey
SI
sacroiliac
SJC
swollen joint count
SpA
spondyloarthritis
SPARCC
Spondyloarthritis Research Consortium of Canada
TA MD
Therapeutic Area Medical Director
TB
tuberculosis
TJC
tender joint count
TNF
tumor necrosis factor
ULN
upper limit of normal
US
United States
VAS
visual analogue scale
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M19-944:  A Phase 3 Randomized, Placebo-Controlled, Double-Blind Program to Evaluate Efficacy and 
Safety of Upadacitinib in Adult Subjects with Axial Spondyloarthritis Followed by a Remission-Withdrawal Period
Protocol Date:  27 October 2022
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation (ICH) 
Good Clinical Practices (GCP) and local regulations and guidelines governing the study at the site location.  In 
signing the Investigator Agreement, the Investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, current 
protocol and operations manual, and making changes to a protocol only after notifying AbbVie and the 
appropriate Institutional Review Board (IRB)/Independent Ethics Committee (IEC), except when necessary 
to protect the subject from immediate harm.
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., 
IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
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 
protocol and all of its amendments.
9.
Reporting promptly (within one calendar day to AbbVie, the ECs/IRBs [as required] and other appropriate 
individuals [e.g., Coordinating Investigator, Institution Director]).

All changes in the research activity and all unanticipated problems involving risks to human subjects 
or others

Any departure from relevant clinical trial law or regulation, GCP, or the trial protocol that has the 
potential to affect the following:

Rights, safety, physical or mental integrity of the subjects in the clinical trial

Scientific value of the clinical trial, reliability or robustness of data generated
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB review, 
and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Immunology Clinical Development
Immunology Clinical Development
Clinical Study Leadership
Data and Statistical Sciences
 
Data and Statistical Sciences
Clinical Pharmacology
Medical Writing
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across Screening and subsequent study visits.  Activities 
are applicable for Study 1 and Study 2 unless specified.  The individual activities are described in detail in 
the operations manual (Appendix G).  Allowed modifications due to the COVID-19 pandemic are detailed 
within the operations manual.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Protocol
Date
Version 1.0
23 August 2019
Version 2.0
13 September 2019
Version 3.0
01 February 2020
Administrative Change 1
06 March 2020
Version 4.0
29 December 2020
Version 4.1 (VHP Countries)
02 March 2021
Version 5.0
12 July 2021
The purpose of this version is to incorporate the following changes:

Changes were made to align with the European Union/Clinical Trial Regulation to Protocol Title 
Page, Section 5.5, Section 5.7, Study Drug, Section 8.3 Subject Confidentiality; Operations 
Manual Section 3.3 Subject Information and Informed Consent, Section 1 Contacts, and 
Section 4.3 Reporting Adverse Events and Intercurrent Illnesses. Changes include a detailed 
study drug definition, description of subject confidentiality measures, and investigator reporting 
requirements, as well as minor updates to contact information and gender pronouns.
Rationale: To align with requirements of the EU Clinical Trial Regulation.

Country-specific changes as required upon marketing approval of upadacitinib in Japan were 
made to Synopsis, Section 1, Investigational Plan; Section 4.1, Overall Study Design and Plan; 
Section 8.2, Ethical Conduct of the Study; Section 5.2, Contraception Recommendations, to 
indicate that M19-944 Study 1 and Study 2 will be changed from Phase 3 studies to post-
marketing clinical studies in Japan, and conducted in compliance with the Ministerial on Good 
Post-marketing Study Practice (GPSP) in Japan 
Rationale: Per Japan post-marketing requirements.

Clarifications were added to Section 5.4, Allowed Therapies, to describe how peripheral joints 
are assessed once injected, and to specify that background medications should remain stable 
during the entire Remission-Withdrawal Period, including withdrawal and re-treatment phases, 
as applicable.
Rationale: For clarity.

Text was revised in Section 6.2, Toxicity Management to align with current upadacitinib toxicity 
management standards, including updated guidance regarding MACE, malignancy, and GI 
perforation events, as well as abnormal laboratory values. Applicable changes were also made 
to Table 3 in the same section.
Rationale: For consistency with updated toxicity management guidelines based on current 
upadacitinib safety information.

The following clarifications were added to Appendix D, Activity Schedule:
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
Instruction to dispense at-home urine pregnancy tests at Week 104 for subjects entering the 
OLE in applicable countries was added to the Activity Table for Study 1 and Study 2.

Instruction to obtain urine pregnancy tests and dispense at-home urine pregnancy tests at 
Week 152 for subjects entering the OLE in applicable countries was added to the Activity 
Tale for Remission-Withdrawal Period (Prior to Retreatment).

Instruction to administer annual TB risk assessment questionnaire, obtain annual chest x-ray 
and TB testing, and dispense at-home urine pregnancy tests (at RT Week 24) was added to 
the Activity Table for the Remission-Withdraw Period (After Retreatment).

Removal of HBV testing at Week 122 (post baseline test for subjects from Japan only) which 
was too frequent beyond local requirements.
Corresponding changes were made to the applicable Individual Treatment Period Visit Activities
tables in the Operations Manual.
Rationale: To correct minor errors and clarify that pregnancy monitoring and TB screening 
activities continue during and after Remission-Withdrawal Period.

The text in Appendix F, Open-Label Extension for Applicable Countries, was updated and 
expanded. Predefined time periods for participating countries were removed, and alternative 
guidance for end of Open-Label Extension period and final visits was added.
Rationale: For clarity and to allow continued access to upadacitinib, as needed, up to July 2025 
across all applicable countries.

eCRFs for retinal detachment and fracture were added to the list of supplemental eCRFs in the 
Operations Manual
Rationale: To collect detailed information about any safety events of fracture or retinal 
detachment.
In addition to the above modifications, this version contains the following minor changes:

Appendix C – Updated list of protocol signatures

The emergency medical contact was updated where applicable in Protocol and Operations 
Manual (Appendix G).

Minor text edits as needed for consistency and clarity

Correct minor clerical errors for consistency throughout the protocol
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APPENDIX F. OPEN-LABEL EXTENSION FOR APPLICABLE 
COUNTRIES
Directions for sites in countries that require continued study drug provision to accommodate country-
specific needs is found throughout this appendix.  Applicable countries include but are not limited to,
Belgium, Bulgaria, China, Czechia, France, Japan, Hungary, Mexico, Russia, Slovakia, Turkey, Korea, and 
New Zealand.
INVESTIGATIONAL PLAN
Overall Study Design and Plan (for additional details please review main Protocol)

Subjects in Study M19-944 from both Study 1 (AS bDMARD-IR) and Study 2 (nr-axSpA) who 
reach Week 104 on study drug (upadacitinib 15 mg QD) will be assessed whether they are in 
remission, defined as achieving ASDAS (CRP) < 1.3 at Week 104 and ASDAS (CRP) < 2.1 at 
Week 88.

Subjects in remission at Week 104 will be eligible for the Remission-Withdrawal Period. 
Subjects will be followed without study drug treatment and assessed for disease flare through 
Week 152.  Flare is defined as an ASDAS (CRP) ≥ 2.1 at 2 consecutive visits, which are at least 
2 weeks apart, or an ASDAS (CRP) > 3.5 at one visit.

Subjects who flare during the Remission-Withdrawal Period will receive open-label 
upadacitinib 15 mg QD from the time of flare for 24 weeks (re-treatment) or until the end of 
the Open-Label Extension period for their respective country, whichever date is later.

Subjects who do not flare during the Remission-Withdrawal Period, will be followed without 
upadacitinib treatment until Week 152 at which point they will have the option to receive 
open label upadacitinib for the predefined time period, if Week 152 is before the end of the 
Open-Label Extension period for their respective country.  If Week 152 is after the end of 
the Open-Label Extension period, the subject will complete the study at Week 152.

Subjects who are not in remission at Week 104 can continue to receive open-label treatment 
with upadacitinib 15 mg QD until the end of the Open-Label Extension period.
Subjects will be offered continued access to upadacitinib every 12 weeks until the end of the Open-Label
Extension period.  There are no safety or efficacy endpoints associated with the Open-Label Extension.
Following country, local (if applicable) regulatory approval, and/or applicable local reimbursement 
approval of the study drug in a country, or at such time that development or pursuit of regulatory 
approval is discontinued, subjects should be brought in for a final visit conducted in place of their 
regularly scheduled Open-Label Extension period study visit.
Note: These Open-Label Extension visits completed for purposes of post-Week 104 or 
post-Remission-Withdrawal access to upadacitinib prior to local regulatory approval/reimbursement 
process are considered optional and do not preclude a subject from being considered as completing the 
main study period (i.e., Week 104) or the Remission-Withdrawal Period.
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Participating sites in applicable countries will be provided with estimated dates of when the subjects'
final visits are expected to occur for planning purposes. It is acknowledged that these dates may change 
at any time during the course of the regulatory approval/reimbursement process.  The final visit dates 
will be communicated to the sites based on actual approval/reimbursement dates or if decision to 
discontinue pursuit of regulatory approval/reimbursement is made.  In the event regulatory approval, 
local reimbursement, or the decision to discontinue pursuit of regulatory approval/reimbursement
occurs at a time point different than the estimated dates, subjects should then be brought in for their 
termination visit based on the actual date as provided by AbbVie. AbbVie reserves the right to 
terminate the study at any time.
The continued access period, also known as Open-Label Extension, is expected to end in approximately 
July 2025.
CONCOMITANT MEDICATION
For subjects who are not in remission at Week 104 and who receive open-label treatment with 
upadacitinib 15 mg QD after Week 104, addition or modification of axSpA medications can be made per 
Investigator judgment regardless of the disease activity status.
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Figure 6.
Study Schematic
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