Clinical trial NCT04169373
Conditions: Spondyloarthritis
Keywords: Upadacitinib Axial Spondyloarthritis (axSpA) Spondyloarthritis Ankylosing Spondylitis (AS)
Sponsor: AbbVie
Start date: 2019-11-26; Completion date: 2025-02-21
Enrollment: 734 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This protocol includes 2 standalone studies with randomization, data collection, analysis and reporting conducted independently.

The main objectives of this protocol are:

* To evaluate the efficacy of upadacitinib compared with placebo on reduction of signs and symptoms in adults with active axial spondyloarthritis (axSpA) including biologic disease-modifying antirheumatic drug inadequate responders (bDMARD-IR) ankylosing spondylitis (AS) (Study 1) and non-radiographic axial spondyloarthritis (nr-axSpA) (Study 2).
* To assess the safety and tolerability of upadacitinib in adults with active axSpA including bDMARD-IR AS (Study 1) and nr-axSpA (Study 2).
* To evaluate the safety and tolerability of upadacitinib in extended treatment in adult participants with active axSpA including bDMARD-IR AS who have completed the Double-Blind Period (Study 1) and nr-axSpA who have completed the Double-Blind Period (Study 2).
* To evaluate the maintenance of disease control after withdrawal of upadacitinib.

Detailed description:
Study 1 (bDMARD-IR AS) is comprised of 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 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.

In the Double-Blind Period for both studies, participants are randomized in a 1:1 ratio to receive either upadacitinib or placebo once daily (QD).

Participants in the placebo group switch 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).

Participants in remission at Week 104 have the option to enroll in a remission-withdrawal period.

Study M19-944 protocol uses a common screening platform for determining eligibility into Study 1 and Study 2. Each study has its own objectives, hypothesis testing, randomization, data collection, and adequate power for primary and secondary endpoints. Analysis and reporting are conducted separately and independently for each study.

Arms: arm 1: Participants receive 15 mg upadacitinib orally once a day for 104 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment). arm 2: Participants receive matching placebo for 14 weeks and then switch to receive 15 mg upadacitinib orally once a day for 90 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment). arm 3: Participants receive 15 mg upadacitinib orally once a day for 104 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment). arm 4: Participants receive matching placebo for 52 weeks and then switch to receive 15 mg upadacitinib orally once a day for 52 weeks. Participants who flare after 104 weeks will receive open-label upadacitinib once daily from the time of flare for 24 weeks (re-treatment).
Interventions: intervention 1: Upadacitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Upadacitinib tablet administered orally intervention 2: Placebo for upadacitinib tablet administered orally

Protocol documents:
Prot_003.pdf: 


  
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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
63
10
DATA QUALITY ASSURANCE
63
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
90
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
83
APPENDIX F.
OPEN-LABEL EXTENSION FOR APPLICABLE COUNTRIES
88
APPENDIX G.
OPERATIONS MANUAL
92
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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 nr-axSpA 
(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 nr-axSpA (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
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).
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,
 
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. 
 
  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 [PF-04965842], 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 
non-childbearing 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:
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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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.

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.
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

Natalizumab

Rituximab
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
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/paraspinal and 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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 combination of 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 corticosteroid equivalent 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.
See Section 5.3 for permitted vaccines.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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 
 
response 
 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 
 response at 
 
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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Background Medication During Remission-Withdrawal Period:
Starting at Week 104, subjects entering the Remission-Withdrawal Period, should keep their 
axSpA-related background medication stable.
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 his/her 
site if he/she has 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 
 
response at 
 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 
 
response at 
 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 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.
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.
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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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)

Group 2:  Placebo QD (N = 193)
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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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No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
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.  In 
addition, SAEs and protocol-related nonserious AEs will be collected from the time the subject signs the 
study-specific informed consent.
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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:  Subjects presenting with the onset of signs or symptoms of a GI 
perforation should be evaluated promptly for early diagnosis and treatment.  Subjects with acute, 
spontaneous perforation of the GI tract that requires inpatient medical care or urgent surgical 
intervention (except for appendicitis or mechanical injury) must be permanently discontinued from 
study drug.
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.
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Malignancy:  Subjects who develop malignancy other than 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 for patients who 
are at increased risk for skin cancer.
Muscle-related symptoms:  If a subject experiences symptoms suggestive of myositis or 
rhabdomyolysis, consider checking CPK and aldolase with clinical management and/or study drug 
interruption as deemed appropriate by the treating physician.
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.  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 hemoglobin decreases ≥ 3.0 g/dL from Baseline without an alternative etiology, 
interrupt study drug dosing and confirm by repeat testing with new sample.

If hemoglobin decreases ≥ 3.0 g/dL from Baseline and an alternative etiology is 
known or the hemoglobin value remains in the normal reference range, the subject
may remain on study drug at the Investigator's discretion.

If confirmed, continue to withhold study drug until hemoglobin value returns to 
normal reference range or its Baseline value.
ANC

If confirmed < 1000/µL by repeat testing with new sample, interrupt study drug 
dosing until ANC value returns to normal reference range or its Baseline value.

Interrupt study drug if confirmed < 500/μL by repeat testing with new sample.  If 
value returns to normal reference range or its Baseline value, restarting study drug 
is allowed if there is an alternative etiology identified; documentation should 
include reason that rechallenge is expected to be safe for the subject.  Study drug 
should be discontinued if no alternative etiology can be found.
ALC

If confirmed < 500/µL by repeat testing with new sample, interrupt study drug 
dosing until ALC returns to normal reference range or its Baseline value.
Total WBC count 

If confirmed < 2000/µL by repeat testing with new sample, interrupt study drug 
dosing until WBC count returns to normal reference range or its Baseline value.
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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 international normalized 
ratio > 1.5.

A separate blood sample for international normalized ratio (INR) testing will be 
needed to measure INR at the time of repeat testing for ALT or AST.  A repeat 
test of INR is not needed for determination if above toxicity management 
criteria are met.

Interrupt study drug if confirmed ALT or AST > 3 × ULN by repeat testing with new 
sample along with new appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5% increase from 
Baseline). 

Interrupt study drug if confirmed ALT or AST > 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 and either a total bilirubin > 2 × ULN or INR > 1.5 OR 

ALT or AST > 3 × ULN along with clinical signs of possible hepatitis.

A separate blood sample for HBV DNA PCR testing will be needed at the time of 
repeat testing for ALT or AST.
A positive result for HBV DNA PCR testing will require immediate interruption of study drug 
(unless not acceptable by local practices) and a hepatologist consultation should occur 
within 1 week for recommendation regarding subsequent treatment.
Subjects who meet any of the above criteria should be evaluated for an alternative etiology 
of the ALT or AST elevation and managed as medically appropriate.  If applicable, the 
alternative etiology should be documented 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, then interrupt study drug and 
restart study drug once serum creatinine returns to ≤ 1.5 × Baseline value 
and ≤ULN.
For the above serum creatinine elevation scenarios, complete the supplemental renal eCRF.
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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 
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
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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.
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
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
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.
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.
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11
COMPLETION OF THE STUDY
For Study 1 and Study 2, the end-of-study is defined as the date of the last subject's last visit or the 
actual date of follow-up contact, whichever is later.  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
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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.
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.
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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
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
IRB
institutional review board
JAK
Janus kinase
KM
Kaplan-Meier
LDA
Low Disease Activity
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
PsA
psoriatic arthritis
PtGA
Patient's Global Assessment of Disease Activity
QD
once daily
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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:  12 July 2021
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, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., Coordinating Investigator, 
Institution Director) and/or directly to the ethics committees and AbbVie.
10. 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 Program Development
Data and Statistical Sciences
Data and Statistical Sciences
Clinical Pharmacology and Pharmacometrics
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
The purpose of this Amendment is to incorporate the following changes:
Summary of Protocol Changes:
The rationale for the following changes was to include the Remission-Withdrawal Period in this study:

Title page, Appendix G – Revised title of study.

Section 3.1 – Added objective for the Remission-Withdrawal Period.

Section 3.4 – Added an additional endpoint relating to the assessment of disease flare.

Section 4.1 – Updated study design study schematic (Figure 1) to include a description of the 
Remission-Withdrawal Period.

Section 4.1 – Updated study schematic (Figure 1) to include the Remission-Withdrawal Period. 

Section 5.1 – Added eligibility criteria for subjects who enter the Remission-Withdrawal Period.

Section 5.3 – Added to include that concomitant biologic therapies and biosimilar versions of 
biologic drugs are prohibited during the Remission-Withdrawal Period.

Section 5.3 – Added to include that initiation of additional systemic immunomodulating therapy 
for the treatment of axSpA is prohibited during the Remission-Withdrawal Period.

Section 5.3 – Added to include that 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 the 
Remission-Withdrawal Period.

Section 5.3 – Added to include that investigational drugs are also prohibited during the 
Remission-Withdrawal Period.

Section 5.3 – Added to include that live vaccinations are prohibited during re-treatment during 
the Remission-Withdrawal Period.

Section 6.2 – Included the Remission-Withdrawal Period in the specific toxicity management 
guidelines for abnormal laboratory values in Table 3.
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
Section 7.3 – Added efficacy analysis during the Remission-Withdrawal Period.

Appendix D – Specified that subject information, informed consent, and eligibility criteria at 
Week 104 in the main study is for the Remission-Withdrawal Period only.

Appendix D – Added study activity tables for the Remission-Withdrawal Period.

Appendix G –

Appendix G –
 

Appendix G – Added subject information, informed consent, and eligibility criteria at Week 104 
for the Remission-Withdrawal Period only.

Appendix G – Updated to include the Follow-Up Visit is not applicable for subjects who continue 
in the Remission-Withdrawal Period.

Appendix G – Added study activities for the Remission-Withdrawal Period.

Appendix G – Added guidance on assessing 
 during the Remission-Withdrawal Period.

Appendix G –
 
 

Appendix G – Added that during the Remission-Withdrawal Period, unscheduled visit can be 
scheduled at any time to assess disease status (e.g., flare) and/or safety between scheduled 
visits, if needed.
The rationale for the following changes was to incorporate modifications due to the COVID-19 
pandemic:

Section 5.4 – Added guidance on COVID-19 pandemic-related vaccination.

Section 5.7 – Included information on DTP study drug shipment and details on time limits for 
study drug interruption.

Section 5.9 – Clarified that protocol deviations may include modifications due to COVID-19.

Appendix G – Added guidance on the assessment of vital signs during the COVID-19 pandemic.

Appendix G – Added guidance on reactions associated with the SARS-CoV-2 vaccine.
The rationale for the following changes was to update the statistical methods for handling of missing 
data and intercurrent events to address regulatory feedback:

Section 7.3 – Clarified that for primary and secondary binary endpoints, the primary method will 
use the composite estimand framework.  Added that the supplementary analysis will use the 
treatment policy estimand framework.  Revised language to state that for secondary continuous 
endpoints, the primary method will use the treatment policy estimand framework.
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
Section 7.3 Primary Efficacy Analysis – Revised to state that 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.

Section 7.3 Secondary Efficacy Analysis – Revised to state that the primary analysis of 
continuous endpoints will use the treatment policy estimand freamework, intending to assess 
the treatment effect regardless of adherence to study drug.  Revised to state that the MMRM 
model included all longitudinal data as observed for subjects in the FAS, regardless of adherence 
to study drug.  Removed information on supplementary analysis for continuous endpoints.  For 
multiplicity-controlled secondary continuous efficacy variables, removed hypothetical estimand 
from additional sensitivity analysis.

Section 7.3 Additional Efficacy Analysis – For missing data, revised statement to state that 
missing data will be imputed similarly as for the primary endpoint.  Removed reference to 
hypothetical estimand.  Replaced reference to hypothetical estimand to treatment policy 
estimand.  Specified that for binary endpoints, supplementary analysis using the treatment 
policy estimand may also be conducted on all data as observed.  Added that handling of data 
observed after rescue will be further detailed in the SAP.
Other protocol changes:

Updated Section 1, Synopsis.
Rationale:  Revised to be consistent with Protocol Version 5.0 revisions.

Section 2.1 – For Study M16-098, revised the duration from Week 14 to Week 64 for no new 
safety risks.
Rationale:  Updated background and rationale information based on more current study 
information.

Section 2.1 – Added international treatment recommendations for axial SpA.
Rationale:  Updated to provide background information on study design.

Section 5.3 – Added that for subjects enrolled in the Remission-Withdrawal Period, use of strong 
CYP3A inhibitors or inducers are not prohibited while off study drug.  Added that high potency 
opiates are not permitted during the Remission-Withdrawal Period.
Rationale:  To provide guidance on handling of concomitant medication during Remission-
Withdrawal Period.

Section 5.4 – Added guidance on background medication during the Remission-Withdrawal 
Period.
Rationale:  To provide guidance on handling of concomitant medication during Remission-
Withdrawal Period.

Section 5.5 – Added that AbbVie may terminate the study prematurely, including the Remission-
Withdrawal Period.
Rationale:  To clarify that the discontinuation criteria apply to Remission-Withdrawal Period.
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
Section 6.2 – Add that toxicity management requirements do not apply to subjects enrolled 
Remission-Withdrawal Period.
Rationale:  For subjects enrolled in the Remission-Withdrawal Period, the toxicity management 
criteria are only applicable if subjects take study drug.

Section 3.3  and Section 7.6 (Figure 5) – Switched the ranking order of ASAS20 and BASFI for 
Study 2 
Rationale:  Ranking order for ASAS20 and BASFI for Study 2 modified to align ranking with 
updated estimated statistical power based on emerging external literature data and clinical 
relevance.

Section 7.3 – Removed reference to use of rescue in the primary analysis.
Rationale:  Use of rescue does not apply to Week 14 endpoints.

Section 7.7 – Removed statement:  This sample size also provides 90% power for ASAS20, with 
assumed response rates for upadacitinib and placebo of 59% and 36%, respectively.  Removed 
change from Baseline in BASFI.
Rationale:  Ranking order for ASAS20 and BASFI for Study 2 modified to align ranking with 
updated estimated statistical power based on emerging external literature data and clinical 
relevance.

Appendix D and Appendix G – Added that study drug will be dispensed at Week 104.
Rationale:  To accommodate subjects who enter the open-label extension for applicable 
countries.

Appendix F – Added appendix to include information on the overall study design and plan for 
applicable countries in the open-label extension period.
Rationale:  To provide continued upadacitinib therapy for subjects in applicable countries to 
accommodate country-specific requests.

Appendix G – Updated hsCRP to be performed by a local clinic/hospital/laboratory at Week 104.
Rationale:  To allow hsCRP to be tested locally if subjects cannot come to the site due to COVID-
19 in order to assess remission status.

Appendix G – Added footnote that pharmacodynamic (PD) samples should only be collected if 
PD occurs after the Double-Blind Period (Week 14 for Study 1 and Week 52 for Study 2).
Rationale:  To clarify that PD samples need to be collected if the subject discontinued after the 
Double-Blind Period.
In addition to the above modifications, this Amendment contains the following minor changes:

Minor text edits as needed for consistency and clarity.

Correct minor clerical errors for consistency throughout the protocol.

Replaced Figure 4 with higher resolution figures.

Added new references throughout the protocol.
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
Appendix C – Updated list of protocol signatures.

Appendix G – Updated contact number and email address for safety concerns, and updated 
contact information for Protocol Deviations and Product Complaints
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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 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
 

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 date 
listed below 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 receive open label 
upadacitinib for the predefined time period, if Week 152 is before the date listed below for 
their respective country.  If Week 152 is after the date listed below, 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 for the following predefined time period per country:
Country
End of Study Date
Belgium
Bulgaria
China
Czechia
France
Hungary
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Japan
Korea
Mexico
New Zealand
Russia
Slovakia
Turkey
Subjects will be evaluated for safety and tolerability of upadacitinib every 12 weeks until the end of the 
study.  Subjects who remain active in this clinical trial 2 weeks prior to the end of study in each 
respective country should be contacted by the site to return for their final visit.  Sites should complete 
the final visit by the date listed above for all the remaining active subjects.
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 return to their next scheduled study visit as specified in the 
protocol.  The dates listed above are an estimation, if regulatory approval, local reimbursement, or the 
decision to discontinue pursuit of regulatory approval occurs prior to the dates listed above, subjects 
should then be brought in for their termination visit based on the actual date. The final visit should be 
conducted in place of their regularly scheduled study visit. These subjects will be considered as having 
completed the study.
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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SAP_001.pdf: 
Upadacitinib
M19-944 – Study 2 Statistical Analysis Plan
Version 4.0 – 15 September 2021
1
Statistical Analysis Plan for Study 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
Study 2:  Non-Radiographic Axial SpondyloArthritis 
(nr-axSpA)
Date:  15 September 2021
Version 4.0
 
NCT04169373


Upadacitinib
M19-944 – Study 2 Statistical Analysis Plan
Version 4.0 – 15 September 2021
2
Table of Contents
1.0
Introduction .............................................................................6
2.0
Study Design and Objectives..................................................7
2.1
Objectives and Hypotheses ........................................................................7
2.2
Study Design Overview .............................................................................8
2.3
Treatment Assignment and Blinding .........................................................8
2.4
Sample Size Determination........................................................................9
3.0
Endpoints for Study 2 ...........................................................10
3.1
Primary Endpoint.....................................................................................10
3.2
Secondary Endpoints ...............................................................................10
3.3
Other Efficacy Endpoints.........................................................................11
3.4
Safety Endpoints ......................................................................................13
3.5
Additional Measures ................................................................................13
4.0
Analysis Populations .............................................................13
5.0
Subject Disposition................................................................14
6.0
Study Drug Duration and Compliance................................15
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................16
7.1
Demographics and Baseline Characteristics............................................16
7.2
Medical History .......................................................................................19
7.3
Prior and Concomitant Medications ........................................................19
8.0
Efficacy Analyses...................................................................20
8.1
General Considerations............................................................................20
8.2
Handling of Missing Data and Intercurrent Events .................................21
8.2.1
Binary Endpoints .....................................................................................22
8.2.2
Continuous Endpoints..............................................................................24
8.2.3
Efficacy Analysis up to Week 52 in the Double-Blind Period ................25
8.2.4
Long-Term Efficacy.................................................................................26
8.3
Primary Efficacy Endpoint and Analyses ................................................26
8.3.1
Primary Efficacy Endpoint ......................................................................26
8.3.2
Handling of Missing Data and Intercurrent Events for the Primary 
Efficacy Endpoint ....................................................................................27
 


Upadacitinib
M19-944 – Study 2 Statistical Analysis Plan
Version 4.0 – 15 September 2021
3
8.3.3
Primary Efficacy Analysis .......................................................................28
8.3.4
Sensitivity Analyses, Supplementary Analyses, and Additional 
Analyses of the Primary Efficacy Endpoint.............................................28
8.4
Secondary Efficacy Analyses...................................................................29
8.4.1
Primary Analyses and Sensitivity Analyses of Secondary Efficacy 
Endpoints .................................................................................................29
8.4.2
Supplementary Analyses of Secondary Binary Efficacy Endpoints........31
8.5
Additional Efficacy Analyses ..................................................................31
8.6
Efficacy Subgroup Analyses....................................................................38
9.0
Safety Analyses ......................................................................39
9.1
General Considerations............................................................................39
9.2
Adverse Events ........................................................................................42
9.2.1
Analysis of Adverse Events up to Week 14.............................................43
9.2.1.1
Adverse Event Overview .........................................................................43
9.2.1.2
Treatment-Emergent Adverse Events by SOC and PT............................44
9.2.1.3
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................45
9.2.1.4
Adverse Events of Special Interest ..........................................................45
9.2.2
Analysis of Adverse Events up to Week 52.............................................48
9.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................48
9.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................48
9.2.2.3
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation per 100 Patient-Years of Study Drug 
Exposure ..................................................................................................48
9.2.2.4
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................49
9.2.3
Analysis of Long-Term Adverse Events..................................................49
9.2.3.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................49
9.2.3.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................50
 


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9.2.3.3
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation per 100 Patient-Years of Study Drug 
Exposure ..................................................................................................50
9.2.3.4
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................50
9.3
Analysis of Laboratory Data....................................................................50
9.3.1
Variables and Units..................................................................................51
9.3.2
Analysis of Laboratory Data up to Week 14 ...........................................53
9.3.2.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables................................................................................53
9.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................54
9.3.2.3
Assessment of Potentially Clinically Significant Laboratory 
Values ......................................................................................................54
9.3.2.4
Assessment of Liver Elevations...............................................................54
9.3.3
Analysis of Laboratory Data up to Week 52 ...........................................55
9.3.4
Analysis of Long-Term Laboratory Data.................................................56
9.3.4.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables................................................................................56
9.3.4.2
Assessment of Potentially Clinically Significant Laboratory 
Values ......................................................................................................56
9.3.4.3
Assessment of Liver Elevations...............................................................57
9.4
Analysis of Vital Signs ............................................................................57
9.4.1
Analysis of Vital Sign up to Week 14 .....................................................57
9.4.2
Analysis of Vital Sign up to Week 52 .....................................................57
9.4.3
Analysis of Long-Term Vital Sign...........................................................58
10.0
Other Analyses.......................................................................58
11.0
Interim Analyses....................................................................58
11.1
Data Monitoring Committee....................................................................58
12.0
Overall Type-I Error Control ..............................................59
13.0
Version History......................................................................61
14.0
References...............................................................................61
 


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List of Tables
Table 1.
ASAS and/or ASDAS Components at Baseline ......................................17
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint...................................................................................................27
Table 3.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints .................................................................................................30
Table 4.
Summary of Analysis for Binary Variables up to Week 14 ....................35
Table 5.
Summary of Analysis for Continuous Variables up to Week 14.............36
Table 6.
Summary of Analysis up to Week 52 ......................................................37
Table 7.
Summary of Long-Term Analysis up to Week 104.................................38
Table 8.
Subgroups for Efficacy Analysis .............................................................39
Table 9.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................46
Table 10.
List of Safety Laboratory Variables.........................................................52
Table 11.
SAP Version History Summary...............................................................61
Table 12.
Criteria for Potentially Clinically Significant Vital Sign Values.............66
List of Figures
Figure 1.
Study Schematic.........................................................................................8
Figure 2.
Sequential Multiple Testing Procedure....................................................60
List of Appendices
Appendix A.
Protocol Deviations..................................................................................64
Appendix B.
EAER and Normal Approximation Based 95% Confidence 
Interval .....................................................................................................65
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............66
Appendix D.
ASAS-NSAID Intake Score for Axial Spondyloarthritis ........................67
Appendix E.
NRI-MI Procedure ...................................................................................70
Appendix F.
Tipping Point Analysis ............................................................................74
 


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1.0
Introduction
The Statistical Analysis Plans (SAPs) describe the statistical analyses for the upadacitinib 
Study M19-944 entitled "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."
Study Protocol M19-944 is a global, multicenter, protocol ("master protocol") with a 
common screening platform for determining subject eligibility into 2 separate studies:  
Study 1 examines the efficacy and safety of upadacitinib in ankylosing spondylitis (AS) 
subjects who had an inadequate response to biologic disease-modifying antirheumatic 
drug therapy (bDMARD-IR).  Study 2 examines the efficacy and safety of upadacitinib in 
non-radiographic axial spondyloarthritis (nr-axSpA) subjects.
This SAP is for Study 2 (nr-axSpA).  The SAP for Study 1 (AS, bDMARD-IR) is 
described in a separate document. The SAP for the Remission-Withdrawal Period will be 
described in a separate document.
Although the M19-944 protocol includes a common screening process and other common 
operational elements 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 multiplicity-controlled 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.
The analyses of pharmacokinetics and biomarkers will not be covered in this SAP.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analyses described in this SAP.  If future protocol 
 


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amendment impacts statistical analyses, this SAP will be amended accordingly.  Details of 
SAP versions are outlined in Section 13.0.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
Objectives
Double-Blind Period (52 weeks):
●
To evaluate the efficacy of upadacitinib compared with placebo on reduction of 
signs and symptoms in adult subjects with active nr-axSpA;
●
To assess the safety and tolerability of upadacitinib in adult subjects with active 
nr-axSpA.
Open-Label Extension Period (52 weeks):
●
To evaluate the long-term safety and tolerability of upadacitinib in extended 
treatment in adult subjects with nr-axSpA who have completed the 
Double-Blind Period.
Hypotheses
●
For the primary efficacy endpoint, the null hypothesis is that upadacitinib 
15 mg is not different from placebo with respect to achieving ASAS40 at Week 
14.  The alternative hypothesis is that upadacitinib 15 mg has a higher response 
rate than placebo with respect to achieving ASAS40 at Week 14. 
●
For the secondary endpoints, the null hypotheses are that upadacitinib 15 mg is 
not different from placebo with respect to the secondary endpoints.  The 
alternative hypotheses are that upadacitinib 15 mg is better than placebo with 
respect to the secondary endpoints.
 




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biological DMARDs (bDMARDs, yes versus no).  At least 20%, but not exceeding 35% 
of subjects with prior exposure to a bDMARD will be enrolled.  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 52 in 
the Open-Label Extension Period.
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 Week 14 primary analysis, while the Investigator, study site 
personnel, and the subject will remain blinded to each subject's treatment until all subjects 
have completed the Week 52 visit or have prematurely discontinued prior to Week 52.  
Sites and subjects will remain blinded to the Double-Blind Period treatment assignments 
for the duration of the 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.
2.4
Sample Size Determination
The planned total sample size of 304 for Study 2 (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.1-7  
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 SI joints, BASDAI 50 response, ASDAS Inactive 
Disease, change from Baseline in Total Back Pain, change from Baseline in Nocturnal 
Back Pain, ASDAS Low Disease Activity, ASAS PR, and Week 52 ASAS40 response 
(multiplicity-controlled for EU/EMA regulatory purpose only).1-7
 


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3.0
Endpoints for Study 2
3.1
Primary Endpoint
The primary endpoint is ASAS40 response at Week 14.
3.2
Secondary Endpoints
The multiplicity-controlled secondary endpoints at Week 14 (unless otherwise noted) are:
1.
Change from Baseline in Ankylosing Spondylitis Disease Activity Score 
(ASDAS(CRP));
2.
Change from Baseline in magnetic resonance imaging (MRI) Spondyloarthritis 
Research Consortium of Canada (SPARCC) score (SI joints);
3.
Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 response 
(defined as at least 50% improvement in the BASDAI);
4.
ASDAS(CRP) Inactive Disease (ASDAS score < 1.3);
5.
Change from Baseline in Patient's Assessment of Total Back Pain NRS score 0 –
10;
6.
Change from Baseline in Patient's Assessment of Nocturnal Back Pain NRS 
score 0 – 10;
7.
ASDAS(CRP) Low Disease Activity (ASDAS score < 2.1);
8.
ASAS partial remission (PR) (an absolute score of ≤2 units for each of the 4 
domains identified in ASAS40);
9.
Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI);
10.
Change from Baseline in Ankylosing Spondylitis Quality of Life (ASQoL);
11.
Change from Baseline in ASAS Health Index (HI);
12.
ASAS20 response;
 


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13.
Change from Baseline in Linear Bath Ankylosing Spondylitis Metrology Index 
(BASMIlin).
14.
Change from Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score 
(MASES) for subjects with baseline enthesitis (MASES > 0);
15.
ASAS40 response at Week 52 (for EU/EMA regulatory purposes).
For US/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);
●
ASDAS Inactive Disease (ASDAS score < 1.3) at Week 52 (for EU/EMA 
regulatory purposes);
●
ASDAS Low Disease Activity (ASDAS score < 2.1) at Week 52 (for EU/EMA 
regulatory purposes).
3.3
Other Efficacy Endpoints
The primary and secondary efficacy endpoints are listed in Section 3.1 and Section 3.2, 
respectively.  Additional endpoints include 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;
 


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●
Inactive Disease based on ASDAS(CRP) and ASDAS(ESR), respectively 
(ASDAS score < 1.3)
●
Low Disease Activity based on ASDAS(CRP) and ASDAS(ESR), respectively 
(ASDAS score < 2.1);
●
Major Improvement based on ASDAS(CRP) and ASDAS(ESR), respectively (a 
change from Baseline of ≤ –2.0);
●
Clinically Important Improvement based on ASDAS(CRP) and ASDAS(ESR), 
respectively (a change from Baseline of ≤ –1.1);
●
Discontinuation of opioids among subjects with opioid use at Baseline.
Change from Baseline in:
●
ASAS HI; 
●
ASDAS(CRP) and ASDAS(ESR) respectively;
●
ASQoL;
●
BASDAI and BASDAI components including mean of question 5 and 6 of the 
BASDAI (Score 0 – 10);
●
BASFI (Score 0 – 10);
●
BASMIlin;
●
High sensitivity C-reactive protein (hsCRP);
●
EuroQoL-5D-5L (EQ-5D-5L);
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);
●
MASES for subjects with baseline enthesitis (MASES > 0);
●
Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with 
conventional radiograph;
●
MRI SPARCC score of SI joints;
●
MRI SPARCC score of spines;
●
Patient's Assessment of Total Back Pain NRS score 0 - 10;
●
Patient's Assessment of Nocturnal Back Pain NRS score 0 - 10;
●
Patient's Global Assessment of Pain NRS score 0 - 10;
●
Physician's Global Assessment of Disease Activity (PGA) NRS score 0 - 10;
 


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●
Patient's Global Assessment of Disease Activity (PtGA) NRS score 0 - 10;
●
36-Item Short Form Health Survey (all subdomain and summary scores);
●
Tender joint count (TJC68) and swollen joint count (SJC66); 
●
Work Productivity and Activity Impairment (WPAI, 4 dimensions:  
Absenteeism, Presenteeism, Percent overall work impairment due to SpA, 
Percent activity impairment due to SpA);
●
NSAID intake score (the derivation is detailed in Appendix D).
3.4
Safety Endpoints
The following safety evaluations will be performed:  adverse events (AEs), serious 
adverse events (SAEs), AE of special interest (AESI), AEs leading to discontinuation, 
vital signs, laboratory tests, and physical examination findings.
3.5
Additional Measures
Patient Experience Data (PED) assessing patient preferences for treatment route of 
administration will be collected at each subject's Baseline visit only.
4.0
Analysis Populations
The following analysis populations will be used for the analyses.
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 
final criteria and the exclusion of subjects from the Per Protocol Analysis Set will be 
finalized before unblinding for the Primary Analysis.
 


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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.
5.0
Subject Disposition
The total number of subjects who were enrolled (randomized) and treated will be 
summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for overall and each treatment group:
●
Subjects enrolled (randomized) in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects who completed study participation;
●
Subjects who prematurely discontinued study participation (all reasons and 
primary reason); 
●
Subjects in each analysis population, as defined in Section 4.0.
Types of impacted visits related to COVID-19 will be collected for the protocol pre-
specified visits.  For each visit, the number and percentage of subjects impacted by 
COVID-19 will be summarized by the types of visit for each randomized treatment group 
as well as overall:
●
In person, partial assessments done
●
Virtual visit
●
Missed visit
 


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6.0
Study Drug Duration and Compliance
The duration of exposure to study drug will be summarized for the Safety Analysis Set by 
the treatment groups (placebo group vs upadacitinib 15 mg QD) up to Week 14 and up to 
Week 52 separately in Double-Blind Period.  For long term, the duration of exposure to 
study drug will be summarized for the Safety Analysis Set only for the Any upadacitinib 
15 mg QD group, which includes upadacitinib 15 mg QD exposure from subjects starting 
on upadacitinib 15 mg QD and subjects switching from placebo to upadacitinib 15 mg 
QD.
Exposure to upadacitinib and placebo is defined as last dose date minus first dose date 
plus 1 day.
The duration of exposure to study drug will be summarized for each group as specified 
above, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values.  In addition, the number and percentage of subjects exposed to study 
drug will be summarized for the following cumulative duration intervals:
●
≥ 2 weeks
●
≥ 1 month
●
≥ 3 months
●
≥ 6 months
●
≥ 9 months
●
≥ 12 months
●
≥ 18 months
●
≥ 2 years
Study drug compliance will be summarized for each treatment group for up to Week 14 
and up to Week 52 separately in Double-Blind Period.  The compliance is defined as the 
number of tablets taken (i.e., the difference between the number of tablets dispensed and 
the number of tablets returned) during the subject's participation divided by the number of 
tablets that should have been taken.  Percent compliance will be summarized.
 


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS overall and by treatment group.  
Categorical variables will be summarized with the number and percentage of subjects.  
Continuous variables will be summarized with descriptive statistics (number of non-
missing observations, mean and standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics information will be collected at the Baseline 
visit of the study and will be summarized for the FAS.  
Main Demographic and Baseline Characteristics
●
Sex (male, female)
●
Age (years)
●
Age Categories (< 40, ≥ 40 and < 65, ≥ 65 years)
●
Race (White, Non-White:  Black or African American, American Indian or 
Alaska Native, Native Hawaiian or Other Pacific Islander, Asian, Other)
●
Geographic Region (North America, South/Central America, Western Europe, 
Eastern Europe, Asia, Other)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
●
Weight (kg)
●
Weight Categories (<60, ≥ 60 and <80 kg, ≥ 80 kg)
●
Height (cm)
●
Body Mass Index (BMI) (kg/m2)
●
Body Mass Index (BMI) Category (kg/m2) (BMI < 25, BMI ≥ 25)
nr-axSpA Medical History and Characteristics at Baseline
●
Duration (years) of nr-axSpA symptoms
 


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●
Duration (years) since nr-axSpA diagnosis
●
Duration since nr-axSpA diagnosis categories (< 5 years, ≥ 5 - 10 years, 
≥10 years)
●
Duration of nr-axSpA symptoms categories (< 5 years, ≥ 5 - 10 years, ≥ 10 
years)
●
HLA-B27 (positive, negative)
●
Number of different NSAIDs discontinued prior to baseline
●
Number of different baselines NSAIDs (started prior to baseline and ongoing at 
baseline)
●
Oral Corticosteroids use at baseline
●
csDMARDs use at baseline
●
Opioid use at baseline
●
NSAID score at baseline
Table 1.
ASAS and/or ASDAS Components at Baseline
ASAS only 
components

Patient's assessment of total back pain (NRS score 0 - 10)

Function – Represented by the BASFI (NRS score 0 - 10)

Inflammation – (mean of items 5 and 6 of the BASDAI NRS score 0 – 10) 
ASDAS only 
components

Patient's assessment of back pain (BASDAI Question 2 NRS score 0 – 10)

Peripheral pain/swelling (BASDAI Question 3 NRS score 0 – 10)

High sensitivity C-reactive protein (hs-CRP) in mg/L

Erythrocyte sedimentation rate (ESR) (mm/hr)

Duration of morning stiffness (BASDAI Question 6 NRS score 0 – 10)
Components for 
both ASAS and 
ASDAS

Patient global assessment of disease activity (NRS score 0 – 10)
Other Baseline nr-axSpA Disease Characteristics
●
ASDAS (CRP) 
●
ASDAS(CRP) categories (ASDAS(CRP) > 3.5 vs ≤ 3.5)
●
Physician's Global Assessment of Disease Activity (NRS score 0 - 10)
●
MRI SPARCC score (Spine)
 


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●
MRI SPARCC score (SI joints)
●
BASMIlin
●
MASES for subjects with baseline enthesitis (MASES > 0)
●
Presence of enthesitis (MASES > 0)
●
Tender Joint Count (TJC68)
●
Swollen Joint Count (SJC66)
●
mSASSS
●
High Sensitivity C-reactive Protein (hsCRP) (mg/L) at Screening
●
Screening hsCRP levels (> ULN vs  ≤ULN, > 5mg/L vs ≤5mg/L)
●
MRI (SI joints) inflammation at screening (positive vs negative)
●
MRI+/hsCRP > ULN, MRI+/hsCRP ≤ ULN, and MRI-/hsCRP > ULN at 
screening
●
Prior failed bDMARDs (yes or no)
Patient Reported Outcomes and Measures at Baseline
●
BASDAI (Score 0-10)
●
FACIT-F
●
WPAI (all dimensions)
●
AS QoL
●
ASAS HI 
●
Patient's Assessment of Nocturnal Back Pain (NRS score 0 - 10)
●
Patient's Global Assessment of Pain (NRS score 0 - 10)
●
EuroQoL-5D-5L (EQ-5D-5L)
●
SF-36 (all subdomain and summary scores)
●
Patient Experience Data (PED)
Clinical Tests at Screening
●
Chest x-ray
●
12-Lead ECG
 


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●
AP Pelvis X-Ray
●
Tuberculosis test result (PPD positive or QuantiFERON positive)
Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [current, former, never, unknown]
●
Alcohol Use [current, former, never, unknown]
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one PT within a SOC will be 
counted only once for that SOC.  No statistical comparison will be performed for medical 
history reporting.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for FAS.  Prior medications are those medications taken prior to 
the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  
Medications taken on the day of the first dose of study drug are not counted as prior 
 


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medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug.  
This includes medications with a start date between first study drug administration and 
last study drug administration + 1 day, as well as medications with a start date prior to 
first dose of study drug and which are ongoing after first dose of study drug.  Medications 
taken on the day of the first dose of study drug are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted in the FAS.  In addition, Per-protocol analysis for 
primary endpoint will be performed.  All tests will be 2-sided at an α level of 0.05.  
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.
There are three sets of planned efficacy analysis:  efficacy analysis up to Week 14 in the 
Double-Blind Period, efficacy analysis up to Week 52 in the Double-Blind Period, and 
long-term efficacy analysis up to Week 104.
The primary analysis will be performed after all subjects have completed the Week 14 
visit or have discontinued the study prior to Week 14 and the database has been locked.  
This will be the only and final analysis for the primary and secondary efficacy endpoints 
at Week 14 as well as all other efficacy endpoints up to Week 14 in the Double-Blind 
Period.  Analyses will be performed for the protocol defined primary time point by 
randomized treatment groups (upadacitinib 15 mg QD and the placebo group).  Formal 
statistical inference will be generated, and results from this set of analyses will be used as 
 


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the key efficacy findings of this study.  Secondary endpoints specified at Week 52 in 
Section 3.2 will be analyzed after the Week 52 database lock.
Efficacy analysis at Week 52 in the Double-Blind Period will be performed after all 
subjects have completed the Week 52 visit or have prematurely discontinued prior to 
Week 52.  Analyses will be performed by randomized treatment group (upadacitinib 
15 mg QD and the placebo group). 
No protocol-defined treatment switching will occur in the Double-Blind Period.
Unless otherwise specified, binary variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, stratified by MRI and screening hsCRP level status (MRI+/hsCRP 
> ULN, MRI+/hsCRP ≤ ULN, and MRI–/hsCRP > ULN).  Continuous variables will be 
analyzed using Mixed-Effect Model Repeat Measurement (MMRM) method or analysis 
of covariance (ANCOVA) method adjusting for MRI and screening hsCRP level status. 
Unless otherwise specified, any subject who is randomized based on a wrong stratum will 
be analyzed according to the actual stratum the subject belongs to.
Long-term analysis at Week 104 will be performed after all subjects have completed the 
Week 104 visit or have prematurely discontinued prior to Week 104. This will be the 
final efficacy analysis for Study 2.  There will be no statistical testing for long-term 
efficacy analysis up to Week 104; descriptive statistics will be provided by randomized 
treatment group sequences as described below:
1.
Placebo →Upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →Upadacitinib 15 mg QD.
8.2
Handling of Missing Data and Intercurrent Events
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistical 
restriction.
 


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The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impact on treatment duration and the collection, analysis, and interpretation of 
clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
The intent is to provide reliable estimates of the treatment effects targeted in the protocol 
under the scenario without the impact of COVID-19 pandemic.  Sensitivity analyses will 
be performed to assess the impact of missing data and the robustness of the conclusion.  
Number of subjects with missing values due to COVID-19 will be presented.
Intercurrent events include discontinuation of study drug and initiation of rescue 
medication.  Missing data and intercurrent events will be handled using the following 
methods for the efficacy analysis.
8.2.1
Binary Endpoints 
The primary estimand for binary endpoints is the composite estimand,8 defined in 
Section 8.3.1.  NRI-MI and NRI analysis will be used for the primary estimand.
Non-Responder Imputation in conjunction with Multiple Imputation (NRI-MI)
For binary endpoints, NRI-MI will be used as the primary approach for handling missing 
data and intercurrent events for the primary estimand (refer to Section 8.3.1).  It will 
handle intercurrent events and missing data as follows.
 


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a.
Subjects who prematurely discontinue study drug or use rescue therapy will be 
categorized as non-responders for visits after study drug discontinuation or 
rescue initiation.
b. Missing data due to COVID-19 infection or logistical restriction will be 
handled by Multiple Imputation.
c.
Additional missing data due to other reasons will be categorized as non-
responders. 
For composite binary endpoints such as ASAS40, ASAS20 and ASAS PR, missing values 
in the continuous component variables will be imputed via MI, and the composite binary 
endpoints will be derived from the multiple imputed continuous component variables, as 
outlined in Appendix E.  For other binary endpoints which are directly dichotomized from 
a continuous score, missing values in the continuous score will be imputed via MI, and 
the dichotomized binary endpoint will be derived from the multiple imputed continuous 
score.  
Non-Responder Imputation (NRI) Approach
NRI will be used as a sensitivity analysis for binary endpoints for the primary estimand 
(refer to Section 8.3.1).  It will handle intercurrent events and missing data as follows.
a.
Subjects who prematurely discontinue study drug or use rescue therapy will be 
categorized as non-responders for visits after study drug discontinuation or 
rescue initiation.
b. Additional missing data including those due to COVID-19 infection or 
logistical restriction will also be categorized as non-responders.
The treatment policy estimand will be used as a supplementary analysis (refer to 
Section 8.3.4), facilitated by the As Observed (AO) data handling, where all observed data 
will be used, regardless of premature discontinuation of study drug or use of rescue 
therapy.  Missing data will be categorized as non-responders.  Sensitivity analyses for 
 


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missing data handling using MI (refer to the MI steps under Appendix E) and tipping 
point (refer to Appendix F) may also be conducted.
8.2.2
Continuous Endpoints 
The primary estimand for continuous endpoints is the treatment policy estimand8 (refer to 
Section 8.4.2), where all observed data will be used, regardless of premature 
discontinuation of study drug. Handling of data observed after rescue will be further 
described in Section 8.2.3.  Mixed-Effect Model Repeat Measurement (MMRM) will be 
used as the primary approach for handling missing data, and Multiple Imputation (MI) 
will be used as a sensitivity analysis.
Mixed-Effect Model Repeat Measurement (MMRM)
MMRM will be utilized for the treatment policy estimand for all continuous endpoints.  
The repeated measure analysis will be conducted using mixed model.  The mixed model 
includes the categorical fixed effects of treatment, visit and treatment-by-visit interaction, 
main stratification factor of MRI and screening hsCRP level status (MRI+/hsCRP > ULN, 
MRI+/hsCRP ≤ ULN, and MRI-/hsCRP > ULN) and the continuous fixed covariates of 
baseline measurement.  An unstructured variance covariance matrix will be used.  The 
parameter estimations are based on the assumption of data being missing at random 
(MAR) and using the method of restricted maximum likelihood (REML).  The MMRM 
approach is appropriate in handling missing data due to COVID-19 infection or logistical 
restriction given the validity of the missing at random assumption.
Multiple Imputation (MI)
As a sensitivity analysis, MI will be utilized to handle missing data for the treatment 
policy estimand for multiplicity controlled secondary continuous endpoints.  The MI 
analysis will impute missing data multiple times under appropriate random variation and 
thus generate multiple imputed "pseudo-complete" datasets.  SAS PROC MI will be used 
to generate 30 datasets using a two-step approach, augmentation step using MCMC and 
imputation step using Monotone Regression, as described in Appendix E.  Specifically, 
 


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treatment group is included in the MI model to enable stratified sampling.  Additionally, 
the imputation model includes demographics variables and baseline disease 
characteristics, as well as longitudinal response observed at any other visits.  An 
ANCOVA model will firstly be performed on each of the multiple imputed datasets 
adjusting for treatment, stratification factor and baseline value.  Subsequently SAS PROC 
MIANALYZE will then be used to aggregate the results for the final statistical inference 
using Rubin's method.  To assess the impact of potential departures from the MAR 
assumption, tipping point analyses (refer to Appendix F) will also be conducted to as a 
sensitivity check for multiplicity-controlled secondary continuous endpoints. 
8.2.3
Efficacy Analysis up to Week 52 in the Double-Blind Period
For analysis of binary endpoints up to Week 52, NRI-MI and NRI will continue to be 
used for the primary estimand (composite estimand). The treatment policy estimand will 
continue to be used as a supplementary analysis, facilitated by the AO data handling,
where all observed data will be used, regardless of premature discontinuation of study 
drug or use of rescue therapy. Missing data will be handled by GLMM as described in 
Section 8.2.4. An additional analysis corresponding to the treatment policy estimand will 
be conducted for secondary endpoints at Week 52, where missing data will be categorized 
as non-responders.  
For analysis of continuous endpoints up to Week 52, MMRM will continue to be used as 
the primary approach for handling missing data. All longitudinal data observed regardless 
of premature discontinuation of study drug will be included in the model. For the primary 
analysis, data after use of rescue will be excluded to examine the treatment effect without 
the impact of rescue medication confounding. In addition, analysis including all data as 
observed, regardless of premature discontinuation of study drug or use of rescue, will be 
conducted as a supplementary analysis. 
For key secondary continuous endpoints between Week 24 and Week 52, additional 
supplementary analysis using the composite strategy will be conducted, where last 
observations are carried forward (LOCF) for visits after premature discontinuation of 
 


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study drug or rescue initiation, assuming the subject is a treatment failure at the time of 
premature discontinuation or rescue initiation, and additional missing data including those 
due to COVID-19 will be handled by multiple imputation.
8.2.4
Long-Term Efficacy
For long-term efficacy analysis for binary endpoints, NRI-MI and NRI will continue to be 
used for the primary estimand (composite estimand). In addition, the AO data handling 
will be used to facilitate the supplementary analysis using the treatment policy estimand; 
regardless of premature discontinuation of study drug or use of rescue therapy, all 
observed data will be used in the analysis and missing data will be handled by GLMM as 
described below.
For continuous endpoints, the treatment policy estimand will continue to be used, 
facilitated by AO data handling. Missing data will be handled by MMRM as described 
below.
MMRM and Generalized Linear Mixed Model (GLMM) for Long-Term Efficacy
The repeated measures analysis will be conducted using mixed model.  MMRM will be 
used for continuous endpoints and GLMM will be used for binary endpoints.  The mixed 
models will include the categorical fixed effects of treatment sequence, visit and treatment 
sequence -by-visit interaction, and main stratification factor MRI and screening hsCRP 
level status (MRI+/hsCRP > ULN, MRI+/hsCRP ≤ ULN, and MRI-/hsCRP > ULN).  For 
the MMRM analysis of change from baseline in continuous endpoints, the baseline 
measurement will be included as a continuous fixed covariate.  Other baseline covariates 
may also be included in the model as appropriate.  Unstructured, Toeplitz, compound 
symmetry, or other covariance structures may be considered.
8.3
Primary Efficacy Endpoint and Analyses
8.3.1
Primary Efficacy Endpoint
The primary endpoint is ASAS40 response at Week 14.
 


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In the composite estimand framework, the primary estimand is the difference in the 
proportion of nr-axSpA patients who achieved an ASAS40 response at Week 14 and did 
not discontinue study drug by Week 14, comparing those who are randomized to the 
upadacitinib 15 mg QD group and received study drug to those who are randomized to 
placebo and received study drug.  The attributes of the primary estimand corresponding to 
the primary efficacy endpoint are summarized in Table 2.
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Intercurrent Events 
(IE)
Statistical 
Summary
Primary:  
Composite 
Estimand
Upadacitinib 
15 mg QD 
vs. placebo
Achievement of 
ASAS40 at Week 
14, remain in the 
study and on 
study drug 
through 14 weeks.
Full 
Analysis Set 
IE: premature 
discontinuation of 
study drug.
Subjects will be 
considered as non-
responders at visits 
after IE. 
Difference in 
the proportion 
of subjects 
achieving the 
endpoint
8.3.2
Handling of Missing Data and Intercurrent Events for the 
Primary Efficacy Endpoint
For the primary estimand, NRI-MI data handling as defined in Section 8.2.1 will be used. 
Subjects who prematurely discontinue study drug prior Week 14 will be categorized as 
non-responders for visits after study drug discontinuation.  Missing data due to COVID-
19 infection or logistic restriction will be handled by MI. Additional missing ASAS40 
response due to other reasons will be categorized as non-responders. To facilitate the 
interpretation of the estimand, ASAS40 response will be summarized into the following 
categories for each randomized treatment group:
1.
Subjects who prematurely discontinue study drug by Week 14;
 


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2.
Subjects who did not discontinue study drug but are missing Week 14 ASAS40 
measurements due to COVID-19 infection or logistical restriction;
3.
Subjects who did not discontinue study drug but are missing Week 14 ASAS40 
measurements due to other reasons;
4.
Subjects with ASAS40 measurements observed and on study drug at Week 14.
8.3.3
Primary Efficacy Analysis
Analysis of the primary endpoint will be conducted on the FAS based on randomized 
treatment groups (upadacitinib 15 mg QD and the placebo group).  The treatment 
comparison will be constructed using the Cochran-Mantel-Haenszel (CMH) model 
adjusted by main stratification factors MRI and screening hsCRP status (MRI+/hsCRP > 
ULN, MRI+/hsCRP ≤ ULN, and MRI–/hsCRP > ULN).  The analysis will be conducted 
on each of the 30 datasets generated by NRI-MI.  Results will be integrated by SAS 
PROC MIANALYZE using Rubin's rule.  The following statistics will be provided: 
response rate for each randomized treatment group and associated 95% CIs; response rate 
difference between upadacitinib group and placebo group, associated 95% CI, and 
p-value.
8.3.4
Sensitivity Analyses, Supplementary Analyses, and 
Additional Analyses of the Primary Efficacy Endpoint
To assess the robustness of the primary analysis using NRI-MI data handling, a sensitivity 
analysis for the primary estimand will be performed using NRI data handling as defined in 
Section 8.2.1.  The same CMH analysis as described for the primary analysis will be 
applied.  The following statistics will be provided: response rate for each randomized 
treatment group and associated 95% CIs; response rate difference between upadacitinib 
group and placebo group, associated 95% CI, and p-value.
As a supplementary analysis for the primary efficacy endpoint under the treatment policy 
estimand, the same CMH method will be repeated using As Observed (AO) data, 
 


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regardless of adherence to study drug, Subjects with missing ASAS40 response will be 
categorized as non-responders.  This will be conducted on the FAS based on randomized 
treatment groups.  The corresponding treatment policy estimand for the supplementary 
analysis is the difference in the proportion of nr-axSpA patients who achieved ASAS40 
response at Week 14, regardless of whether the subject had discontinued study drug by 
Week 14, comparing upadacitinib 15 mg QD vs placebo for those who are randomized, 
and received study drug.
For the treatment policy estimand, additional sensitivity analyses using AO data will also 
be conducted using MI to handle missing ASAS40 responses (as outlined in Section 8.2.1
and details in Appendix E).  In order to assess the deviation from missing at random 
(MAR) assumptions, tipping point analysis will also be conducted for the primary 
endpoint.  Details of the analysis are outlined in Appendix F.
Supportive analyses will also be conducted on the Per Protocol Analysis Set using the 
same CMH model and NRI-MI data handling as the primary analysis.
8.4
Secondary Efficacy Analyses
8.4.1
Primary Analyses and Sensitivity Analyses of Secondary 
Efficacy Endpoints
The secondary endpoints are defined in Section 3.2.  The attributes of the estimands 
corresponding to the secondary efficacy endpoints are summarized in Table 3.
 


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Table 3.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling 
Intercurrent 
Events (IE)
Statistical 
Summary
Binary 
Secondary:  
Composite 
Estimand  
Upadacitinib 
15 mg QD vs. 
placebo
Remain in the 
study and on 
study drug 
through 
protocol 
defined 
timepoint; 
achievement of 
each secondary 
endpoint 
respectively
Full Analysis 
Set
IE: premature 
discontinuation of 
study drug; use of 
rescue therapy.
Subjects will be 
considered as non-
responders at 
visits after IE.
Difference in 
proportion of 
subjects 
achieving each 
binary 
secondary 
endpoint
Continuous 
Secondary:  
Treatment 
Policy 
Estimand
Upadacitinib 
15 mg QD vs. 
placebo
Change from 
Baseline in each 
respective 
secondary 
endpoint
Full Analysis 
Set
IE: premature 
discontinuation of 
study drug.
All observed data 
will be used 
regardless of IE.
Difference in 
the mean 
change from 
Baseline in 
each 
continuous 
secondary 
endpoint
For binary endpoints, the primary estimand and analysis method are the same as that for 
the primary efficacy endpoint as defined in Section 8.3.1, except for the definition of the 
efficacy measurement.  NRI-MI and NRI data handling will be used to analyze the 
primary estimand. For the endpoint "initiation of rescue between Week 24 and Week 52" 
descriptive summaries will be provided based on AO data.
For secondary continuous efficacy endpoints, the primary analyses will be performed 
using all data as observed, regardless of adherence to study drug, using the treatment 
policy estimand framework.  The corresponding estimand is the difference in the mean 
change from baseline in the efficacy endpoints regardless of premature discontinuation of 
study drug.  The statistical inference will be conducted using the MMRM model and the 
associated data handling as described in Section 8.2.2, with the main stratification factor 
 


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of MRI and screening hsCRP status (MRI+/hsCRP > ULN, MRI+/hsCRP ≤ ULN, and 
MRI–/hsCRP > ULN).  For the analysis of change from baseline in MRI SPARCC SI 
joint score at Week 14, the ANCOVA model will also include the interaction between 
treatment group and the stratification factor of MRI and screening hsCRP status, to 
account for the potential differences between the MRI+ and MRI- strata. The LS mean 
and 95% CI will be reported for each randomized treatment group; the LS mean treatment 
difference and associated 95% CI and p-value will be reported comparing upadacitinib 
with the placebo group. For this estimand, additional sensitivity analyses will be 
conducted using MI under MAR assumption as outlined in Section 8.2.2 for multiplicity-
controlled secondary continuous endpoints. To assess deviations from MAR, the tipping 
point analyses will also be conducted as additional sensitivity analyses.  Details of the MI 
and tipping point analysis are outlined in Appendix E and Appendix F.
8.4.2
Supplementary Analyses of Secondary Binary Efficacy 
Endpoints
For binary endpoints at Week 14, similar analyses as the supplementary analyses for the 
primary endpoint will be conducted using CMH including all data as observed, regardless 
of adherence to study drug, with subjects missing response treated as non-responders.  
The corresponding supplementary estimand is the same as defined in Section 8.3.4 except 
for the definition of the efficacy measurement.
For multiplicity-controlled secondary binary variables at Week 14, additional sensitivity 
analyses for the treatment policy estimand will be conducted using MI as outlined in 
Section 8.2 under MAR assumption.  To assess deviations from MAR, the tipping point 
analyses will also be conducted as additional sensitivity analyses.  Details of the MI and 
tipping point analysis are outlined in Appendix E and Appendix F.
8.5
Additional Efficacy Analyses
Additional endpoints defined in Section 3.3 will be analyzed at scheduled time points 
other than those specified for the primary and secondary variables.
 


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Additional Efficacy Analyses up to Week 14 in the Double-Blind Period
Additional endpoints will be analyzed for each randomized treatment group for all visits 
up to Week 14 in the Double-Blind Period using similar statistical methods as for the 
primary estimand for the primary and secondary endpoints.
For binary endpoints, the following statistics will be provided: response rate for each 
randomized treatment group and associated 95% CIs; response rate difference between 
upadacitinib group and placebo group and associated 95% CIs.  Only nominal p-values 
will be provided.  The primary estimand and analysis method are the same as that for the 
primary efficacy endpoint as defined in Section 8.3, except for the definition of the 
efficacy measurement.  NRI-MI and NRI data handling as described in Section 8.2.1 will 
be used.
For continuous endpoints, the LS mean and 95% CI will be reported for each randomized 
treatment group.  The LS mean treatment difference and associated 95% CI and p-values 
between upadacitinib and the placebo group will be provided using MMRM model with 
fixed effects of treatment, visit and treatment-by-visit interaction, main stratification 
factor of MRI and screening hsCRP status (MRI+/hsCRP > ULN, MRI+/hsCRP ≤ ULN, 
and MRI–/hsCRP > ULN) and baseline value as covariate.  Only nominal p-values will be 
provided.  
For the ASAS components (the 4 components are Patient's Global Assessment of Disease 
Activity NRS score; Patient's Assessment of Total Back Pain NRS score; BASFI; 
Inflammation (mean of items 5 and 6 of BASDAI NRS scores 0 - 10)), the mean and 
standard deviation at baseline and Week 14 will be provided based on AO data.  
Additional Efficacy Analyses up to Week 52 in the Double-Blind Period 
Placebo-controlled analyses will be conducted for all visits up to Week 52 in the Double-
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For binary endpoints (except the endpoints "discontinuation of opioids use" and "initiation 
of rescue between Week 24 and Week 52"), NRI-MI and NRI will be used for data 
handling, corresponding to the composite estimand. Point estimate, 95% CI and p-value 
will be provided for the treatment comparison between upadacitinib and the placebo 
group using the same CMH analysis method as the primary endpoint.  A supplementary 
analysis, corresponding to the treatment policy estimand, will be carried out using GLMM 
defined in Section 8.2.4 based on AO data. Estimated response rate with confidence 
intervals from GLMM will be provided, in addition to descriptive statistics. Point 
estimate, 95% CI and p-value will also be provided for the treatment comparison between 
upadacitinib and the placebo group based on the GLMM analysis. An additional analysis 
corresponding to the treatment policy estimand will be conducted for multiplicity-
controlled and additional secondary endpoints defined at Week 52, where missing data 
will be categorized as non-responders. Point estimate, 95% CI and p-value will be 
provided for the treatment comparison between upadacitinib and the placebo group using 
the same CMH analysis method as the primary endpoint.  
For the endpoint "discontinuation of opioids among subjects with opioid use at Baseline," 
and "initiation of rescue between Week 24 and Week 52," descriptive summaries will be 
provided based on AO data.
For continuous endpoints, similar statistical methods as described in Section 8.4.1 for the 
secondary continuous efficacy endpoints will be carried out using the MMRM (as 
described in Section 8.2.4). Mean estimate, 95% CI and p-value will be provided for the 
treatment comparison between upadacitinib and the placebo group. Observed data 
regardless of adherence to study drug will be used. Data after use of rescue will be 
excluded. Analysis including all data as observed, regardless of premature 
discontinuation of study drug or use of rescue, will be conducted as a supplementary 
analysis. For key secondary continuous endpoints between Week 24 and Week 52, 
additional supplementary analysis using LOCF will be conducted, as described in 
Section 8.2.3. 
 


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Long-Term Efficacy Analyses (up to Week 104)
Assessments to evaluate long-term efficacy will be analyzed for all efficacy 
measurements at scheduled visits.
For binary endpoints, NRI-MI and NRI will be used for data handling, corresponding to 
the composite estimand.  Descriptive statistics, including point estimate and 95% CI, will 
be provided for each randomized treatment sequence as defined in Section 8.1.  A 
supplementary analysis, corresponding to the treatment policy estimand, will be carried 
out using GLMM defined in Section 8.2.4 based on AO data.  Estimated response rate 
with confidence intervals from GLMM will be provided, in addition to descriptive 
statistics.  
For continuous endpoints, corresponding to the treatment policy estimand, MMRM model 
(as described in Section 8.2.4) will be used on AO data.  Mean estimates with confidence 
intervals will be provided for each randomized treatment sequence.  In addition, 
descriptive statistics on AO data will be provided, including the number of observations, 
mean, standard deviation, and 95% CI.  
Plots for each randomized treatment group sequence over time will be provided for 
primary and multiplicity-controlled secondary endpoints and selected additional 
endpoints.
A summary of the primary, sensitivity and supplementary analyses for the Week 14, 
Week 52 and long-term analyses are provided in Table 4, Table 5, Table 6 and Table 7
below.
 


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Table 4.
Summary of Analysis for Binary Variables up to Week 14
Endpoints
Estimand
Analysis
Missing Data and 
Intercurrent 
Event Handling
Model
Primary endpoint, 
secondary 
endpoints,* and 
additional 
endpoints#
Composite 
estimand on Full 
Analysis Set
Primary
NRI-MI 
Comparison of 
upadacitinib vs 
placebo using 
CMH test adjusted 
by main 
stratification 
factor.
Sensitivity
NRI
Primary endpoint
Composite 
estimand on per 
protocol analysis 
set
Supportive
NRI-MI
Primary endpoint 
and secondary 
endpoints*
Treatment policy 
estimand on Full 
Analysis Set
Supplementary 
As Observed, with 
Non-responder 
imputation for 
missing data
Primary endpoint 
and multiplicity-
controlled 
secondary 
endpoints*
Sensitivity
As Observed, with 
MI for missing 
data; and 
additional Tipping 
point analysis
NRI = Non-Responder Imputation; MI = Multiple Imputation; CMH = Cochran–Mantel–Haenszel
*
Secondary endpoints include endpoints listed in Section 3.2 except those endpoints defined at Week 52.  Week 52 
endpoints will be described in Table 6.
#
Additional endpoints include binary endpoints listed in Section 3.3 except discontinuation of opioids among 
subjects with opioid use at Baseline.  For this endpoint, descriptive summaries will be provided based on As 
Observed data.
 


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Table 5.
Summary of Analysis for Continuous Variables up to Week 14
Endpoints
Estimand
(on FAS)
Analysis
Missing Data 
and Intercurrent 
Event Handling
Model
Secondary 
endpoints and 
additional 
endpoints
Treatment policy 
estimand
Primary
As Observed 
MMRM
Multiplicity-
controlled 
secondary 
endpoints
Sensitivity
As Observed, 
with missing data 
handled by MI; 
including Tipping 
point analysis 
using MI
ANCOVA
FAS = Full Analysis Set; MMRM = Mixed-Effect Model Repeat Measurement; ANCOVA = Analysis of Covariance; 
MI = Multiple Imputation
 


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Table 6.
Summary of Analysis up to Week 52
Endpoints
Estimand
(on FAS)
Analysis
Missing Data and 
Intercurrent Event 
Handling
Model
All Binary 
Endpoints#
Composite estimand
Primary
NRI-MI 
Comparison of 
upadacitinib vs 
placebo using CMH 
test adjusted by 
main stratification 
factor.
Sensitivity
NRI
Treatment policy 
estimand
Supplementary
As Observed with 
Non-responder 
imputation*
As Observed
GLMM, with 
comparison of 
upadacitinib vs 
placebo
All 
Continuous 
Endpoints
Treatment policy 
estimand
Primary 
As Observed, 
excluding data after 
rescue
MMRM, with 
comparison of 
upadacitinib vs 
placebo
Supplementary
As Observed
Supplementary
LOCF for visits after 
study drug 
discontinuation or 
rescue; missing data 
will be handled by 
Multiple Imputation 
(MI)
ANCOVA, with 
comparison of 
upadacitinib vs 
placebo
FAS = Full Analysis Set; NRI = Non-Responder Imputation; MI = Multiple Imputation; MMRM = Mixed-Effect Model 
Repeat Measurement; ANCOVA = Analysis of Covariance; GLMM = Generalized Linear Mixed Model; CMH = 
Cochran–Mantel–Haenszel
*
Only applicable to multiplicity-controlled and additional secondary endpoints ASAS40, ASDAS ID, ASDAS MI, 
ASDAS LDA at Week 52.
#
All binary endpoints include endpoints listed in Section 3.2 specified at Week 52 and Section 3.3, except two 
endpoints:  Initiation of Rescue between Week 24 and Week 52, and Discontinuation of opioids among subjects 
with opioid use at Baseline.  For these two endpoints, descriptive summaries will be based on As Observed data.
 


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Table 7.
Summary of Long-Term Analysis up to Week 104
Endpoints
Estimand
(on FAS)
Analysis
Missing Data and 
Intercurrent 
Event Handling
Model
All Binary 
Endpoints#
Composite 
estimand
Primary
NRI-MI 
Descriptive Only
Sensitivity
NRI
Descriptive Only
Treatment policy 
estimand
Supplementary
As Observed
GLMM
All Continuous 
Endpoints
Treatment policy 
estimand
Primary 
As Observed 
MMRM
FAS = Full Analysis Set; NRI = Non-Responder Imputation; MI = Multiple Imputation; MMRM = Mixed-Effect Model 
Repeat Measurement; GLMM = Generalized Linear Mixed Model
#
All binary endpoints include binary endpoints listed in Section 3.3 except discontinuation of opioids among 
subjects with opioid use at Baseline.  For this endpoint, descriptive summaries will be provided based on As 
Observed data.
8.6
Efficacy Subgroup Analyses
The primary efficacy endpoint will be examined in the subgroups listed in Table 8 below.  
If any of the subgroup categories has fewer than 30 subjects per treatment, the category 
may be merged with other categories for analysis.  Treatment difference between 
upadacitinib and the placebo group will be presented with point estimate and 95% 
confidence interval using the same analysis method as the primary analysis, adjusting for 
the main stratification factor MRI and screening hsCRP level status.  For any subgroup, if 
there are zero subjects within a stratum in any treatment group, the analysis will not be 
adjusted by the stratification factor.  No p-value will be provided for subgroup analysis.  
A forest plot will be provided for the subgroup analyses.
 


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Table 8.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 40, ≥ 40
Sex
Male or Female
BMI
< 25, ≥ 25
Race
White vs non-White 
Geographic Region
North America, South/Central America, Eastern 
Europe, Western Europe, Asia, Other
hsCRP level at screening
≤ ULN vs > ULN
prior bDMARD exposure
Yes vs No
MRI (SI joints) inflammation at screening
Positive vs negative
MRI inflammation /hsCRP level at screening
MRI+/hsCRP > ULN, MRI+/hsCRP ≤ ULN, and 
MRI-/hsCRP > ULN
Duration of nr-axSpA symptom
< 5, [5, 10), ≥ 10 years
Duration since nr-axSpA diagnosis
< 5, [5, 10), ≥ 10 years
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the safety population.  For the safety analysis, subjects 
are assigned to a treatment group based on the treatment actually received, regardless of 
the treatment randomized.  A subject's actual treatment will be determined by the most 
frequent dose regimen received.  Missing safety data will not be imputed.
There are three sets of planned safety analysis:  safety analysis up to Week 14, up to 
Week 52, and long-term safety analysis.
Safety Analysis up to Week 14 within the Double-Blind Period 
Standard safety analysis by the actual treatment groups of upadacitinib 15 mg QD and 
placebo group will be performed on safety data up to Week 14.  No protocol-defined 
treatment switching will occur in the Double-Blind Period.
 


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The standard safety analyses will include reporting of adverse events (AEs), laboratory, 
and vital signs measurements.  Frequency tables of subjects with treatment-emergent 
adverse events (TEAEs) by system organ class (SOC) and by preferred term (PT) as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be provided by 
treatment group.  All continuous laboratory parameters and vital signs variables at each 
visit will also be summarized by actual treatment group.  Frequency tables of subjects 
meeting criteria for potentially clinically significant vital sign values (defined in 
Appendix C) and for potentially clinically significant laboratory values (Grade 3 and 
Grade 4 in severity based on CTCAE V4.03) will be provided by treatment group.  Shift 
of laboratory values from Baseline to defined time points will be tabulated.
Safety Analysis up to Week 52 (Double-Blind Period)
Standard safety analysis, as described for analysis up to Week 14, by the actual treatment 
groups of upadacitinib 15 mg QD and placebo group will be performed on safety data up 
to Week 52.  No protocol-defined switching of study drug treatment will occur prior to 
Week 52.
In addition, Exposure-adjusted event rate (EAER) will also be provided to adjust for 
potentially different follow-up time between treatment groups.  For the purpose of event 
rate calculation, the numerator will be the total number of AEs reported for the event (i.e., 
a subject can contribute more than one event to the numerator) and the denominator will 
be the total exposure time among subjects under the treatment group.  The number of AEs 
reported (numerator), the total number of years of study drug exposure (denominator 
calculated as total number of days exposed to study drug for all treated subjects divided 
by 365.25), and the exposure-adjusted AE event rate per 100 patient-years calculated as 
([numerator (number of AEs)/denominator]) • 100 will be presented for each treatment 
group.
Additionally, the exposure-adjusted incidence rate (EAIR) (censored at first event) will be 
conducted for AESI endpoints as deemed appropriate.  For the purpose of incidence rate 
calculation, the numerator will be the number of subjects with AE reported for the event 
 


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(i.e., a subject can contribute at most once to the numerator) and the denominator will be 
the total exposure time among subjects in the treatment group and at risk of an initial 
occurrence of the event, i.e., for subjects with no event, it is the total exposure time under 
the treatment group; for subjects with an event, it is the exposure time to the first event.  
The numerator, denominator (calculated as total number of days exposed to study drug for 
all treated subjects divided by 365.25), and the exposure-adjusted incidence rate per 100 
patient-years calculated as ([numerator /denominator]) • 100 will be presented for each 
treatment group.
The EAER and EAIR adjusted by cumulative exposure will be presented by actual 
treatment received at the time of AE.  Listing of subjects with TEAEs by SOC and PT 
will be provided.  All continuous laboratory parameters and vital signs variables at each 
visit will be summarized by actual treatment.  Frequency tables and listings of subjects 
meeting criteria for potentially clinically significant vital sign values (defined in 
Appendix C) and for potentially clinically significant laboratory values (Grade 3 and 
Grade 4 in severity based on CTCAE V4.03) will be provided by actual treatment 
received at the time of event.
Long-Term Safety Analysis
To adjust for potentially different follow-up time between treatment groups, EAER and 
EAIR will be provided for long-term safety analysis.  The EAER will be the main 
approach to evaluate AEs in the long-term analysis.  In addition, the exposure-adjusted 
incidence rate (EAIR) (censored at first event) may be conducted for selected AESI 
endpoints as deemed appropriate for long-term analysis.
Long-term safety analyses that account for protocol-defined treatment switching include 
reporting of AE rate adjusted by cumulative exposure, descriptive summary in laboratory 
parameters and vital sign variables, and frequency and percentage of potentially clinically 
significant laboratory and vital signs values.  The EAER and EAIR will be presented by 
actual treatment received at the time of AE.  Listing of subjects with TEAEs by SOC and 
PT will be provided.  Frequency tables and listings of subjects meeting criteria for 
 


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potentially clinically significant vital sign values and for potentially clinically significant 
laboratory values for Any upadacitinib group will be provided by actual treatment 
received at the time of event.  All continuous laboratory parameters and vital signs 
variables at each visit will be summarized by actual treatment group sequences defined as 
follows.
Actual treatment group sequences:
1.
Placebo →Upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →Upadacitinib 15 mg QD
9.2
Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is after the first dose of study drug, and no more than 30 days of the drug after 
the last dose of study drug.  Events where the onset date is the same as the study drug start 
date are assumed to be treatment-emergent, unless the study drug start time and the 
adverse event start time are collected, and the adverse event start time is prior to the study 
drug start time.  If an incomplete onset date was collected for an adverse event, the event 
will be assumed to be treatment-emergent unless there is other evidence that confirms that 
the event was not treatment-emergent (e.g., the event end date was prior to the study drug 
start date).
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) using MedDRA Version 22.0 or most up 
to date version.  The actual version of the MedDRA coding dictionary used will be noted 
in the AE tables and in the clinical study report.  Specific adverse events will be counted 
once for each subject for calculating percentages, unless stated otherwise.  In addition, if 
the same adverse event occurs multiple times within a subject, the highest severity and 
level of relationship to investigational product will be reported.
 


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9.2.1
Analysis of Adverse Events up to Week 14
9.2.1.1
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any COVID-19 related TEAEs
●
TEAEs reasonably possibly related to study drug
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
All deaths
○
Deaths occurring after the first dose date and ≤ 30 days after last dose of 
study drug
●
COVID-19 related deaths occurring ≤ 30 days after last dose of study 
drug
○
Deaths occurring > 30 days after last dose of study drug.
●
COVID-19 related deaths occurring > 30 days after last dose of study 
drug
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.  Any event with an unknown severity 
will be considered as severe and any AE with an unknown relationship will be considered 
as drug related.
The number and percentage of subjects experiencing at least one event of treatment-
emergent AEs will be summarized for each treatment group.  The point estimate and 95% 
CI (using normal approximation and separate group variance) will be provided for the 
treatment difference in AE percentage between upadacitinib group and the placebo group.  
 


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An overview of the AE of special interest (AESI) will be provided similarly and the 
categories of AESI is defined in Section 9.2.1.4.
9.2.1.2
Treatment-Emergent Adverse Events by SOC and PT
Treatment-emergent adverse events will be summarized by SOC and PT, the following 
summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
●
COVID-19 related TEAE
●
Frequent AEs (reported in 2% of subjects or more in any treatment group)
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity tables and most 
related incident for the relationship tables).  Subjects reporting more than one type of 
adverse event within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.
TEAEs will also be summarized by relationship to Upadacitinib and Placebo, as assessed 
by the investigator, by treatment groups.  If a subject has a TEAE with an unknown 
relationship, then the subject will be counted in the relationship category of "unknown," 
even if the subject has another occurrence of the same event with a relationship present.  
The only exception is if the subject has another occurrence of the same TEAE with a 
relationship assessment of "reasonable possibility."  In this case, the subject will be 
counted under the "reasonable possibility" category.
 


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TEAEs will also be summarized by maximum severity by treatment groups.  If a subject 
has an AE with an unknown severity, then the subject will be counted in the severity 
category of unknown, even if the subject has another occurrence of the same event with a 
severity present.  The only exception is that if the subject has another occurrence of the 
same AE with the most extreme severity – severe.  In this case, the subject will be counted 
under the severe category.
The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the treatment groups will be summarized by MedDRA PT and sorted by decreasing 
frequency for the active group separately.
9.2.1.3
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation, and AEs related 
to COVID-19 will be listed in tables, besides summary by SOC and PT covered in 
Section 9.2.1.2.
9.2.1.4
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs).  Adverse events of 
special interest are categorized in Table 9 below.  Adjudicated cardiovascular events will 
be summarized and presented by treatment group using the CAC adjudicated categories.
 


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Table 9.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection 
excluding Tuberculosis and 
Herpes Zoster
CMQ
"Opportunistic Infection excluding 
Tuberculosis and Herpes Zoster"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
Narrow
"Malignant tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Narrow
Skin Malignant tumours (Narrow 
SMQ) removing Melanoma CMQ
Malignancy excluding NMSC
"Malignant tumours" SMQ
(Narrow) removing NMSC output
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders"
comprehensive search
Adjudicated Gastrointestinal 
Perforations
Output from 
adjudication
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Neutropenia
CMQ
"Hematological Toxicity –
Neutropenia"
Lymphopenia
CMQ
"Hematological Toxicity –
Lymphopenia"
Herpes Zoster
CMQ
"Herpes Zoster"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"
Active Tuberculosis
CMQ
"Active Tuberculosis"
 


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Table 9.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches 
(Continued)
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow Search
SMQ/CMQ Search Criteria
Adjudicated Cardiovascular 
Events
Output from 
CAC
MACE* 
Cardiovascular Death
Non-fatal Myocardial 
Infarction
Non-fatal Stroke
Undetermined/Unknown 
Cause of Deaths 
Other Cardiovascular 
events
Adjudicated Thrombotic Events
Output From 
CAC
Venous Thromboembolic 
Events**
Deep Vein Thrombosis
Pulmonary Embolism
Other Venous Thrombosis 
Arterial Thromboembolic 
Events (non-cardiac, non-
neurologic)
CAC = Cardiovascular Adjudication Committee; CMQ = company MedDRA query; PT = preferred term; 
SMQ = standard MedDRA query
*
MACE; Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction 
and non-fatal stroke.
**
Venous thromboembolic events (VTE) include deep vein thrombosis (DVT) and pulmonary embolism (PE) (fatal 
and non-fatal).
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
 


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9.2.2
Analysis of Adverse Events up to Week 52
Analysis described in Section 9.2.1.1 will also be performed for up to Week 52.  Besides, 
analyses described below will be performed.
9.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
An overview of AEs per 100 patient-years of study exposure will be presented for the AE 
categories defined in Section 9.2.1.1.
The number of TEAEs reported, the total number of years of study drug exposure, and the 
TEAE rate per 100 patient-years will be presented.  An overview of AESIs per 
100 patient-years of study exposure will be presented similarly.  Any event with an 
unknown severity will be considered as severe and any AE with an unknown relationship 
will be considered as drug related.
9.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
The TEAE rate per 100 patient-years of exposure will be calculated overall, for each SOC 
and PT, for the same events defined in Section 9.2.1.2 and reported for each treatment 
group.
The TEAE rate per 100 patient-years of exposure will be summarized by relationship and 
by severity for each treatment group.
9.2.2.3
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation per 100 Patient-Years of Study 
Drug Exposure
SAEs (including deaths) and AEs leading to study drug discontinuation, and AEs related 
to COVID-19 will be listed in tables, besides summary by SOC and PT covered in 
Section 9.2.2.2.
 


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9.2.2.4
Adverse Events of Special Interest Rates per 100 Patient-
Years of Study Drug Exposure
The Adverse Events of Special Interest (AESI) will be summarized and presented for each 
treatment group using SOC and MedDRA PT (for adjudicated cardiovascular events, the 
CAC adjudicated categories will be used).  The AESI will be identified per the search 
criteria as specified in Table 9.
The Adverse Events of Special Interest (AESI) rate per 100 patient-years of exposure will 
be calculated overall and for each of the AESI listed in Section 9.2.1.4 for each SOC and 
each PT.
9.2.3
Analysis of Long-Term Adverse Events 
9.2.3.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
An overview of AEs per 100 patient-years of study exposure will be presented for the AE 
categories defined in Section 9.2.1.1.
The number of TEAEs reported, the total number of years of study drug exposure, and the 
TEAE rate per 100 patient-years will be presented for the Any upadacitinib 15 mg QD 
group.  The Any upadacitinib 15 mg QD treatment group is defined as subjects who 
receive at least one dose of upadacitinib 15 mg QD at any time during the study.  This 
includes AEs occurring under upadacitinib 15 mg QD exposure from subjects starting on 
upadacitinib 15 mg QD and subjects switching from placebo to upadacitinib 15 mg QD.
An overview of AESIs per 100 patient-years of study exposure will be presented 
similarly.  Any event with an unknown severity will be considered as severe and any AE 
with an unknown relationship will be considered as drug related.
 


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9.2.3.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
The TEAE rate per 100 patient-years of exposure will be calculated overall, for each SOC 
and PT, for the same events defined in short term and reported for Any upadacitinib 
15 mg QD group.
The TEAE rate per 100 patient-years of exposure will be summarized by relationship and 
by severity for the Any upadacitinib 15 mg QD group.
9.2.3.3
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation per 100 Patient-Years of Study 
Drug Exposure
SAEs (including deaths) and AEs leading to study drug discontinuation, and AEs related 
to COVID-19 will be listed in tables, besides summary by SOC and PT covered in 
Section 9.2.2.2.
9.2.3.4
Adverse Events of Special Interest Rates per 100 Patient-
Years of Study Drug Exposure
The Adverse Events of Special Interest (AESI) categories will be summarized and 
presented for the Any upadacitinib 15 mg QD treatment group using SOC and MedDRA 
PT (for adjudicated cardiovascular events, the CAC adjudicated categories will be used).  
The AESI categories will be identified per the search criteria as specified in Table 9. 
The Adverse Events of Special Interest (AESI) rate per 100 patient-years of exposure as 
outlined in Section 9.2.1.1 will be calculated overall and for each of the AESI listed in 
Section 9.2.1.4 for each SOC and each PT.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  
 


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Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between treatment groups (upadacitinib vs. 
placebo).
Changes in laboratory parameters will be tabulated using shift tables by CTCAE criteria 
v4.03.9  A shift table from baseline to the worse value (based on CTCAE criteria v4.03) 
during treatment will be created.  A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value.
Laboratory abnormalities will be evaluated based on Potentially Clinically Significant 
(PCS) criteria (Appendix C).  For each laboratory PCS criterion, the number and 
percentage of subjects who have a laboratory value meeting CTCAE criteria grade 3 and 4 
will be summarized.  Listings will be provided to summarize subject-level laboratory data 
for subjects meeting PCS criteria.  A listing of possible Hy's Law cases will be provided.
9.3.1
Variables and Units
Safety laboratory parameters to be summarized in this study are listed below.  Laboratory 
parameters will be reported using the standard international (SI) units.
 


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Table 10.
List of Safety Laboratory Variables
Laboratory Variables
Hematology
Leukocytes (White Blood Cell Count)
Erythrocytes (Red Blood Cell Count)
Hemoglobin
Hematocrit
Platelets 
Neutrophils
Basophils
Eosinophils
Lymphocytes
Monocytes
Erythrocytes Mean Corpuscular Volume 
Reticulocytes/Erythrocytes
Chemistry
Total Bilirubin
Alkaline Phosphatase (ALP)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
Potassium
Calcium
Inorganic Phosphorus
Chloride
Bicarbonate
Cholesterol
 


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Table 10.
List of Safety Laboratory Variables (Continued)
Chemistry (Continued)
LDL cholesterol
HDL cholesterol
LDL/HDL ratio
Cholesterol/HDL ratio
Urinalysis
Specific Gravity
pH
9.3.2
Analysis of Laboratory Data up to Week 14
The laboratory data will be summarized by the "as treated" treatment groups (upadacitinib 
15 mg QD and placebo group).
9.3.2.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables
Analyses of key continuous hematology, chemistry, and urinalysis variables which are 
measured longitudinally will be performed by visits and by treatment group.  For each 
parameter at each visit, the following summary statistics will be presented for each 
treatment group:  sample size, mean, standard deviation, minimum, median and 
maximum.
An ANOVA model with treatment as a factor will be used to compare change from 
baseline between different treatment groups for selected laboratory parameters.  Mean 
difference from placebo and associated 95% CIs will be presented.  The analysis applies 
to the following laboratory parameters of clinical interest:  hemoglobin, platelets, 
lymphocytes, neutrophils, leukocytes, creatinine, AST, ALT, Total bilirubin, LDL, HDL, 
the ratio of LDL to HDL, and total cholesterol.
 


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9.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables
The baseline and post-baseline laboratory observations will be categorized as Grade 0, 
Grade 1, Grade 2, Grade 3, and Grade 4 and shifts from baseline grade to worst on-
therapy grade will be summarized.  Toxicity grading scale is based on CTCAE 
version 4.03.  Shift tables from baseline according to the grades will be provided for 
laboratory variables.
Note that the minimum/maximum category is used, rather than the category of the
minimum/maximum value.  The two may be different due to variation in the reference 
range.
No statistical tests will be performed for this analysis.
9.3.2.3
Assessment of Potentially Clinically Significant Laboratory 
Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 3 or higher.  The number and percentage of subjects meeting the 
criteria for potentially clinically significant laboratory values will be summarized by "as 
treated" treatment group.  Only subjects with worsening in grade compared to baseline 
grade will be captured.
A listing of all subjects with any laboratory determination meeting CTCAE criteria of 
Grade 3 or higher will be provided by Grade.
9.3.2.4
Assessment of Liver Elevations
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (Total 
bilirubin elevation > 2 × ULN), in the absence of evidence of biliary obstruction 
(i.e., significant elevation of ALP) or some other explanation of the injury (e.g., viral 
 


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hepatitis, alcohol hepatitis), the combined finding (i.e., Hy's Law cases) represents a 
signal of a potential for the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized.  Listings will be provided to 
summarize subject-level laboratory data for subjects meeting liver elevations based on 
criteria specified below:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
9.3.3
Analysis of Laboratory Data up to Week 52
The laboratory data will be summarized by the "as treated" treatment groups (upadacitinib 
15 mg QD and placebo group) same as described in Section 9.3.2.
 


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9.3.4
Analysis of Long-Term Laboratory Data 
9.3.4.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables
Analyses of specified continuous hematology, chemistry, and urinalysis variables which 
are measured longitudinally will be performed by visits and by "as treated" treatment 
group sequences as described in Section 9.1.  For each parameter, the following summary 
statistics will be presented for each treatment group sequence:  sample size, mean, 
standard deviation, minimum, median and maximum.
Analyses will be performed for change from baseline in hemoglobin, platelets, 
lymphocytes, neutrophils, leukocytes, creatinine, AST, ALT, total bilirubin, LDL, HDL, 
the ratio of LDL to HDL, and total cholesterol.
9.3.4.2
Assessment of Potentially Clinically Significant Laboratory 
Values
Long-term laboratory data will also be summarized based on the number and percentage 
of subjects meeting the criteria for potentially clinically significant laboratory values for 
the Any Upadacitinib 15 mg QD group.
The baseline value will be determined by the last non-missing measurement recorded on 
or before the date of the first dose of upadacitinib 15 mg QD.  For a subject who started 
on placebo and switched to upadacitinib 15 mg QD at Week 52, lab values under 
upadacitinib 15 mg QD exposure would be evaluated against the baseline value defined as 
above. Only subjects with worsening in grade compared to baseline grade will be 
captured.
A listing of all subjects with any laboratory determination meeting CTCAE criteria of 
Grade 3 or higher will be provided by Grade.  For each of these subjects, the whole course 
of the respective parameter will be listed.
 


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9.3.4.3
Assessment of Liver Elevations
The frequencies and percentages of subjects with post-baseline liver-specific function test 
values that meet the criteria of potential clinical interest defined in Section 9.3.2.4 will be 
summarized for Any upadacitinib 15 mg QD group as described in Section 6.0.
A listing of liver elevations based on criteria specified above will be provided.  For each 
of these subjects, the whole course of the respective parameter will be listed.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, respiratory 
rate, body temperature, and weight will be summarized.
Vital sign variables will be evaluated based on potentially clinically significant (PCS) 
criteria (Appendix C).
9.4.1
Analysis of Vital Sign up to Week 14
Analyses of continuous vital sign variables which are measured longitudinally will be 
performed by visits and by the treatment groups of upadacitinib 15 mg QD and placebo 
group.  For each analysis, the following summary statistics will be presented for each 
treatment group:  sample size, mean, standard deviation, minimum, median and 
maximum.
The number and percentage of subjects meeting the criteria for PCS vital sign values will 
be summarized by actual treatment group.  Listings will be provided to summarize 
subject-level vital sign data for subjects meeting PCS criteria.  For each of these subjects, 
the whole course of the respective parameter will be listed.
9.4.2
Analysis of Vital Sign up to Week 52
Analyses of vital sign variables up to Week 52 will be conducted same as described in 
Section 9.4.1.
 


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9.4.3
Analysis of Long-Term Vital Sign 
Analyses of continuous vital signs variables which are measured longitudinally will be 
performed by visits and by "as treated" treatment group sequences as described in 
Section 9.1.
Long-Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for PCS vital sign values for the Any Upadacitinib 15 mg QD 
group as described in Section 6.0.  Similar baseline definition as Section 9.3.4.2 will be 
applied.  A listing of all subjects with any vital sign values meeting the criteria for PCS 
vital signs will also be provided.
10.0
Other Analyses
Not Applicable.
11.0
Interim Analyses
There are no interim analyses planned for efficacy endpoints.  Information on the interim 
safety monitoring DMC is described in Section 11.1.
11.1
Data Monitoring Committee
An independent external Data Monitoring Committee (DMC) is used to review unblinded 
safety data at regular intervals during the conduct of the study.  The DMC will provide 
recommendations to an AbbVie Point of Contact on whether to continue, modify, or 
terminate studies after each review.  The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in this study.  When needed, high-level 
unblinded efficacy data may also be requested by the DMC and be reviewed so that the 
DMC can assess benefit:risk of any emerging safety differences.
A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no α adjustment is needed.
 


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12.0
Overall Type-I Error Control
A multiple testing procedure will be used to provide strong control of the type I error rate 
at α = 0.05 (2-sided) across analyses with respect to the primary endpoint and 
multiplicity-controlled secondary endpoints.  Since all efficacy comparisons target 
superior efficacy from placebo, this is equivalent to a one-sided test at a level of 0.025.  
Specifically, testing will utilize a sequence of hypothesis testing for the primary endpoint 
followed by the 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 endpoints in the sequence meet the requirement of 
significance.  The testing sequence is shown in Figure 2.  All endpoints are assessed at 
Week 14 unless otherwise noted.  Endpoints at Week 14 will be tested at the primary 
database lock.  The last ranked endpoint ASAS40 at Week 52 (for EU/EMA) will be 
tested at the Week 52 database lock.  The primary and Week 52 database locks were 
defined in Section 2.2.
 


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Figure 2.
Sequential Multiple Testing Procedure
*
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. 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.0
Version History
Table 11.
SAP Version History Summary
Version
Date
Summary
1.0
27 Jan 2020
Original version
2.0
08 Jan 2021
The following changes have occurred 

Updated to align with protocol amendment 4.0 

Updated missing data handling due to COVID-19 
infection or logistical restrictions.

Updated analyses related to COVID-19.
3.0
19 Aug 2021
The following changes have occurred 

Updated methods for handling missing data and 
intercurrent events to address regulatory feedback. 

Updated efficacy subgroup analyses categories. 

Updated AESI list by removing CPK elevation and 
aligning with PSSAP Version 5.0.

Updated safety lab parameter list (Table 10) to only 
include those reported in CSR safety section.

Aligned with Protocol Version 5.0, including 
updated study title and study schematic to 
incorporate the remission-withdrawal period, and 
updated order of multiplicity-controlled secondary 
endpoints.
4.0
15 Sep 2021
Added statistical model details for the analysis of change 
from baseline in MRI SPARCC SI joint score at Week 14.
14.0
References
1.
Landewé 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.
2.
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.
 


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3.
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.
4.
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.
5.
Deodhar A, van der Heijde D, Gensler L, et al.  Ixekizumab in Non-Radiographic 
Axial Spondyloarthritis:  Primary Results from a Phase 3 Trial [abstract].  Arthritis 
Rheumatol.  2019;71 (suppl 10).  Available from:  
https://acrabstracts.org/abstract/ixekizumab-in-non-radiographic-axial-
spondyloarthritis-primary-results-from-a-phase-3-trial/.
6.
Deodhar A, Blanco R, Dokoupilova E, et al.  Secukinumab 150 mg Significantly 
Improved Signs and Symptoms of Non-radiographic Axial Spondyloarthritis:  
Results from a Phase 3 Double-blind, Randomized, Placebo-controlled Study 
[abstract].  Arthritis Rheumatol.  2019;71 (suppl 10).  Available from:  
https://acrabstracts.org/abstract/secukinumab-150-mg-significantly-improved-
signs-and-symptoms-of-non-radiographic-axial-spondyloarthritis-results-from-a-
phase-3-double-blind-randomized-placebo-controlled-study/.
7.
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.
8.
Food and Drug Administration.  E9(R1) Statistical Principles for Clinical Trials:  
Addendum:  Estimands and Sensitivity Analysis in Clinical Trials.  Rockville, MD:  
FDA; 2017.
9.
National Cancer Institute.  CTCAE v. 4.0.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.  
Accessed on:  August 10, 2017.
 


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10.
Liu GF, Wang J, Liu K, et al.  Confidence intervals for an exposure adjusted 
incidence rate difference with applications to clinical trials.  Stat Med.  
2006;25(8):1275-86.
11.
Dougados M, Simon P, Braun J, et al.  ASAS recommendations for collecting, 
analysing and reporting NSAID intake in clinical trials/epidemiological studies in 
axial spondyloarthritis.  Ann Rheum Dis.  2011;70(2):249-51.
12.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data: a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
EAER and Normal Approximation Based 95% Confidence Interval
Assume the occurrence of TEAE of special interest follows a Poisson distribution and let 
λ denote the rate of occurrence of TEAE under the total exposure time for a treatment 
group.  Let n be the number of AEs reported in Any upadacitinib 15 mg QD group.  Let T 
be the total time exposed to study drug summed across all treated subjects in Any 
upadacitinib 15 mg QD group.  Under the assumption that n follow Poisson distribution 
with parameters λT, the = n/T. 
Using normal approximation, the 95% confidence interval can be calculated by (Liu GF, 
et al.  2006.10):
  ± ⍺/

Where  = 


 


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The criteria for Potentially Clinically Significant (PCS) vital sign findings are described in 
Table 12.
Table 12.
Criteria for Potentially Clinically Significant Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Important Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
 


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Appendix D.
ASAS-NSAID Intake Score for Axial Spondyloarthritis
ASAS-NSAID Intake Score for Axial Spondyloarthritis:  The amount of NSAID 
intake could be considered as a clinically relevant outcome measure in ankylosing 
spondylitis (AS)/axial spondyloarthritis.
To be able to calculate the ASAS-NSAID Intake Score11, the following information is 
required:
(1) Type of NSAID/Cox2 inhibitor:  Each NSAID has a corresponding weight factor.  
The weight is determined by the maximum dose of each NSAID to achieve a score of 100.  
The goal is to analyze/report the data in terms of NSAID equivalent dose in mg/day on a 
0 - 100 scale.  The 150 mg equivalent diclofenac is set to 100.  For instance, 150 mg 
diclofenac is equivalent to 1000 mg naproxen, so the weight for diclofenac is 100/150, 
and the weight for naproxen is 100/1000.  For other NSAIDs/Cox2 inhibitors not 
described in the table, the weight factor will be determined based on medical review using 
the local label as a guide.
 


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NSAID
Weights
Diclofenac
100/150
Naproxen
100/1000
Aceclofenac
100/200
Celecoxib
100/400
Etodolac
100/600
Etoricoxib
100/90
Flurbiprofen
100/200
Ibuprofen
100/2400
Indomethacin
100/150
Ketoprofen
100/200
Meloxicam
100/15
Nimesulide
100/200
Phenylbutazone
100/400
Piroxicam
100/20
Tenoxicam
100/20
(2) Dose:  mg per intake
(3) Frequency:  days of intake per week (the times of intake daily)
Frequency Description
Numeric Frequency
QD
1
BID
2
TID
3
QID
4
1 time per week
1/7
2 times per week
2/7
3 times per week
3/7
4 times per week
4/7
5 times per week
5/7
6 times per week 
6/7
 


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(4) Days of intake during the period of interest:  can be calculated by NSAID end date 
- start date + 1.
(5) Days stayed on study in the clinical trial:  is defined as the total number of days in 
the study = last visit date – baseline date + 1.
Then, two scores can be calculated:
1. Equivalent NSAID score = weights * dose (mg) * (numeric frequency),
where weights can be obtained from the weight table (above and Dougados et al.  
Ann Rheum Dis 2011;70:249–51), and dose is the number of mg per intake 
numeric frequency is the number of intakes per day.  The equivalent NSAID score 
is a scoring system to refer to a scale in which 0 equals no intake, and 100 equals 
150 mg diclofenac, or 1000 mg naproxen, or 200 mg aceclofenac, or 400 mg 
celecoxib etc. per daily dose.
2. ASAS-NSAID Intake Score =
(Equivalent NSAID score) * (days of intake during period of interest)/(days stayed 
on study in the clinical trial)
 


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Appendix E.
NRI-MI Procedure
Non-responder imputation in conjunction with multiple imputation (NRI-MI) will handle 
intercurrent events and missing data as follows:
1.
Subjects who prematurely discontinue study drug or use rescue therapy will be 
categorized as non-responders for visits after study drug discontinuation or rescue 
initiation.
2.
Missing data due to COVID-19 infection or logistical restriction will be handled 
by Multiple Imputation.
3.
Additional missing data due to other reasons will be categorized as non-responders. 
Assessments at visits after discontinuation of study drug or rescue initiation will not 
contribute to the imputation. 
NRI-MI will be implemented as follows.
Binary Endpoints Dichotomized from Continuous Variable
Step 1:  Imputation of original continuous variable
When a binary variable is dichotomized from a continuous variable, the MI is applied to 
the original continuous variable.  Missing values are imputed via MI in two steps: 
augmentation step and imputation step.
Augmentation Step:
Markov Chain Monte Carlo (MCMC) will be applied to augment the data to achieve 
monotone missing pattern using PROC MI with the MCMC IMPUTE=monotone 
statement, assuming a multivariate normal distribution.  The imputation model includes 
screening hsCRP, screening MRI status (+/-), gender, race (white vs. non-white), 
ethnicity, age, baseline BMI, geographic region, duration since nr-axSpA diagnosis, 
duration of nr-axSpA symptom, prior bDMARD use, baseline value for the outcome 
 


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variable, as well as longitudinal values for the outcome variable observed at any other 
visits according to the pre-specified order.  Of note, categorical variables are included 
using dummy variables.  30 augmented datasets with monotone missing pattern will be 
generated.
Imputation Step:
For each of the 30 augmented datasets, using SAS PROC MI with MONOTONE REG 
model statement, the missing values for the outcome variable will be imputed for each 
post-baseline visit sequentially, regressing upon the outcomes from previous visits.
Sample codes are as follows:
PROC MI DATA=WIDEDATA OUT=MI_MONO NIMPUTE=30 SEED=&seed1;
MCMC IMPUTE=MONOTONE ;
By treatment;
VAR &predcont &predcate_num &wk1 &wk2 &wk4 &wk8 &wk12 &wk14;
RUN;
PROC MI DATA=MI_MONO OUT=MI_FULL NIMPUTE=1 SEED=&seed2;
CLASS &predcate;
VAR &predcont &predcate &wk1 &wk2 &wk4 &wk8 &wk12 &wk14;
MONOTONE REG (&wk1 &wk2 &wk4 &wk8 &wk12 &wk14); 
BY _IMPUTATION_ treatment;
RUN;
&predcate_num (categorical covariates ): gender, race (white vs. non-
white), ethnicity, geographic regions, prior bDMARD use,
screening MRI 
status. 
&predcate_num are dummy values of categorical covariates.
&predcont (continuous covariates): screening hsCRP, age, baseline BMI, 
duration since nr-axSpA diagnosis, duration of nr-axSpA symptom, 
baseline value for the outcome variable.
&wk1, &wk2, … ,&wk14: the outcome variable values at week 1, week 2, …, 
week14.
 


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Step 2:  Derivation of binary variable
The binary variable is then derived by dichotomizing the continuous variable for each 
imputed complete dataset.  In addition, subjects who prematurely discontinue study drug 
or use rescue therapy will be overwritten as non-responders for visits after study drug 
discontinuation or rescue initiation; missing data not due to COVID-19 will also be 
overwritten as non-responders.  
Step 3:  Analysis and synthesis of results for statistical inference
For each of the 'complete' binary endpoint datasets, the CMH test is performed adjusting 
for the main stratification factor to test the treatment difference of upadacitinib versus 
placebo.
The results from the 30 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula (Rubin, 1987).12
Composite Binary Endpoints
Step 1:  Imputation of original continuous variables
Composite binary endpoints are derived from multiple continuous components.  All 
missing component values are imputed via MI in two steps: augmentation step and 
imputation step. 
Augmentation Step:
Markov Chain Monte Carlo (MCMC) will be applied to augment the data to achieve 
monotone missing pattern using PROC MI with the MCMC IMPUTE=monotone 
statement, assuming a multivariate normal distribution.  The imputation model includes 
the same variables as for dichotomized binary endpoints.  In particular, the baseline values 
as well as longitudinal values observed at any other visits for all components of the 
composite binary endpoint are included in the model.  Of note, categorical variables are 
 


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included using the form of dummy variables.  30 augmented datasets with monotone 
missing pattern will be generated.
Imputation Step:
For each of the 30 augmented datasets, using SAS PROC MI with MONOTONE REG 
model statement, the missing values for each component will be imputed for each post-
baseline visit sequentially, regressing upon the previous visits.
Step 2:  Derivation of binary variable
The composite binary variable is then derived from each imputed dataset.  In addition, 
subjects who prematurely discontinue study drug or use rescue therapy will be overwritten 
as non-responders for visits after study drug discontinuation or rescue initiation. Missing 
data not due to COVID-19 will also be overwritten as non-responders.  
Step 3:  Analysis and synthesis of results for statistical inference
For each of the 'complete' binary endpoint datasets, the CMH test is performed adjusting 
for the main stratification factors to test the treatment difference of upadacitinib versus 
placebo.
The results from the 30 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula (Rubin, 1987).12
 


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Appendix F.
Tipping Point Analysis
Tipping Point Analysis for Binary Endpoints
To assess the robustness of the primary analysis under MNAR, tipping point analysis is 
conducted on the primary endpoint and multiplicity-controlled secondary endpoints at 
Week 14.  The analysis is conducted on the FAS using all observed data regardless of 
treatment adherence. 
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on the upadacitinib treatment group and the placebo group can vary 
independently.  The response rate among those subjects with missing response is assumed 
to be p0 for placebo group and p1 for upadacitinib group, and the response rate p0 and p1 
systematically vary from 0% to 100% by every 10% respectively.  Given a set of (p0, p1), 
the subjects with missing response will be randomly assigned as responders or non-
responders using binomial distribution to generate 30 imputed datasets, and the same 
CMH method used for the primary analysis will be performed on each of the multiple 
imputed datasets to obtain the results for each comparison of the upadacitinib treatment 
group versus the placebo group.  These results will then be aggregated using Rubin's 
method.  
If one pair of shift parameters are found to just reverse the study conclusion, in terms of 
p-value larger than 0.05, then the shift parameters are identified as the tipping point.  The 
results for a grid of shift parameter combinations are provided in tabular format. 
Tipping Point Analysis for Continuous Endpoints
To assess the impact of potential departures from the missing-at-random assumption, 
tipping point analyses are conducted as a sensitivity check for change from baseline in 
multiplicity-controlled secondary continuous endpoints at Week 14.
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on the upadacitinib treatment group and the placebo group can vary 
 


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independently.  In addition, the focus is on scenarios where missing outcomes on 
upadacitinib are worse than the imputed values on upadacitinib, while missing outcomes 
on placebo are better than the imputed values on placebo.  Missing values are 
first imputed via MI under MAR assumption using AO data, and then a shift parameter is 
applied to the imputed values (a different shift parameter may be specified for each 
treatment group).  This is implemented by PROC MI using the MNAR statement.  The 
imputation uses a two-step approach, augmentation step using MCMC and imputation 
step using Monotone Regression, as described in Appendix E.  The MNAR statement is 
applied in the imputation step.  The number of imputed datasets is 30.
In cases where the shifted values are smaller than the minimum or larger than maximum 
value of the endpoint, (i.e., out of range), the minimum or maximum value of the endpoint 
is used in further analysis steps.  For each pair of shift parameters, the SAS procedure 
PROC MIXED is used for ANCOVA model which includes the fixed effects of treatment, 
stratification factor and the continuous fixed covariate of baseline measurement on each 
of the imputed datasets to obtain the results for each upadacitinib treatment group versus 
the placebo group comparison.  These results will be aggregated using Rubin's method.
If one pair of shift parameters are found to just reverse the study conclusion, in terms of 
p-value larger than 0.05), then the shift parameters are identified as the tipping point.  The 
results for a grid of shift parameter combinations are provided in tabular format.
 


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Statistical Analysis Plan for Study 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
Study 1:  bDMARD-IR AS
Date:  19 August 2021
Version 3.0
 


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Table of Contents
1.0
Introduction .............................................................................6
2.0
Study Design and Objectives..................................................7
2.1
Objectives and Hypotheses ........................................................................7
2.2
Study Design Overview .............................................................................8
2.3
Treatment Assignment and Blinding .........................................................9
2.4
Sample Size Determination........................................................................9
3.0
Endpoints for Study 1 ...........................................................10
3.1
Primary Endpoint.....................................................................................10
3.2
Secondary Endpoints ...............................................................................10
3.3
Other Efficacy Endpoints.........................................................................11
3.4
Safety Endpoints ......................................................................................13
3.5
Additional Measures ................................................................................13
4.0
Analysis Populations .............................................................13
5.0
Subject Disposition................................................................14
6.0
Study Drug Duration and Compliance................................15
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................16
7.1
Demographics and Baseline Characteristics............................................16
7.2
Medical History .......................................................................................19
7.3
Prior and Concomitant Medications ........................................................19
8.0
Efficacy Analyses...................................................................20
8.1
General Considerations............................................................................20
8.2
Handling of Missing Data and Intercurrent Events .................................21
8.2.1
Binary Endpoints .....................................................................................22
8.2.2
Continuous Endpoints..............................................................................23
8.2.3
Long-Term Efficacy.................................................................................25
8.3
Primary Efficacy Endpoint and Analyses ................................................25
8.3.1
Primary Efficacy Endpoint ......................................................................25
8.3.2
Handling of Missing Data and Intercurrent Events for the Primary 
Efficacy Endpoint ....................................................................................26
8.3.3
Primary Efficacy Analysis .......................................................................27
 


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8.3.4
Sensitivity Analyses, Supplementary Analyses, and Additional 
Analyses of the Primary Efficacy Endpoints ...........................................27
8.4
Secondary Efficacy Analyses...................................................................28
8.4.1
Primary Analyses and Sensitivity Analyses of Secondary Efficacy 
Endpoints .................................................................................................28
8.4.2
Supplementary Analyses of Secondary Binary Efficacy Endpoints........30
8.5
Additional Efficacy Analyses ..................................................................30
8.6
Efficacy Subgroup Analyses....................................................................34
9.0
Safety Analyses ......................................................................35
9.1
General Considerations............................................................................35
9.2
Adverse Events ........................................................................................38
9.2.1
Analysis of Adverse Events for Double-Blind Period.............................38
9.2.1.1
Adverse Event Overview .........................................................................38
9.2.1.2
Treatment-Emergent Adverse Events by SOC and PT............................39
9.2.1.3
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................41
9.2.1.4
Adverse Events of Special Interest ..........................................................41
9.2.2
Analysis of Long-Term Adverse Events..................................................43
9.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................43
9.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT ........................................................................43
9.2.2.3
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation per 100 Patient-Years of Study Drug 
Exposure ..................................................................................................44
9.2.2.4
Adverse Events of Special Interest Rates per 100 Patient-Years of 
Study Drug Exposure...............................................................................44
9.3
Analysis of Laboratory Data....................................................................44
9.3.1
Variables and Units..................................................................................45
9.3.2
Analysis of Laboratory Data for Double-Blind Period............................46
9.3.2.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables................................................................................47
9.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables ..................................................................................................47
 


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9.3.2.3
Assessment of Potentially Clinically Significant Laboratory 
Values ......................................................................................................48
9.3.2.4
Assessment of Liver Elevations...............................................................48
9.3.3
Analysis of Long-Term Laboratory Data.................................................49
9.3.3.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables................................................................................49
9.3.3.2
Assessment of Potentially Clinically Significant Laboratory 
Values ......................................................................................................49
9.3.3.3
Assessment of Liver Elevations...............................................................50
9.4
Analysis of Vital Signs ............................................................................50
9.4.1
Analysis of Vital Sign for Double-Blind Period......................................50
9.4.2
Analysis of Long-Term Vital Sign...........................................................51
10.0
Other Analyses.......................................................................51
11.0
Interim Analyses....................................................................51
11.1
Data Monitoring Committee....................................................................51
12.0
Overall Type-I Error Control ..............................................52
13.0
Version History......................................................................54
14.0
References...............................................................................54
List of Tables
Table 1.
ASAS and/or ASDAS Components at Baseline ......................................17
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint...................................................................................................26
Table 3.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints .................................................................................................29
Table 4.
Summary of Analysis for Binary Variables in DB Period.......................33
Table 5.
Summary of Analysis for Continuous Variables in DB Period ...............34
Table 6.
Summary of Long-Term Analysis ...........................................................34
Table 7.
Subgroups for Efficacy Analysis .............................................................35
Table 8.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches........................41
Table 9.
List of Safety Laboratory Variables.........................................................45
Table 10.
SAP Version History Summary...............................................................54
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values.............58
 


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List of Figures
Figure 1.
Study Schematic.........................................................................................8
Figure 2.
Sequential Multiple Testing Procedure....................................................53
List of Appendices
Appendix A.
Protocol Deviations..................................................................................56
Appendix B.
EAER and Normal Approximation Based 95% Confidence 
Interval .....................................................................................................57
Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints..............58
Appendix D.
ASAS-NSAID Intake Score for Axial Spondyloarthritis ........................59
Appendix E.
NRI-MI Procedure ...................................................................................62
Appendix F.
Tipping Point Analysis ............................................................................66
 


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1.0
Introduction
The Statistical Analysis Plans (SAPs) describe the statistical analyses for the upadacitinib 
Study M19-944 entitled "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."
Study Protocol M19-944 is a global, multicenter, protocol ("master protocol") with a 
common screening platform for determining subject eligibility into 2 separate studies.  
Study 1 examines the efficacy and safety of upadacitinib in ankylosing spondylitis (AS) 
subjects who had an inadequate response to biologic disease-modifying antirheumatic 
drug therapy (bDMARD-IR).  Study 2 examines the efficacy and safety of upadacitinib in 
non-radiographic axial spondyloarthritis (nr-axSpA) subjects.
This SAP is for Study 1 (AS, bDMARD-IR).  The SAP for Study 2 (nr-axSpA) is 
described in a separate document. The SAP for the Remission-Withdraw Period will be 
described in a separate document.
Although this protocol includes a common screening process and other common 
operational elements 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 multiplicity-controlled 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.
The analyses of pharmacokinetic and biomarker will not be covered in this SAP.
Physical activity endpoints including step counts, physical activity measures, and spinal 
range of motion tasks will be collected through a digital device in this study.  A detailed 
 


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analysis plan of these data will be described in a separate Digital Data Analysis Plan 
(DDAP) document.
The SAP will not be updated in case of administrative changes or amendments to the 
protocol, unless the changes impact the analyses described in this SAP.  If future protocol 
amendment impacts statistical analyses, this SAP will be amended accordingly.  Details of 
SAP versions are outlined in Section 13.0.
Unless noted otherwise, all analyses will be performed using SAS Version 9.4 (SAS 
Institute Inc., Cary, NC  27513) or later under the UNIX operating system.
2.0
Study Design and Objectives
2.1
Objectives and Hypotheses
Objectives
Double-Blind Period:
●
To evaluate the efficacy of upadacitinib compared with placebo on reduction 
of signs and symptoms in adult subjects with active AS who have an 
inadequate response to biologic DMARDs (bDMARD-IR).
●
To assess the safety and tolerability of upadacitinib in adult subjects with 
active AS who are bDMARD-IR.
Open-Label Extension Period:
●
To evaluate the long-term safety and tolerability of upadacitinib in extended 
treatment in adult subjects with active AS who are bDMARD-IR and who 
have completed the Double-Blind Period.
Hypotheses
●
For the primary efficacy endpoint, the null hypothesis is that upadacitinib 
15 mg is not different from placebo with respect to achieving ASAS40 at 
 


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Week 14.  The alternative hypothesis is that upadacitinib 15 mg has a higher 
response rate than placebo with respect to achieving ASAS40 at Week 14.
●
For secondary efficacy endpoints, the null hypotheses are that upadacitinib 
15 mg is not different from placebo with respect to secondary endpoints.  The 
alternative hypothesis is that upadacitinib 15 mg is better than placebo with 
respect to secondary endpoints.
2.2
Study Design Overview
Figure 1 shows the design of Study M19-944.  Study 1 is illustrated in the upper portion.
Figure 1.
Study Schematic
AS = ankylosing spondylitis; ASAS = Assessment of Spondyloarthritis International Society; bDMARD-IR = biologic 
disease-modifying antirheumatic drug inadequate responder; EMA = European Medicines Agency; FDA = Food and 
Drug Administration; MRI = magnetic resonance imaging; nr-axSpA = non-radiographic axial spondyloarthritis; 
QD = once daily; SI = sacroiliac; UPA = upadacitinib
The primary database lock and analysis will be conducted after all subjects have 
completed the Week 14 visit or have prematurely discontinued prior to Week 14.  Another 
database lock and 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 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 


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additional database lock and analysis may be conducted for regulatory purposes after all 
subjects have completed the Week 52 visit or have prematurely discontinued prior to 
Week 52.  Analyses at Week 52 and Week 104 are long-term analyses.
2.3
Treatment Assignment and Blinding
Subjects will be randomized to upadacitinib 15 mg or placebo in a 1:1 ratio.  
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.
Subjects in the placebo group will be switched to upadacitinib 15 mg QD at Week 14 in 
the Open-Label Extension Period.
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.  Sites and subjects will remain blinded to the Double-Blind 
Period treatment assignments for the duration of the 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.
2.4
Sample Size Determination
The planned total sample size of 386 subjects for Study 1 (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 
 


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24% and 6%, respectively.  This sample size also provides 90% power for ASAS20, with 
assumed response rates for upadacitinib and placebo of 41% and 24%, respectively.1-3
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 inactive 
disease, change from Baseline in total back pain, change from Baseline in nocturnal back 
pain, ASDAS LDA, change from Baseline in BASFI and ASAS PR.1-3
3.0
Endpoints for Study 1
3.1
Primary Endpoint
The primary endpoint is ASAS40 response at Week 14.
3.2
Secondary Endpoints
The multiplicity-controlled secondary endpoints at Week 14 are:
1.
Change from Baseline in Ankylosing Spondylitis Disease Activity Score 
(ASDAS(CRP));
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 
(defined as at least 50% improvement in the BASDAI);
4.
ASAS20 response;
5.
ASDAS(CRP) Inactive Disease (ASDAS score < 1.3);
6.
Change from Baseline in Patient's Assessment of Total Back Pain NRS 
(Score 0 – 10);
7.
Change from Baseline in Patient's Assessment of Nocturnal Back Pain NRS 
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8.
ASDAS(CRP) Low Disease Activity (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);
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) for subjects with baseline Enthesitis (MASES > 0).
Additional secondary endpoint at Week 14:
●
Change from Baseline in MRI SPARCC score (SI joints).
3.3
Other Efficacy Endpoints
The primary and secondary efficacy endpoints are listed in Section 3.1 and Section 3.2, 
respectively.  The additional efficacy endpoints include the following measurements 
assessed at scheduled time points other than those specified for the primary and secondary 
endpoints:
Binary variables:
●
ASAS20 response;
●
ASAS40 response;
●
ASAS PR;
●
BASDAI 50 response;
●
Inactive Disease based on ASDAS(CRP) and ASDAS(ESR), respectively 
(ASDAS score < 1.3);
 


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●
Low Disease Activity based on ASDAS(CRP) and ASDAS(ESR), respectively 
(ASDAS score < 2.1);
●
Major Improvement based on ASDAS(CRP) and ASDAS(ESR), respectively 
(a change from Baseline of ≤ –2.0);
●
Clinically Important Improvement based on ASDAS(CRP) and ASDAS(ESR), 
respectively (a change from Baseline of ≤ –1.1);
●
Discontinuation of opioids among subjects with opioid use at Baseline.
Change from Baseline in:
●
ASAS HI;
●
ASDAS(CRP) and ASDAS(ESR), respectively;
●
ASQoL;
●
BASDAI and BASDAI components including mean of question 5 and 6 of the 
BASDAI (Score 0 – 10);
●
BASFI (Score 0 – 10);
●
BASMIlin;
●
High sensitivity C-reactive protein (hsCRP);
●
EuroQoL-5D-5L (EQ-5D-5L);
●
Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F);
●
MASES for subjects with baseline Enthesitis (MASES > 0);
●
Modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) with 
conventional radiograph;
●
MRI SPARCC score of SI joints;
●
MRI SPARCC score of spine;
●
Patient's Assessment of Total Back Pain NRS (Score 0 – 10);
●
Patient's Assessment of Nocturnal Back Pain NRS (Score 0 – 10);
●
Patient's Global Assessment of Pain NRS (Score 0 – 10);
●
Physician's Global Assessment of Disease Activity (PGA) NRS (Score 0 – 10);
●
Patient's Global Assessment of Disease Activity (PtGA) NRS (Score 0 – 10);
 


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●
36-Item Short Form Health Survey (SF-36) (all subdomain and summary 
scores);
●
Tender joint count (TJC68) and swollen joint count (SJC66); 
●
Work Productivity and Activity Impairment (WPAI, 4 dimensions:  
Absenteeism, Presenteeism, Percent overall work impairment due to SpA, 
Percent activity impairment due to SpA);
●
NSAID intake score (the derivation is detailed in Appendix D);
●
Physical Activity Assessment (step count, physical activity, and spinal range 
of motion tasks) as measured by a wearable device (in countries where the 
digital health technology device is approved).
3.4
Safety Endpoints
The following safety evaluations will be performed:  adverse events (AEs), serious 
adverse events (SAEs), AE of special interest (AESI), AEs leading to discontinuation, 
laboratory tests, vital signs, and physical examination findings.
3.5
Additional Measures
Patient Experience Data (PED) assessing patient preferences for treatment route of 
administration will be collected at each subject's Baseline Visit only.
4.0
Analysis Populations
The following analysis populations will be used for the analyses.
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 
 


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final criteria and the exclusion of subjects from the per-protocol analysis set will be 
finalized before unblinding for the Primary Analysis.
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.
5.0
Subject Disposition
The total number of subjects who were screened, enrolled (randomized), and treated will 
be summarized.
A summary of subject accountability will be provided where the number of subjects in 
each of the following categories will be summarized for each treatment group and overall:
●
Subjects enrolled (randomized) in the study;
●
Subjects who took at least one dose of study drug;
●
Subjects who completed study drug;
●
Subjects who prematurely discontinued study drug (all reasons and primary 
reason);
●
Subjects who completed study participation;
●
Subjects who prematurely discontinued study participation (all reasons and 
primary reason);
●
Subjects in each analysis population, as defined in Section 4.0.
Types of impacted visits related to COVID-19 will be collected for the protocol pre-
specified visits.  For each visit, the number and percentage of subjects impacted by 
COVID-19 will be summarized by the types of visit for each randomized treatment group 
as well as overall:
●
In person, partial assessments done
●
Virtual visit
●
Missed visit
 


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6.0
Study Drug Duration and Compliance
The duration of exposure to study drug will be summarized for the safety analysis set by 
the treatment groups (placebo group vs upadacitinib 15 mg QD) in Double-Blind Period.  
For long term, the duration of exposure to study drug will be summarized for the safety 
analysis set only for the Any Upadacitinib 15 mg QD group, which includes upadacitinib 
15 mg QD exposure from subjects starting on upadacitinib 15 mg QD and subjects 
switching from placebo to upadacitinib 15 mg QD.
Exposure to upadacitinib and placebo is defined as last dose date minus first dose date 
plus 1 day.
The duration of exposure to study drug will be summarized for each group as specified 
above, with the number of subjects, mean, standard deviation, median, minimum and 
maximum values.  In addition, the number and percentage of subjects exposed to study 
drug will be summarized for the following cumulative duration intervals.
●
≥ 2 weeks
●
≥ 1 month
●
≥ 3 months
●
≥ 6 months
●
≥ 9 months
●
≥ 12 months
●
≥ 18 months
●
≥ 2 years
Study drug compliance will be summarized for each treatment group for Double-Blind 
Period up to Week 14.  The compliance is defined as the number of tablets taken (i.e., the 
difference between the number of tablets dispensed and the number of tablets returned) 
during the subject's participation divided by the number of tablets that should have been 
taken.  Percent compliance will be summarized.
 


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7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, baseline or disease characteristics, medical history, and prior and 
concomitant medications will be summarized for the FAS overall and by treatment group.  
Categorical variables will be summarized with the number and percentage of subjects.  
Continuous variables will be summarized with descriptive statistics (number of non-
missing observations, mean and standard deviation, median, minimum and maximum).
7.1
Demographics and Baseline Characteristics
Demographic and baseline characteristics information will be collected at the Baseline 
visit of the study and will be summarized for the FAS.
Main Demographic and Baseline Characteristics
●
Sex (male, female)
●
Age (years)
●
Age Categories (< 40, ≥ 40 and < 65, ≥ 65 years)
●
Race (White, Non-White:  Black or African American, American Indian or 
Alaska Native, Native Hawaiian or Other Pacific Islander, Asian, Other)
●
Geographic Region (North America, South/Central America, Western Europe, 
Eastern Europe, Asia, Other)
●
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
●
Weight (kg)
●
Weight Categories (< 60 kg, ≥ 60 and < 80 kg, ≥ 80 kg)
●
Height (cm)
●
Body Mass Index (BMI) (kg/m2)
●
Body Mass Index (BMI) Category (kg/m2) (BMI < 25, BMI ≥ 25)
AS Medical History and Characteristics at Baseline
●
Duration (years) of AS symptoms
 


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●
Duration (years) since AS diagnosis
●
Duration since AS diagnosis categories (< 5, ≥ 5 and < 10, ≥ 10 years)
●
Duration of AS symptoms categories (< 5, ≥ 5 and < 10, ≥ 10 years)
●
HLA-B27 (positive, negative)
●
Number of different NSAIDs discontinued prior to baseline
●
Number of different baseline NSAIDs (started prior to baseline and ongoing at 
baseline)
●
Oral Corticosteroids use at baseline
●
csDMARD use at baseline
●
Opioid use at baseline
●
NSAID score at baseline
ASAS and/or ASDAS Components at Baseline
Table 1.
ASAS and/or ASDAS Components at Baseline
ASAS only 
components

Patient's assessment of total back pain (NRS score 0 - 10)

Function - Represented by the BASFI (NRS score 0 - 10)

Inflammation - (mean of items 5 and 6 of the BASDAI NRS score 0 - 10)
ASDAS only 
components

Patient's assessment of back pain (BASDAI Question 2 NRS score 0 - 10)

Peripheral pain/swelling (BASDAI Question 3 NRS score 0 - 10)

High sensitivity C-reactive protein (hs-CRP) in mg/L

Erythrocyte sedimentation rate (ESR) (mm/hr)

Duration of morning stiffness (BASDAI Question 6 NRS score 0 - 10)
Components for both 
ASAS and ASDAS

Patient global assessment of disease activity (NRS score 0 - 10)
Other Baseline AS Disease Characteristics
●
ASDAS (CRP)
●
ASDAS(CRP) categories (ASDAS(CRP) > 3.5 vs ≤ 3.5)
●
Physician's Global Assessment of Disease Activity (NRS score 0 – 10)
●
MRI SPARCC score (Spine)
●
MRI SPARCC score (SI joints)
 


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●
BASMIlin
●
MASES for subjects with baseline enthesitis (MASES > 0)
●
Presence of enthesitis (MASES > 0)
●
Tender Joint Count (TJC68)
●
Swollen Joint Count (SJC66)
●
mSASSS
●
High Sensitivity C-reactive Protein (hsCRP) (mg/L) at Screening
●
Screening hsCRP levels (hsCRP > ULN vs ≤ ULN, > 5mg/L vs ≤5mg/L)
●
Proportion of prior bDMARD use (1 TNF inhibitor, 1 IL-17 inhibitor, and 
"other")
Patient Reported Outcomes and Measures at Baseline
●
BASDAI (Score 0-10)
●
FACIT-F
●
WPAI (all dimensions)
●
AS QoL
●
ASAS HI
●
Patient's Assessment of Nocturnal Back Pain (NRS score 0 – 10)
●
Patient's Global Assessment of Pain (NRS score 0 – 10)
●
EuroQoL-5D-5L (EQ-5D-5L)
●
SF-36 (all subdomain and summary scores)
●
Patient Experience Data (PED)
Clinical Tests at Screening
●
Chest x-ray
●
12-Lead ECG
●
AP Pelvis X-Ray
●
Tuberculosis test result (PPD positive or QuantiFERON positive)
 


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Immunization History
●
BCG immunization
●
Herpes Zoster immunization
●
Hepatitis B immunization
Tobacco/Nicotine and Alcohol Use
●
Tobacco/Nicotine Use [current, former, never, unknown]
●
Alcohol Use [current, former, never, unknown]
7.2
Medical History
Medical history data will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA).  The actual version of the MedDRA coding dictionary will be noted in the 
statistical tables and clinical study report.  The number and percentage of subjects in each 
medical history category (by MedDRA system organ class and preferred term) will be 
summarized overall and by treatment group.  The system organ class (SOC) will be 
presented in alphabetical order, and the preferred terms will be presented in alphabetical 
order within each SOC.  Subjects reporting more than one PT within a SOC will be 
counted only once for that SOC.  No statistical comparison will be performed for medical 
history reporting.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by each randomized treatment 
group as well as overall for FAS.  Prior medications are those medications taken prior to 
the first dose of study drug.  This includes medications with a start date before the 
first study drug administration date, regardless of the end date of these medications.  
Medications taken on the day of the first dose of study drug are not counted as prior 
medications.  Concomitant medications are those medications, other than study drug, 
taken after the first dose of study drug and within 1 day of the last dose of study drug.  
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last study drug administration + 1 day, as well as medications with a start date prior to 
first dose of study drug and which are ongoing after first dose of study drug.  Medications 
taken on the day of the first dose of study drug are counted as concomitant medications.
The number and percentage of subjects who received a prior medication and the number 
and percentage of subjects who received a concomitant medication will be tabulated 
separately by the generic name assigned by the most current version of the World Health 
Organization (WHO) Drug Dictionary.
8.0
Efficacy Analyses
8.1
General Considerations
All efficacy analyses will be conducted in the FAS.  In addition, Per-protocol analysis for 
primary endpoint will be performed.  All tests will be 2-sided at an α level of 0.05.  
"Baseline" refers to the last non-missing observation before the first administration of 
study drug or randomization if no study drug is given.
There are two sets of planned efficacy analysis: efficacy analysis for Double-Blind Period 
and long-term efficacy analysis.
The primary analysis will be performed after all subjects have completed the Double-
Blind Period or have discontinued study in the Double-Blind Period and the database has 
been locked.  This will be the only and final analysis for the primary and secondary 
efficacy endpoints as well as all other efficacy endpoints in the Double-Blind Period.  
Analyses will be performed for the protocol defined primary time point by randomized 
treatment groups (upadacitinib 15 mg QD and the placebo group).  No protocol-defined 
treatment switching will occur in the Double-Blind Period.  Formal statistical inference 
will be generated, and results from this set of analyses will be used as the key efficacy 
findings of this study.
Unless otherwise specified, binary variables will be analyzed using Cochran-Mantel-
Haenszel (CMH) test, stratified by screening hsCRP level status (hsCRP > ULN, 
 


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hsCRP ≤ULN).  Continuous variables will be analyzed using Mixed-Effect Model Repeat 
Measurement (MMRM) method or Analysis of Covariance (ANCOVA) method adjusting 
for screening hsCRP level status.  Unless otherwise specified, any subject who is 
randomized based on a wrong stratum will be analyzed according to the actual stratum the 
subject belongs to.
Long-term efficacy analysis at Week 104 will be performed after all subjects have 
completed the Week 104 visit or have prematurely discontinued prior to Week 104. This 
will be the final efficacy analysis for Study 1.  There will be no statistical testing for long-
term efficacy analysis up to Week 104; descriptive statistics will be provided by 
randomized treatment group sequences as described below:
1.
Placebo →Upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →Upadacitinib 15 mg QD
8.2
Handling of Missing Data and Intercurrent Events
Missing data could occur due to various reasons, including missing visits/assessments, 
early withdrawal from the study, or missing due to COVID-19 infection or logistic 
restriction.
The COVID-19 pandemic is interfering with the conduct of many ongoing trials, with 
potential impact on treatment duration and the collection, analysis, and interpretation of 
clinical trial data.  Some protocol-specified visits in the clinical trials may be impacted 
due to COVID-19 infection or logistical restrictions during the pandemic.  For example, 
some scheduled visits may be missed due to self-quarantine or local government 
restrictions on travel; some visits may also be delayed or canceled due to healthcare 
resource constraints during the pandemic.  Impacted visits due to COVID-19 will be 
recorded in the database.  The probability of having missed visits and missing data due to 
COVID-19 infection or logistical restrictions related to the COVID-19 pandemic can be 
reasonably assumed to be unrelated to the unobserved values.  Therefore, for the purpose 
 


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of statistical analysis, it is reasonable to assume that these missing data are missing at 
random (MAR) and the statistical models that require MAR assumption are appropriate.  
The intent is to provide reliable estimates of the treatment effects targeted in the protocol
under the scenario without the impact of COVID-19 pandemic.  Sensitivity analyses will 
be performed to assess the impact of missing data and the robustness of the conclusion.  
Number of subjects with missing values due to COVID-19 will be presented.
Intercurrent events include discontinuation of study drug and initiation of rescue 
medication.  Missing data and intercurrent events will be handled using the following 
methods for efficacy analysis.
8.2.1
Binary Endpoints
The primary estimand for binary endpoints is the composite estimand,4 defined in 
Section 8.3.1.  NRI-MI and NRI analysis will be used for the primary estimand.
Non-Responder Imputation in conjunction with Multiple Imputation (NRI-MI)
For binary endpoints, NRI-MI will be used as the primary approach for handling missing 
data and intercurrent events for the primary estimand (refer to Section 8.3.1).  It will 
handle intercurrent events and missing data as follows.
1.
Subjects who prematurely discontinue study drug or use rescue therapy will be 
categorized as non-responders for visits after study drug discontinuation or rescue 
initiation.
2.
Missing data due to COVID-19 infection or logistical restriction will be handled by 
Multiple Imputation.
3.
Additional missing data due to other reasons will be categorized as non-responders.
For composite binary endpoints such as ASAS40, ASAS20 and ASAS PR, missing values 
in the continuous component variables will be imputed via MI, and the composite binary 
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outlined in Appendix E.  For other binary endpoints which are directly dichotomized from 
a continuous score, missing values in the continuous score will be imputed via MI, and 
the dichotomized binary endpoint will be derived from the multiple imputed continuous 
scores.
Non-Responder Imputation (NRI)
NRI will be used as a sensitivity analysis for binary endpoints for the primary estimand 
(refer to Section 8.3.1).  It will handle intercurrent events and missing data as follows.
1.
Subjects who prematurely discontinue study drug or use rescue therapy will be 
categorized as non-responders for visits after study drug discontinuation or rescue 
initiation.
2.
Additional missing data including those due to COVID-19 infection or logistical 
restriction will also be categorized as non-responders.
The treatment policy estimand4 will be used as a supplementary analysis (refer to 
Section 8.3.4), facilitated by the As Observed (AO) data handling, where all observed data 
will be used, regardless of premature discontinuation of study drug or use of rescue 
therapy.  Missing data will be categorized as non-responders.  Sensitivity analyses for 
missing data handling using MI (refer to the MI steps under Appendix E) and tipping 
point analysis (refer to Appendix F) will also be conducted.
8.2.2
Continuous Endpoints
The primary estimand for continuous endpoints is the treatment policy estimand4 (refer to 
Section 8.4.2), where all observed data will be used, regardless of premature 
discontinuation of study drug or use of rescue therapy.  Mixed-Effect Model Repeat 
Measurement (MMRM) will be used as the primary approach for handling missing data, 
and Multiple Imputation (MI) will be used as a sensitivity analysis.
 


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Mixed-effect Model Repeat Measurement (MMRM)
MMRM will be utilized for the treatment policy estimand for all continuous endpoints.  
The repeated measure analysis will be conducted using mixed model.  The mixed model 
includes the categorical fixed effects of treatment, visit and treatment-by-visit interaction, 
main stratification factor of screening hsCRP level (> ULN vs ≤ ULN) and the continuous 
fixed covariates of baseline measurement.  An unstructured variance covariance matrix 
will be used.  The parameter estimations are based on the assumption of data being 
missing at random and using the method of restricted maximum likelihood (REML).  The 
MMRM approach is appropriate in handling missing data due to COVID-19 infection or 
logistical restriction given the validity of the missing at random assumption.
Multiple Imputation (MI)
As a sensitivity analysis, MI will be utilized to handle missing data for the treatment 
policy estimand for multiplicity controlled secondary continuous endpoints.  The MI 
analysis will impute missing data multiple times under appropriate random variation and 
thus generate multiple imputed "pseudo-complete" datasets.  SAS PROC MI will be used 
to generate 30 datasets using a two-step approach, augmentation step using MCMC and 
imputation step using Monotone Regression, as described in Appendix E.  Specifically, 
treatment group is included in the MI model to enable stratified sampling.  Additionally, 
the imputation model includes demographics variables and baseline disease 
characteristics, as well as longitudinal response observed at any other visits.  An 
ANCOVA model will be performed on each of the multiple imputed datasets adjusting for 
treatment, stratification factor and baseline value.  Subsequently SAS PROC 
MIANALYZE will be used to aggregate the results for the final statistical inference using 
Rubin's method.  To assess the impact of potential departures from the MAR assumption, 
tipping point analyses (refer to Appendix F) will also be conducted to as a sensitivity 
check for multiplicity-controlled secondary continuous endpoints.
 


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8.2.3
Long-Term Efficacy
For long-term efficacy analysis for binary endpoints, NRI-MI and NRI will continue to be 
used for the primary estimand (composite estimand).  In addition, the AO data handling 
will be used to facilitate the supplementary analysis using the treatment policy estimand, 
regardless of premature discontinuation of study drug or use of rescue therapy, all 
observed data will be used in the analysis and missing data will be handled by GLMM as 
described below.
For continuous endpoints, the treatment policy estimand will continue to be used, 
facilitated by AO data handling. Missing data will be handled by MMRM as described 
below.
MMRM and Generalized Linear Mixed Model (GLMM) for Long-Term Efficacy
The repeated measures analysis will be conducted using mixed model.  MMRM will be 
used for continuous endpoints and GLMM will be used for binary endpoints.  The mixed 
models will include the categorical fixed effects of treatment sequence, visit and treatment 
sequence -by-visit interaction, and stratification factor screening hsCRP level (≤ ULN vs. 
> ULN).  For the MMRM analysis of change from baseline in continuous endpoints, the 
baseline measurement will be included as a continuous fixed covariate.  Other baseline 
covariates may also be included in the model as appropriate.  Unstructured, Toeplitz, 
compound symmetry, or other covariance structures may be considered.
8.3
Primary Efficacy Endpoint and Analyses
8.3.1
Primary Efficacy Endpoint
The primary efficacy endpoint is ASAS40 response at Week 14.  In the composite 
estimand framework, the primary estimand is the difference in the proportion of AS 
patients who achieved an ASAS40 response at Week 14 and did not discontinue study 
drug by Week 14, comparing those who are randomized to the upadacitinib 15 mg QD 
group and received study drug to those who are randomized to placebo and received study 
 


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drug.  The attributes of the primary estimand corresponding to the primary efficacy 
endpoint are summarized in Table 2.
Table 2.
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
Population
Intercurrent Events 
(IE)
Statistical 
Summary
Primary:  
Composite 
Estimand
Upadacitinib 
15 mg QD 
vs. placebo
Achievement 
of ASAS40 at 
Week 14, 
remain in the 
study and on 
study drug 
through 
14 weeks.
Full 
Analysis Set
IE: premature 
discontinuation of study 
drug.
Subjects will be 
considered as non-
responders at visits after 
IE.
Difference 
in the 
proportion 
of subjects 
achieving 
the endpoint
8.3.2
Handling of Missing Data and Intercurrent Events for the 
Primary Efficacy Endpoint
For the primary estimand, NRI-MI data handling as defined in Section 8.2.1 will be used:  
Subjects who prematurely discontinue study drug prior to Week 14 will be categorized as 
non-responders for visits after study drug discontinuation.  Missing data due to 
COVID- 19 infection or logistic restriction will be handled by MI. Additional missing 
ASAS40 response due to other reasons will be categorized as non-responders.  To 
facilitate the interpretation of the estimand, ASAS40 response will be summarized into the 
following categories for each randomized treatment group:
1.
Subjects who prematurely discontinue study drug by Week 14
2.
Subjects who did not discontinue study drug but are missing Week 14 
ASAS40 measurements due to COVID-19 infection or logistical restriction.
3.
Subjects who did not discontinue study drug but are missing Week 14 
ASAS40 measurements due to other reasons.
 


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4.
Subjects with ASAS40 measurements observed and on study drug at Week 14
8.3.3
Primary Efficacy Analysis
Analysis of the primary endpoint will be conducted on the FAS based on randomized 
treatment groups (upadacitinib 15 mg QD and the placebo group).  The treatment 
comparison will be conducted using the Cochran-Mantel-Haenszel (CMH) model adjusted 
by main stratification factor of screening hsCRP level (> ULN vs ≤ ULN).  The analysis 
will be conducted on each of the 30 datasets generated by NRI-MI.  Results will be 
integrated by SAS PROC MIANALYZE using Rubin's rule.  The following statistics will 
be provided: response rate for each randomized treatment group and associated 95% CIs; 
response rate difference between upadacitinib group and placebo group, associated 95% 
CI, and p-value.
8.3.4
Sensitivity Analyses, Supplementary Analyses, and 
Additional Analyses of the Primary Efficacy Endpoints
To assess the robustness of the primary analysis using NRI-MI, a sensitivity analysis for 
the primary estimand will be performed for the primary endpoint using NRI data handling 
as defined in Section 8.2.1.  The same CMH analysis as described for the primary analysis 
will be applied. The following statistics will be provided: response rate for each 
randomized treatment group and associated 95% CIs; response rate difference between 
upadacitinib group and placebo group, assocated 95% CI, and p-value.
As a supplementary analysis for the primary efficacy endpoint under the treatment policy 
estimand, the same CMH analysis will be repeated using As Observed (AO) data, 
regardless of adherence to study drug.  Subjects with missing ASAS40 response will be 
treated as non-responders.  This will be conducted on the FAS based on randomized 
treatment groups.  The corresponding treatment policy estimand for the supplementary 
analysis is the difference in the proportion of AS patients who achieved ASAS40 response 
at Week 14, regardless of whether the subject had discontinued study drug by Week 14, 
 


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comparing upadacitinib 15 mg QD vs placebo for those who are randomized and received 
study drug.
For the treatment policy estimand, additional sensitivity analyses using AO data will also 
be conducted using MI to handle missing ASAS40 responses (as outlined in Section 8.2.1
and details in Appendix E).  In order to assess the deviation from missing at random 
(MAR) assumptions, tipping point analysis will also be conducted for the primary 
endpoint.  Details of the analysis are outlined in Appendix F.
Supportive analyses will also be conducted on the Per Protocol Analysis Set using the 
same CMH model and NRI-MI data handling as the primary analysis.
8.4
Secondary Efficacy Analyses
8.4.1
Primary Analyses and Sensitivity Analyses of Secondary 
Efficacy Endpoints
The secondary endpoints are defined in Section 3.2.  The attributes of the estimands 
corresponding to the secondary efficacy endpoints are summarized in Table 3.
 


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Table 3.
Summary of the Estimand Attributes of the Secondary Efficacy 
Endpoints
Estimand 
Label
Attributes of the Estimand
Treatment
Endpoint
(at Week 14)
Population
Handling 
Intercurrent Events
Statistical 
Summary
Binary 
Secondary:  
Composite 
Estimand
Upadacitinib 
15 mg QD 
vs. placebo
Remain in the 
study and on 
study drug 
through 14 
weeks; and 
achievement of 
each secondary 
endpoint 
respectively.  
Full 
Analysis 
Set 
IE (Intercurrent 
Events): premature 
discontinuation of 
study drug
Subjects will be 
considered as non-
responders at visits 
after IE.
Difference in 
proportion of 
subjects 
achieving each 
binary 
secondary 
endpoint
Continuous 
Secondary:  
Treatment 
Policy
Estimand
Upadacitinib 
15 mg QD 
vs. placebo
Change from 
Baseline in the 
respective 
secondary 
endpoints
Full 
Analysis 
Set 
IE: premature 
discontinuation of 
study drug.
All Observed data 
will be used 
regardless of IE. 
Difference in 
the mean 
change from 
Baseline in 
each 
continuous 
secondary 
endpoint
For binary endpoints, the primary estimand and analysis method are the same as that for 
the primary efficacy endpoint as defined in Section 8.3.1, except for the definition of the 
efficacy measurement.  NRI-MI and NRI data handling will be used to analyze the 
primary estimand.
For secondary continuous efficacy endpoints, the primary analyses will be performed 
using all data as observed, regardless of adherence to study drug, using the treatment 
policy estimand framework.  The statistical inference will be conducted using the MMRM 
model and the associated data handling as described in Section 8.2.2, with the main 
stratification factor of screening hsCRP status (hsCRP > ULN, hsCRP ≤ ULN).  The 
corresponding estimand is the difference in the mean change from baseline in the efficacy 
endpoints regardless of premature discontinuation of study drug.  The LS mean and 95% 
CI will be reported for each randomized treatment group; the LS mean treatment
 


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difference and associated 95% CI and p-value will be reported comparing upadacitinib 
with the placebo group. For this estimand, sensitivity analyses will be conducted using 
MI under MAR assumption as outlined in Section 8.2.2 for multiplicity-controlled 
secondary continuous endpoints. To assess deviations from MAR, the tipping point 
analyses will also be conducted as additional sensitivity analyses. Details of the MI and 
tipping point analysis are outlined in Appendix E and Appendix F.
8.4.2
Supplementary Analyses of Secondary Binary Efficacy 
Endpoints
For binary endpoints, similar analysis as the supplementary analysis for the primary 
endpoint will be conducted using CMH including all data as observed, regardless of 
adherence to study drug, with missing response treated as non-responders.  The 
corresponding supplementary estimand is the same as defined in Section 8.3.4 except for 
the definition of the efficacy measurement.
For multiplicity-controlled secondary binary variables, additional sensitivity analyses for 
the treatment policy estimand will be conducted using MI as outlined in Section 8.2 under 
MAR assumption.  To assess deviations from MAR, the tipping point analysis will also be 
conducted as additional sensitivity analysis.  Details of the MI and tipping point analysis 
are outlined in Appendix E and Appendix F.
8.5
Additional Efficacy Analyses
Additional endpoints defined in Section 3.3 will be analyzed at scheduled time points 
other than those specified for the primary and secondary variables.
Additional Efficacy Analyses for the Double-Blind Period
Additional endpoints will be analyzed for each randomized treatment group for all visits 
in the Double-Blind Period using similar statistical methods as for the primary estimand 
for the primary and secondary endpoints.
 


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For binary endpoints, the following statistics will be provided: response rate for each 
randomized treatment group and associated 95% CIs; response rate difference between 
upadacitinib group and placebo group and associated 95% CIs.  Only nominal p-values 
will be provided.  The primary estimand and analysis method are the same as that for the 
primary efficacy endpoint as defined in Section 8.3, except for the definition of the 
efficacy measurement.  NRI-MI and NRI data handling as described in Section 8.2.1 will 
be used.
For continuous endpoints, the LS mean and 95% CI will be reported for each randomized 
treatment group.  The LS mean treatment difference and associated 95% CI and p-values 
between upadacitinib and the placebo group will be provided using MMRM model with 
fixed effects of treatment, visit and treatment-by-visit interaction, screening hsCRP level 
(≤ ULN vs. > ULN) and baseline value as covariate.  Only nominal p-values will be 
provided.  
For the ASAS components (the 4 components are Patient's Global Assessment of Disease 
Activity NRS score; Patient's Assessment of Total Back Pain NRS score; BASFI; 
Inflammation (mean of items 5 and 6 of BASDAI NRS scores 0 – 10)), the mean and 
standard deviation at baseline and Week 14 will be provided based on AO data.  
Long-Term Efficacy Analyses
Assessments to evaluate long-term efficacy will be analyzed for all efficacy 
measurements at scheduled visits.
For binary endpoints (except discontinuation of opioids use), NRI-MI and NRI will be 
used for data handling, corresponding to the composite estimand.  Descriptive statistics, 
including point estimate and 95% CI, will be provided for each randomized treatment 
sequence as defined in Section 8.1.  A supplementary analysis, corresponding to the 
treatment policy estimand, will be carried out using GLMM defined in Section 8.2.3
based on AO data.  Estimated response rate with 95% CI from GLMM will be provided, 
in addition to descriptive statistics.  For the endpoint "discontinuation of opioids among 
 


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subjects with opioid use at Baseline," descriptive statistics will be provided based on AO 
data.
For continuous endpoints, corresponding to the treatment policy estimand, MMRM model 
(as described in Section 8.2.3) will be used on AO data.  Mean estimates with 95% CIs 
will be provided for each randomized treatment sequence.  In addition, descriptive 
statistics on AO data will be provided, including the number of observations, mean, 
standard deviation, and 95% CI.
Plots for each randomized treatment group sequence over time will be provided for the 
primary and multiplicity-controlled secondary endpoints and selected additional 
endpoints.
A summary of the primary, sensitivity and supplementary analyses for the DB Period and 
long-term analyses are provided in Table 4, Table 5 and Table 6 below. 
 


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Table 4.
Summary of Analysis for Binary Variables in DB Period
Endpoints
Estimand
Analysis
Missing Data 
and Intercurrent 
Event Handling
Model
Primary endpoint, 
secondary 
endpoints, and 
additional 
endpoints#
Composite estimand 
on Full Analysis Set
Primary
NRI-MI 
Comparison of 
upadacitinib vs 
placebo using 
CMH test adjusted 
by main 
stratification 
factor.
Sensitivity
NRI
Primary endpoint
Composite estimand 
on per protocol 
analysis set
Supportive
NRI-MI
Primary endpoint 
and secondary 
endpoints
Treatment policy 
estimand on Full 
Analysis Set
Supplementary 
As Observed, 
with Non-
responder 
imputation for 
missing data
Primary endpoint 
and multiplicity-
controlled 
secondary 
endpoints
Sensitivity
As Observed, 
with MI for 
missing data; 
Tipping point 
analysis 
NRI = Non-Responder Imputation; MI = Multiple Imputation; CMH = Cochran–Mantel–Haenszel
#
Additional endpoints include binary endpoints listed in Section 3.3 except Discontinuation of opioids among 
subjects with opioid use at Baseline.  For this endpoint, descriptive summaries will be based on As Observed data.
 


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Table 5.
Summary of Analysis for Continuous Variables in DB Period
Endpoints
Estimand
(on FAS)
Analysis
Missing Data and 
Intercurrent Event 
Handling
Model
Secondary 
endpoints 
and 
additional 
endpoints
Treatment policy 
estimand
Primary 
As Observed 
MMRM 
Multiplicity-
controlled 
secondary 
endpoints
Sensitivity
As Observed, with 
missing data handled 
by MI, including 
tipping point analysis 
using MI
ANCOVA 
FAS = Full Analysis Set; MMRM = Mixed-Effect Model Repeat Measurement; ANCOVA = Analysis of Covariance; 
MI = Multiple Imputation
Table 6.
Summary of Long-Term Analysis
Endpoints
Estimand
(on FAS)
Analysis
Missing Data 
and Intercurrent 
Event Handling
Model
All Binary 
Endpoints#
Composite estimand
Primary
NRI-MI 
Descriptive Only
Sensitivity
NRI
Descriptive Only
Treatment policy 
estimand
Supplementary
As Observed
GLMM
All 
Continuous 
Endpoints
Treatment policy 
estimand
Primary 
As Observed 
MMRM
FAS = Full Analysis Set; NRI = Non-Responder Imputation; MI = Multiple Imputation; MMRM = Mixed-Effect Model 
Repeat Measurement; GLMM = Generalized Linear Mixed Model
#
All binary endpoints include binary endpoints listed in Section 3.3 except Discontinuation of opioids among 
subjects with opioid use at Baseline.  For this endpoint, descriptive summaries will be based on As Observed data.
8.6
Efficacy Subgroup Analyses
The primary efficacy endpoint will be examined in the subgroups listed in Table 7 below.  
If any of the subgroup categories has fewer than 30 subjects per treatment, the category 
may be merged with other categories for analysis.  Treatment difference between 
 


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upadacitinib and the placebo group will be presented with point estimate and 95% 
confidence interval using the same analysis method as the primary analysis, adjusting for 
the main stratification factor of screening hsCRP level. For any subgroup, if there are 
zero subjects within a stratum in any treatment group, the analysis will not be adjusted by 
the stratification factor.  No p-value will be provided for subgroup analysis.  A forest plot 
will be provided for the subgroup analyses.
Table 7.
Subgroups for Efficacy Analysis
Subgroup Factor
Categories
Age
< 40, ≥ 40
Sex
Male or Female
BMI
< 25, ≥ 25
Race
White vs non-White 
Geographic Region
North America, South/Central America, Western 
Europe, Eastern Europe, Asia, Other
hsCRP level at screening
prior bDMARD exposure
Duration of AS symptom
Duration since AS diagnosis
≤ ULN vs > ULN
One TNF Inhibitor, One IL-17 Inhibitor, Other
< 5, [5, 10), ≥ 10 years
< 5, [5, 10), ≥ 10 years
9.0
Safety Analyses
9.1
General Considerations
Safety data will be summarized for the Safety Analysis Set.  For the safety analysis, 
subjects are assigned to a treatment group based on the treatment actually received, 
regardless of the treatment randomized.  A subject's actual treatment will be determined 
by the most frequent dose regimen received.  Missing safety data will not be imputed.
There are two sets of planned safety analysis:  safety analysis for the Double-Blind 
Period, and long-term safety analysis.
 


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Safety Analysis for the Double-Blind Period
Standard safety analysis by the actual treatment groups of upadacitinib 15 mg QD and 
placebo group will be performed on safety data in the Double-Blind Period.  No protocol-
defined treatment switching will occur in the Double-Blind Period.
The standard safety analyses will include reporting of adverse events (AEs), laboratory, 
and vital signs measurements.  Frequency tables of subjects with treatment-emergent 
adverse events (TEAEs) by system organ class (SOC) and by preferred term (PT) as in the 
Medical Dictionary for Regulatory Activities (MedDRA) dictionary will be provided by 
treatment group.  All continuous laboratory parameters and vital signs variables at each 
visit will also be summarized by actual treatment group.  Frequency tables of subjects 
meeting criteria for potentially clinically significant vital sign values (defined in 
Appendix C) and for potentially clinically significant laboratory values (Grade 3 and 
Grade 4 in severity based on CTCAE V4.03) will be provided by treatment group.  Shift 
of laboratory values from Baseline to defined time points will be tabulated.
Long-Term Safety Analysis
To adjust for potentially different follow-up time between treatment groups, exposure-
adjusted event rate (EAER) will be provided for long-term safety analysis.  For the 
purpose of event rate calculation, the numerator will be the total number of AEs reported 
for the event (i.e., a subject can contribute more than one event to the numerator) and the 
denominator will be the total exposure time among subjects under the treatment group.  
The number of AEs reported (numerator), the total number of years of study drug 
exposure (denominator calculated as total number of days exposed to study drug for all 
treated subjects divided by 365.25), and the exposure-adjusted AE event rate per 
100 patient-years calculated as ([numerator (number of AEs)/denominator]) • 100 will be 
presented for each treatment group.  The EAER will be the main approach to evaluate 
AEs in the long-term analysis.
 


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In addition, treatment-adjusted incidence rate (EAIR) (censored at first event) will be 
conducted for AESI endpoints as deemed appropriate for long-term analysis.  For the 
purpose of incidence rate calculation, the numerator will be the number of subjects with 
AE reported for the event (i.e., a subject can contribute at most once to the numerator) and 
the denominator will be the total exposure time among subjects in the treatment group and 
at risk of an initial occurrence of the event, i.e., for subjects with no event, it is the total 
exposure time under the treatment group; for subjects with an event, it is the exposure 
time to the first event.  The numerator, denominator (calculated as total number of days 
exposed to study drug for all treated subjects divided by 365.25), and the exposure-
adjusted incidence rate per 100 patient-years calculated as ([numerator/denominator]) • 
100 will be presented for each treatment group.
Long-term safety analyses that account for protocol-defined treatment switching include 
reporting of AE rate adjusted by cumulative exposure, descriptive summary in laboratory 
parameters and vital sign variables, and frequency and percentage of potentially clinically 
significant laboratory and vital signs values.  The EAER will be presented by actual 
treatment received at the time of AE.  Listing of subjects with TEAEs by SOC and PT 
will be provided.  Frequency tables and listings of subjects meeting criteria for potentially 
clinically significant vital sign values and for potentially clinically significant laboratory 
values will be provided by actual treatment received at the time of event.  All continuous 
laboratory parameters and vital signs variables at each visit will be summarized by actual 
treatment group sequences defined as follows.
Actual treatment group sequences:
1.
Placebo →Upadacitinib 15 mg QD
2.
Upadacitinib 15 mg QD →Upadacitinib 15 mg QD
 


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9.2
Adverse Events
A treatment-emergent Adverse Event (TEAE) is defined as an adverse event with an onset 
date that is after the first dose of study drug, and no more than 30 days of the drug after 
the last dose of study drug.  Events where the onset date is the same as the study drug start 
date are assumed to be treatment-emergent, unless the study drug start time and the 
adverse event start time are collected and the adverse event start time is prior to the study 
drug start time.  If an incomplete onset date was collected for an adverse event, the event 
will be assumed to be treatment-emergent unless there is other evidence that confirms that 
the event was not treatment-emergent (e.g., the event end date was prior to the study drug 
start date).
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) using MedDRA Version 22.0 or most up 
to date version.  The actual version of the MedDRA coding dictionary used will be noted 
in the AE tables and in the clinical study report.  Specific adverse events will be counted 
once for each subject for calculating percentages, unless stated otherwise.  In addition, if 
the same adverse event occurs multiple times within a subject, the highest severity and 
level of relationship to investigational product will be reported.
9.2.1
Analysis of Adverse Events for Double-Blind Period
9.2.1.1
Adverse Event Overview
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE
●
Any COVID-19 related TEAEs
●
TEAEs reasonably possibly related to study drug
●
Any severe treatment-emergent AE
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
 


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●
Any treatment-emergent AE leading to death
●
All deaths
○
Deaths occurring ≤ 30 days after last dose of study drug
●
COVID-19 related deaths occurring ≤ 30 days after last dose of study 
drug
○
Deaths occurring > 30 days after last dose of study drug.
●
COVID-19 related deaths occurring > 30 days after last dose of study
drug
Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.  Any event with an unknown severity 
will be considered as severe and any AE with an unknown relationship will be considered 
as drug related.
The number and percentage of subjects experiencing at least one event of treatment-
emergent AEs will be summarized for each treatment group.  The point estimate and 
95% CI (using normal approximation and separate group variance) will be provided for 
the treatment difference in AE percentage between upadacitinib group and the placebo 
group.  An overview of the AE of special interest (AESI) will be provided similarly and 
the categories of AESI is defined in Section 9.2.1.4.
9.2.1.2
Treatment-Emergent Adverse Events by SOC and PT
Treatment-emergent adverse events will be summarized by SOC and PT, the following 
summaries of adverse events will be generated:
●
All TEAEs
●
Treatment-emergent serious adverse events (SAEs)
●
Treatment-emergent severe adverse events
●
TEAEs reasonably possibly related to study drug
●
TEAEs leading to discontinuation of study drug
●
TEAE leading to death
 


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●
COVID-19 related TEAEs
●
Frequent AEs (reported in 2% of subjects or more in any treatment group)
Subjects reporting more than one adverse event for a given MedDRA preferred term will 
be counted only once for that term (most severe incident for the severity tables and most 
related incident for the relationship tables).  Subjects reporting more than one type of 
adverse event within a SOC will be counted only once for that SOC.  Subjects reporting 
more than one type of adverse event will be counted only once in the overall total.
TEAEs will also be summarized by relationship to upadacitinib and placebo, as assessed 
by the investigator, by treatment groups.  If a subject has a TEAE with an unknown 
relationship, then the subject will be counted in the relationship category of "unknown," 
even if the subject has another occurrence of the same event with a relationship present.  
The only exception is if the subject has another occurrence of the same TEAE with a 
relationship assessment of "reasonable possibility."  In this case, the subject will be 
counted under the "reasonable possibility" category.
TEAEs will also be summarized by maximum severity by treatment groups.  If a subject 
has an AE with an unknown severity, then the subject will be counted in the severity 
category of unknown, even if the subject has another occurrence of the same event with a 
severity present.  The only exception is that if the subject has another occurrence of the 
same AE with the most extreme severity – severe.  In this case, the subject will be counted 
under the severe category.
The SOCs will be presented in alphabetical order, and the PTs will be presented in 
alphabetical order within each SOC.
TEAEs and reasonably possibly related AEs occurring for more than 2% of the subjects in 
any of the treatment groups will be summarized by MedDRA PT and sorted by decreasing 
frequency for the active group separately.
 


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9.2.1.3
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
SAEs (including deaths) and AEs leading to study drug discontinuation, and any AEs 
related to COVID-19 will be listed in tables, besides summary by SOC and PT covered in 
Section 9.2.1.2.
9.2.1.4
Adverse Events of Special Interest
Adverse events of special interest will be summarized by SOC and PT and will be based 
on standardized or company MedDRA queries (SMQs or CMQs).  Adverse events of 
special interest are categorized in Table 8 below.  Adjudicated cardiovascular events will 
be summarized and presented by treatment group using the CAC adjudicated categories.
Table 8.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Serious Infections
CMQ
"Infections" – Subset for SAEs
Opportunistic Infection
excluding Tuberculosis and 
Herpes Zoster
CMQ
"Opportunistic Infection excluding 
Tuberculosis and Herpes Zoster"
Possible Malignancy
SMQ
Narrow
"Malignancies"
Malignancy
SMQ
Narrow
"Malignant tumours"
Non-Melanoma Skin Cancer 
(NMSC)
SMQ
Narrow
Skin Malignant tumours (Narrow SMQ) 
removing Melanoma CMQ
Malignancy excluding NMSC
"Malignant tumours" SMQ (Narrow) 
removing NMSC output
Lymphoma
SMQ
Broad
"Malignant Lymphomas"
Hepatic Disorder
SMQ
Narrow
"Drug Related Hepatic Disorders" 
comprehensive search
Adjudicated Gastrointestinal 
Perforations
Output from 
adjudication
Anemia
CMQ
"Non-Hemolytic and Non-Aplastic 
Anemias"
Neutropenia
CMQ
"Hematological Toxicity – Neutropenia"
 


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Table 8.
AESI for Upadacitinib with SMQs/CMQs/PTs Searches 
(Continued)
AESI
Type of 
MedDRA 
Query
Broad or 
Narrow 
Search
SMQ/CMQ Search Criteria
Lymphopenia
CMQ
"Hematological Toxicity – Lymphopenia"
Herpes Zoster
CMQ
"Herpes Zoster"
Renal Dysfunction
SMQ
Narrow
"Acute Renal Failure"
Active Tuberculosis
CMQ
"Active Tuberculosis"
Adjudicated Cardiovascular 
Events
Output from 
CAC
MACE*
Cardiovascular Death
Non-fatal Myocardial 
Infarction
Non-fatal Stroke
Undetermined/Unknown 
Cause of Deaths
Other Cardiovascular events
Adjudicated Thrombotic Events
Output From 
CAC
Venous Thromboembolic 
Events**
Deep Vein Thrombosis
Pulmonary Embolism
Other Venous Thrombosis
Arterial Thromboembolic 
Events (non-cardiac, non-
neurologic)
CAC = Cardiovascular Adjudication Committee; CMQ = company MedDRA query; PT = preferred term; 
SMQ = standard MedDRA query
*
MACE; Major Adverse Cardiovascular Events, defined as cardiovascular death, non-fatal myocardial infarction 
and non-fatal stroke.
**
Venous thromboembolic events (VTE) include deep vein thrombosis (DVT) and pulmonary embolism (PE) (fatal 
and non-fatal).
 


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Additional AEs may be considered for tabulation/summary based on recommendations 
from Clinical and Safety as deemed appropriate.
9.2.2
Analysis of Long-Term Adverse Events 
9.2.2.1
Overview of Adverse Events Rates per 100 Patient-Years of 
Study Drug Exposure
An overview of AEs per 100 patient-years of study exposure will be presented for the AE 
categories defined in short term.
The number of TEAEs reported, the total number of years of study drug exposure, and the 
TEAE rate per 100 patient-years will be presented for the Any Upadacitinib 15 mg QD 
group.  The Any Upadacitinib 15 mg QD treatment group is defined as subjects who 
receive at least one dose of upadacitinib 15 mg QD at any time during the study.  This 
includes AEs occurring under upadacitinib 15 mg QD exposure from subjects starting on 
upadacitinib 15 mg QD and subjects switching from placebo to upadacitinib 15 mg QD.
An overview of AESIs per 100 patient-years of study exposure will be presented 
similarly.  Any event with an unknown severity will be considered as severe and any AE 
with an unknown relationship will be considered as drug related.
9.2.2.2
Adverse Events Rates per 100 Patient-Years of Study Drug 
Exposure by SOC and PT
The TEAE rate per 100 patient-years of exposure will be calculated overall, for each SOC 
and PT, for the same events defined in short term and reported for Any Upadacitinib 15 
mg QD group.
The TEAE rate per 100 patient-years of exposure will be summarized by relationship and 
by severity for the Any Upadacitinib 15 mg QD group.
 


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9.2.2.3
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation per 100 Patient-Years of Study 
Drug Exposure
SAEs (including deaths) and AEs leading to study drug discontinuation, and any AEs 
related to COVID-19 will be listed in tables, besides summary by SOC and PT covered in 
Section 9.2.2.2.
9.2.2.4
Adverse Events of Special Interest Rates per 100 Patient-
Years of Study Drug Exposure
The Adverse Events of Special Interest (AESI) will be summarized and presented for the 
Any Upadacitinib 15 mg QD treatment group using MedDRA SOC and PT (for 
adjudicated cardiovascular events, the CAC adjudicated categories will be used).  The 
AESIs will be identified per the search criteria as specified in Table 8.
The Adverse Events of Special Interest (AESI) rate per 100 patient-years of exposure will 
be calculated overall, for each SOC and each PT, for each of the AESI listed in 
Section 9.2.1.4.
9.3
Analysis of Laboratory Data
Data collected from central and local laboratories, including additional laboratory testing 
due to an SAE, will be used in all analyses, except for Baseline where SAE-related 
laboratory assessments on or before the first dose of study drug will be excluded.  
Each laboratory variable will be summarized for all time points (starting with Baseline) 
with the number of non-missing observations, mean and standard deviation, median, 
minimum and maximum.  Mean change from baseline to each applicable post-baseline 
visit will be summarized for selected laboratory variables, with the number of 
observations, baseline mean, and visit mean.  The change from baseline mean, standard 
error, and 95% confidence interval will be presented for the mean change from baseline 
within each treatment group and difference between treatment groups (upadacitinib vs. 
placebo).
 


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Changes in laboratory parameters will be tabulated using shift tables by CTCAE 
criteria 4.032.  A shift table from baseline to the worse value (based on CTCAE criteria) 
during treatment will be created.  A similar shift table will be provided to summarize 
shifts from baseline to the final post-baseline value.
Laboratory abnormalities will be evaluated based on Potentially Clinically Significant 
(PCS) criteria (Appendix B).  For each laboratory PCS criterion, the number and 
percentage of subjects who have a laboratory value meeting CTCAE criteria grade 3 and 4 
will be summarized.  Listings will be provided to summarize subject-level laboratory data 
for subjects meeting PCS criteria.  A listing of possible Hy's Law cases will be provided.
9.3.1
Variables and Units
Safety laboratory parameters to be summarized in this study are listed below.  Laboratory 
parameters will be reported using the standard international (SI) units.
Table 9.
List of Safety Laboratory Variables
Laboratory Variables
Hematology
Leukocytes (White Blood Cell Count)
Erythrocytes (Red Blood Cell Count)
Hemoglobin
Hematocrit
Platelets 
Neutrophils
Basophils
Eosinophils
Lymphocytes
Monocytes
Erythrocytes Mean Corpuscular Volume
Reticulocytes/Erythrocytes
 


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Table 9.
List of Laboratory Variables (Continued)
Laboratory Variables
Chemistry
Total Bilirubin
Alkaline Phosphatase (ALP)
Aspartate aminotransferase (AST)
Alanine aminotransferase (ALT)
Total Protein
Albumin
Glucose
Triglycerides
Blood Urea Nitrogen (BUN)
Creatinine
Uric acid
Sodium
Potassium
Calcium
Inorganic Phosphorus
Chloride
Bicarbonate
Cholesterol
LDL cholesterol
HDL cholesterol
LDL/HDL ratio
Cholesterol/HDL ratio
Urinalysis
Specific Gravity
pH
9.3.2
Analysis of Laboratory Data for Double-Blind Period
The laboratory data will be summarized by the "as treated" treatment groups (upadacitinib 
15 mg QD and placebo group).
 


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9.3.2.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables
Analyses of key continuous hematology, chemistry, and urinalysis variables which are 
measured longitudinally will be performed by visits and by treatment group.  For each 
parameter at each visit, the following summary statistics will be presented for each 
treatment group:  sample size, mean, standard deviation, minimum, median and 
maximum.
An ANOVA model with treatment as a factor will be used to compare change from 
baseline between different treatment groups for selected laboratory parameters.  Mean 
difference from placebo and associated 95% CIs will be presented.  The analysis applies 
to the following laboratory parameters of clinical interest: hemoglobin, platelets, 
lymphocytes, neutrophils, leukocytes, creatinine, AST, ALT, Total Bilirubin, LDL, HDL, 
the ratio of LDL to HDL, and total cholesterol.
9.3.2.2
Assessment of Shift from Baseline in Clinical Laboratory 
Variables
The baseline and post-baseline laboratory observations will be categorized as Grade 0, 
Grade 1, Grade 2, Grade 3, and Grade 4 and shifts from baseline grade to worst on-
therapy grade will be summarized.  Toxicity grading scale is based on National Cancer 
Institute Common Toxicity Criteria (NCI CTC) AE version 4.03.  Shift tables from 
Baseline according to the grades will be provided for laboratory variables.
Note that the minimum/maximum category is used, rather than the category of the 
minimum/maximum value.  The two may be different due to variation in the reference 
range.
No statistical tests will be performed for this analysis.
 


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9.3.2.3
Assessment of Potentially Clinically Significant Laboratory 
Values
The criteria for potentially clinically significant laboratory values will be determined by 
CTCAE criteria of Grade 3 or higher.  The number and percentage of subjects meeting the 
criteria for potentially clinically significant laboratory values will be summarized by "as 
treated" treatment group.  Only subjects with worsening in grade compared to baseline 
grade will be captured.
A listing of all subjects with any laboratory determination meeting CTCAE criteria of 
Grade 3 or higher will be provided by Grade.
9.3.2.4
Assessment of Liver Elevations
According to FDA's Guidance for Industry "Drug-Induced Liver Injury:  Premarketing 
clinical evaluation" (July 2009), when aminotransferase (AT) abnormalities indicating 
hepatocellular injury are accompanied by evidence of impaired hepatic function (Total 
Bilirubin elevation > 2 × ULN), in the absence of evidence of biliary obstruction (i.e., 
significant elevation of ALP) or some other explanation of the injury (e.g., viral hepatitis, 
alcohol hepatitis), the combined finding (i.e., Hy's Law cases) represents a signal of a 
potential for the drug to cause severe DILI.
For the purpose of assessing for potential Hy's law cases, the frequencies and percentages 
of subjects with post baseline liver specific function test values that meet the following 
criteria of potential clinical interest will be summarized.  Listings will be provided to 
summarize subject-level laboratory data for subjects meeting liver elevations based on 
criteria specified below:
●
ALT ≥ 3 × ULN
●
ALT ≥ 5 × ULN
●
ALT ≥ 10 × ULN
●
ALT ≥ 20 × ULN
●
AST ≥ 3 × ULN
 


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●
AST ≥ 5 × ULN
●
AST ≥ 10 × ULN
●
AST ≥ 20 × ULN
●
TBL ≥ 2 × ULN
●
Alkaline phosphatase ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 1.5 × ULN
●
ALT and/or AST ≥ 3 × ULN and concurrent TBL ≥ 2 × ULN
9.3.3
Analysis of Long-Term Laboratory Data
9.3.3.1
Assessment of Mean Change from Baseline in Clinical 
Laboratory Variables
Analyses of specified continuous hematology, chemistry, and urinalysis variables which 
are measured longitudinally will be performed by visits and by "as treated" treatment 
group sequences as described in Section 9.1.  For each parameter, the following summary 
statistics will be presented for each treatment group sequence:  sample size, mean, 
standard deviation, minimum, median and maximum.
Analyses will be performed for change from baseline in hemoglobin, platelets, 
lymphocytes, neutrophils, leukocytes, creatinine, AST, ALT, total bilirubin, LDL, HDL, 
the ratio of LDL to HDL, and total cholesterol.
9.3.3.2
Assessment of Potentially Clinically Significant Laboratory 
Values
Long-term laboratory data will also be summarized based on the number and percentage 
of subjects meeting the criteria for potentially clinically significant laboratory values for 
the Any Upadacitinib 15 mg QD group as described in Section 6.0.
The baseline value will be determined by the last non-missing measurement recorded on 
or before the date of the first dose of upadacitinib 15 mg QD.  For a subject who started 
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upadacitinib 15 mg QD exposure would be evaluated against the baseline value defined as 
above. Only subjects with worsening in grade compared to baseline grade will be 
captured.
A listing of all subjects with any laboratory determination meeting CTCAE criteria of 
Grade 3 or higher will be provided by Grade.  For each of these subjects, the whole course 
of the respective parameter will be listed.
9.3.3.3
Assessment of Liver Elevations
The frequencies and percentages of subjects with post-baseline liver-specific function test 
values that meet the criteria of potential clinical interest defined in Section 9.3.2.4 will be 
summarized for Any Upadacitinib 15 mg QD group as described in Section 6.0.
A listing of liver elevations based on criteria specified above will be provided.  For each 
of these subjects, the whole course of the respective parameter will be listed.
9.4
Analysis of Vital Signs
Vital sign measurements of systolic and diastolic blood pressure, pulse rate, respiratory 
rate, body temperature, and weight will be summarized.
Vital sign variables will be evaluated based on potentially clinically significant (PCS) 
criteria (Appendix B).
9.4.1
Analysis of Vital Sign for Double-Blind Period
Analyses of continuous vital sign variables which are measured longitudinally will be 
performed by visits and by the treatment groups of upadacitinib 15 mg QD and placebo 
group.  For each analysis, the following summary statistics will be presented for each 
treatment group:  sample size, mean, standard deviation, minimum, median and 
maximum.
The number and percentage of subjects meeting the criteria for PCS vital sign values will 
be summarized by actual treatment group.  Listings will be provided to summarize 
 


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subject-level vital sign data for subjects meeting PCS criteria.  For each of these subjects,
the whole course of the respective parameter will be listed.
9.4.2
Analysis of Long-Term Vital Sign
Analyses of continuous vital signs variables which are measured longitudinally will be 
performed by visits and by "as treated" treatment group sequences as described in 
Section 9.1.
Long-Term Vital Sign will also be summarized based on the number and percentage of 
subjects meeting the criteria for PCS vital sign values for the Any Upadacitinib 15 mg QD 
group as described in Section 6.0.  Similar baseline definition in Section 9.3.3.2 will be 
applied.  A listing of all subjects with any vital sign values meeting the criteria for PCS 
vital signs will also be provided.
10.0
Other Analyses
Not applicable.
11.0
Interim Analyses
There are no interim analyses planned for efficacy endpoints.  Information on the interim 
safety monitoring DMC is described in Section 11.1.
11.1
Data Monitoring Committee
An independent external Data Monitoring Committee (DMC) is used to review unblinded 
safety data at regular intervals during the conduct of the study.  The DMC will provide 
recommendations to an AbbVie Point of Contact on whether to continue, modify, or 
terminate studies after each review.  The primary responsibility of the DMC will be to 
protect the safety of the subjects participating in this study.  When needed, high-level 
unblinded efficacy data may also be requested by the DMC and be reviewed so that the 
DMC can assess benefit: risk of any emerging safety differences.
 


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A separate DMC charter describes the roles and responsibilities of the DMC members, 
frequency of data reviews, relevant data to be assessed, and general operations.
Since there are no efficacy analyses for early stopping, no α adjustment is needed.
12.0
Overall Type-I Error Control
A multiple testing procedure will be used to provide strong control of the type I error rate 
at α = 0.05 (2-sided) across analyses with respect to the primary endpoint and 
multiplicity-controlled secondary endpoints.  Since all efficacy comparisons target 
superior efficacy from placebo, this is equivalent to a one-sided test at a level of 0.025.  
Specifically, testing will utilize a sequence of hypothesis testing for the primary endpoint 
followed by the 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 endpoints in the sequence meet the requirement of 
significance.  The testing sequence is shown in below figure.  All endpoints are assessed 
at Week 14.
 


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Figure 2.
Sequential Multiple Testing Procedure
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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13.0
Version History
Table 10.
SAP Version History Summary
Version
Date
Summary
1.0
27 Jan 2020
Original version
2.0
08 Jan 2021
The following changes have occurred 

Updated to align with protocol amendment 4.0. 

Updated missing data handling due to COVID-19 
infection or logistic restrictions.

Updated analyses related to COVID-19.
3.0
19 Aug 2021
The following changes have occurred 

Updated methods for handling missing data and 
intercurrent events to address regulatory feedback. 

Updated efficacy subgroup analyses categories.

Updated AESI list by removing CPK elevation and 
aligning with PSSAP Version 5.0.

Updated safety lab parameter list (Table 9) to only 
include those reported in CSR safety section.

Aligned with Protocol Version 5.0, including updated 
study title and study schematic to incorporate the 
remission-withdrawal period.
14.0
References
1.
Sieper J, Deodhar A, Marzo-Ortega H, et al.  Secukinumab efficacy in anti-TNF 
naive and anti-TNF-experienced subjects with active ankylosing spondylitis:  
results from the MEASURE 2 Study.  Ann Rheum Dis.  2017;76(3):571-92.
2.
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.
3.
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.
 


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4.
Food and Drug Administration.  E9(R1) Statistical Principles for Clinical Trials:  
Addendum:  Estimands and Sensitivity Analysis in Clinical Trials.  Rockville, MD:  
FDA; 2017.
5.
National Cancer Institute.  CTCAE v. 4.0.  Available from:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc.  
Accessed on:  10 August 2017.
6.
Liu GF, Wang J, Liu K, et al.  Confidence intervals for an exposure adjusted 
incidence rate difference with applications to clinical trials.  Stat Med.  
2006;25(8):1275-86.
7.
Dougados M, Simon P, Braun J, et al.  ASAS recommendations for collecting, 
analysing and reporting NSAID intake in clinical trials/epidemiological studies in 
axial spondyloarthritis.  Ann Rheum Dis.  2011;70(2):249-51.
8.
Rubin DB, Schenker N.  Interval estimation from multiply-imputed data:  a case 
study using agriculture industry codes.  J Am Stat Assoc.  1987;81:366-74.
 


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Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.
●
Subject entered into the study even though s/he did not satisfy entry criteria.
●
Subject developed withdrawal criteria during the study and was not 
withdrawn.
●
Subject received wrong treatment or incorrect dose of study.
●
Subject took prohibited concomitant medication.
 


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Appendix B.
EAER and Normal Approximation Based 95% Confidence Interval
Assume the occurrence of TEAE of special interest follows a Poisson distribution and let 
λ denote the rate of occurrence of TEAE under the total exposure time for a treatment 
group.  Let n be the number of AEs reported in Any Upadacitinib 15 mg QD group.  Let T 
be the total time exposed to study drug summed across all treated subjects in Any 
Upadacitinib 15 mg QD group.  Under the assumption that n follow Poisson distribution 
with parameters λT, the = n/T.
Using normal approximation, the 95% confidence interval can be calculated by (Liu 
GF, et al.  20066.):
  ± ⍺/

Where   = 


 


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Appendix C.
Potentially Clinically Significant Criteria for Safety Endpoints
The criteria for Potentially Clinically Significant (PCS) laboratory findings are described 
in CTCAE V4.03.5
The criteria for Potentially Clinically Significant (PCS) vital sign findings are described in 
Table 11.
Table 11.
Criteria for Potentially Clinically Significant Vital Sign Values
Vital Sign
Category
Criteria for Potential Clinically Important Vital Signs
Systolic blood pressure
Low
Value ≤ 90 mmHg and decrease ≥ 20 mmHg from Baseline
High
Value ≥ 160 mmHg and increase ≥ 20 mmHg from Baseline
Diastolic blood pressure
Low
Value ≤ 50 mmHg and decrease ≥ 10 mmHg from Baseline
High
Value ≥ 100 mmHg and increase ≥ 10 mmHg from Baseline
Weight
High
> 7% increase from baseline
Low
> 7% decrease from baseline
 


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Appendix D.
ASAS-NSAID Intake Score for Axial Spondyloarthritis
ASAS-NSAID Intake Score for Axial Spondyloarthritis:  The amount of NSAID 
intake could be considered as a clinically relevant outcome measure in ankylosing 
spondylitis (AS)/axial spondyloarthritis.
To be able to calculate the ASAS-NSAID Intake Score,7 the following information is 
required:
(1) Type of NSAID/Cox2 inhibitor:  Each NSAID has a corresponding weight factor.  
The weight is determined by the maximum dose of each NSAID to achieve a score of 100.  
The goal is to analyze/report the data in terms of NSAID equivalent dose in mg/day on a 
0 - 100 scale.  The 150 mg equivalent diclofenac is set to 100.  For instance, 150 mg 
diclofenac is equivalent to 1000 mg naproxen, so the weight for diclofenac is 100/150, 
and the weight for naproxen is 100/1000.  For other NSAIDs/Cox2 inhibitors not 
described in the table, the weight factor will be determined based on medical review using 
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NSAID
Weights
Diclofenac
100/150
Naproxen
100/1000
Aceclofenac
100/200
Celecoxib
100/400
Etodolac
100/600
Etoricoxib
100/90
Flurbiprofen
100/200
Ibuprofen
100/2400
Indomethacin
100/150
Ketoprofen
100/200
Meloxicam
100/15
Nimesulide
100/200
Phenylbutazone
100/400
Piroxicam
100/20
Tenoxicam
100/20
(2) Dose:  mg per intake
(3) Frequency:  days of intake per week (the times of intake daily)
Frequency Description
Numeric Frequency
QD
1
BID
2
TID
3
QID
4
1 time per week
1/7
2 times per week
2/7
3 times per week
3/7
4 times per week
4/7
5 times per week
5/7
6 times per week 
6/7
 


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(4) Days of intake during the period of interest:  can be calculated by NSAID end 
date - start date + 1.
(5) Days stayed on study in the clinical trial:  is defined as the total number of days in 
the study = last visit date – baseline date + 1.
Then, two scores can be calculated:
1.
Equivalent NSAID score = weights * dose (mg) * (numeric frequency), where 
weights can be obtained from the weight table (above and Dougados et al.  Ann 
Rheum Dis.  2011; 70:249-51), and dose is the number of mg per intake, numeric 
frequency is the number of intakes per day.  The equivalent NSAID score is a 
scoring system to refer to a scale in which 0 equals no intake, and 100 equals 150 
mg diclofenac, or 1000 mg naproxen, or 200 mg aceclofenac, or 400 mg celecoxib 
etc. per daily dose.
2.
ASAS-NSAID Intake Score =
(Equivalent NSAID score) * (days of intake during period of interest)/(days stayed 
on study in the clinical trial)
 


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Appendix E.
NRI-MI Procedure
Non-responder imputation in conjunction with multiple imputation (NRI-MI) will handle 
intercurrent events and missing data as follows:
1.
Subjects who prematurely discontinue study drug or use rescue therapy will be 
categorized as non-responders for visits after study drug discontinuation or rescue 
initiation.
2.
Missing data due to COVID-19 infection or logistical restriction will be handled by 
Multiple Imputation.
3.
Additional missing data due to other reasons will be categorized as non-responders.
Assessments at visits after discontinuation of study drug or rescue initiation will not 
contribute to the imputation.
NRI-MI will be implemented as follows.
Binary Endpoints Dichotomized from Continuous Variable
Step 1: Imputation of original continuous variable
When a binary variable is dichotomized from a continuous variable, the MI is applied to 
the original continuous variable.  Missing values are imputed via MI in two steps: 
augmentation step and imputation step.
Augmentation Step:
Markov Chain Monte Carlo (MCMC) will be applied to augment the data to achieve 
monotone missing pattern using PROC MI with the MCMC IMPUTE=monotone 
statement, assuming a multivariate normal distribution.  The imputation model includes 
screening hsCRP, gender, race (white vs. non-white), ethnicity, age, baseline BMI, 
geographic region, duration since AS diagnosis, duration of AS symptom, prior 
bDMARD class, baseline value for the outcome variable, as well as longitudinal values 
 


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for the outcome variable observed at any other visits according to the pre-specified order.  
Of note, categorical variables are included using dummy variables.  30 augmented 
datasets with monotone missing pattern will be generated.
Imputation Step:
For each of the 30 augmented datasets, using SAS PROC MI with MONOTONE REG 
model statement, the missing values for the outcome variable will be imputed for each 
post-baseline visit sequentially, regressing upon the outcomes from previous visits.
Sample codes are as follows:
PROC MI DATA=WIDEDATA OUT=MI_MONO NIMPUTE=30 SEED=&seed1;
MCMC IMPUTE=MONOTONE ;
By treatment;
VAR &predcont &predcate_num &wk1 &wk2 &wk4 &wk8 &wk12 &wk14;
RUN;
PROC MI DATA=MI_MONO OUT=MI_FULL NIMPUTE=1 SEED=&seed2;
CLASS &predcate;
VAR &predcont &predcate &wk1 &wk2 &wk4 &wk8 &wk12 &wk14;
MONOTONE REG (&wk1 &wk2 &wk4 &wk8 &wk12 &wk14); 
BY _IMPUTATION_ treatment;
RUN;
&predcate (categorical covariates): gender, race (white vs. non-white), 
ethnicity, geographic regions, prior bDMARD class. 
&predcate_num are dummy values of categorical covariates
&predcont (continuous covariates): screening hsCRP, age, baseline BMI, 
duration since AS diagnosis, duration of AS symptom, baseline value for 
the outcome variable. 
&wk1, &wk2,… &wk14: the outcome variable values at week 1, week 2, … 
week 14.
Step 2: Derivation of binary variable
The binary variable is then derived by dichotomizing the continuous variable for each 
imputed complete dataset.  In addition, subjects who prematurely discontinue study drug 
or use rescue therapy will be overwritten as non-responders for visits after study drug 
 


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discontinuation or rescue initiation, the missing data not due to Covid-19 will also be 
overwritten as non-responders.
Step 3: Analysis and synthesis of results for statistical inference
For each of the 'complete' binary endpoint datasets, the CMH test is performed adjusting 
for the main stratification factor to test the treatment difference of upadacitinib versus 
placebo.
The results from the 30 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula (Rubin, 1987).8
Composite Binary Endpoints
Step 1: Imputation of original continuous variables
Composite binary endpoints are derived from multiple continuous components.  All 
missing component values are imputed via MI in two steps: augmentation step and 
imputation step.
Augmentation Step:
Markov Chain Monte Carlo (MCMC) will be applied to augment the data to achieve 
monotone missing pattern using PROC MI with the MCMC IMPUTE=monotone 
statement, assuming a multivariate normal distribution.  The imputation model includes 
the same variables as for dichotomized binary endpoints.  In particular, the baseline values 
as well as longitudinal values observed at any other visits for all components of the 
composite binary endpoint are included in the model.  Of note, categorical variables are 
included using the form of dummy variables.  30 augmented datasets with monotone 
missing pattern will be generated.
 


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Imputation Step:
For each of the 30 augmented datasets, using SAS PROC MI with MONOTONE REG 
model statement, the missing values for each component will be imputed for each post-
baseline visit sequentially, regressing upon the previous visits.
Step 2: Derivation of binary variable
The composite binary variable is then derived from each imputed dataset.  In addition, 
subjects who prematurely discontinue study drug or use rescue therapy will be overwritten 
as non-responders for visits after study drug discontinuation or rescue initiation, the 
missing data not due to Covid-19 will also be overwritten as non-responders.
Step 3: Analysis and synthesis of results for statistical inference
For each of the 'complete' binary endpoint datasets, the CMH test is performed adjusting 
for the main stratification factor to test the treatment difference of upadacitinib versus 
placebo.
The results from the 30 'complete' datasets will be synthesized using the SAS procedure 
PROC MIANALYZE, following Rubin's formula (Rubin, 1987).8
 


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Appendix F.
Tipping Point Analysis
Tipping Point Analysis for Binary Endpoints
To assess the robustness of the primary analysis under MNAR, tipping point analysis is 
conducted on the primary endpoint ASAS40 and multiplicity-controlled secondary 
endpoints at Week 14.  The analysis is conducted on the FAS using all observed data 
regardless of treatment adherence.
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on the upadacitinib treatment group and the placebo group can vary 
independently.  The response rate among those subjects with missing response is assumed 
to be p0 for placebo group and p1 for upadacitinib group, and the response rate p0 and p1 
systematically vary from 0% to 100% by every 10% respectively.  Given a set of (p0, p1), 
the subjects with missing response will be randomly assigned as responders or non-
responders using binomial distribution to generate 30 imputed datasets, and the same 
CMH method used for the primary analysis will be performed on each of the multiple 
imputed datasets to obtain the results for each comparison of the upadacitinib treatment 
group versus the placebo group. These results will then be aggregated using Rubin's 
method.  
If one pair of (p0, p1) is found to just reverse the study conclusion, in terms of p-value 
larger than 0.05, then the (p0, p1) is identified as the tipping point.  The results for a grid 
of (p0, p1) combinations are provided in tabular format.
Tipping Point Analysis for Continuous Endpoints
To assess the impact of potential departures from the missing-at-random assumption, 
tipping point analyses are conducted as a sensitivity check for change from baseline in 
multiplicity-controlled secondary continuous endpoints at Week 14.
The tipping point analyses are two-dimensional, i.e., assumptions about the missing 
outcomes on the upadacitinib treatment group and the placebo group can vary 
 


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independently.  In addition, the focus is on scenarios where missing outcomes on 
upadacitinib are worse than the imputed values on upadacitinib, while missing outcomes 
on placebo are better than the imputed values on placebo.  Missing values are 
first imputed via MI under MAR assumption using AO data, and then a shift parameter is 
applied to the imputed values (a different shift parameter may be specified for each 
treatment group).  This is implemented by PROC MI using the MNAR statement.  The 
imputation uses a two-step approach, augmentation step using MCMC and imputation 
step using Monotone Regression, as described in Appendix E.  The MNAR statement is 
applied in the imputation step.  The number of imputed datasets is 30.
In cases where the shifted values are smaller than the minimum or larger than the 
maximum value of the endpoint, (i.e., out of range), the minimum or maximum value of 
the endpoint is used in further analysis steps.  For each pair of shift parameters, the SAS 
procedure PROC MIXED is used for ANCOVA model which includes the fixed effects of 
treatment, screening hsCRP level and the continuous fixed covariate of baseline 
measurement on each of the imputed datasets to obtain the results for each upadacitinib 
treatment group versus the placebo group comparison.  These results will be aggregated 
using Rubin's method.
If one pair of shift parameters are found to just reverse the study conclusion, in terms of 
p-value larger than 0.05, then the shift parameters are identified as the tipping point.  The 
results for a grid of shift parameter combinations are provided in tabular format.